The dormant blood microbiome in chronic, inflammatory diseases

Marnie Potgieter; Janette Bester; Douglas B. Kell; Etheresia Pretorius

doi:10.1093/femsre/fuv013

The dormant blood microbiome in chronic, inflammatory diseases

Potgieter, Marnie; Bester, Janette; Kell, Douglas B.; Pretorius, Etheresia 2015-07-01 00:00:00 Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 FEMS Microbiology Reviews, fuv013, 39, 2015, 567–591 doi: 10.1093/femsre/fuv013 Advance Access Publication Date: 4 May 2015 Review Article REVIEW ARTICLE The dormant blood microbiome in chronic, inflammatory diseases 1 1 2,∗ 1 Marnie Potgieter , Janette Bester ,DouglasB.Kell and Etheresia Pretorius Department of Physiology, Faculty of Health Sciences, University of Pretoria, Arcadia 0007, South Africa and School of Chemistry and The Manchester Institute of Biotechnology, The University of Manchester, 131, Princess St, Manchester M1 7DN, Lancs, UK Corresponding author: School of Chemistry and The Manchester Institute of Biotechnology, The University of Manchester, 131, Princess St, Manchester M1 7DN, Lancs, UK. Tel: (+44)161 306 4492; E-mail: dbk@manchester.ac.uk One sentence summary: Atopobiosis of microbes (the term describing microbes that appear in places other than where they should be), as well as the products of their metabolism, seems to correlate with, and may contribute to, the dynamics of a variety of inflammatory diseases. Editor: Prof. Antoine Danchin ABSTRACT Blood in healthy organisms is seen as a ‘sterile’ environment: it lacks proliferating microbes. Dormant or not-immediately-culturable forms are not absent, however, as intracellular dormancy is well established. We highlight here that a great many pathogens can survive in blood and inside erythrocytes. ‘Non-culturability’, reflected by discrepancies between plate counts and total counts, is commonplace in environmental microbiology. It is overcome by improved culturing methods, and we asked how common this would be in blood. A number of recent, sequence-based and ultramicroscopic studies have uncovered an authentic blood microbiome in a number of non-communicable diseases. The chief origin of these microbes is the gut microbiome (especially when it shifts composition to a pathogenic state, known as ‘dysbiosis’). Another source is microbes translocated from the oral cavity. ‘Dysbiosis’ is also used to describe translocation of cells into blood or other tissues. To avoid ambiguity, we here use the term ‘atopobiosis’ for microbes that appear in places other than their normal location. Atopobiosis may contribute to the dynamics of a variety of inflammatory diseases. Overall, it seems that many more chronic, non-communicable, inflammatory diseases may have a microbial component than are presently considered, and may be treatable using bactericidal antibiotics or vaccines. Keywords: ‘sterile’ blood microbiome; culturability; dormancy; dysbiosis; atopobiosis; Parkinson’s disease; Alzheimer disease INTRODUCTION (Marshall and Warren 1984) being a particularly well-known ex- ample. There have also been hints for a microbial component to ‘Overall, it seems inevitable that the availability of these meth- many other non-communicable diseases, but culturing the rele- ods will cause the catalog of disease states recognized as having vant organisms has rarely been successful. However, there is in- a microbial contribution to their etiology to expand enormously creasing recognition that microbes may be present in forms that in the short term, particularly as improved methods for resusci- are not easily culturable, and a number of recent articles have tation of small cell numbers are found’ (Davey and Kell 1996). brought these possibilities more sharply into focus. Our aim is to Over the years, a variety of diseases that were previously con- review these developments. The manuscript structure is shown sidered non-communicable have been found to have a micro- in Fig. 1. bial component, the role of Helicobacter pylori in ulcerogenesis Received: 26 January 2015; Accepted: 2 March 2015 FEMS 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 567 Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 568 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 Figure 1. An overview figure summarizing the contents of this manuscript. Table 1. Operational definitions of viable, non-viable and dormant A note on terminology: viable, culturable, dormant and microbes. These are the three terms we consider best suited to de- sterile scribe the macroscopic physiological states of microbes as regards their ability to replicate. We note that the terms ‘not immediately In this field, much confusion has arisen historically because of culturable’ (NIC) and ‘active but not culturable’ (ABNC) can also have a failure to recognize that most microbes reproduce by binary some utility (Kell et al. 1998), while dormant cells are sometimes fission and that this reproduction must be a minimal property referred to as ‘persisters’. Other variants of ‘dormancy’ that have or hallmark of a microbial cell that possesses ‘life’ or is ‘alive’ been used include ‘anabiosis’ (Keilin 1959) and ‘cryptobiosis’ (e.g. (Proal, Albert and Marshall 2011). Thus, as with Schroding ¨ er’s cat Clegg 2001;Neuman 2006); all these terms imply a reversible state between the appearance of being living and non-living in differ- (e.g. Primas 1981; Gribbin 1985), we cannot say that an individ- ent circumstances. This definition of dormancy also likely includes ual microbial cell ‘is’ alive, only (if true) that it ‘was’ alive, since cells that may operationally be ‘injured’, and possibly wall-less L- it will by then have become two cells. This implies that being forms (Domingue and Woody 1997; Mattman 2001; Allan, Hoischen alive is not best treated as though it were an innate property of a and Gumpert 2009;Dom´ınguez-Cuevas et al. 2012; Errington 2013; cell, but the definition must be operational, and include both the Mercier, Kawai and Errington 2013, 2014) provided they are or may cell and the ‘environment’ (experiment) used to detect the status become culturable. ‘Sterile’ refers to an absence of operationally vi- able organisms as defined in this table. a posteriori (Kell et al. 1998). Thus, as with Postgate (e.g. Postgate 1967, 1969, 1976), we equate viability with culturability, and stress that culturability— Term Properties the ability to reproduce—is to be determined operationally. Other methods that do not determine culturability are not tests Viable Capable of observable replication, i.e. of viability per se, but merely measure what they measure (e.g. culturable, by any stated means. the content of a chemical such as ATP, membrane permeability Non-viable Incapable of observable replication by any to a dye, enzymatic activity, macromolecular sequences and so stated means normally capable of effecting on). In addition, it is impossible in principle to (cor)relate macro- replication in the relevant organism. scopic measurements of a culture with the ability of individual Dormant Not viable in the sense of not being more or cells to divide (Kell et al. 1991; Davey and Kell 1996). In other less immediately culturable, but may be words, if the macroscopic ATP content of say a starving culture returned to a state of viability or culturability were to decrease by 50%, we would not know if all of the cells by preincubation under suitable conditions. had lost half their ATP or half of the cells had lost all of their ATP (or anything in between). The culturability of the former would likely be 50% and of the latter 100%, despite the same macro- scopic ATP content. scathing about the term ‘unculturable’ (Gest 2008), noting that A lack of culturability may mean that a cell is non-viable one just needs to try harder to culture organisms. Table 1 shows under the circumstances tested, but viability or non-viability the three terms best suited to discuss these issues, while Fig. 2 are not the only two possible states here. An apparent non- shows a diagrammatic representation of the macroscopic phys- culturability of a surviving cell also admits another possibility, iological microbial states we mostly consider. for which the natural term is ‘dormant’ (Kaprelyants, Gottschal The assessment of replication potential (culturability) of in- and Kell 1993;Epstein 2013). This is that the cell is not presently dividual cells may be done microscopically (e.g. by microscopic culturable (viable), but it is not ‘dead’ (in the sense of an oper- counts) or macroscopically (e.g. via colony formation on an agar ationally irreversible loss of viability) in that it may be induced plate or through the ‘most probable number’ technique). The to return to a state of culturability (by a process or processes latter has the advantage of potentially assessing dormancy in typically referred to as ‘resuscitation’). This also means that the the absence of any contaminating culturable cells that might term ‘viable-but-non-culturable’, while quite common in use, is proliferate during the assay (Kaprelyants, Mukamolova and Kell in fact an oxymoron that is to be discouraged (Kell et al. 1998). 1994; Votyakova, Kaprelyants and Kell 1994;Kell et al. 1998). For The eminent microbial physiologist Howard Gest is similarly assessing culturability (=viability), we do not therefore include Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 569 Figure 2. A diagrammatic representation of the major macroscopic physiological states of microbes and their interrelationships. other strategies in which cells do not actually divide, such as the diseased humans and from 7% of supposedly healthy humans, so-called direct viable count of Kogure, Simidu and Taga (1979). when RBCs were lysed (Domingue and Schlegel 1977). A year Thus, we here highlight the point that the possibility of micro- later, corynebacteria-like microorganisms developing in hemo- bial dormancy means that a system that appears to be devoid cultures were shown within RBCs (Tedeschi et al. 1978), and in of culturable microbes may still contain dormant cells or forms 2001 it was found that even ‘healthy’ blood specimens can con- that may become culturable. tain bacterial 16S ribosomal DNA (Nikkari et al. 2001). Domingue and Woody (1997) and Domingue (2010) summarizes much of this earlier literature. L-forms are bacterial variants that lack The ‘sterile’ blood microbiome brought into question some or all of a cell wall. Nonetheless they can divide, especially in osmotically stabilized media, by processes that variously in- The circulation is a closed system and the blood in healthy or- volve membrane blebbing, tubulation, vesiculation and fission ganisms was first believed to be a sterile environment (Drennan (Allan, Hoischen and Gumpert 2009; Errington 2013; Mercier, 1942; Proal, Albert and Marshall 2014). This definition is used Kawai and Errington 2014). While it remains unclear whether in the most usual sense of an absence of culturable microbes, what was seen in these earlier studies (Domingue and Woody since blood can of course provide a suitable growth medium 1997; Domingue 2010) may have been L-forms (Mattman 2001), for microbes (as in blood culture; Wilson and Weinstein 1994; that could in time revert to normal bacteria under the correct Weinstein 1996; Schroeter et al. 2012; cf. Valencia-Shelton and conditions (Casadesus ´ 2007), L-forms are becoming a topic of Loeffelholz 2014), and any bacteraemia or sepsis, even at 1– −1 considerable current research (Devine 2012;Dom´ınguez-Cuevas 10 cells mL (Murray 2015), is potentially life-threatening (e.g. et al. 2012; Mercier, Kawai and Errington 2013, 2014). Vincent et al. 2009; Eleftheriadis et al. 2011; Havey, Fowler and The presence of a blood bacterial microbiome has also been Daneman 2011; Montassier et al. 2013). However, the principle associated with a variety of infectious, as well as non-infectious of the presence of truly sterile blood in healthy humans has disease states (Huang et al. 2006; Thwaites and Gant 2011; been challenged, as operationally it does not mean that dormant Nielsen et al. 2012; Prajsnar et al. 2012;Wang et al. 2012a; Ki- or non-culturable forms of organisms are absent (Kaprelyants, bru et al. 2014;Sato et al. 2014). It is, for example, known that Gottschal and Kell 1993;Kell et al. 1998; McLaughlin et al. 2002) H. pylori can exist not only in the gastric mucosa but also in (see Table 1). Nearly 50 years ago, the existence of a novel bacte- peripheral blood, where it could cause bacteremia (Huang et al. riological system was noted in 71% of blood samples taken from Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 570 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 2006), and could contribute to Parkinson’s disease (PD) or related (II) A second argument is that the morphological type of organ- pathologies that precede motor symptoms (Nielsen et al. 2012). ism (e.g. coccus versus bacillus) seems to be characteristic Helicobacter pylori was also previously implicated in the develop- of particular diseases. ment of anemia (Wang et al. 2012b; Kibru et al. 2014). Staphylo- (III) A third argument is that in many cases (see below) relevant coccus aureus can also use neutrophils as ‘Trojan horses’ to dis- organisms lurk intracellularly, which is hard to explain by seminate infection (Thwaites and Gant 2011; Prajsnar et al. 2012), contamination. while many other pathogens, such as Listeria monocytogenes (Xa- (IV) A fourth argument is that there are just too many diseases yarath and Freitag 2012), Salmonella typhimurium (Eisenreich et al. where bacteria have been found to play a role in the patho- 2010; Claudi et al. 2014; Holden 2015)and Yersinia pestis (Isberg genesis, that all of them may be caused by contamination. 1991), are well known to persist intracellularly; Gest (2008)gives (V) Finally, the actual numbers of cells involved seem far too other historical examples. The same is true for viruses, which great to be explicable by contamination; given that blood 9 −1 are not discussed here. contains more than 10 erythrocytes mL , if there was The presence of an aberrant blood microbiota (as assessed by just one bacterial cell per 100 000 erythrocytes (see below 4 −1 sequencing) has been implicated in type II diabetes and cardio- and Amar et al. 2011), this will equate to 10 bacteria mL . vascular disease (Amar et al. 2011, 2013;Sato et al. 2014). There These are not small numbers. is also growing evidence that periodontal disease and gingivi- It is important to point out that molecular methods have been tis are closely linked to cardiovascular disease (Yang et al. 2013; used frequently to detect active sepsis. These selfsame meth- Ram´ırez et al. 2014). Oral bacterial translocation into the blood ods are also used in environmental biology (as we pointed has been implicated in the development of periodontal disease- out in this review), without undue concern about the poten- induced endocarditis and myocardial and/or cerebral infarction, tial for contamination. Contamination will always be a concern, especially in patients with heart valve dysfunction (Koren et al. of course, as noted by Nikkari et al. (2001), but many papers 2011; Amar and Engelke 2014;Seringec et al. 2014). since 2001 have documented strategies for detecting prokaryotic We will argue in the next sections that the existence of poten- DNA in blood and serum using appropriate and careful controls tially viable (but possibly non-proliferating) pleomorphic bac- (Anthony et al. 2000; Mylotte and Tayara 2000;Jiang et al. 2009; teria in the blood of healthy humans (McLaughlin et al. 2002) Varani et al. 2009;Mancini et al. 2010; Chang et al. 2011; Grif et al. may therefore be of some significance in pathology. If such a 2012a;Fernandez-Cruz ´ et al. 2013;Gaibani et al. 2013). Also, de- microbiome can disrupt homeostasis, it can ultimately play a tecting bacteria in blood cultures during sepsis is considered the fundamental role in disease development and progression. It standard diagnostic tool for blood stream infections (Munoz ˜ et al. has therefore been proposed that the blood microbiota might 2008; Varani et al. 2009), and some laboratories consider that e.g. therefore represent or contribute to the first step in the kinetics PCR testing should always be a complement for the traditional of atherosclerosis (Sato et al. 2014), cardiovascular disease and blood culture test (Grif et al. 2012b). type II diabetes (Amar et al. 2011), and therefore ultimately serve as biomarkers for cardiovascular disease risk (Amar et al. 2013). Theroleofdormancy However, in the quest to use the blood microbiota as biomarkers, the question of detectability and cultivability are key concepts. Dormancy in microbiology is of course well known, even for non- In particular, the existence of a blood microbiome is only sporulating bacteria, and has been defined as a stable but re- really meaningful and of scientific interest if it represents an versible nonreplicating state (Mariotti et al. 2013; see also Table 1 undisturbed state, and is not, for instance, an artefact caused and Kaprelyants, Gottschal and Kell 1993;Kell et al. 1998, 2003). by the external introduction of microbes through human in- The importance of dormant or non-cultured (as opposed to ‘non- tervention, reagent contamination (Schroeter et al. 2012;Salter culturable’) organisms has long been recognized in environmen- et al. 2014) and so forth. We therefore rehearse the evidence tal microbiology (e.g. Mason, Hamer and Bryers 1986; Amann, that while such artefacts are certainly possible, and must be Ludwig and Schleifer 1995; Eilers et al. 2000; Hugenholtz 2002; excluded rigorously, the phenomenon of a human blood micro- Keller and Zengler 2004; Pham and Kim 2012;Epstein 2013), be- biome cannot be dismissed as such an artefact in toto. cause of the 100-fold or greater difference between microscopi- cally observable cells and those capable of forming a colony on Evidence that these observations are not due to an agar plate (‘the great plate count anomaly’, see below). contamination Of the four main possibilities, what we do not know in gen- eral is whether the ‘missing’ cells While contamination from reagents (e.g. Schroeter et al. 2012; Salter et al. 2014), or simply poor sterile technique with nee- (i) are incapable of growth on the enrichment/isolation media, dles and so on, can lead to an artefactual appearance of a blood (ii) are killed by the enrichment/isolation media (e.g. Tanaka microbiome, we consider that the following arguments, taken et al. 2014), together, exclude the thought that the entire (and consider- (iii) have lost viability irreversibly (i.e. are operationally dead) or able) literature on a blood microbiome can be explained via (iv) are in a dormant or not-immediately-culturable state from contamination. which we might resuscitate them (to effect culturability) if only we knew how. The fact that typical isolation media and incubation conditions (I) The first argument is that there are significant differences do not admit the measurable growth of all strains is certainly between the blood microbiomes of individuals harboring well known (indeed it is the basis for selective isolation media!), disease states and nominally healthy controls, despite the and it took a good while to learn how to culture pathogens such fact that samples are treated identically (see later). Some as H. pylori (Marshall and Warren 1984; Marshall 2006), Legionella similar arguments apply to the assessment of drug trans- pneumophila (Feeley et al. 1978;Saito et al. 1981;Meyer 1983), porters under different conditions (Kell and Oliver 2014). Tropheryma whipplei (Maiwald and Relman 2001;Maiwald et al. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 571 2003; Renesto et al. 2003) and so on (Singh et al. 2013). The major- The development of sequence-based methods for microbes ity of bacteria that persist in a ‘non-culturable’ form in wounds (and especially non-eukaryotes) owes much to the pioneering (e.g. Dowd et al. 2008;Percival et al. 2012), or in diseases such work of Carl Woese and colleagues, who recognized the util- as cystic fibrosis (Lewis 2010) or tuberculosis (Young, Stark and ity of small subunit ribosomal RNA (based on both its essen- Kirschner 2008; Zhang, Yew and Barer 2012), and even simply tiality and the small but significant sequence variations) and in conventional cultures of Escherichia coli (e.g. Koch 1987;Bal- applied it with great effect in molecular phylogenetics (Woese aban et al. 2004; Keren et al. 2004a,b; Gerdes and Maisonneuve and Fox 1977; Woese, Kandler and Wheelis 1990). Notwithstand- 2012; Amato, Orman and Brynildsen 2013; Germain et al. 2013; ing modern reinterpretations of the taxonomic details derived Maisonneuve, Castro-Camargo and Gerdes 2013; Maisonneuve therefrom (e.g. Williams et al. 2013), there can be little doubt and Gerdes 2014; Holden 2015), where phenotypic culture dif- that this work drew the attention of microbiologists to the po- ferentiation is well established (Koch 1971), are also ‘normally tential of sequence-based methods for detecting microbes that culturable’ by established means. Thus, the existence of oper- were then invisible to methods based solely on culture, e.g. in ationally ‘non-culturable’ forms of only moderately fastidious clinical microbiology (Didelot et al. 2012; Loman et al. 2012;Proal bacteria is very well established, and more and more bacteria et al. 2013; Fricke and Rasko 2014). rRNA remains a widely used previously thought ‘unculturable’ are being brought into culture strategy for detecting specific microbes. This has of course led to (e.g. Zengler et al. 2002; Keller and Zengler 2004; Stevenson et al. metagenomics, the large-scale sequencing of macromolecules 2004; Gich et al. 2005; Kamagata and Tamaki 2005; D’Onofrio et al. and indeed (statistically) entire genomes from complex (non- 2010; Nichols et al. 2010; Vartoukian, Palmer and Wade 2010; axenic) environments, increasing the requirement for a full set Dedysh 2011; Pham and Kim 2012; Puspita et al. 2012, 2013; Stew- of complete reference sequences (Kyrpides et al. 2014) and not art 2012; Allen-Vercoe 2013; Narihiro and Kamagata 2013;Singh just those of 16S rRNA (Yarza et al. 2013). Even the coupling of et al. 2013;Walker et al. 2014;Lagier et al. 2015a,b;Ling et al. 2015). sequences to activities has now become possible (e.g. Radajew- In environmental microbiology, some bacteria pass through ski et al. 2000;Wang et al. 2012c). the usual 0.2 μm filters, and have been referred to as ‘ultrami- crobacteria’ (Macdonell and Hood 1982; Morita 1997). It was pro- Microbiome analyses: latest technologies employed posed (Kaprelyants, Gottschal and Kell 1993) that rather than More recently, gut metagenomics has been systematized with being small (starved) forms of normal bacteria they were more likely to be normal forms of small bacteria, and this seems to NIH’s Human Microbiome project (HMP) and the European MetaHIT project aiming to deciphering the structure and func- have been accepted (Lysak et al. 2010;Sahin et al. 2010; Duda et al. tion of the human gut microbiota (Fredricks 2013; Robles-Alonso 2012;Soina et al. 2012). and Guarner 2014). The HMP has developed a reference collec- The ability to culture certain kinds of soil bacteria by prein- tion of 16S ribosomal RNA gene sequences collected from sites cubation in weak broth is also well established (e.g. Bakken and across the human body (Koren et al. 2013; Ding and Schloss 2014). Olsen 1987; Kaprelyants, Gottschal and Kell 1993), and our own This information can be used to associate changes in the micro- experiments showed very high levels of resuscitability of dor- biome with changes in health, and particularly also the blood mant cells of Micrococcus luteus (e.g. Kaprelyants and Kell 1993; microbiome. The Integrative Human Microbiome Project (iHMP, Kaprelyants, Mukamolova and Kell 1994; Kaprelyants et al. 1996, http://hmp2.org), the second phase of the NIH HMP, aims to 1999;Kell et al. 1998, 2003; Mukamolova et al. 1998a,b, 1999, study the interactions by analyzing microbiome and host ac- 2002a,b). In a similar way, substrate-accelerated death of non- or slowly growing microorganisms has been known for decades tivities in longitudinal studies of disease-specific cohorts and by creating integrated data sets of microbiome and host func- (Postgate 1967; Calcott and Postgate 1972; Calcott and Calvert 1981). tional properties (The Integrative HMP (iHMP) Research Network Consortium 2014), ultimately allowing us to analyze host and Thus, any of several well-established mechanisms may con- microbial DNA (genome) and RNA (transcriptome) sequences tribute to the (often) large differences observable between mi- (Morgan and Huttenhower 2014). However, in the HMP study, croscopic counts and the number of operationally culturable the main anatomic sites where samples are collected are skin, microbes, with the greatest likelihood being that we simply mouth, nose, colon and vagina (ElRakaiby et al. 2014). So far as we have to develop more and better methods to bring these strains are aware, these projects do not focus on the blood microbiome back into culture, i.e. to resuscitate them. In particular, however, (which is probably unsurprising when most commentators as- this ‘great plate count anomaly’ has, of course, been brought sume that it does not exist). into much sharper focus because of the advent of culture- independent, sequence-based means for detecting and (to a cer- The gut microbiome is by far the largest numerically, and our purpose here is not to review it in any detail, since this has been tain extent) enumerating microbes (though not, of course, of as- sessing their culturability). done very well in terms of Sequence-based methods for detecting (i) its constitution (Lozupone et al. 2012;Weinstock 2012), non-proliferating microbes (ii) temporal variation (Caporaso et al. 2011;Flores et al. 2014; Thaiss et al. 2014), The vast majority of microbial species remain uncultivated and, (iii) changes associated with diet (Muegge et al. 2011), until recently, about half of all known bacterial phyla were iden- (iv) obesity (Turnbaugh et al. 2006, 2009), tified only from their 16S ribosomal RNA gene sequence (Lasken (v) age and geography (Delzenne and Cani 2011; Delzenne and McLean 2014). Also, single-cell genomics is a powerful tool et al. 2011; Yatsunenko et al. 2012), for accessing genetic information from uncultivated microor- (vi) inflammation (Cani et al. 2008, 2012), ganisms (Lasken 2012;Rinke et al. 2013;Cavanagh et al. 2014; (vii) the immune system (Kau et al. 2011; McDermott and Huff- Clingenpeel et al. 2014). Bacterial single-cell genome sequenc- nagle 2014) ing and bioinformatics are, however, challenging (Pallen, Loman (viii) and various pathologies (Pflughoeft and Versalovic 2012; and Penn 2010;Didelot et al. 2012; Loman et al. 2012;Frickeand Schulz et al. 2014). Rasko 2014). Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 572 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 It was implied that a better understanding of microbiome- inflammation leading to tissue injury, organ failure, etc. (Stein- encoded pathways for xenobiotic metabolism might also have berg 2003; Wiest and Rath 2003;Balzan et al. 2007). We stress implications for improving the efficacy of pharmacologic inter- that they may be found in both infectious and non-infectious ventions with neuromodulatory agents (Gonzalez et al. 2011), diseases as well as being translocated during surgery, and and that the exploration of microbiome and metagenome might that atopobiosis of bacteria originating in the oral cavity, e.g. give us insightful new perspectives regarding human genet- in periodontal disease, may also be significant in rheumatoid ics and how the microbiota contribute to immunity, as well as arthritis, for instance (see below). Fig. 3 provides a schematic to metabolic and inflammatory diseases (Cho and Blaser 2012; representation of dysbiosis, bacterial translocation and Blaser et al. 2013; Blaser 2014; Leslie and Young 2015). This atopobiosis. is because it is assumed in such studies that it is the small- molecule products of the gut microbiome that can appear in How do gut bacteria escape into blood? the human serum metabolome, and thus influence the rest of If the gut microbiome is seen as the main source of the blood the human body (e.g. Wikoff et al. 2009; Holmes et al. 2011; microbiome, it is necessary to establish which kinds of condi- Le Chatelier et al. 2013, and see Table 2). Here we also need tions might permit this in the absence of real physical damage to mention lipopolysaccharide (LPS), a main constituent of the (as may, for instance, be caused by surgery) leading to micro- Gram-negative outer membrane that induces the production of bial translocation. Wiest, Lawson and Geuking (2014) mention cytokines and/or chemokines, which in turn regulate inflamma- three possible points of entrance for bacteria into the surround- tory and innate and subsequent adaptive immune responses ing (sterile) tissue: (Glaros et al. 2013;Rhee 2014; Ronco 2014). The release of LPS may therefore change gut homeostasis, may play a role in e.g. (i) by dendritic cells via processes between epithelial cells, not inflammatory bowel disease and necrotizing enterocolitis (Rhee 2014), and may certainly act as an acute phase protein in sepsis affecting tight junction function, (ii) via injured/inflamed epithelium with dysfunctional epithe- (Ding and Jin 2014). By contrast, our theme here is that it is additionally the mi- lial barrier, crobes themselves that can pass from the gut (and other ‘exter- (iii) and via M cells overlying Peyer’s patches as specialized cells providing access of microbial products to antigen- nal’ surfaces) into the human body, a phenomenon sometimes known as ‘dysbiosis’, albeit this term is more commonly used presenting cells. with another meaning. We here need to discriminate a changed (pathologic) microbiota in the place of origin from the results of a We discuss bacterial translocation in this context in the fol- translocation of microbiota to other areas of the body. In the fol- lowing sections. lowing sections, we use the term dysbiosis to describe changes in a microbiome in its main origin (typically the gut), and we The role of M cells and Peyer’s patches in gut microbial coin the term ‘atopobiosis’ to describe microbes that appear in translocation and atopobiosis places other than where they should be. While the gut epithelium represents the largest mucosal tissue, the mechanisms underlying the interaction between the micro- The origin of detectable but non-proliferating microbes biome and the epithelial cells remain poorly understood (Math- appears to be mainly via ‘atopobiosis’ of the gut ias et al. 2014). Although this is a vast and complex field that microbiome warrants a review of its own, we briefly argue that gut dysbio- Dysbiosis, also known as dysbacteriosis, particularly referring to sis results in an atypical interaction of both the microbiota, as microbial imbalance in the digestive tract, has been widely dis- well as their secretory products, with the gut epithelial layer. cussed (e.g. Scher and Abramson 2011;Scanlan et al. 2012; Amar This results in an altered barrier function, which may also lead et al. 2013; Bested, Logan and Selhub 2013; Duytschaever et al. to changed mucosal immunity and ultimately to atopobiosis. 2013; Vaarala 2013). Core to this literature is the idea that factors The gut epithelium is necessarily normally quite impermeable that lead to significant changes in the gut microbiota composi- to microbes, but there is increasing evidence that direct chem- tion (dysbiosis) ultimately result in pathology (Larsen et al. 2010; ical communication between the microbiota and the epithelial Amar et al. 2011, 2013; Bested, Logan and Selhub 2013; Burcelin cells regulates mucosal integrity (Venkatesh et al. 2014). A pos- et al. 2013; De Angelis et al. 2013; Fremont et al. 2013; Lanter, Sauer sible point of entry is by direct cellular uptake, and there is and Davies 2014; Petriz et al. 2014;Power et al. 2014; Tojo et al. one type of cell that can take up microbes, and these are the 2014). Table 3 gives a list of diseases, largely inflammatory dis- M cells overlaying the Peyer’s patches (Kerneis ´ et al. 1997;Jep- eases, which have been associated with gut dysbiosis. son and Clark 1998; Clark and Jepson 2003; Corr, Gahan and In addition, we argue here that as well as gut dysbiosis, a Hill 2008; Lelouard et al. 2010; Fukuda, Hase and Ohno 2011). derangement of the gut microbiome, what we are seeing here, Peyer’s patches are seen as the ‘immune sensors’ of the gut ep- often called ‘translocation’ in the context of surgery (Swank ithelium. Considerable evidence exists that they provide a pri- and Deitch 1996;MacFie 2004) and various diseases (Berg 1995) mary route for the limited translocation of microbes between (see Table 4 that lists diseases and conditions where bacterial the gut epithelium and the blood system (Jung, Hugot and Bar- translocation is specifically implicated), is what might better be reau 2010). These interactions with the cells of the gut may called atopobiosis (Greek ατ ¨ oπoς or atopos, in the wrong place), suggest that changes in the intestinal microbiota also influ- i.e. an appearance of members of the gut (or other) microbiome ence mucosal immunity (Sato, Kiyono and Fujihashi et al. 2014). in the wrong place. Bacterial translocation is therefore discussed This is indeed the case, and gut dysbiosis has been shown to in the context of the movement of gut origin microbes [that play a significant role in the development of autoimmune dis- changed from normal (dysbiosis)] that moved across the ‘intact’ eases, in particular inflammatory bowel diseases (Clemente et al. gastrointestinal tract into normally sterile tissues, including 2012; Morgan et al. 2012; Hold et al. 2014; Kostic, Xavier and blood, where the organisms may then directly cause infection or Gevers 2014;Owyangand Wu 2014;Ma et al. 2015). It was also Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 573 Table 2. Some examples of small molecule gut metabolites whose secretion has been implicated in various disease states. Role in health and Metabolite Intermediates/products Synthesis disease References Amino acids The gut microbiota is not itself an important source Faure et al. (2006); Devaraj, of amino acids during periods of adequate protein Hemarajata and Versalovic intake. Some commensal members produce biolog- (2013); Bergen (2014) ically active components from amino acids. Amino acid supplementation in a mouse model of ulcerative colitis has been shown to promote overall growth of commensal microbiota. The effect was considered to be mediated via the stimulatory effect on mucin pro- duction by amino acid supplementation. Benzoates Benzoic acid, hippurate, Gut microbiota in mice with active colitis displayed Rechner et al. (2002); 2-hydroxyhippurate enrichment for genes involved in benzoate degrada- Aronov et al. (2011); De tion. Hippurate derives from plant food polyphenols Preter and Verbeke (2013); and is a conjugate of benzoic acid with glycine. In Rooks et al. (2014) humans a large portion of hippurate is believed to be derived from precursors absorbed in the small in- testines. It is reliably decreased in IBD. Bile acids Bile acids are synthesized from cholesterol in the Martin et al. (2007); Bennett liver and further metabolized into secondary bile et al. (2013); Ger ´ ard (2013); acids by the gut microbiota. The amino acid sides Kakiyama et al. (2013); chain of glyco- and tauro-conjugated bile acids are Mart´ınez et al. (2013); Sayin cleaved by bacterial bile salt hydrolase (BSH) enzyme et al. (2013); Joyce et al. to yield unconjugated bile acids (cholic and chen- (2014) odeoxycholic acids). These products will then be fur- ther modified by gut bacteria to produce secondary bile acids. A decrease in this conversion is positively correlated with liver cirrhosis. Bile acids can mod- ulate the composition of the microbiota in the gut, where they function as signaling molecules and may constitute a mechanism of quorum sensing. In turn, the microbiota strongly affect bile acid metabolism by promoting deconjugation, dehydrogenation and dehydroxylation. It can also inhibit bile acid synthe- sis in the liver by alleviation of farnesoid X receptor inhibition in the ileum. Bile acids can induce FMO3 expression by an FXR-dependent mechanism. Lipids Cholesterol The gut microbiota impact on the host systemic lipid Martin et al. (2007); metabolism. When administered as probiotics Bifi- Mart´ınez et al. (2009, 2013); dobacteria and Lactobacillus can enhance dyslipidemia Yu et al. (2013); Joyce et al. and insulin resistance. Microbiota have an influence (2014 on cholesterol metabolism and weight gain in the host via the bacterial BSH mechanism. Methylamines and Methylamine, Cleavage of choline and phosphatidylcholine (PC) by Wang et al. (2011); Craciun products of choline dimethylamine, the gut microbiota via the enzyme choline TMA-lyase and Balskus (2012); Koeth metabolism dimethylglycine, produces TMA. Oxidation of TMA by hepatic flavin- et al. (2013); Tang et al. trimethylamine (TMA) and containing monooxygenase 3 (FMO3) forms TMAO. (2013); Zhu et al. (2014) trimethylamine N-oxide Microbial metabolism of L-carnitine also produces (TMAO) TMA via a novel Rieske-type protein. Risk for major adverse cardiovascular events coincides with higher levels of TMAO. Neurotransmitters Serotonin, melatonin, It was recently discovered that gut microbiota pro- Desbonnet et al. (2008); glutamate, GABA, duce tryptophan decarboxylase, the enzyme respon- Bravo et al. (2011); Rooks noradrenaline, dopamine sible for decarboxylasing tryptophan to tryptamine. et al. (2014); Williams et al. and acetylcholine Tryptamine promotes the release of serotonin by en- (2014); O’Mahony et al. terochromaffincells.Inaratmodelitwas shownthat (2015) Bifidobacteria treatment resulted in increased tryp- tophan and kynurenic acid levels. Another study in mice showed the potential of Lactobacillus rhamnosus to modulate the GABAergic system. Decreased levels of dopamine were measured in fecal samples from active colitis mice. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 574 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 Table 2. (Continued.) Role in health and Metabolite Intermediates/products Synthesis disease References Phytochemicals, Chlorogenic acids, A significant amount of polyphenols reaches the Tomas-Barberan et al. particularly hydrolysable tannins and colon and is believed to contribute to gut health (2014); Kahle et al. (2006); polyphenolic flavonoids by promoting the growth of some commen- Aronov et al. (2011); van compounds sals. Polyphenolic bioconversion by microbiota Duynhoven et al. (2011); is paramount in the production of a large range Cardona et al. (2013); Mar´ın of bioactive molecules. The exact roles of these et al. (2015) molecules in health and disease are yet to be fully understood. Nonetheless epidemiological stud- ies have tied polyphenols to health benefits such as antioxidative, anticarinogenic, antiadipogenic, antidiabetic and neuroprotective properties. Gut microbiota can also convert dietary polyphenols to benzoate. Polyunsaturated Omega3and 6 L. plantarum has genes encoding for the enzyme in- Kishino et al. (2013) fatty acids (PUFA) volved in saturation metabolism of PUFA. Short-chain fatty Most abundant acetate, The SCFAs are produced from bacterial fermentation Bergman (1990); Maslowski acids (SCFAs) propionate, butyrate; to a of non-digestible polysaccharides. They play a role in et al. (2009); den Besten et al. lesser extent—formate, metabolic syndrome prevention and treatment. Evi- (2013); Kimura et al. (2013); fumarate, malonate, dence point to their potential to promote metabolic Natarajan and Pluznick succinate, caproate and control in type 2 diabetes. SCFAs are a major source (2014); Puddu et al. (2014) valerate of energy for colonocytes and also contribute up to 10% of the host’s daily caloric requirements. They are further involved in the control of energy utiliza- tion and maintenance of metabolic homeostasis via the G Protein coupled Receptor 43 (GPR43) receptor. SCFA products also dampen inflammatory response through this receptor. SCFAs have also been shown to affect cell proliferation and apoptosis (in cancer cells), and in epigenetic machinery such as histone acetylation by butyrate. Vitamins B-group vitamins, vitamin It is well established that the gut microbiota synthe- Hill (1997); Cooke, Behan B12; vitamin C, biotin, size a large number of vitamins de novo.Thisisim- and Costello (2006); vitamin K portant since humans lack biosynthetic pathways for Arumugam et al. (2011); vitamins. The deleterious effects of vitamin deficien- LeBlanc et al. (2013); cies are well known. It has only recently been sug- Degnan, Taga and gested that vitamin B12 may also contribute to shap- Goodman (2014) ing the structure and function of microbial commu- nities in the human gut. Other noteworthy bioactives Conjugated linoleic acid (CLA), bacteriocin CLA is associated with a diverse array of biological Bowdish, Davidson and activities, and predominantly associated with acti- Hancock (2005); Ross et al. vation of peroxisome proliferator activated receptors (2010) (PPARs) and the associated switching on and off of genes. Some Bifidobacteria and Lactobacillus species have been shown to produce CLA. Bacteriocins are peptides synthesized by bacteria and have narrow (same species) or broad (across genera) spectrum ac- tivity against other bacteria. A large number of ar- chaea and bacteria are believed to produce at least one bacteriocin. Tetrathionate and nitric oxide Tetrathionate and nitric oxide are produced in an in- Winter et al. (2010); Bergen flammatory environment and are central to the fit- (2014); Rooks et al. (2014) ness of several Enterobacteriaceae. Tetrathionate uti- lization positively correlated with active colitis in a mouse model. Bacterial growth depends on the pres- ence of nitrogen. Synthesis of amino acids by the mi- crobiome depends on the recycling of nitrogen back into gastrointestinal organs. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 575 Table 3. Various pathologies that have been associated with dysbiosis of the gut. Condition References Asthma Abrahamsson et al. (2014) AD Karri, Martinez and Coimbatore (2010); Alam et al. (2014) Atherosclerosis Koren et al. (2011) Autism spectrum disorders Parracho et al. (2005); Finegold et al. (2010); Adams et al. (2011); Williams et al. (2011, 2012); De Angelis et al. (2013); Kang et al. (2013) β-Cell autoimmunity de Goffau et al. (2014) Cardiovascular disease Amar et al. (2011) Crohn’s disease Seksik et al. (2003) Chronic fatigue syndrome Sheedy et al. (2009); Proal et al. (2013) Cystic fibrosis Scanlan et al. (2012); Bruzzese et al. (2014);Sanc ´ hez-Calvo et al. (2008); Duytschaever et al. (2011, 2013); Madan et al. (2012) HIV/AIDS Lozupone et al. (2013); McHardy et al. (2013); Vujkovic-Cvijin et al. (2013) IgE-associated eczema Abrahamsson et al. (2012) Inflammation Cani et al. (2008, 2012); Delzenne and Cani (2011); Delzenne et al. (2011) Inflammatory bowel disease Conte et al. (2006); Clemente et al. (2012); Manichanh et al. (2012); Morgan et al. (2012); Nagalingam and Lynch (2012); Bakhtiar et al. (2013) Iron deficiency Balamurugan et al. (2010); Zimmermann et al. (2010); Dostal et al. (2012, 2014) Liver disease Schnabl and Brenner (2014) Multiple sclerosis Berer et al. (2011) Obesity Delzenne and Cani (2011); Geurts et al. (2014) Rheumatoid arthritis Detert et al. (2010); Berer et al. (2011); Scher and Abramson (2011); Bingham and Moni (2013); Brusca, Abramson and Scher (2014); Catrina, Deane and Scher (2014); Cenit ´ et al. (2014); Demoruelle, Deane and Holers (2014); Taneja (2014) Parkinson’s Disease Scheperjans et al. (2015); Vizcarra et al. (2015) Sarcoidosis Almenoff et al. (1996) Systemic lupus erythematosus Hevia et al. (2014); Zhang et al. (2014a) Symptomatic atherosclerosis/stroke Karlsson et al. (2012) Type 1 diabetes Brown et al. (2012); Owen and Mohamadzadeh (2013); Petersen and Round (2014) Type 2 diabetes Larsen et al. (2010); Brown et al. (2012); Qin et al. (2012); Karlsson et al. (2013); Everard et al. (2014) Table 4. Diseases and conditions where bacterial translocation (of gut or oral origin) and consequent chronic infection are specifically implicated Diseases and conditions where translocation of bacteria are present References Communicable diseases Fibrosis stage in HIV/HCV coinfection Balagopal et al. (2008); Montes-de-Oca et al. (2011); Page, Nelson and Kelleher (2011); Lin, Weinberg and Chung (2013); Sacchi et al. (2015) Hepatitis C virus (HCV) infection French et al. (2013); Munteanu et al. (2014) HIV/AIDS infection Sandler and Douek (2012); Klatt, Funderburg and Brenchley (2013); Vazquez-Castellanos et al. (2014) Pneumonia in immunocompromised Sawa (2014) patients Diseases usually seen as non-communicable Abdominal compartment syndrome Mifkovic et al. (2013) Alcoholic liver disease Chen and Schnabl (2014); Malaguarnera et al. (2014) Allergic disease: bacterial translocation Abrahamsson Wu and Jenmalm (2015) during pregnancy Atherosclerosis Epstein, Zhou and Zhu (1999); Kozarov et al. (2006); Erridge (2008); Renko et al. (2008); Epstein et al. (2009); Nagata, de Toledo and Oho (2011); Rosenfeld and Campbell (2011); Hopkins (2013); Dinakaran et al. (2014); Rogler and Rosano (2014); Trøseid et al. (2014) Burn wounds Macintire and Bellhorn (2002); Sharma (2007); Aboelatta et al. (2013) Cirrhosis Wiest and Garcia-Tsao (2005); Jun et al. (2010); Giannelli et al. (2014); Wiest, Lawson and Geuking (2014) Chronic kidney disease Anders, Andersen and Stecher (2013); Sabatino et al. (2014) Metabolic syndrome Festi et al. (2014) Non-alcoholic fatty liver disease Bieghs and Trautwein (2014) Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 576 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 Table 4. (Continued.) Diseases and conditions where translocation of bacteria are present References Obesity Vajro, Paolella and Fasano (2013); Sanz and Moya-Per ´ ez (2014) Pancreatitis Mifkovic et al. (2009); Guo et al. (2014); Olah ´ and Romics (2014) Rheumatoid arthritis Ogrendik (2009b, 2013b); Ebringer and Rashid (2014); Koziel, Mydel and Potempa (2014) Schizophrenia Severance et al. (2013); Severance, Yolken and Eaton (2014) Sepsis and Septic shock Tsujimoto, Ono and Mochizuki (2009); Wallet et al. (2011); Deitch (2012); Leli et al. (2014) Stroke Syrjanen ¨ et al. (1988); Emsley and Tyrrell (2002); Emsley et al. (2003); Emsley and Hopkins (2008); McColl, Allan and Rothwell (2009); Emsley and Chamorro (2010); Grau, Urbanek and Palm (2010); Wang et al. (2012a); Chien et al. (2013); Dalager-Pedersen et al. (2014); Fugate et al. (2014) Surgical procedures Bariatric surgery Festi et al. (2014) Cardiac surgery Allen (2014) Multiple organ failure (MOF) Swank and Deitch (1996) Sepsis due to surgery MacFie (2004); Puleo et al. (2011) ‘Sepsis’ is widely used to imply living microbes, but as is now well known it can also occur in the absence of any culturable microbes, including those incapable of proliferation due to antibiotic activity. Sepsis may commonly result simply from the effects of molecules such as LPS on the generation of inflammator y cytokines (Kotsaki and Giamarellos-Bourboulis 2012; Balakrishnan et al. 2013). suggested that a changed gut microbiota represents the initial well as other microorganisms can reside inside RBCs (e.g. Mi- site of autoimmunity generation, and might be a critical epige- nasyan 2014), and thus able to cross the RBC membrane some- netic factor in autoimmune diseases such as rheumatoid arthri- how (see Table 5). Transmission electron microscopy (TEM) anal- tis (Scher and Abramson 2011; Luckey et al. 2013; Brusca, Abram- ysis showing bacteria inside cells would also tend to imply that son and Scher 2014; Catrina, Deane and Scher 2014;Cenit ´ et al. the bacteria were not externally introduced artefactually during 2014; Taneja 2014). There is also evidence that regulatory T cells the preparation of the samples. in the gut are influenced by microbial factors, and that a changed For the current paper, we have revisited our AD and PD microbiota (dysbiosis) may influence the induction and suppres- samples and figures from Pretorius et al. (2014a) and Lipinski sor functions of these cells, in turn leading to a changed gut mu- and Pretorius (2013) and noted the prevalence of bacteria in al- cosal immunity (Kinoshita and Takeda 2014). most all of the AD and PD samples, in numbers much in ex- We have earlier reviewed the literature that suggests that cess of those seen in our database of thousands micrographs dysbiosis can cause gut epithelial barrier dysfunction, and from healthy individuals. Here we show additional micrographs thereby provide a point of entry into the body, including the from the previously published samples (see Figs 5 and 6). In blood, resulting in atopobiosis. This is supported by recent re- both conditions (see Figs 5AD and 6PD), microbes were noted search that has suggested that blood microbiota might be impli- in close proximity to RBCs, and in some cases RBCs extended cated in various (cardiovascular and other) diseases. Sequence- pseudopodia-like projections towards the microbiota. SEM anal- based techniques provided evidence for the presence of such ysis of AD whole blood (Fig. 5) shows that mostly coccus-shaped a blood microbiome. The question now arises as to whether bacteria are present. White blood cells are seen in close proxim- such a microbiome’s presence can be directly measured by e.g. ity to these bacteria in AD patients (see Fig. 5A–C). SEM anal- ultrastructural (microscopic) methods, since a consequence of yses of PD patients (Fig. 6) show both coccus- and bacillus- any translocation of microbes between the gut microbiome and shaped bacteria in close proximity to RBCs. We also observed blood is that they should then be observable in blood. The next that RBCs extend pseudopodia towards these bacteria and this sections will provide visual evidence of the presence of such might be part of the mechanism by which the bacteria en- a microbiota in Alzheimer’s disease (AD) and PD. As shown in ter the RBCs (see Fig. 6C–F). We also note possibly dividing Table 3, these conditions are known to be associated with the coccus-shaped bacteria in both these conditions, indicated with presence of dysbiosis. blue arrows on Fig. 5A (AD patient) and Fig. 6D (PD patient). This might suggest that these bacteria may be(come) cultur- able under appropriate conditions (see also Soina et al. 2012; Direct measurement by ultrastructural (microscopic) Epstein 2013). methods TEM analysis of the samples from Lipinski and Pretorius Direct measurement by ultrastructural (microscopic) methods of (2013) and Pretorius et al. (2014a) showed the presence in- side RBCs of cells that appeared to be microbial in nature analysis shows that microbes are in fact common constituents of blood in inflammatory diseases [previously seen in PD—Fig. 8 (unpublished data). These internalized cells further provide evidence for a sustained presence of such a blood micro- in (Pretorius et al. 2014a and in AD—Fig. 2 in (Lipinski and Pre- biota (and one hardly explained by contamination) (see Fig. 7A torius 2013). We show and annotate selected micrographs from and B: AD and C and D: PD). Bacteria are shown with ar- these papers in Fig. 4]. An important concern that needs to be rows in the micrographs. No bacterial membrane was noted; addressed, as is also the case with sequence-based methods, is therefore, the bacteria may be L-forms. There seems to be whether the presence of microbiota in whole blood is indeed bacterial species selectivity for a given disease, as our pre- not the result of introduced external contamination. There is liminary observations suggest a prevalence for bacillus-type in fact considerable evidence in the literature that bacteria as Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 577 Figure 3. Schematic representation of dysbiosis, bacterial translocation and atopobiosis. (A) When intestinal microbiota are associated with dysbiosis,(B) the gut barrier (1 and 2) becomes compromised; this leads to (C), a route of entry via the gut epithelia causing (D) bacterial translocation. Bacterial translocation is also associated with a compromised systemic immune system barrier (3). Therefore, intestinal microbiota dysbiosis (A) followed by bacterial translocation (D) results in (E) atopobiosis. (F) The results of bacterial translocation are seen in various conditions (see Table 4). bacteria in AD, but both coccus- and bacillus-shaped bacteria however, dormancy and viability versus non-viability issues per- in PD patients. tain (as discussed above). Our observations suggest that the presence of bacteria in We found a definite association between RBCs and bacteria, these two diseases occurs in only a small fraction of the RBC with RBCs (see Figs 6 and 7) forming pseudopodia-like extension, population, which is why we had not really noted them in our as if in the process of engulfing bacteria. Both coccoid (round) previous studies (e.g. Bester et al. 2013; Pretorius et al. 2013, and bacillary (elongated) bacteria were found in PD whole blood 2014a,b; Pretorius and Kell 2014), and SEM and TEM analysis con- SEM micrographs, but only coccoid forms in AD whole blood firms this observation. We have never (or not yet) found bacte- SEM micrographs. Samples from 25 diagnosed AD patients were ria inside RBCs from healthy controls (these without overt, diag- studied and bacteria were detected in 14 individuals from this nosed diseases) when studying blood smears using TEM analy- AD sample, while samples from 30 PD patients were studied, sis. The microscopy preparation methods involve a washing pro- in 21 of whom we detected bacteria. Obviously, the type of bac- cess, and this may wash away some of the bacteria, or RBCs and teria cannot be identified from ultrastructural observations. As white blood cells associated with bacteria. Therefore, the actual with the timeline of established cases such as the role of H. quantification of the bacteria can only be done by other means; pylori in ulcers and colon cancer, the next tasks are to bring Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 578 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 these microscopically observed bacteria into culture and to carry out sequence-based studies to establish their role (if any) in non-communicable diseases. However, to illustrate that the bac- teria may indeed be engulfed by the RBCs, and to confirm that the phenomenon is not due to external contamination, we show TEM micrographs from both of the studied diseases (see Fig. 7, AD and PD). CONCLUDING REMARKS AND PROSPECTIVE EXPERIMENTS ‘Non-culturable’ (which should be called ‘not-easily-culturable’ or ‘not-yet-cultured’) microbes are commonplace in the ‘envi- ronmental microbiology’ of soil and water, and the blood cer- tainly represents an ‘environment’. As we show here, there is a large and scattered literature, increasing in size, to the effect that there might be a (mainly dormant) microbial component Figure 4. Micrographs taken from previously published manuscripts. (A–C)Bac- in a variety of chronic diseases that are normally considered to terial presence in PD, originally shown in Fig. 8A, C and G in Pretorius et al. (2014a). (D) Bacterial presence in AD, originally shown in Fig. 2 in Lipinski and be non-microbial or non-communicable in nature, even when Pretorius (2013). microbes appear absent by culturability criteria. Our previous Table 5. Some microorganisms that are known to invade red blood cells. Pathogen Type of microorganism Mechanism of invasion References Anaplasma marginale A tick-borne pathogen that causes Via major surface protein 1a (MSP1a) Kocan et al. the disease anaplasmosis in cattle. (2004) Bartonella bacilliformis Bartonella species are fastidious The Trw T4SS mediates attachment of Bartonella to Iwaki-Egawa and B.quintana Gram-negative bacteria, which red blood cells in Bartonella lineage 4. Bartonella is Ihler (1997); belong to the alpha group of the collected in pits and trenches that form as a result Coleman and domain Proteobacteria. of deformation factor. Invaginations supposedly Minnick (2001); pinch off to carry the content in a vacuole structure Rolain et al. to the cytoplasm of the red blood cell where the (2003); Eicher organism persists. and Dehio (2012) Brucella melitensis Facultative intracellular Invasion shown in mouse erythrocytes. Mechanism Vitry et al. (2014) Gram-negative coccobacilli. to be identified. Francisella tularensis Highly infectious bacterium, Via serum complement-dependent and Conlan (2011); which can cause severe disease independent mechanisms. Horzempa et al. tularemia with an infection of (2011) fewer than 10 bacteria Mycoplasma suis A member or the hemotrophic Invasion occurs in a similar manner to that of P. Groebel et al. mycoplasma group that parasitize falciparum and B. bacilliformis. Attachment via MSG1 (2009); Zhang erythrocytes in pigs. (GAPDH) protein. et al. (2014c) M. bovis Small cell wall-less bacterium that Undetermined. van der Merwe, contributes to a number of chronic Prysliak and inflammatory diseases in dairy Perez-Casal and feedlot cattle. (2010) M. gallisepticum Mycoplasmas are small cell Not known. Vogl et al. (2008) wall-less prokaryotes. Plasmodium falciparum The main malaria parasite, part of Recognition of surface receptors precedes a Cowman and whose life cycle involves reorientation where the apical end is adjusted to Crabb (2006) inhabiting RBCs. the erythrocyte. A tight junction that involves high-affinity ligand receptor interactions is formed. The tight junction moves from the apical to posterior pole and is powered by the actin-myosin motor of the parasite. The adhesive proteins at the junction are proteolytically removed when the posterior pole is reached, most likely by a rhomboid resident protease in a process that facilitates membrane resealing. The invasion process produces a parasitophorous vacuole containing the merozoite. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 579 Table 5. (Continued.) Pathogen Type of microorganism Mechanism of invasion References Streptococcus pneumoniae Gram-positive bacterium which LPXTG motif-containing pneumococcal proteins, Yamaguchi et al. causes infection-related diseases. erythrocyte lipid rafts and erythrocyte actin (2013) remodeling are involved in the invasion mechanism. Theileria sporozites Intracellular protozoan Occurs in a similar manner to sporozoite entry. Shaw (2003); transmitted by ixodid ticks. Infect Bishop et al. wild and domesticated ruminants. (2004) Phylogenetically most closely related to Babesia. Figure 6. RBCs with microbiota from patients with diagnosed PD (additional mi- crographs from sample used in Pretorius et al. 2014a). These micrographs are rep- Figure 5. RBCs with microbiota from patients with diagnosed AD (additional mi- resentative of bacteria found in smears of 21 of the 30 PD individuals. (A) A col- crographs from sample used in Lipinski and Pretorius 2013). These micrographs lection of coccus- and bacillus-shaped bacteria; (B) coccus- and bacillus-shaped are representative of bacteria found in smears of 14 of the 30 AD individuals. bacteria associated with erythrocyte; (C) bacillus-shaped bacteria in close prox- (A and B) coccus-shaped bacteria associated with white blood cell; (B) coccus- imity with erythrocyte. Erythrocyte forms extensions towards bacteria; (D and E) shaped bacteria associated with an erythrocyte and white blood cell; (C)two bacillus-shaped bacteria associated with elongated erythrocytes; (F) coccus- and white blood cells associated with coccus-shaped bacteria; (D) a string of cocci- bacillus-shaped bacteria close to erythrocyte that extends pseudopodia towards blue arrow shows possibly dividing coccoid bacteria; (E) an erythrocyte associ- the bacteria. Coccus-shaped bacteria shown with pink arrows; bacillus-shaped ated with coccus-shaped bacteria; (F) a high machine magnification of a coccus- bacteria shown with white arrows. Dividing coccus-shaped bacteria shown with shaped bacteria associated with a dense matted fibrin deposit. Scale bar: 1 μm. blue arrow. Scale bar: 1 μm. work (e.g. Bester et al. 2013; Pretorius et al. 2013, 2014a;Kelland Pretorius 2014, 2015; Pretorius and Kell 2014) has implied iron dysregulation as a regular accompaniment to, and probable con- We have here pointed up the likelihood of a steady crop tributory factor for, a variety of similar diseases, all of which of effectively dormant microbes being a feature of blood bi- have an inflammatory component. We argue here that there is ology in chronically diseased humans, including those with also a microbial contribution to this in the blood, and it is not un- non-communicable diseases. As with any complex system, the reasonable that the microbial requirement for iron means that, magnitude of any component is affected by the kinetics of every despite the oxidative stress it can entail (Touati 2000;Kell 2009, relevant step; while the precise nature of all the interactions is 2010), microbes may be anticipated to increase in prevalence uncertain, Fig. 8 describes the general network—the first step in when iron is free (e.g. Ratledge 2007; Clifton, Corrent and Strong any systems analysis (Kell 2006; Kell and Knowles 2006). 2009; Sia, Allred and Raymond 2013; Chu et al. 2014) and avail- Consequently, we recognize that the analysis above has able (D’Onofrio et al. 2010), probably behaving in a social manner largely been qualitative (the ‘presence’ of a microbial compo- (Kell, Kaprelyants and Grafen 1995; West and Buckling 2003;Dig- nent in a specific disease is a qualitative statement). However, gle et al. 2007; Harrison and Buckling 2009). chronic, non-communicable diseases are very far from being Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 580 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 tectable blood microbiome in this and other diseases that show such flares. As with H. pylori and stomach ulcers (and cancer), the simple prediction is that bactericidal antibiotics should be of value in the treatment of such supposedly non-communicable diseases. Indeed, this prediction is borne out for diseases such as rheumatoid arthritis (Ogrendik 2009a, 2013a; Kwiatkowska and Masli ´ nska ´ 2012) and multiple sclerosis (Ochoa-Repar ´ az et al. 2009; 2011), while antipneumococcal vaccination has shown ef- ficacy in preventing stroke (Vila-Corcoles et al. 2014). Of course, events such as heart attacks and strokes (and see Table 4)may also be seen as sudden increases in severity of an underlying condition, and in some cases (such as the much increased like- lihood of strokes after subarachnoid haemorrhages; McMahon et al. 2013), analysis of changes in the blood microbiome might prove predictive. The obvious next tasks are thus to relate the number and nature of blood microbes observed in cases such as the above to microbial sequences and antigens that can be detected in aliquots of the same samples (e.g. Salipante et al. 2013, 2015), to determine the physiological state of the various microbes (in- Figure 7. TEM confirming the presence of bacteria inside erythrocytes of ( A and cluding e.g. whether they are L-forms), and to establish methods B)AD,(C and D) PD. (Additional micrographs from sample used in Lipinski and to bring them (back) into culture. Since microbes, inflammation Pretorius (2013) and Pretorius et al. (2014a). Arrows in each micrograph show the and various syndromes are such common co-occurrences (as presence of cellular inclusions, without visible membranes. Inclusions are not typically noted in erythrocytes. We suggest that these inclusions are bacteria, are coagulopathies; Kell and Pretorius 2015), longitudinal stud- possibly as L-forms. Scale bar = 1 μm (A, C, D); 200 nm (D). ies will have a specially important role, as they will both show the dynamics and be able to help discriminate cause and ef- fect during the time evolution of chronic, non-communicable diseases in ageing populations. The immunogenicity of per- static (and thousands of human genes change their expression sisters, and their ability to induce various kinds of inflamma- at least 2-fold even on a diurnal basis; Zhang et al. 2014b). Thus, a tion, must be rather different from that of replicating organ- clear further issue is to seek to understand how the blood micro- isms, and this must be investigated. Armed with such collec- biome may co-vary with the day-to-day dynamics of chronic dis- tive knowledge, we might be better placed to develop thera- eases. For example, rheumatoid arthritis has circadian rhythms peutics such as pre- and probiotics and bactericidal antibiotics (Straub and Cutolo 2007) and is well known to provide signifi- for use in such cases previously thought to lack a microbial cant variations (‘flares’; Flurey et al. 2014) in severity at different contribution. times. A reasonable strategy is thus to look for changes in a de- Figure 8. Relationships between a dormant blood microbiome and chronic disease dyamics. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 581 FUNDING Phylogenetics: a discipline of evolutionary biology that stud- ies the relationships between organisms based on how closely We thank the Biotechnology and Biological Sciences Research similar some of their macromolecular sequences are. Council (grant BB/L025752/1) as well as the National Re- Pleomorphic: possessing the ability to change shape or size search Foundation (NRF) of South Africa for supporting this in response to environmental stimuli. collaboration. Resuscitation: induction of apparently non-culturable cells to a state of culturability. Conflict of interest. None declared. Sterile: refers to an absence of operationally viable organ- isms. Viable: capable of observable replication, i.e. culturable, by any stated means. GLOSSARY 16S ribosomal RNA: a component of the 30S small subunit of REFERENCES prokaryotic ribosomes. The 16S rRNA gene is found in all bacte- Aboelatta YA, Abd-Elsalam AM, Omar AH, et al. Selective diges- ria and archaea and consists of nine short hypervariable regions tive decontamination (SDD) as a tool in the management of that may be used to distinguish bacterial taxa. bacterial translocation following major burns. Ann Burns Fire Anabiosis: when an organism is in a state of very low Disasters 2013;26:182–8. metabolic activity to the extent where it is hardly measurable Abrahamsson TR, Jakobsson HE, Andersson AF, et al. Low diver- and in some cases come to a standstill. The physiological and sity of the gut microbiota in infants with atopic eczema. J biochemical processes are arrested for different periods of time Allergy Clin Immun 2012;129:434–40,440 e431–32. but can be reversed. Abrahamsson TR, Jakobsson HE, Andersson AF, et al. Low gut mi- Atopobiosis (Greek ατooπoς or atopos) appearance of the gut crobiota diversity in early infancy precedes asthma at school or other microbiome in the wrong place. age. Clin Exp Allergy 2014;44:842–50. Bacterial translocation: the passage of viable resident bac- Abrahamsson TR, Wu RY, Jenmalm MC. Gut microbiota and al- teria from the gastrointestinal tract to normally sterile tissues lergy: the importance of the pregnancy period. Pediatr Res such as the mesenteric lymph nodes and the other internal 2015;77:214–9. organs. Adams JB, Johansen LJ, Powell LD, et al. Gastrointestinal Cryptobiosis: refers to latent life or a state where an organism flora and gastrointestinal status in children with autism— lacks any visible signs of life but is not dead in that it may revert comparisons to typical children and correlation with autism to a state of aliveness as usually defined. Its metabolic activity severity. BMC Gastroenterol 2011;11:22. becomes hardly measurable, or comes reversibly to a standstill. Alam MZ, Alam Q, Kamal MA, et al. A possible link of gut micro- Culturability: the ability of a cell to reproduce. biota alteration in type 2 diabetes and Alzheimer’s disease Direct viable count: the original method comprises incuba- pathogenicity: an update. CNS Neurol Disord-Dr 2014;13:383– tion of samples with nutrients (yeast extract) and a single an- timicrobial agent that specifically inhibits DNA synthesis but not Allan EJ, Hoischen C, Gumpert J. Bacterial L-forms. Adv Appl Mi- RNA synthesis (nalidixic acid). Cell division ceases as a result crobiol 2009;68:1–39. of DNA synthesis inhibition but other cellular metabolic activ- Allen SJ. Gastrointestinal complications and cardiac surgery. J ities remain unaffected and therefore cells continue to metab- Extra-Corp Technol 2014;46:142–9. olize nutrients and grow in size, which allows their detection Allen-Vercoe E. Bringing the gut microbiota into focus through microscopically in situ. microbial culture: recent progress and future perspective. Dormant: notviableinthe senseofnotbeingmoreorlessim- Curr Opin Microbiol 2013;16:625–9. mediately culturable, but may be returned to a state of viability Almenoff PL, Johnson A, Lesser M, et al. Growth of acid fast L or culturability by preincubation under suitable conditions. forms from the blood of patients with sarcoidosis. Thorax Dysbiosis: derangement of the species distribution in the 1996;51:530–3. normal microbiome. Amann RI, Ludwig W, Schleifer KH. Phylogenetic identification L-forms: these bacteria are cell wall-deficient forms of nor- and in situ detection of individual microbial cells without mal bacteria. They are able to proliferate as sphaeroplasts or cultivation. Microbiol Rev 1995;59:143–69. protoplasts under certain conditions. Amar J, Lange C, Payros G, et al. Blood microbiota dysbiosis Metagenomics: direct genetic analysis of a collection of is associated with the onset of cardiovascular events in genomes contained in an environmental sample. a large general population: the D.E.S.I.R. study. PLoS One Microbiome: the genetic sum of the ecological community 2013;8:e54461. of commensal, symbiotic and pathogenic microorganisms that Amar J, Serino M, Lange C, et al. Involvement of tissue bacteria lives on and inside our bodies. in the onset of diabetes in humans: evidence for a concept. ‘Most Probable Number’ technique: is a method used to Diabetologia 2011;54:3055–61. quantify the concentration of viable microorganisms in a sam- Amar S, Engelke M. Periodontal innate immune mecha- ple. It involves replicate liquid broth growth in 10-fold dilutions. nisms relevant to atherosclerosis. Mol Oral Microbiol 2014, When a dilution lacks growth, it is assumed not to have any or- DOI:10.1111/omi.12087. ganisms. Back-calculation via a Poissonian distribution leads to Amato SM, Orman MA, Brynildsen MP. Metabolic control of the ‘most probable number’ in the original sample persister formation in Escherichia coli. Mol Cell 2013;50: Non-axenic culture: contains more than one species, variety 475–87. or strain of organism. Anders HJ, Andersen K, Stecher B. The intestinal microbiota, a Non-viable: incapable of observable replication by any stated leaky gut, and abnormal immunity in kidney disease. Kidney means normally capable of effecting replication in the relevant Int 2013;83:1010–6. organism. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 582 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 Anthony RM, Brown TJ, French GL. Rapid diagnosis of bacteremia Bowdish DM, Davidson DJ, Hancock R. A re-evaluation of the role by universal amplification of 23S ribosomal DNA followed of host defence peptides in mammalian immunity. Curr Pro- by hybridization to an oligonucleotide array. J Clin Microbiol tein Pept Sc 2005;6:35–51. 2000;38:781–8. Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus Aronov PA, Luo FJ, Plummer NS, et al. Colonic contribution to strain regulates emotional behavior and central GABA recep- uremic solutes. J Am Soc Nephrol 2011;22:1769–76. tor expression in a mouse via the vagus nerve. P Natl Acad Sci Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human 2011;108:16050–5. gut microbiome. Nature 2011;473:174–80. Brown K, DeCoffe D, Molcan E, et al. Diet-induced dysbiosis of Bakhtiar SM, LeBlanc JG, Salvucci E, et al. Implications of the hu- the intestinal microbiota and the effects on immunity and man microbiome in inflammatory bowel diseases. FEMS Mi- disease. Nutrients 2012;4:1095–119. crobiol Lett 2013;342:10–7. Brusca SB, Abramson SB, Scher JU. Microbiome and mucosal in- Bakken LR, Olsen RA. The relationship between cell size and vi- flammation as extra-articular triggers for rheumatoid arthri- ability of soil bacteria. Microb Ecol 1987;13:103–14. tis and autoimmunity. Curr Opin Rheumatol 2014;26:101–7. Balaban NQ, Merrin J, Chait R, et al. Bacterial persistence as a Bruzzese E, Callegari ML, Raia V, et al. Disrupted intestinal mi- phenotypic switch. Science 2004;305:1622–5. crobiota and intestinal inflammation in children with cys- Balagopal A, Philp FH, Astemborski J, et al. Human immunodefi- tic fibrosis and its restoration with Lactobacillus GG: a ran- ciency virus-related microbial translocation and progression domised clinical trial. PLoS One 2014;9:e87796. of hepatitis C. Gastroenterology 2008;135:226–33. Burcelin R, Serino M, Chabo C, et al. Metagenome and Balakrishnan A, Marathe SA, Joglekar M, et al. Bacterici- metabolism: the tissue microbiota hypothesis. Diabetes Obes dal/permeability increasing protein: a multifaceted protein Metab 2013;15 (Suppl 3):61–70. with functions beyond LPS neutralization. Innate Immun Calcott PH, Calvert TJ. Characterization of 3’: 5’ -cyclic 2013;19:339–47. AMP phosphodiesterase in Klebsiella aerogenes and its role Balamurugan R, Mary RR, Chittaranjan S, et al. Low levels of fae- in substrate-accelerated death. J Gen Microbiol 1981;122: cal lactobacilli in women with iron-deficiency anaemia in 313–21. south India. Brit J Nutr 2010;104:931–4. Calcott PH, Postgate JR. On substrate-accelerated death in Kleb- Balzan S, de Almeida Quadros C, de Cleva R, et al. Bacterial siella aerogenes. J Gen Microbiol 1972;70:115–22. translocation: overview of mechanisms and clinical impact. Cani PD, Bibiloni R, Knauf C, et al. Changes in gut micro- J Gastroen Hepatol 2007;22:464–71. biota control metabolic endotoxemia-induced inflammation Bennett BJ, de Aguiar Vallim TQ, Wang Z, et al. Trimethylamine- in high-fat diet-induced obesity and diabetes in mice. Dia- N-oxide, a metabolite associated with atherosclerosis, ex- betes 2008;57:1470–81. hibits complex genetic and dietary regulation. Cell Metab Cani PD, Osto M, Geurts L, et al. Involvement of gut microbiota 2013;17:49–60. in the development of low-grade inflammation and type 2 BererK,MuesM,KoutrolosM, et al. Commensal microbiota and diabetes associated with obesity. Gut Microbes 2012;3:279–88. myelin autoantigen cooperate to trigger autoimmune de- Caporaso JG, Lauber CL, Costello EK, et al. Moving pictures of the myelination. Nature 2011;479:538–41. human microbiome. Genome Biol 2011;12:R50. Berg RD. Bacterial translocation from the gastrointestinal tract. Cardona F, Andres-Lacueva C, Tulipani S, et al. Benefits of Trends Microbiol 1995;3:149–54. polyphenols on gut microbiota and implications in human Bergen WG. Small-intestinal or colonic microbiota as a potential health. J Nutr Biochem 2013;24:1415–22. amino acid source in animals. Amino Acids 2014;47:251–8. Casadesus ´ J. Bacterial L-forms require peptidoglycan synthesis Bergman E. Energy contributions of volatile fatty acids from for cell division. Bioessays 2007;29:1189–91. the gastrointestinal tract in various species. Physiol Rev Catrina AI, Deane KD, Scher JU. Gene, environment, micro- 1990;70:567–90. biome and mucosal immune tolerance in rheumatoid arthri- Bested AC, Logan AC, Selhub EM. Intestinal microbiota, probi- tis. Rheumatology 2014, DOI:10.1093/rheumatology/keu469. otics and mental health: from Metchnikoff to modern ad- Cavanagh JP, Hjerde E, Holden MT, et al. Whole-genome se- vances: part III - convergence toward clinical trials. Gut Pathog quencing reveals clonal expansion of multiresistant Staphy- 2013;5:4. lococcus haemolyticus in European hospitals. J Antimicrob Bester J, Buys AV, Lipinski B, et al. High ferritin levels have ma- Chemoth 2014;69:2920–7. jor effects on the morphology of erythrocytes in Alzheimer’s Cenit ´ MC, Matzaraki V, Tigchelaar EF, et al. Rapidly expanding disease. Front Aging Neurosci 2013;5:00088. knowledge on the role of the gut microbiome in health and Bieghs V, Trautwein C. Innate immune signaling and gut-liver disease. Biochim Biophys Acta 2014;1842:1981–92. interactions in non-alcoholic fatty liver disease. Hepatobiliary Chang SS, Hsu HL, Cheng JC, et al. An efficient strategy for Surg Nutr 2014;3:377–85. broad-range detection of low abundance bacteria without Bingham CO III,Moni M. Periodontal disease and rheuma- DNA decontamination of PCR reagents. PLoS One 2011;6: toid arthritis: the evidence accumulates for complex e20303. pathobiologic interactions. Curr Opin Rheumatol 2013;25: Chen P, Schnabl B. Host-microbiome interactions in alcoholic 345–53. liver disease. Gut Liver 2014;8:237–41. Bishop R, Musoke A, Morzaria S, et al. Theileria: intracellular pro- Chien LN, Chi NF, Hu CJ, et al. Central nervous system infections tozoan parasites of wild and domestic ruminants transmit- and stroke—a population-based analysis. Acta Neurol Scand ted by ixodid ticks. Parasitology 2004;129:S271–83. 2013;128:241–8. Blaser M, Bork P, Fraser C, et al. The microbiome explored: recent Cho I, Blaser MJ. The human microbiome: at the interface of insights and future challenges. Nat Rev Microbiol 2013;11:213– health and disease. Nat Rev Genet 2012;13:260–70. 7. Chu BC, Otten R, Krewulak KD, et al. The solution structure, bind- Blaser MJ. The microbiome revolution. J Clin Invest 2014;124: ing properties, and dynamics of the bacterial siderophore- 4162–5. binding protein FepB. J Biol Chem 2014;289:29219–34. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 583 Clark MA, Jepson MA. Intestinal M cells and their role in bacterial Delzenne NM, Neyrinck AM, Bac ¨ khed F, et al. Targeting gut mi- infection. Int J Med Microbiol 2003;293:17–39. crobiota in obesity: effects of prebiotics and probiotics. Nat Claudi B, Sprote P, Chirkova A, et al. Phenotypic variation of Rev Endocrinol 2011;7:639–46. Salmonella in host tissues delays eradication by antimicro- Demoruelle MK, Deane KD, Holers VM. When and where does in- bial chemotherapy. Cell 2014;158:722–33. flammation begin in rheumatoid arthritis? Curr Opin Rheuma- Clegg JS. Cryptobiosis—a peculiar state of biological organiza- tol 2014;26:64–71. tion. Comp Biochem Phys B 2001;128:613–24. den Besten G, van Eunen K, Groen AK, et al. The role of short- Clemente JC, Ursell LK, Parfrey LW, et al. The impact of the chain fatty acids in the interplay between diet, gut micro- gut microbiota on human health: an integrative view. Cell biota, and host energy metabolism. J Lipid Res 2013;54:2325– 2012;148:1258–70. 40. Clifton MC, Corrent C, Strong RK. Siderocalins: siderophore- Desbonnet L, Garrett L, Clarke G, et al. The probiotic Bifidobacte- binding proteins of the innate immune system. Biometals ria infantis: an assessment of potential antidepressant prop- 2009;22:557–64. erties in the rat. J Psychiatr Res 2008;43:164–74. Clingenpeel S, Schwientek P, Hugenholtz P, et al. Effects of sam- Detert J, Pischon N, Burmester GR, et al. The association between ple treatments on genome recovery via single-cell genomics. rheumatoid arthritis and periodontal disease. Arthritis Res ISME J 2014;8:2546–9. Ther 2010;12:218. Coleman SA, Minnick MF. Establishing a direct role for the Devaraj S, Hemarajata P, Versalovic J. The human gut micro- Bartonella bacilliformis invasion-associated locus B (IalB) biome and body metabolism: implications for obesity and di- protein in human erythrocyte parasitism. Infect Immun abetes. Clin Chem 2013;59:617–28. 2001;69:4373–81. Devine KM. Bacterial L-forms on tap: an improved methodology Conlan JW. Francisella tularensis: a red-blooded pathogen. JInfect to generate Bacillus subtilis L-forms heralds a new era of re- Dis 2011;204:6–8. search. Mol Microbiol 2012;83:10–3. Conte MP, Schippa S, Zamboni I, et al. Gut-associated bacterial Didelot X, Bowden R, Wilson DJ, et al. Transforming clinical mi- microbiota in paediatric patients with inflammatory bowel crobiology with bacterial genome sequencing. Nat Rev Genet disease. Gut 2006;55:1760–7. 2012;13:601–12. Cooke G, Behan J, Costello M. Newly identified vitamin K- Diggle SP, Griffin AS, Campbell GS, et al. Cooperation and producing bacteria isolated from the neonatal faecal flora. conflict in quorum-sensing bacterial populations. Nature Microb Ecol Health D 2006;18:133–8. 2007;450:411–4. Corr SC, Gahan CC, Hill C. M-cells: origin, morphology and role Dinakaran V, Rathinavel A, Pushpanathan M, et al. Elevated lev- in mucosal immunity and microbial pathogenesis. FEMS Im- els of circulating DNA in cardiovascular disease patients: munol Med Mic 2008;52:2–12. metagenomic profiling of microbiome in the circulation. PLoS Cowman AF, Crabb BS. Invasion of red blood cells by malaria par- One 2014;9:e105221. asites. Cell 2006;124:755–66. Ding PH, Jin LJ. The role of lipopolysaccharide-binding pro- Craciun S, Balskus EP. Microbial conversion of choline to tein in innate immunity: a revisit and its relevance to trimethylamine requires a glycyl radical enzyme. P Natl Acad oral/periodontal health. J Periodontal Res 2014;49:1–9. Sci USA 2012;109:21307–12. Ding T, Schloss PD. Dynamics and associations of micro- Dalager-Pedersen M, Sogaard M, Schonheyder HC, et al. Risk for bial community types across the human body. Nature myocardial infarction and stroke after community-acquired 2014;509:357–60. bacteremia: a 20-year population-based cohort study. Circu- Domingue GJ. Demystifying pleomorphic forms in persistence lation 2014;129:1387–96. and expression of disease: Are they bacteria, and is peptido- Davey HM, Kell DB. Flow cytometry and cell sorting of heteroge- glycan the solution? Discov Med 2010;10:234–46. neous microbial populations: the importance of single-cell Domingue GJ, Schlegel JU. Novel bacterial structures in human analyses. Microbiol Rev 1996;60:641–96. blood: cultural isolation. Infect Immun 1977;15:621–7. De Angelis M, Piccolo M, Vannini L, et al. Fecal microbiota Domingue GJ, Sr, Woody HB. Bacterial persistence and expres- and metabolome of children with autism and pervasive sion of disease. Clin Microbiol Rev 1997;10:320–44. developmental disorder not otherwise specified. PLoS One Dom´ınguez-Cuevas P, Mercier R, Leaver M, et al. The rod to L- 2013;8:e76993. form transition of Bacillus subtilis is limited by a requirement de Goffau MC, Fuentes S, van den Bogert B, et al. Aberrant gut mi- for the protoplast to escape from the cell wall sacculus. Mol crobiota composition at the onset of type 1 diabetes in young Microbiol 2012;83:52–66. children. Diabetologia 2014;57:1569–77. D’Onofrio A, Crawford JM, Stewart EJ, et al. Siderophores from De Preter V, Verbeke K. Metabolomics as a diagnostic tool in gas- neighboring organisms promote the growth of uncultured troenterology. World J Gastrointest Pharmacol Ther 2013;4:97– bacteria. Chem Biol 2010;17:254–64. 107. Dostal A, Baumgartner J, Riesen N, et al. Effects of iron sup- Dedysh SN. Cultivating uncultured bacteria from northern wet- plementation on dominant bacterial groups in the gut, fae- lands: knowledge gained and remaining gaps. Front Microbiol cal SCFA and gut inflammation: a randomised, placebo- 2011;2:184. controlled intervention trial in South African children. Brit Degnan PH, Taga ME, Goodman AL. Vitamin B as a mod- JNutr 2014;112:547–56. ulator of gut microbial ecology. Cell Metab 2014;20: Dostal A, Chassard C, Hilty FM, et al. Iron depletion and repletion 769–78. with ferrous sulfate or electrolytic iron modifies the compo- Deitch EA. Gut-origin sepsis: evolution of a concept. Surgeon sition and metabolic activity of the gut microbiota in rats. J 2012;10:350–6. Nutr 2012;142:271–7. Delzenne NM, Cani PD. Interaction between obesity and the gut Dowd SE, Sun Y, Secor PR, et al. Survey of bacterial diversity in microbiota: relevance in nutrition. Annu Rev Nutr 2011;31:15– chronic wounds using pyrosequencing, DGGE, and full ribo- 31. some shotgun sequencing. BMC Microbiol 2008;8:43. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 584 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 Drennan M. What is ‘Sterile Blood’? Brit Med J 1942;2:526. plicated bloodstream infections caused by Gram-positive Duda VI, Suzina NE, Polivtseva VN, et al. Ultramicrobacteria: for- bacteria or Candida species. J Clin Microbiol 2013;51:1130–6. mation of the concept and contribution of ultramicrobacteria FestiD,SchiumeriniR,EusebiLH, et al. Gut microbiota and to biology. Mikrobiologiia 2012;81:415–27. metabolic syndrome. World J Gastroenterol 2014;20:16079–94. Duytschaever G, Huys G, Bekaert M, et al. Cross-sectional and Finegold SM, Dowd SE, Gontcharova V, et al. Pyrosequencing longitudinal comparisons of the predominant fecal micro- study of fecal microflora of autistic and control children. biota compositions of a group of pediatric patients with cys- Anaerobe 2010;16:444–53. tic fibrosis and their healthy siblings. Appl Environ Microb Flores GE, Caporaso JG, Henley JB, et al. Temporal variability is a 2011;77:8015–24. personalized feature of the human microbiome. Genome Biol Duytschaever G, Huys G, Bekaert M, et al. Dysbiosis of bifidobac- 2014;15:531. teria and Clostridium cluster XIVa in the cystic fibrosis fecal Flurey CA, Morris M, Richards P, et al. It’s like a juggling microbiota. JCystFibros 2013;12:206–15. act: rheumatoid arthritis patient perspectives on daily life Ebringer A, Rashid T. Rheumatoid arthritis is caused by a Proteus and flare while on current treatment regimes. Rheumatology urinary tract infection. APMIS 2014;122:363–8. 2014;53:696–703. Eicher SC, Dehio C. Bartonella entry mechanisms into mam- Fredricks DN. The Human Microbiota: How Microbial Communities malian host cells. Cell Microbiol 2012;14:1166–73. Affect Health and Disease. Hoboken, NJ: Wiley, 2013. Eilers H, Pernthaler J, Glockner FO, et al. Culturability and In situ Fremont M, Coomans D, Massart S, et al. High-throughput 16S abundance of pelagic bacteria from the North Sea. Appl Env- rRNA gene sequencing reveals alterations of intestinal mi- iron Microb 2000;66:3044–51. crobiota in myalgic encephalomyelitis/chronic fatigue syn- Eisenreich W, Dandekar T, Heesemann J, et al. Carbon drome patients. Anaerobe 2013;22:50–6. metabolism of intracellular bacterial pathogens and French AL, Evans CT, Agniel DM, et al. Microbial translocation possible links to virulence. Nat Rev Microbiol 2010;8: and liver disease progression in women coinfected with HIV 401–12. and hepatitis C virus. J Infect Dis 2013;208:679–89. Eleftheriadis T, Liakopoulos V, Leivaditis K, et al. Infections in Fricke WF, Rasko DA. Bacterial genome sequencing in the hemodialysis: a concise review—Part 1: bacteremia and res- clinic: bioinformatic challenges and solutions. Nat Rev Genet piratory infections. Hippokratia 2011;15:12–7. 2014;15:49–55. ElRakaiby M, Dutilh BE, Rizkallah MR, et al. Pharmacomicro- Fugate JE, Lyons JL, Thakur KT, et al. Infectious causes of stroke. biomics: the impact of human microbiome variations on sys- Lancet Infect Dis 2014;14:869–80. tems pharmacology and personalized therapeutics. Omics Fukuda S, Hase K, Ohno H. Application of a mouse ligated Peyer’s 2014;18:402–14. patch intestinal loop assay to evaluate bacterial uptake by M Emsley HC, Chamorro A. Stroke bugs: current and emerging con- cells. JVis Exp 2011;e3225–30. cepts relevant to infection in cerebrovascular disease. Infect Gaibani P, Mariconti M, Bua G, et al. Development of a broad- Disord Drug Targets 2010;10:65–6. range 23S rDNA real-time PCR assay for the detection and Emsley HC, Hopkins SJ. Acute ischaemic stroke and infection: quantification of pathogenic bacteria in human whole blood recent and emerging concepts. Lancet Neurol 2008;7:341–53. and plasma specimens. Biomed Res Int 2013;2013:264651. Emsley HC, Smith CJ, Gavin CM, et al. An early and sustained pe- Gerard P. Metabolism of cholesterol and bile acids by the gut mi- ripheral inflammatory response in acute ischaemic stroke: crobiota. Pathogens 2013;3:14–24. relationships with infection and atherosclerosis. J Neuroim- Gerdes K, Maisonneuve E. Bacterial persistence and toxin- munol 2003;139:93–101. antitoxin loci. Annu Rev Microbiol 2012;66:103–23. Emsley HC, Tyrrell PJ. Inflammation and infection in clinical Germain E, Castro-Roa D, Zenkin N, et al. Molecular mech- stroke. J Cerebr Blood F Met 2002;22:1399–419. anism of bacterial persistence by HipA. Mol Cell 2013;52: Epstein SE, Zhou YF, Zhu J. Infection and atherosclerosis: emerg- 248–54. ing mechanistic paradigms. Circulation 1999;100:e20–8. Gest H. The Modern Myth of ‘Unculturable’ Bacteria: Scotoma of Con- Epstein SE, Zhu J, Najafi AH, et al. Insights into the role of in- temporary Microbiology. Faculty Research (Bloomington), 2008, fection in atherogenesis and in plaque rupture. Circulation http://hdl.handle.net/2022/3149 (19 March 2015, date last ac- 2009;119:3133–41. cessed). Epstein SS. The phenomenon of microbial uncultivability. Curr Geurts L, Neyrinck AM, Delzenne NM, et al. Gut microbiota Opin Microbiol 2013;16:636–42. controls adipose tissue expansion, gut barrier and glucose Erridge C. The roles of pathogen-associated molecular patterns metabolism: novel insights into molecular targets and inter- in atherosclerosis. Trends Cardiovas Med 2008;18:52–6. ventions using prebiotics. Benef Microbes 2014;5:3–17. Errington J. L-form bacteria, cell walls and the origins of life. Open Giannelli V, DiGregorio V, Iebba V, et al. Microbiota and the gut- Biol 2013;3:120143. liver axis: bacterial translocation, inflammation and infec- Everard A, Matamoros S, Geurts L, et al. Saccharomyces boulardii tion in cirrhosis. World J Gastroenterol 2014;20:16795–810. administration changes gut microbiota and reduces hepatic Gich F, Schubert K, Bruns A, et al. Specific detection, isola- steatosis, low-grade inflammation, and fat mass in obese tion, and characterization of selected, previously uncultured and type 2 diabetic db/db mice. MBio 2014;5:e01011–4. members of the freshwater bacterioplankton community. Faure M, Mettraux C, Moennoz D, et al. Specific amino acids in- Appl Environ Microb 2005;71:5908–19. crease mucin synthesis and microbiota in dextran sulfate Glaros TG, Chang S, Gilliam EA, et al. Causes and consequences sodium-treated rats. JNutr 2006;136:1558–64. of low grade endotoxemia and inflammatory diseases. Front Feeley JC, Gorman GW, Weaver RE, et al. Primary isolation Biosci 2013;5:754–65. media for Legionnaires disease bacterium. J Clin Microbiol Gonzalez A, Stombaugh J, Lozupone C, et al. The mind-body- 1978;8:320–5. microbial continuum. Dialogues Clin Neurosci 2011;13:55–62. Fernandez-Cruz ´ A, Marin M, Kestler M, et al. The value of com- Grau AJ, Urbanek C, Palm F. Common infections and the risk of bining blood culture and SeptiFast data for predicting com- stroke. Nat Rev Neurol 2010;6:681–94. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 585 Gribbin JR. In Search of Schrodinger’ ¨ s Cat: Quantum Physics and Re- Kahle K, Kraus M, Scheppach W, et al. Studies on apple and blue- ality. London: Bantam Books, 1985. berry fruit constituents: do the polyphenols reach the colon Grif K, Fille M, Wurzner ¨ R, et al. Rapid detection of bloodstream after ingestion? Mol Nutr Food Res 2006;50:418–23. pathogens by real-time PCR in patients with sepsis. Wien Klin Kakiyama G, Pandak WM, Gillevet PM, et al. Modulation of the Wochenschr 2012a;124:266–70. fecal bile acid profile by gut microbiota in cirrhosis. J Hepatol Grif K, Heller I, Prodinger WM, et al. Improvement of detection 2013;58:949–55. of bacterial pathogens in normally sterile body sites with Kamagata Y, Tamaki H. Cultivation of uncultured fastidious mi- a focus on orthopedic samples by use of a commercial 16S crobes. Microbes Environ 2005;20:85–91. rRNA broad-range PCR and sequence analysis. J Clin Microbiol Kang DW, Park JG, Ilhan ZE, et al. Reduced incidence of Prevotella 2012b;50:2250–4. and other fermenters in intestinal microflora of autistic chil- Groebel K, Hoelzle K, Wittenbrink MM, et al. Mycoplasma suis dren. PLoS One 2013;8:e68322. invades porcine erythrocytes. Infect Immun 2009;77:576–84. Kaprelyants AS, Gottschal JC, Kell DB. Dormancy in non- Guo ZZ, Wang P, Yi ZH, et al. The crosstalk between gut inflam- sporulating bacteria. FEMS Microbiol Rev 1993;10:271–85. mation and gastrointestinal disorders during acute pancre- Kaprelyants AS, Kell DB. Dormancy in stationary-phase cul- atitis. Curr Pharm Des 2014;20:1051–62. tures of Micrococcus luteus: flow cytometric analysis of Harrison F, Buckling A. Cooperative production of siderophores starvation and resuscitation. Appl Environ Microb 1993;59: by Pseudomonas aeruginosa. Front Biosci 2009;14:4113–26. 3187–96. Havey TC, Fowler RA, Daneman N. Duration of antibiotic therapy Kaprelyants AS, Mukamolova GV, Davey HM, et al. Quantitative for bacteremia: a systematic review and meta-analysis. Crit analysis of the physiological heterogeneity within starved Care 2011;15:R267. cultures of Micrococcus luteus by flow cytometry and cell Hevia A, Milani C, Lopez P, et al. Intestinal dysbiosis associated sorting. Appl Environ Microb 1996;62:1311–6. with systemic lupus erythematosus. MBio 2014;5:e01548–14. Kaprelyants AS, Mukamolova GV, Kell DB. Estimation of dor- Hill MJ. Intestinal flora and endogenous vitamin synthesis. Eur J mant Micrococcus luteus cells by penicillin lysis and by resus- Cancer Prev 1997;6 (Suppl 1):S43–5. citation in cell-free spent medium at high dilution. FEMS Mi- Hold GL, Smith M, Grange C, et al. Role of the gut microbiota crobiol Lett 1994;115:347–52. in inflammatory bowel disease pathogenesis: what have we Kaprelyants AS, Mukamolova GV, Kormer SS, et al. Intercellular learnt in the past 10 years? World J Gastroenterol 2014;20:1192– signalling and the multiplication of prokaryotes: bacterial cy- 210. tokines. Symp Soc Gen Microbi 1999;57:33–69. Holden DW. Microbiology. Persisters unmasked. Science Karlsson FH, Fak F, Nookaew I, et al. Symptomatic atherosclero- 2015;347:30–2. sis is associated with an altered gut metagenome. Nat Com- Holmes E, Li JV, Athanasiou T, et al. Understanding the role of mun 2012;3:1245. gut microbiome-host metabolic signal disruption in health Karlsson FH, Tremaroli V, Nookaew I, et al. Gut metagenome in and disease. Trends Microbiol 2011;19:349–59. European women with normal, impaired and diabetic glu- Hopkins PN. Molecular biology of atherosclerosis. Physiol Rev cose control. Nature 2013;498:99–103. 2013;93:1317–542. Karri S, Martinez VA, Coimbatore G. Effect of dihydrotestos- Horzempa J, O’Dee DM, Stolz DB, et al. Invasion of erythrocytes terone on gastrointestinal tract of male Alzheimer’s disease by Francisella tularensis. J Infect Dis 2011;204:51–9. transgenic mice. 2010;48:453–65. Huang Y, Fan XG, Tang ZS, et al. Detection of Helicobacter pylori Kau AL, Ahern PP, Griffin NW, et al. Human nutrition, the gut DNA in peripheral blood from patients with peptic ulcer or microbiome and the immune system. Nature 2011;474:327– gastritis. APMIS 2006;114:851–6. 36. Hugenholtz P. Exploring prokaryotic diversity in the genomic Keilin D. The problem of anabiosis or latent life: history and cur- era. Genome Biol 2002;3:0003.1–0003.8. rent concept. PRoy SocLondBBio 1959;150:149–91. Isberg RR. Discrimination between intracellular uptake and Kell DB. Metabolomics, modelling and machine learning in sys- surface adhesion of bacterial pathogens. Science 1991;252: tems biology: towards an understanding of the languages of 934–8. cells. The 2005 Theodor Buc ¨ her lecture. FEBS J 2006;273:873– Iwaki-Egawa S, Ihler GM. Comparison of the abilities of proteins 94. from Bartonella bacilliformis and Bartonella henselae to de- Kell DB. Iron behaving badly: inappropriate iron chelation as a form red cell membranes and to bind to red cell ghost pro- major contributor to the aetiology of vascular and other pro- teins. FEMS Microbiol Lett 1997;157:207–17. gressive inflammatory and degenerative diseases. BMC Med Jepson MA, Clark MA. Studying M cells and their role in infection. Genomics 2009;2:2. Trends Microbiol 1998;6:359–65. Kell DB. Towards a unifying, systems biology understanding of Jiang W, Lederman MM, Hunt P, et al. Plasma levels of bacterial large-scale cellular death and destruction caused by poorly DNA correlate with immune activation and the magnitude liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, pri- of immune restoration in persons with antiretroviral-treated ons, bactericides, chemical toxicology and others as exam- HIV infection. J Infect Dis 2009;199:1177–85. ples. Arch Toxicol 2010;84:825–89. Joyce SA, MacSharry J, Casey PG, et al. Regulation of host weight Kell DB, Kaprelyants AS, Grafen A. Pheromones, social behaviour gain and lipid metabolism by bacterial bile acid modification and the functions of secondary metabolism in bacteria. in the gut. P Natl Acad Sci USA 2014;111:7421–6. Trends Ecol Evol 1995;10:126–9. Jun DW, Kim KT, Lee OY, et al. Association between small in- Kell DB, Kaprelyants AS, Weichart DH, et al. Viability and activity testinal bacterial overgrowth and peripheral bacterial DNA in readily culturable bacteria: a review and discussion of the in cirrhotic patients. Dig Dis Sci 2010;55:1465–71. practical issues. Anton Leeuw 1998;73:169–87. Jung C, Hugot JP, Barreau F. Peyer’s patches: the immune sensors Kell DB, Knowles JD. The role of modeling in systems biology. of the intestine. Int J Inflam 2010;2010:823710. In: Szallasi Z, Stelling J, Periwal V (eds). System Modeling in Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 586 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 Cellular Biology: From Concepts to Nuts and Bolts. Cambridge: across the human body: meta-analysis of microbial commu- MIT Press, 2006, 3–18. nity structures in human microbiome datasets. PLoS Comput Kell DB, Mukamolova GV, Finan CL Resuscitation of ‘uncultured’ Biol 2013;9:e1002863. microorganisms. In: Bull AT, et al. (ed). Microbial Diversity and Koren O, Spor A, Felin J, et al. Human oral, gut, and plaque mi- Bioprospecting. Washington, DC: American Society for Micro- crobiota in patients with atherosclerosis. P Natl Acad Sci USA biology, 2003, 100–8. 2011;108:4592–8. Kell DB, Oliver SG. How drugs get into cells: tested and testable Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory predictions to help discriminate between transporter- bowel disease: current status and the future ahead. Gastroen- mediated uptake and lipoidal bilayer diffusion. Front Pharma- terology 2014;146:1489–99. col 2014;5:231. Kotsaki A, Giamarellos-Bourboulis EJ. Emerging drugs for the Kell DB, Pretorius E. Serum ferritin is an important inflamma- treatment of sepsis. Expert Opin Emerg Dr 2012;17:379–91. tory disease marker, as it is mainly a leakage product from Kozarov E, Sweier D, Shelburne C, et al. Detection of bacterial damaged cells. Metallomics 2014;4:748–73. DNA in atheromatous plaques by quantitative PCR. Microbes Kell DB, Pretorius E. The simultaneous occurrence of both hyper- Infect 2006;8:687–93. coagulability and hypofibrinolysis in blood and serum dur- Koziel J, Mydel P, Potempa J. The link between periodontal ing systemic inflammation, and the roles of iron and fib- disease and rheumatoid arthritis: an updated review. Curr rin(ogen). Integr Biol 2015;7:24–52. Rheumatol Rep 2014;16:408. Kell DB, Ryder HM, Kaprelyants AS, et al. Quantifying hetero- Kwiatkowska B, Masli ´ nska ´ M. Macrolide therapy in chronic in- geneity: flow cytometry of bacterial cultures. Anton Leeuw flammatory diseases. Mediat Inflamm 2012;2012:636157. 1991;60:145–58. Kyrpides NC, Hugenholtz P, Eisen JA, et al. Genomic encyclopedia Keller M, Zengler K. Tapping into microbial diversity. Nat Rev Mi- of bacteria and archaea: sequencing a myriad of type strains. crobiol 2004;2:141–50. PLoS Biol 2014;12:1001920. Keren I, Kaldalu N, Spoering A, et al. Persister cells and tolerance Lagier JC, Edouard S, Pagnier I, et al. Current and past strategies to antimicrobials. FEMS Microbiol Lett 2004a;230:13–8. for bacterial culture in clinical microbiology. Clin Microbiol Rev Keren I, Shah D, Spoering A, et al. Specialized persister cells and 2015a;28:208–36. the mechanism of multidrug tolerance in Escherichia coli. J Lagier JC, Hugon P, Khelaifia S, et al. The rebirth of culture in Bacteriol 2004b;186:8172–80. microbiology through the example of culturomics to study Kerneis ´ S, Bogdanova A, Kraehenbuhl JP, et al. Conversion by human gut microbiota. Clin Microbiol Rev 2015b;28:237–64. Peyer’s patch lymphocytes of human enterocytes into M cells Lanter BB, Sauer K, Davies DG. Bacteria present in carotid arterial that transport bacteria. Science 1997;277:949–52. plaques are found as biofilm deposits which may contribute Kibru D, Gelaw B, Alemu A, et al. Helicobacter pylori infection to enhanced risk of plaque rupture. MBio 2014;5:e01206–14. and its association with anemia among adult dyspeptic pa- Larsen N, Vogensen FK, van den Berg FW, et al. Gut microbiota in tients attending Butajira Hospital, Ethiopia. BMC Infect Dis human adults with type 2 diabetes differs from non-diabetic 2014;14:656. adults. PLoS One 2010;5:e9085. Kimura I, Ozawa K, Inoue D, et al. The gut microbiota suppresses Lasken RS. Genomic sequencing of uncultured microorganisms insulin-mediated fat accumulation via the short-chain fatty from single cells. Nat Rev Microbiol 2012;10:631–40. acid receptor GPR43. Nat Commun 2013;4:1829. Lasken RS, McLean JS. Recent advances in genomic DNA se- Kinoshita M, Takeda K. Microbial and dietary factors modu- quencing of microbial species from single cells. Nat Rev Genet lating intestinal regulatory T cell homeostasis. FEBS Lett 2014;15:577–84. 2014;588:4182–7. Le Chatelier E, Nielsen T, Qin J, et al. Richness of human Kishino S, Takeuchi M, Park S-B, et al. Polyunsaturated fatty acid gut microbiome correlates with metabolic markers. Nature saturation by gut lactic acid bacteria affecting host lipid com- 2013;500:541–6. position. P Natl Acad Sci USA 2013;110:17808–13. LeBlanc JG, Milani C, de Giori GS, et al. Bacteria as vitamin sup- Klatt NR, Funderburg NT, Brenchley JM. Microbial transloca- pliers to their host: a gut microbiota perspective. Curr Opin tion, immune activation, and HIV disease. Trends Microbiol Biotechnol 2013;24:160–8. 2013;21:6–13. Leli C, Cardaccia A, Ferranti M, et al. Procalcitonin better than C- Kocan KM, de la Fuente J, Blouin EF, et al. Anaplasma marginale reactive protein, erythrocyte sedimentation rate, and white (Rickettsiales: Anaplasmataceae): recent advances in defin- blood cell count in predicting DNAemia in patients with sep- ing host-pathogen adaptations of a tick-borne rickettsia. Par- sis. Scand J Infect Dis 2014;46:745–52. asitology 2004;129 (Suppl):285–300. Lelouard H, Henri S, De Bovis B, et al. Pathogenic bacteria and Koch AL. The adaptive responses of Escherichia coli to a feast and dead cells are internalized by a unique subset of Peyer’s famine existence. Adv Microb Physiol 1971;6:147–217. patch dendritic cells that express lysozyme. Gastroenterology Koch AL. The variability and individuality of the bacterium. In: 2010;138:173–84, e171–73. Neidhardt FC, et al. (eds). Escherichia coli and Salmonella Ty- Leslie JL, Young VB. The rest of the story: the microbiome and phimurium: Cellular and Molecular Biology. Washington, DC: gastrointestinal infections. Curr Opin Microbiol 2015;23c:121– American Society for Microbiology, 1987, 1606–14. 5. Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota Lewis K. Persister cells. Annu Rev Microbiol 2010;64:357–72. metabolism of L-carnitine, a nutrient in red meat, promotes Lin W, Weinberg EM, Chung RT. Pathogenesis of accelerated fi- atherosclerosis. Nat Med 2013;19:576–85. brosis in HIV/HCV co-infection. J Infect Dis 2013;207 (Suppl Kogure K, Simidu U, Taga N. A tentative direct microscopic 1):S13–8. method for counting living marine bacteria. Can J Microbiol Ling LL, Schneider T, Peoples AJ, et al. A new antibi- 1979;25:415–20. otic kills pathogens without detectable resistance. Nature Koren O, Knights D, Gonzalez A, et al. A guide to enterotypes 2015;517:455–9. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 587 Lipinski B, Pretorius E. The role of iron-induced fibrin in the Mar´ın L, Miguelez ´ EM, Villar CJ, et al. Bioavailability of dietary pathogenesis of Alzheimer’s disease and the protective role polyphenols and gut microbiota metabolism: antimicrobial of magnesium. Front Hum Neurosci 2013;7:735. properties. BioMed Res Int 2015;2015:905215. Loman NJ, Constantinidou C, Chan JZ, et al. High-throughput Mariotti S, Pardini M, Gagliardi MC, et al. Dormant Mycobac- bacterial genome sequencing: an embarrassment of choice, terium tuberculosis fails to block phagosome maturation and a world of opportunity. Nat Rev Microbiol 2012;10:599–606. shows unexpected capacity to stimulate specific human T Lozupone CA, Li M, Campbell TB, et al. Alterations in the gut lymphocytes. JImmunol 2013;191:274–82. microbiota associated with HIV-1 infection. Cell Host Microbe Marshall B. Helicobacter connections. ChemMedChem 2013;14:329–39. 2006;1:783–802. Lozupone CA, Stombaugh JI, Gordon JI, et al. Diversity, sta- Marshall BJ, Warren JR. Unidentified curved bacilli in the stom- bility and resilience of the human gut microbiota. Nature ach of patients with gastritis and peptic ulceration. Lancet 2012;489:220–30. 1984;1:1311–5. Luckey D, Gomez A, Murray J, et al. Bugs, us: the role of the gut Martin F-PJ, Dumas M-E, Wang Y, et al. A top-down systems biol- in autoimmunity. Indian J Med Res 2013;138:732–43. ogy view of microbiome-mammalian metabolic interactions Lysak LV, Lapygina EV, Konova IA, et al. Quantity and taxo- in a mouse model. Mol Syst Biol 2007;3:112. nomic composition of ultramicrobacteria in soils. Microbiol- Mart´ınez I, Perdicaro DJ, Brown AW, et al. Diet-induced alter- ogy 2010;79:408–12. ations of host cholesterol metabolism are likely to affect the Ma HD, Wang YH, Chang C, et al. The intestinal microbiota and gut microbiota composition in hamsters. Appl Environ Microb microenvironment in liver. Autoimmun Rev 2015;14:183–91. 2013;79:516–24. McColl BW, Allan SM, Rothwell NJ. Systemic infection, in- Mart´ınez I, Wallace G, Zhang C, et al. Diet-induced metabolic im- flammation and acute ischemic stroke. Neuroscience provements in a hamster model of hypercholesterolemia are 2009;158:1049–61. strongly linked to alterations of the gut microbiota. Appl En- McDermott AJ, Huffnagle GB. The microbiome and regulation of viron Microb 2009;75:4175–84. mucosal immunity. Immunology 2014;142:24–31. Maslowski KM, Vieira AT, Ng A, et al. Regulation of inflammatory Macdonell MT, Hood MA. Isolation and characterization of ultra- responses by gut microbiota and chemoattractant receptor microbacteria from a gulf coast estuary. Appl Environ Microb GPR43. Nature 2009;461:1282–6. 1982;43:566–71. Mason CA, Hamer G, Bryers JD. The death and lysis of mi- MacFie J. Current status of bacterial translocation as a cause of croorganisms in environmental processes. FEMS Microbiol Rev surgical sepsis. Brit Med Bull 2004;71:1–11. 1986;39:373–401. McHardy IH, Li X, Tong M, et al. HIV Infection is associated with MathiasA,PaisB,Favre L, et al. Role of secretory IgA in compositional and functional shifts in the rectal mucosal the mucosal sensing of commensal bacteria. Gut Microbes microbiota. Microbiome 2013;1:26. 2014;5:688–95. Macintire DK, Bellhorn TL. Bacterial translocation: clinical im- Mattman L. Cell Wall Deficient Forms: Stealth Pathogens . Boca Raton, plications and prevention. Vet Clin N Am-Small 2002;32: FL: CRC Press, 2001. 1165–78. Mercier R, Kawai Y, Errington J. Excess membrane synthe- McLaughlin RW, Vali H, Lau PCK, et al. Are there naturally occur- sis drives a primitive mode of cell proliferation. Cell ring pleomorphic bacteria in the blood of healthy humans? J 2013;152:997–1007. Clin Microbiol 2002;40:4771–5. Mercier R, Kawai Y, Errington J. General principles for the forma- McMahon CJ, Hopkins S, Vail A, et al. Inflammation as a predic- tion and proliferation of a wall-free (L-form) state in bacteria. tor for delayed cerebral ischemia after aneurysmal subarach- Elife 2014;3:e04629. noid haemorrhage. J Neurointerv Surg 2013;5:512–7. Meyer RD. Legionella infections: a review of five years of re- Madan JC, Koestler DC, Stanton BA, et al. Serial analysis of the search. Rev Infect Dis 1983;5:258–78. gut and respiratory microbiome in cystic fibrosis in infancy: Mifkovic A, Skultety J, Pindak D, et al. Specific aspects of acute interaction between intestinal and respiratory tracts and im- pancreatitis. Bratisl Lek Listy 2009;110:544–52. pact of nutritional exposures. MBio 2012;3:e00251–12. Mifkovic A, Skultety J, Sykora P, et al. Intra-abdominal hyperten- Maisonneuve E, Castro-Camargo M, Gerdes K. (p)ppGpp con- sion and acute pancreatitis. Bratisl Lek Listy 2013;114:166–71. trols bacterial persistence by stochastic induction of toxin- Minasyan H. Erythrocyte and blood antibacterial defense. Eur J antitoxin activity. Cell 2013;154:1140–50. Microbiol Immunol 2014;4:138–43. Maisonneuve E, Gerdes K. Molecular mechanisms underlying Montassier E, Batard E, Gastinne T, et al. Recent changes in bacterial persisters. Cell 2014;157:539–48. bacteremia in patients with cancer: a systematic review of Maiwald M, Relman DA. Whipple’s disease and Tropheryma epidemiology and antibiotic resistance. Eur J Clin Microbiol whippelii: secrets slowly revealed. Clin Infect Dis 2001;32:457– 2013;32:841–50. 63. Montes-de-Oca M, Blanco MJ, Marquez M, et al. Haemodynamic Maiwald M, von Herbay A, Fredricks DN, et al. Cultivation of derangement in human immunodeficiency virus-infected Tropheryma whipplei from cerebrospinal fluid. J Infect Dis patients with hepatitis C virus-related cirrhosis: the role of 2003;188:801–8. bacterial translocation. Liver Int 2011;31:850–8. Malaguarnera G, Giordano M, Nunnari G, et al. Gut microbiota Morgan XC, Huttenhower C. Meta’omic analytic techniques in alcoholic liver disease: pathogenetic role and therapeutic for studying the intestinal microbiome. Gastroenterology perspectives. World J Gastroenterol 2014;20:16639–48. 2014;146:1437–48. Mancini N, Carletti S, Ghidoli N, et al. The era of molecular and Morgan XC, Tickle TL, Sokol H, et al. Dysfunction of the intestinal other non-culture-based methods in diagnosis of sepsis. Clin microbiome in inflammatory bowel disease and treatment. Microbiol Rev 2010;23:235–51. Genome Biol 2012;13:R79. Manichanh C, Borruel N, Casellas F, et al. The gut microbiota in Morita RY. Bacteria in Oligotrophic Environments: Starvation-Survival IBD. Nat Rev Gastroentero 2012;9:599–608. Lifestyle. New York: Chapman and Hall, 1997. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 588 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 Muegge BD, Kuczynski J, Knights D, et al. Diet drives convergence ized, double-blind, placebo-controlled trial. Clin Ther in gut microbiome functions across mammalian phylogeny 2009a;31:1754–64. and within humans. Science 2011;332:970–4. Ogrendik M. Rheumatoid arthritis is linked to oral bacteria: eti- Mukamolova GV, Kaprelyants AS, Young DI, et al. A bacterial cy- ological association. Mod Rheumatol 2009b;19:453–6. tokine. P Natl Acad Sci USA 1998a;95:8916–21. Ogrendik M. Antibiotics for the treatment of rheumatoid arthri- Mukamolova GV, Kormer SS, Kell DB, et al. Stimulation of the tis. Int J Gen Med 2013a;7:43–7. multiplication of Micrococcus luteus by an autocrine growth Ogrendik M. Rheumatoid arthritis is an autoimmune disease factor. Arch Microbiol 1999;172:9–14. caused by periodontal pathogens. Int J Gen Med 2013b;6:383– Mukamolova GV, Turapov OA, Kazarian K, et al. The rpf gene of 6. Micrococcus luteus encodes an essential secreted growth fac- Olah A, Romics L, Jr. Enteral nutrition in acute pancreati- tor. Mol Microbiol 2002a;46:611–21. tis: a review of the current evidence. World J Gastroenterol Mukamolova GV, Turapov OA, Young DI, et al. A family of au- 2014;20:16123–31. tocrine growth factors in Mycobacterium tuberculosis. Mol Mi- Owen JL, Mohamadzadeh M. Microbial activation of gut dendritic crobiol 2002b;46:623–35. cells and the control of mucosal immunity. J Interf Cytok Res Mukamolova GV, Yanopolskaya ND, Kell DB, et al. On resuscita- 2013;33:619–31. tion from the dormant state of Micrococcus luteus. Anton Leeuw Owyang C, Wu GD. The gut microbiome in health and disease. 1998b;73:237–43. Gastroenterology 2014;146:1433–6. Munoz ˜ P, Cruz AF, Rodr´ıguez-Creixems ´ M, et al. Gram-negative Page EE, Nelson M, Kelleher P. HIV and hepatitis C coinfec- bloodstream infections. Int J Antimicrob Ag 2008;32 (Suppl tion: pathogenesis and microbial translocation. Curr Opin HIV 1):S10–14. AIDS 2011;6:472–7. Munteanu D, Negru A, Radulescu M, et al. Evaluation of bacterial Pallen MJ, Loman NJ, Penn CW. High-throughput sequencing translocation in patients with chronic HCV infection. Rom J and clinical microbiology: progress, opportunities and chal- Intern Med 2014;52:91–6. lenges. Curr Opin Microbiol 2010;13:625–31. Murray PR. The clinician and the microbiology laboratory. In: Parracho HM, Bingham MO, Gibson GR, et al. Differences between Bennett JE, Dolin R, Blaser MJ (eds). Mandell, Douglas and Ben- the gut microflora of children with autistic spectrum disor- nett’s Principles and Practice of Infectious Diseases. Philadelphia: ders and that of healthy children. J Med Microbiol 2005;54:987– Saunders Elsevier, 2015. 91. Mylotte JM, Tayara A. Blood cultures: clinical aspects and con- Percival SL, Hill KE, Williams DW, et al. A review of the scien- troversies. Eur J Clin Microbiol 2000;19:157–63. tific evidence for biofilms in wounds. Wound Repair Regen Nagalingam NA, Lynch SV. Role of the microbiota in inflamma- 2012;20:647–57. tory bowel diseases. Inflamm Bowel Dis 2012;18:968–84. Petersen C, Round JL. Defining dysbiosis and its influence on host Nagata E, de Toledo A, Oho T. Invasion of human aortic en- immunity and disease. Cell Microbiol 2014;16:1024–33. dothelial cells by oral viridans group streptococci and induc- Petriz BA, Castro AP, Almeida JA, et al. Exercise induction of gut tion of inflammatory cytokine production. Mol Oral Microbiol microbiota modifications in obese, non-obese and hyperten- 2011;26:78–88. sive rats. BMC Genomics 2014;15:511. Narihiro T, Kamagata Y. Cultivating yet-to-be cultivated Pflughoeft KJ, Versalovic J. Human microbiome in health and dis- microbes: the challenge continues. Microbes Environ ease. Annu Rev Pathol 2012;7:99–122. 2013;28:163–5. Pham VH, Kim J. Cultivation of unculturable soil bacteria. Trends Natarajan N, Pluznick JL. From microbe to man: the role of mi- Biotechnol 2012;30:475–84. crobial short chain fatty acid metabolites in host cell biology. Postgate JR. Viability measurements and the survival of mi- Am J Physiol-Cell Ph 2014;307:C979–85. crobes under minimum stress. Adv Microb Physiol 1967;1:1– Neuman Y. Cryptobiosis: a new theoretical perspective. Prog Bio- 23. phys Mol Bio 2006;92:258–67. Postgate JR. Viable counts and viability. Methods Microbiol Nichols D, Cahoon N, Trakhtenberg EM, et al. Useofichip for 1969;1:611–28. high-throughput in situ cultivation of ‘uncultivable’ micro- Postgate JR. Death in Microbes and Macrobes. Cambridge: Cam- bial species. Appl Environ Microb 2010;76:2445–50. bridge University Press, 1976. Nielsen HH, Qiu J, Friis S, et al. Treatment for Helicobacter pylori Power SE, O’Toole PW, Stanton C, et al. Intestinal microbiota, diet infection and risk of Parkinson’s disease in Denmark. Eur J and health. Brit J Nutr 2014;111:387–402. Neurol 2012;19:864–9. Prajsnar TK, Hamilton R, Garcia-Lara J, et al. A privileged in- Nikkari S, McLaughlin IJ, Bi W, et al. Does blood of healthy traphagocyte niche is responsible for disseminated infection subjects contain bacterial ribosomal DNA? J Clin Microbiol of Staphylococcus aureus in a zebrafish model. Cell Microbiol 2001;39:1956–9. 2012;14:1600–19. O’Mahony SM, Clarke G, Borre YE, et al. Serotonin, tryptophan Pretorius E, Bester J, Vermeulen N, et al. Profound morphological metabolism and the brain-gut-microbiome axis. Behav Brain changes in the erythrocytes and fibrin networks of patients Res 2015;277:32–48. with hemochromatosis or with hyperferritinemia, and their Ochoa-Repar ´ az J, Mielcarz DW, Begum-Haque S, et al. Gut, bugs, normalization by iron chelators and other agents. PlosOne and brain: role of commensal bacteria in the control of cen- 2014a;9:e85271. tral nervous system disease. Ann Neurol 2011;69:240–7. Pretorius E, Kell DB. Diagnostic morphology: biophysical in- Ochoa-Repar ´ az J, Mielcarz DW, Ditrio LE, et al. Role of gut com- dicators for iron-driven inflammatory diseases. Integr Biol mensal microflora in the development of experimental au- 2014;6:486–510. toimmune encephalomyelitis. JImmunol 2009;183:6041–50. Pretorius E, Swanepoel AC, Buys AV, et al. Eryptosis as a marker Ogrendik M. Efficacy of roxithromycin in adult patients with of Parkinson’s disease. Aging 2014b;6:788–818. rheumatoid arthritis who had not received disease- Pretorius E, Vermeulen N, Bester J, et al. A novel method for modifying antirheumatic drugs: a 3-month, random- assessing the role of iron and its functional chelation in Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 589 fibrin fibril formation: the use of scanning electron mi- Rosenfeld ME, Campbell LA. Pathogens and atherosclerosis: up- croscopy. Toxicol Mech Method 2013;23:352–9. date on the potential contribution of multiple infectious Primas H. Chemistry, Quantum Mechanics and Reductionism. Berlin: organisms to the pathogenesis of atherosclerosis. Thromb Springer, 1981. Haemostasis 2011;106:858–67. Proal AD, Albert PJ, Marshall TG. Autoimmune disease and the Ross R, Mills S, Hill C, et al. Specific metabolite production by human metagenome. In: Nelson KE (ed). Metagenomics of the gut microbiota as a basis for probiotic function. Int Dairy J Human Body. New York: Springer Science and Business Media, 2010;20:269–76. 2011. Sabatino A, Regolisti G, Brusasco I, et al. Alterations of intestinal Proal AD, Albert PJ, Marshall TG, et al. Immunostimulation in barrier and microbiota in chronic kidney disease. Nephrol Dial the treatment for chronic fatigue syndrome/myalgic en- Transpl 2014, DOI:10.1093/ndt/gfu287. cephalomyelitis. Immunol Res 2013;56:398–412. Sacchi P, Cima S, Corbella M, et al. Liver fibrosis, microbial Proal AD, Albert PJ, Marshall TG. Inflammatory disease and the translocation and immune activation markers in HIV and human microbiome. Discov Med 2014;17:257–65. HCV infections and in HIV/HCV co-infection. Dig Liver Dis Puddu A, Sanguineti R, Montecucco F, et al. Evidence for 2015;47:218–25. the gut microbiota short-chain fatty acids as key patho- Sahin N, Gonzalez JM, Iizuka T, et al. Characterization of two physiological molecules improving diabetes. Mediat Inflamm aerobic ultramicrobacteria isolated from urban soil and a de- 2014;2014:162021. scription of Oxalicibacterium solurbis sp. nov. FEMS Microbiol Puleo F, Arvanitakis M, Van Gossum A, et al. Gut failure in the Lett 2010;307:25–9. ICU. Semin Respir Crit Care 2011;32:626–38. Saito A, Rolfe RD, Edelstein PH, et al. Comparison of liquid Puspita DI, Kamagata Y, Tanaka M, et al. Are unculti- growth media for Legionella pneumophila. J Clin Microbiol vated bacteria really uncultivable? Microbes Environ 2012;27: 1981;14:623–7. 356–66. Salipante SJ, Roach DJ, Kitzman JO, et al. Large-scale ge- Puspita DI, Uehara M, Katayama T, et al. Resuscitation promoting nomic sequencing of extraintestinal pathogenic Escherichia factor (Rpf) from Tomitella biformata AHU 1821(T) promotes coli strains. Genome Res 2015;25:119–28. growth and resuscitates non-dividing cells. Microbes Environ Salipante SJ, Sengupta DJ, Rosenthal C, et al. Rapid 16S rRNA 2013;28:58–64. next-generation sequencing of polymicrobial clinical sam- QinJ,LiY,Cai Z, et al. A metagenome-wide association study of ples for diagnosis of complex bacterial infections. PLoS One gut microbiota in type 2 diabetes. Nature 2012;490:55–60. 2013;8:e65226. Radajewski S, Ineson P, Parekh NR, et al. Stable-isotope probing Salter SJ, Cox MJ, Turek EM, et al. Reagent and laboratory contam- as a tool in microbial ecology. Nature 2000;403:646–9. ination can critically impact sequence-based microbiome Ram´ırez JH, Parra B, Gutierrez S, et al. Biomarkers of cardiovascu- analyses. BMC Biol 2014;12:87. lar disease are increased in untreated chronic periodontitis: Sanc ´ hez-Calvo JM, Garc´ıa-Castillo M, Lamas A, et al. Gut mi- a case control study. Aust Dent J 2014;59:29–36. crobiota composition in cystic fibrosis patients: molecu- Ratledge C. Iron metabolism and infection. Food Nutr Bull lar approach and classical culture. JCystFibros 2008;7: 2007;28:S515–23. S50. Rechner AR, Kuhnle G, Hu H, et al. The metabolism of dietary Sandler NG, Douek DC. Microbial translocation in HIV infection: polyphenols and the relevance to circulating levels of conju- causes, consequences and treatment opportunities. Nat Rev gated metabolites. Free Radical Res 2002;36:1229–41. Microbiol 2012;10:655–66. Renesto P, Crapoulet N, Ogata H, et al. Genome-based design of Sanz Y, Moya-Per ´ ez A. Microbiota, inflammation and obesity. a cell-free culture medium for Tropheryma whipplei. Lancet Adv Exp Med Biol 2014;817:291–317. 2003;362:447–9. Sato J, Kanazawa A, Ikeda F, et al. Gut dysbiosis and detection of Renko J, Lepp PW, Oksala N, et al. Bacterial signatures in ‘live gut bacteria’ in blood of Japanese patients with type 2 atherosclerotic lesions represent human commensals and diabetes. Diabetes Care 2014;37:2343–50. pathogens. Atherosclerosis 2008;201:192–7. Sato S, Kiyono H, Fujihashi K. Mucosal immunosenescence in Rhee SH. Lipopolysaccharide: basic biochemistry, intracellular the gastrointestinal tract: a mini-review. Gerontology 2014. signaling, and physiological impacts in the gut. Intest Res Sawa T. The molecular mechanism of acute lung injury caused 2014;12:90–5. by Pseudomonas aeruginosa: from bacterial pathogenesis to Rinke C, Schwientek P, Sczyrba A, et al. Insights into the phy- host response. J Intensive Care 2014;2:10. logeny and coding potential of microbial dark matter. Nature Sayin SI, Wahlstrom A, Felin J, et al. Gut microbiota regulates 2013;499:431–7. bile acid metabolism by reducing the levels of tauro-beta- Robles-Alonso V, Guarner F. From basic to applied research: muricholic acid, a naturally occurring FXR antagonist. Cell lessons from the human microbiome projects. J Clin Gastroen- Metab 2013;17:225–35. terol 2014;48 (Suppl 1):S3–4. Scanlan PD, Buckling A, Kong W, et al. Gut dysbiosis in cystic Rogler G, Rosano G. The heart and the gut. Eur Heart J fibrosis. JCystFibros 2012;11:454–5. 2014;35:426–30. Scheperjans F, Aho V, Pereira PA, et al. Gut microbiota are related Rolain JM, Maurin M, Mallet MN, et al. Culture and antibiotic sus- to Parkinson’s disease and clinical phenotype. Movement Dis- ceptibility of Bartonella quintana in human erythrocytes. An- ord 2015;30:350–8. timicrob Agents Ch 2003;47:614–9. Scher JU, Abramson SB. The microbiome and rheumatoid arthri- Ronco C. Endotoxin removal: history of a mission. Blood Purif tis. Nat Rev Rheumatol 2011;7:569–78. 2014;37 (Suppl 1):5–8. Schnabl B, Brenner DA. Interactions between the intestinal mi- Rooks MG, Veiga P, Wardwell-Scott LH, et al. Gut microbiome crobiome and liver diseases. Gastroenterology 2014;146:1513– composition and function in experimental colitis during 24. active disease and treatment-induced remission. ISME J Schroeter J, Wilkemeyer I, Schiller RA, et al. Validation of 2014;8:1403–17. the microbiological testing of tissue preparations using the Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 590 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 BACTEC blood culture system. Transfus Med Hemoth 2012;39: The Integrative HMP (iHMP) Research Network Consortium. 387–90. The Integrative Human Microbiome Project: dynamic anal- Schulz MD, Atay C, Heringer J, et al. High-fat-diet-mediated dys- ysis of microbiome-host omics profiles during periods biosis promotes intestinal carcinogenesis independently of of human health and disease. Cell Host Microbe 2014;16: obesity. Nature 2014;514:508–12. 276–89. Seksik P, Rigottier-Gois L, Gramet G, et al. Alterations of the dom- Thwaites GE, Gant V. Are bloodstream leukocytes Trojan Horses inant faecal bacterial groups in patients with Crohn’s disease for the metastasis of Staphylococcus aureus? Nat Rev Microbiol of the colon. Gut 2003;52:237–42. 2011;9:215–22. Seringec N, Guncu G, Arihan O, et al. Investigation of hemorhe- Tojo R, Suar ´ ez A, Clemente MG, et al. Intestinal microbiota in ological parameters in periodontal diseases. Clin Hemorheol health and disease: role of bifidobacteria in gut homeosta- Micro 2014, DOI:10.3233/CH-141892. sis. World J Gastroenterol 2014;20:15163–76. Severance EG, Gressitt KL, Stallings CR, et al. Discordant pat- Tomas-Barberan F, Garcia-Villalba R, Quartieri A, et al. In vitro terns of bacterial translocation markers and implications for transformation of chlorogenic acid by human gut microbiota. innate immune imbalances in schizophrenia. Schizophr Res Mol Nutr Food Res 2014;58:1122–31. 2013;148:130–7. Touati D. Iron and oxidative stress in bacteria. Arch Biochem Bio- Severance EG, Yolken RH, Eaton WW. Autoimmune dis- phys 2000;373:1–6. eases, gastrointestinal disorders and the microbiome in Trøseid M, Manner IW, Pedersen KK, et al. Microbial translocation schizophrenia: more than a gut feeling. Schizophr Res 2014, and cardiometabolic risk factors in HIV infection. AIDS Res DOI:10.1016/j.schres.2014.06.027. Hum Retrov 2014;30:514–22. Sharma BR. Infection in patients with severe burns: causes and Tsujimoto H, Ono S, Mochizuki H. Role of translocation of prevention thereof. Infect Dis Clin N Am 2007;21:745–59. pathogen-associated molecular patterns in sepsis. Digest Shaw MK. Cell invasion by Theileria sporozoites. Trends Parasitol Surg 2009;26:100–9. 2003;19:2–6. Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut micro- Sheedy JR, Wettenhall RE, Scanlon D, et al. Increased d-lactic biome in obese and lean twins. Nature 2009;457:480–4. acid intestinal bacteria in patients with chronic fatigue syn- Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated drome. In Vivo 2009;23:621–8. gut microbiome with increased capacity for energy harvest. Sia AK, Allred BE, Raymond KN. Siderocalins: siderophore bind- Nature 2006;444:1027–131. ing proteins evolved for primary pathogen host defense. Curr Vaarala O. Human intestinal microbiota and type 1 diabetes. Curr Opin Chem Biol 2013;17:150–7. Diabetes Rep 2013;13:601–7. Singh S, Eldin C, Kowalczewska M, et al. Axenic culture of fas- Vajro P, Paolella G, Fasano A. Microbiota and gut-liver axis: their tidious and intracellular bacteria. Trends Microbiol 2013;21: influences on obesity and obesity-related liver disease. JPe- 92–9. diatr Gastr Nutr 2013;56:461–8. Soina VS, Lysak LV, Konova IA, et al. Study of ultramicrobacte- Valencia-Shelton F, Loeffelholz M. Nonculture techniques for ria (nanoforms) in soils and subsoil deposits by electron mi- the detection of bacteremia and fungemia. Future Microbiol croscopy. Eurasian Soil Sci 2012;45:1048–56. 2014;9:543–59. Steinberg SM. Bacterial translocation: what it is and what it is van der Merwe J, Prysliak T, Perez-Casal J. Invasion of bovine not. Am J Surg 2003;186:301–5. peripheral blood mononuclear cells and erythrocytes by My- Stevenson BS, Eichorst SA, Wertz JT, et al. New strategies for coplasma bovis. Infect Immun 2010;78:4570–8. cultivation and detection of previously uncultured microbes. van Duynhoven J, Vaughan EE, Jacobs DM, et al. Metabolic fate Appl Environ Microb 2004;70:4748–55. of polyphenols in the human superorganism. P Natl Acad Sci Stewart EJ. Growing unculturable bacteria. J Bacteriol USA 2011;108 (Suppl 1):4531–8. 2012;194:4151–60. Varani S, Stanzani M, Paolucci M, et al. Diagnosis of blood- Straub RH, Cutolo M. Circadian rhythms in rheumatoid arthritis: stream infections in immunocompromised patients by real- implications for pathophysiology and therapeutic manage- time PCR. JInfect 2009;58:346–51. ment. Arthritis Rheum 2007;56:399–408. Vartoukian SR, Palmer RM, Wade WG. Strategies for culture Swank GM, Deitch EA. Role of the gut in multiple organ fail- of ‘unculturable’ bacteria. FEMS Microbiol Lett 2010;309: ure: bacterial translocation and permeability changes. World 1–7. JSurg 1996;20:411–7. Vazquez-Castellanos ´ JF, Serrano-Villar S, Latorre A, et al. Al- Syrjanen ¨ J, Valtonen VV, Iivanainen M, et al. Preceding infection tered metabolism of gut microbiota contributes to chronic as an important risk factor for ischaemic brain infarction in immune activation in HIV-infected individuals. Mucosal Im- young and middle aged patients. Brit Med J 1988;296:1156–60. munol 2014, DOI:10.1038/mi.2014.107. Tanaka T, Kawasaki K, Daimon S, et al. Ahiddenpitfallinthe Venkatesh M, Mukherjee S, Wang H, et al. Symbiotic bacte- preparation of agar media undermines microorganism cul- rial metabolites regulate gastrointestinal barrier function via tivability. Appl Environ Microb 2014;80:7659–66. the xenobiotic sensor PXR and Toll-like receptor 4. Immunity Taneja V. Arthritis susceptibility and the gut microbiome. FEBS 2014;41:296–310. Lett 2014;588:4244–9. Vila-Corcoles A, Ochoa-Gondar O, Rodriguez-Blanco T, et al. Eval- Tang WH,WangZ,LevisonBS, et al. Intestinal microbial uating clinical effectiveness of pneumococcal vaccination in metabolism of phosphatidylcholine and cardiovascular risk. preventing stroke: the CAPAMIS Study 3-year follow-up. J New Engl J Med 2013;368:1575–84. Stroke Cerebrovasc 2014;23:1577–84. Tedeschi GG, Bondi A, Paparelli M, et al. Electron microscopical Vincent JL, Rello J, Marshall J, et al. International study of the evidence of the evolution of corynebacteria-like microorgan- prevalence and outcomes of infection in intensive care units. isms within human erythrocytes. Experientia 1978;34:458–60. JAMA 2009;302:2323–9. Thaiss CA, Zeevi D, Levy M, et al. Transkingdom control of micro- Vitry MA, Hanot Mambres D, Deghelt M, et al. Brucella melitensis biota diurnal oscillations promotes metabolic homeostasis. invades murine erythrocytes during infection. Infect Immun Cell 2014;159:514–29. 2014;82:3927–38. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 591 Vizcarra JA, Wilson-Perez HE, Espay AJ. The power in num- logenetic characterization of Sutterella species in intestinal bers: gut microbiota in Parkinson’s disease. Movement Disord biopsy samples from children with autism and gastrointesti- 2015;30:296–8. nal disturbances. MBio 2012;3:00261–11. Vogl G, Plaickner A, Szathmary S, et al. Mycoplasma gallisep- Williams TA, Foster PG, Cox CJ, et al. An archaeal origin of eu- ticum invades chicken erythrocytes during infection. Infect karyotes supports only two primary domains of life. Nature Immun 2008;76:71–7. 2013;504:231–6. Votyakova TV, Kaprelyants AS, Kell DB. Influence of vi- Wilson ML, Weinstein MP. General principles in the labora- able cells on the resuscitation of dormant cells in Mi- tory detection of bacteremia and fungemia. Clin Lab Med crococcus luteus cultures held in an extended stationary 1994;14:69–82. phase: the population effect. Appl Environ Microb 1994;60: Winter SE, Thiennimitr P, Winter MG, et al. Gut inflammation 3284–91. provides a respiratory electron acceptor for Salmonella. Na- Vujkovic-Cvijin I, Dunham RM, Iwai S, et al. Dysbiosis of the gut ture 2010;467:426–9. microbiota is associated with HIV disease progression and Woese CR, Fox GE. Phylogenetic structure of the prokary- tryptophan catabolism. Sci Transl Med 2013;5:193–1. otic domain: the primary kingdoms. P Natl Acad Sci USA Walker AW, Duncan SH, Louis P, et al. Phylogeny, culturing, and 1977;74:5088–90. metagenomics of the human gut microbiota. Trends Microbiol Woese CR, Kandler O, Wheelis ML. Towards a natural sys- 2014;22:267–74. tem of organisms: proposal for the domains Archaea, Wallet F, Loiez C, Herwegh S, et al. Usefulness of real-time PCR Bacteria, and Eucarya. P Natl Acad Sci USA 1990;87: for the diagnosis of sepsis in ICU-acquired infections. Infect 4576–79. Disord Drug Targets 2011;11:348–53. Xayarath B, Freitag NE. Optimizing the balance between host and Wang Y, Chen Y, Zhou Q, et al. A culture-independent approach environmental survival skills: lessons learned from Listeria to unravel uncultured bacteria and functional genes in a monocytogenes. Future Microbiol 2012;7:839–52. complex microbial community. PLoS One 2012c;7:e47530. Yamaguchi M, Terao Y, Mori-Yamaguchi Y, et al. Streptococcus Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of pneumoniae invades erythrocytes and utilizes them to evade phosphatidylcholine promotes cardiovascular disease. Na- human innate immunity. PLoS One 2013;8:e77282. ture 2011;472:57–63. Yang J, Feng L, Ren J, et al. Correlation between the severity of Wang Z, Zhang L, Guo Z, et al. A unique feature of iron loss via periodontitis and coronary artery stenosis in a Chinese pop- close adhesion of Helicobacter pylori to host erythrocytes. PLoS ulation. Aust Dent J 2013;58:333–8. One 2012b;7:e50314. Yarza P, Sproer ¨ C, Swiderski J, et al. Sequencing orphan species Wang ZW, Li Y, Huang LY, et al. Helicobacter pylori infection con- initiative (SOS): filling the gaps in the 16S rRNA gene tributes to high risk of ischemic stroke: evidence from a sequence database for all species with validly published meta-analysis. JNeurol 2012a;259:2527–37. names. Syst Appl Microbiol 2013;36:69–73. Weinstein MP. Current blood culture methods and systems: clin- Yatsunenko T, Rey FE, Manary MJ, et al. Human gut micro- ical concepts, technology, and interpretation of results. Clin biome viewed across age and geography. Nature 2012;486: Infect Dis 1996;23:40–6. 222–7. Weinstock GM. Genomic approaches to studying the human mi- Young D, Stark J, Kirschner D. Systems biology of persistent crobiota. Nature 2012;489:250–6. infection: tuberculosis as a case study. Nat Rev Microbiol West SA, Buckling A. Cooperation, virulence and siderophore 2008;6:520–8. production in bacterial parasites. Proc R Soc B 2003;270:37–44. Yu RQ, Yuan JL, Ma LY, et al. Probiotics improve obesity- Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis. associated dyslipidemia and insulin resistance in high-fat Hepatology 2005;41:422–33. diet-fed rats. Zhongguo Dang Dai Er Ke Za Zhi 2013;15:1123–7. Wiest R, Lawson M, Geuking M. Pathological bacterial transloca- Zengler K, Toledo G, Rappe M, et al. Cultivating the uncultured. tion in liver cirrhosis. J Hepatol 2014;60:197–209. P Natl Acad Sci USA 2002;99:15681–6. Wiest R, Rath HC. Gastrointestinal disorders of the critically Zhang H, Liao X, Sparks JB, et al. Dynamics of gut microbiota in ill. Bacterial translocation in the gut. Best Pract Res Cl Ga autoimmune lupus. Appl Environ Microb 2014a;80:7551–60. 2003;17:397–425. Zhang R, Lahens NF, Ballance HI, et al. A circadian gene ex- Wikoff WR, Anfora AT, Liu J, et al. Metabolomics anal- pression atlas in mammals: implications for biology and ysis reveals large effects of gut microflora on mam- medicine. P Natl Acad Sci USA 2014b;111:16219–24. malian blood metabolites. P Natl Acad Sci USA 2009;106: Zhang Y, Yew WW, Barer MR. Targeting persisters for tuberculo- 3698–703. sis control. Antimicrob Agents Ch 2012;56:2223–30. Williams BB, Van Benschoten AH, Cimermancic P, et al. Discov- Zhang Y, Zou Y, Ma P, et al. Identification of Mycoplasma suis ery and characterization of gut microbiota decarboxylases MSG1 interaction proteins on porcine erythrocytes. Arch Mi- that can produce the neurotransmitter tryptamine. Cell Host crobiol 2014c;80:7551–60. Microbe 2014;16:495–503. Zhu Y, Jameson E, Crosatti M, et al. Carnitine metabolism to Williams BL, Hornig M, Buie T, et al. Impaired carbohydrate trimethylamine by an unusual Rieske-type oxygenase from digestion and transport and mucosal dysbiosis in the in- human microbiota. P Natl Acad Sci USA 2014;111:4268–73. testines of children with autism and gastrointestinal distur- Zimmermann MB, Chassard C, Rohner F, et al. The effects of bances. PLoS One 2011;6:e24585. iron fortification on the gut microbiota in African children: Williams BL, Hornig M, Parekh T, et al. Application of novel a randomized controlled trial in Cote d’Ivoire. Am J Clin Nutr PCR-based methods for detection, quantitation, and phy- 2010;92:1406–15. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png FEMS Microbiology Reviews Oxford University Press http://www.deepdyve.com/lp/oxford-university-press/the-dormant-blood-microbiome-in-chronic-inflammatory-diseases-UQ1LQ3t5PH

Loading next page...

References (512)

N. Natarajan, J. Pluznick (2014)
From microbe to man: the role of microbial short chain fatty acid metabolites in host cell biology.
American journal of physiology. Cell physiology, 307 11
G. Besten, K. Eunen, A. Groen, K. Venema, D. Reijngoud, Barbara Bakker (2013)
The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism
Journal of Lipid Research, 54
P. Seksik, L. Rigottier-Gois, G. Gramet, M. Sutren, P. Pochart, P. Marteau, R. Jian, J. Doré (2002)
INFLAMMATION AND INFLAMMATORY BOWEL DISEASE Alterations of the dominant faecal bacterial groups in patients with Crohn’s disease of the colon
G. Vogl, Astrid Plaickner, S. Szathmary, L. Stipkovits, R. Rosengarten, M. Szostak (2007)
Mycoplasma gallisepticum Invades Chicken Erythrocytes during Infection
Infection and Immunity, 76
D. Kell (2010)
Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples
Archives of Toxicology, 84
Yan Huang, X. Fan, Zhu-Sheng Tang, Li Liu, X. Tian, Ning Li (2006)
Detection of Helicobacter pylori DNA in peripheral blood from patients with peptic ulcer or gastritis
APMIS, 114
R. Amann, W. Ludwig, K. Schleifer (1995)
Phylogenetic identification and in situ detection of individual microbial cells without cultivation.
Microbiological reviews, 59 1
Manimozhiyan Arumugam, J. Raes, É. Pelletier, D. Paslier, Takuji Yamada, D. Mende, G. Fernandes, J. Tap, T. Bruls, Jean-Michel Batto, Marcelo Bertalan, N. Borruel, F. Casellas, Leyden Fernández, L. Gautier, T. Hansen, M. Hattori, Tetsuya Hayashi, M. Kleerebezem, K. Kurokawa, M. Leclerc, F. Levenez, C. Manichanh, H. Nielsen, T. Nielsen, N. Pons, J. Poulain, J. Qin, Thomas Sicheritz-Pontén, S. Tims, D. Torrents, Edgardo Ugarte, E. Zoetendal, Junwang, F. Guarner, O. Pedersen, W. Vos, S. Brunak, J. Doré, MetaHIT consortium, J. Weissenbach, S. Ehrlich, P. Bork (2011)
Enterotypes of the human gut microbiome
Nature, 474
P. Murray (2014)
The Clinician and the Microbiology Laboratory
Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases
K. Asano, E. Tryka, J. Cho, N. Keicho (2012)
Macrolide Therapy in Chronic Inflammatory Diseases
Mediators of Inflammation, 2012
(2013)
589 fibrin fibril formation: the use of scanning electron microscopy
V. Pham, Jaisoo Kim (2012)
Cultivation of unculturable soil bacteria.
Trends in biotechnology, 30 9
S. Rhee (2014)
Lipopolysaccharide: Basic Biochemistry, Intracellular Signaling, and Physiological Impacts in the Gut
Intestinal Research, 12
M. Rooks, Patrick Veiga, Leslie Wardwell-Scott, Timothy Tickle, Nicola Segata, M. Michaud, C. Gallini, C. Béal, Johan Hylckama-Vlieg, S. Ballal, Xochitl Morgan, Jonathan Glickman, D. Gevers, C. Huttenhower, W. Garrett (2014)
Gut microbiome composition and function in experimental colitis during active disease and treatment-induced remission
The ISME Journal, 8
D. Kell, Joshua Knowles (2005)
The role of modeling in systems biology
P. Kovatcheva-Datchary, V. Tremaroli, F. Bäckhed (2013)
The Gut Microbiota
B. Petriz, Alinne Castro, J. Almeida, Clarissa Gomes, G. Fernandes, R. Kruger, R. Pereira, O. Franco (2014)
Exercise induction of gut microbiota modifications in obese, non-obese and hypertensive rats
BMC Genomics, 15
Frances Valencia-Shelton, M. Loeffelholz (2014)
Nonculture techniques for the detection of bacteremia and fungemia.
Future microbiology, 9 4
F. Puleo, M. Arvanitakis, A. Gossum, J. Preiser (2011)
Gut failure in the ICU.
Seminars in respiratory and critical care medicine, 32 5
J. Goust, G. Tsokos (1976)
Systemic lupus erythematosus.
Immunology series, 58
M. Salter, Richard Knowles, C. Pogson (1994)
Metabolic control.
Essays in biochemistry, 28
Sama Sayin, A. Wahlström, Jenny Felin, S. Jäntti, H. Marschall, K. Bamberg, B. Angelin, T. Hyötyläinen, M. Orešič, F. Bäckhed (2013)
Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist.
Cell metabolism, 17 2
B. McColl, S. Allan, N. Rothwell (2009)
Systemic infection, inflammation and acute ischemic stroke
Neuroscience, 158
C. Werning (1983)
[Rheumatoid arthritis].
Medizinische Monatsschrift fur Pharmazeuten, 6 12
D. Kell, S. Oliver (2014)
How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion
Frontiers in Pharmacology, 5
C. Jung, J. Hugot, F. Barreau (2010)
Peyer's Patches: The Immune Sensors of the Intestine
International Journal of Inflammation, 2010
N. Delzenne, A. Neyrinck, F. Bäckhed, Patrice Cani (2011)
Targeting gut microbiota in obesity: effects of prebiotics and probiotics
Nature Reviews Endocrinology, 7
HC Emsley, PJ Tyrrell (2002)
Inflammation and infection in clinical stroke
J Cerebr Blood F Met, 22
S. Diggle, A. Griffin, G. Campbell, S. West (2007)
Cooperation and conflict in quorum-sensing bacterial populations
Nature, 450
J. Madan, D. Koestler, B. Stanton, L. Davidson, Lisa Moulton, M. Housman, Jason Moore, M. Guill, H. Morrison, Mitch Sogin, T. Hampton, M. Karagas, P. Palumbo, J. Foster, P. Hibberd, G. O’Toole (2012)
Serial Analysis of the Gut and Respiratory Microbiome in Cystic Fibrosis in Infancy: Interaction between Intestinal and Respiratory Tracts and Impact of Nutritional Exposures
mBio, 3
P. Domínguez-Cuevas, R. Mercier, M. Leaver, Y. Kawai, J. Errington (2012)
The rod to L‐form transition of Bacillus subtilis is limited by a requirement for the protoplast to escape from the cell wall sacculus
Molecular Microbiology, 83
Joseph Horzempa, Dawn O'Dee, D. Stolz, J. Franks, D. Clay, G. Nau (2011)
Invasion of erythrocytes by Francisella tularensis.
The Journal of infectious diseases, 204 1
P. Turnbaugh, M. Hamady, Tanya Yatsunenko, B. Cantarel, A. Duncan, R. Ley, M. Sogin, W. Jones, B. Roe, J. Affourtit, M. Egholm, B. Henrissat, A. Heath, R. Knight, J. Gordon (2008)
A core gut microbiome in obese and lean twins
Nature, 457
S. Winter, Parameth Thiennimitr, Parameth Thiennimitr, M. Winter, B. Butler, D. Huseby, R. Crawford, J. Russell, C. Bevins, L. Adams, R. Tsolis, J. Roth, A. Bäumler (2010)
Gut inflammation provides a respiratory electron acceptor for Salmonella
Nature, 467
J. Smilack (1995)
Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases
JAMA, 274
M. Montes‐de‐Oca, M. Blanco, M. Márquez, M. Soto, C. Fernández‐Gutiérrez, C. Rodríguez-Ramos, J. Girón-González (2011)
THIS ARTICLE HAS BEEN RETRACTED: Haemodynamic derangement in human immunodeficiency virus‐infected patients with hepatitis C virus‐related cirrhosis: the role of bacterial translocation
Liver International, 31
A. Hevia, C. Milani, P. López, A. Cuervo, S. Arboleya, S. Duranti, F. Turroni, Sonia González, A. Suárez, M. Gueimonde, M. Ventura, B. Sánchez, A. Margolles (2014)
Intestinal Dysbiosis Associated with Systemic Lupus Erythematosus
mBio, 5
K. Kahle, M. Kraus, W. Scheppach, Matthias Ackermann, Friederike Ridder, E. Richling (2006)
Studies on apple and blueberry fruit constituents: do the polyphenols reach the colon after ingestion?
Molecular nutrition & food research, 50 4-5
C. Woese, O. Kandler, M. Wheelis (1990)
Towards a natural system of organisms: proposal for the domains Archaea, Bacteria, and Eucarya.
Proceedings of the National Academy of Sciences of the United States of America, 87
G. Domingue, J. Schlegel (1977)
Novel bacterial structures in human blood: cultural isolation
Infection and Immunity, 15
Ren-Qiang Yu, Jingyi Yuan, Lu-Yi Ma, Qing-Xu Qin, Xiao-You Wu (2013)
[Probiotics improve obesity-associated dyslipidemia and insulin resistance in high-fat diet-fed rats].
Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics, 15 12
D. Keilin (1959)
The Leeuwenhoek Lecture - The problem of anabiosis or latent life: history and current concept
Proceedings of the Royal Society of London. Series B - Biological Sciences, 150
C. Ratledge (2007)
Iron Metabolism and Infection
Food and Nutrition Bulletin, 28
R. Wiest, Melissa Lawson, M. Geuking (2014)
Pathological bacterial translocation in liver cirrhosis.
Journal of hepatology, 60 1
V. Robles-Alonso, F. Guarner (2014)
From basic to applied research: lessons from the human microbiome projects.
Journal of clinical gastroenterology, 48 Suppl 1
J. Gribbin (1984)
In search of Schrödinger's cat : quantum physics and reality
L. Mattman (1992)
Cell Wall Deficient Forms: Stealth Pathogens
Yaning Zhang, Yao Zou, Peipei Ma, H. Muhammad, Yufeng Li, P. Jiang (2014)
Identification of Mycoplasma suis MSG1 interaction proteins on porcine erythrocytes
Archives of Microbiology, 197
A. Proal, Paul Albert, T. Marshall (2014)
Inflammatory disease and the human microbiome.
Discovery medicine, 17 95
P. Aronov, F. Luo, Natalie Plummer, Zhe Quan, S. Holmes, T. Hostetter, T. Meyer (2011)
Colonic contribution to uremic solutes.
Journal of the American Society of Nephrology : JASN, 22 9
(2015)
Microbiology. Persisters unmasked. Science
Horacio Perez, Maria Menezes, Armando D'acampora (2014)
[Intestinal microbiota].
Acta gastroenterologica Latinoamericana, 44 3
M. Atkinson, G. Eisenbarth, A. Michels (2014)
Type 1 diabetes
The Lancet, 383
V. Preter, K. Verbeke (2013)
Metabolomics as a diagnostic tool in gastroenterology.
World journal of gastrointestinal pharmacology and therapeutics, 4 4
Iris Keren, N. Kaldalu, A. Spoering, Yipeng Wang, K. Lewis (2004)
Persister cells and tolerance to antimicrobials.
FEMS microbiology letters, 230 1
R. Straub, M. Cutolo (2007)
Circadian rhythms in rheumatoid arthritis: implications for pathophysiology and therapeutic management.
Arthritis and rheumatism, 56 2
E. Quigley (2011)
Faculty Opinions recommendation of Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.
P. Calcott, J. Postgate (1972)
On substrate-accelerated death in Klebsiella aerogenes.
Journal of general microbiology, 70 1
A. Kostic, R. Xavier, D. Gevers (2014)
The microbiome in inflammatory bowel disease: current status and the future ahead.
Gastroenterology, 146 6
S. Balzan, Claudio Quadros, R. Cleva, B. Zilberstein, I. Cecconello (2007)
Bacterial translocation: Overview of mechanisms and clinical impact
Journal of Gastroenterology and Hepatology, 22
Yun Wang, Yin Chen, Qian-Xiong Zhou, Shi Huang, K. Ning, Jian Xu, R. Kalin, S. Rolfe, Wei Huang (2012)
A Culture-Independent Approach to Unravel Uncultured Bacteria and Functional Genes in a Complex Microbial Community
PLoS ONE, 7
G. Thwaites, V. Gant (2011)
Are bloodstream leukocytes Trojan Horses for the metastasis of Staphylococcus aureus?
Nature Reviews Microbiology, 9
H. Tsujimoto, S. Ono, H. Mochizuki (2009)
Role of Translocation of Pathogen-Associated Molecular Patterns in Sepsis
Digestive Surgery, 26
E. Pretorius, A. Swanepoel, A. Buys, N. Vermeulen, W. Duim, D. Kell (2014)
Eryptosis as a marker of Parkinson's disease
Aging (Albany NY), 6
J. Errington (2013)
L-form bacteria, cell walls and the origins of life
Open Biology, 3
X. Morgan, Timothy Tickle, H. Sokol, D. Gevers, K. Devaney, D. Ward, Joshua Reyes, Samir Shah, N. LeLeiko, S. Snapper, A. Bousvaros, J. Korzenik, B. Sands, R. Xavier, C. Huttenhower (2012)
Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment
Genome Biology, 13
E. Bergman (1990)
Energy contributions of volatile fatty acids from the gastrointestinal tract in various species.
Physiological reviews, 70 2
S. Clingenpeel, P. Schwientek, P. Hugenholtz, T. Woyke (2014)
Effects of sample treatments on genome recovery via single-cell genomics
The ISME Journal, 8
E. Chatelier, T. Nielsen, J. Qin, Edi Prifti, F. Hildebrand, G. Falony, Mathieu Almeida, Manimozhiyan Arumugam, Jean-Michel Batto, S. Kennedy, Pierre Leonard, Junhua Li, K. Burgdorf, N. Grarup, T. Jørgensen, I. Brandslund, H. Nielsen, A. Juncker, Marcelo Bertalan, F. Levenez, N. Pons, Simon Rasmussen, S. Sunagawa, J. Tap, S. Tims, E. Zoetendal, S. Brunak, K. Clément, J. Doré, M. Kleerebezem, K. Kristiansen, P. Renault, Thomas Sicheritz-Pontén, W. Vos, Jean-Daniel Zucker, J. Raes, T. Hansen, P. Bork, Jun Wang, S. Ehrlich, O. Pedersen (2013)
Richness of human gut microbiome correlates with metabolic markers
Nature, 500
B. Lipinski, E. Pretorius, Keith Vossel
Human Neuroscience Hypothesis and Theory Article
Gwen Duytschaever, G. Huys, Maarten Bekaert, L. Boulanger, K. Boeck, P. Vandamme (2011)
Cross-Sectional and Longitudinal Comparisons of the Predominant Fecal Microbiota Compositions of a Group of Pediatric Patients with Cystic Fibrosis and Their Healthy Siblings
Applied and Environmental Microbiology, 77
P. Renesto, N. Crapoulet, H. Ogata, La Bernard, Guy Scola, Jean-Michel Vestris, Didier Claverie, Raoult
For Personal Use. Only Reproduce with Permission from the Lancet. Genome-based Design of a Cell-free Culture Medium for Tropheryma Whipplei
(2012)
Symptomatic atherosclerosis is associated with an altered gut metagenome
Nature Communications, 3
B. Muegge, Justin Kuczynski, D. Knights, J. Clemente, Antonio Gonzalez, L. Fontana, B. Henrissat, R. Knight, J. Gordon (2011)
Diet Drives Convergence in Gut Microbiome Functions Across Mammalian Phylogeny and Within Humans
Science, 332
F. Hoffbauer (2005)
Liver disease
The American Journal of Digestive Diseases, 4
P. Angulo, K. Lindor (2002)
Non‐alcoholic fatty liver disease
Alimentary Pharmacology & Therapeutics, 17
B. Williams, M. Hornig, Tanmay Parekh, W. Lipkin (2012)
Application of Novel PCR-Based Methods for Detection, Quantitation, and Phylogenetic Characterization of Sutterella Species in Intestinal Biopsy Samples from Children with Autism and Gastrointestinal Disturbances
mBio, 3
H. Ducklow (1998)
Bacteria in oligotrophic environments: Starvation-survival lifestyle
Limnology and Oceanography, 43
Alison Bested, A. Logan, Eva Selhub (2013)
Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: part III – convergence toward clinical trials
Gut Pathogens, 5
I. Martínez, D. Perdicaro, A. Brown, S. Hammons, Trevor Carden, T. Carr, K. Eskridge, J. Walter (2012)
Diet-Induced Alterations of Host Cholesterol Metabolism Are Likely To Affect the Gut Microbiota Composition in Hamsters
Applied and Environmental Microbiology, 79
A. Rechner, Gunter Kuhnle, Henglong Hu, A. Roedig-Penman, M. Braak, K. Moore, C. Rice-evans (2002)
The Metabolism of Dietary Polyphenols and the Relevance to Circulating Levels of Conjugated Metabolites
Free Radical Research, 36
R. Meyer (1983)
Legionella infections: a review of five years of research.
Reviews of infectious diseases, 5 2
Jun-Ying Yang, Lei Feng, Jun Ren, Gang Wu, Shan Chen, Q. Zhou, Z. Du, S. Zhang, C. Hu, Xiaojun Wu, L. Ling (2013)
Correlation between the severity of periodontitis and coronary artery stenosis in a Chinese population.
Australian dental journal, 58 3
S. Amar, M. Engelke (2015)
Periodontal innate immune mechanisms relevant to atherosclerosis.
Molecular oral microbiology, 30 3
J. Conlan (2011)
Francisella tularensis: a red-blooded pathogen.
The Journal of infectious diseases, 204 1
C. Lozupone, Marcella Li, T. Campbell, S. Flores, Derek Linderman, Matthew Gebert, R. Knight, A. Fontenot, B. Palmer (2013)
Alterations in the gut microbiota associated with HIV-1 infection.
Cell host & microbe, 14 3
T. Sawa (2014)
The molecular mechanism of acute lung injury caused by Pseudomonas aeruginosa: from bacterial pathogenesis to host response
Journal of Intensive Care, 2
K. Grif, Ingrid Heller, W. Prodinger, K. Lechleitner, C. Lass‐Flörl, D. Orth (2012)
Improvement of Detection of Bacterial Pathogens in Normally Sterile Body Sites with a Focus on Orthopedic Samples by Use of a Commercial 16S rRNA Broad-Range PCR and Sequence Analysis
Journal of Clinical Microbiology, 50
Thomas Havey, R. Fowler, N. Daneman (2011)
Duration of antibiotic therapy for bacteremia: a systematic review and meta-analysis
Critical Care, 15
J. Vázquez-Castellanos, S. Serrano-Villar, Amparo Latorre, Alejandro Artacho, María Ferrús, N. Madrid, A. Vallejo, T. Sainz, Javier Martínez-Botas, S. Ferrando-Martínez, Mar Vera, F. Dronda, Manuel Leal, J. Romero, Santiago Moreno, V. Estrada, M. Gosalbes, Andrés Moya (2014)
Altered metabolism of gut microbiota contributes to chronic immune activation in HIV-infected individuals
Mucosal Immunology, 8
M. Pallen, N. Loman, C. Penn (2010)
High-throughput sequencing and clinical microbiology: progress, opportunities and challenges.
Current opinion in microbiology, 13 5
J. Lagier, S. Edouard, I. Pagnier, O. Mediannikov, M. Drancourt, D. Raoult (2015)
Current and Past Strategies for Bacterial Culture in Clinical Microbiology
Clinical Microbiology Reviews, 28
X. Didelot, R. Bowden, Daniel Wilson, T. Peto, D. Crook (2012)
Transforming clinical microbiology with bacterial genome sequencing
Nature Reviews Genetics, 13
D. Bowdish, D. Davidson, R. Hancock (2005)
A re-evaluation of the role of host defence peptides in mammalian immunity.
Current protein & peptide science, 6 1
G. Swank, E. Deitch (1996)
Role of the Gut in Multiple Organ Failure: Bacterial Translocation and Permeability Changes
World Journal of Surgery, 20
R. Mercier, Y. Kawai, J. Errington (2013)
Excess Membrane Synthesis Drives a Primitive Mode of Cell Proliferation
Cell, 152
Karla Davis (2015)
Low Gut Microbiota Diversity in Early Infancy Precedes Asthma at School Age
Pediatrics, 136
Patrice Cani, R. Bibiloni, C. Knauf, A. Waget, A. Neyrinck, N. Delzenne, R. Burcelin (2008)
Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet–Induced Obesity and Diabetes in Mice
Diabetes, 57
D. Kell, E. Pretorius (2015)
The simultaneous occurrence of both hypercoagulability and hypofibrinolysis in blood and serum during systemic inflammation, and the roles of iron and fibrin(ogen).
Integrative biology : quantitative biosciences from nano to macro, 7 1
Shy-Shin Chang, Hsung-Ling Hsu, Ju-Chien Cheng, C. Tseng (2011)
An Efficient Strategy for Broad-Range Detection of Low Abundance Bacteria without DNA Decontamination of PCR Reagents
PLoS ONE, 6
(2014)
Adv Exp Med Biol
KJ Pflughoeft, J Versalovic (2012)
Human microbiome in health and disease
Annu Rev Pathol, 7
C. Petersen, J. Round (2014)
Defining dysbiosis and its influence on host immunity and disease
Cellular Microbiology, 16
Fredrik Karlsson, V. Tremaroli, I. Nookaew, G. Bergström, C. Behre, B. Fagerberg, J. Nielsen, F. Bäckhed (2013)
Gut metagenome in European women with normal, impaired and diabetic glucose control
Nature, 498
(2008)
Plasmodium falciparum The main malaria parasite, part of whose life cycle involves inhabiting RBCs
Sachiko Iwaki-Egawa, Garret Ihler (1997)
Comparison of the abilities of proteins from Bartonella bacilliformis and Bartonella henselae to deform red cell membranes and to bind to red cell ghost proteins.
FEMS microbiology letters, 157 1
Helena Parracho, M. Bingham, G. Gibson, A. McCartney (2005)
Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children.
Journal of medical microbiology, 54 Pt 10
B. Williams, Andrew Benschoten, Peter Cimermancic, M. Donia, Michael Zimmermann, Mao Taketani, A. Ishihara, P. Kashyap, J. Fraser, M. Fischbach (2014)
Discovery and characterization of gut microbiota decarboxylases that can produce the neurotransmitter tryptamine.
Cell host & microbe, 16 4
S. Percival, K. Hill, D. Williams, S. Hooper, David Thomas, J. Costerton (2012)
A review of the scientific evidence for biofilms in wounds
Wound Repair and Regeneration, 20
E. Holmes, Jia Li, T. Athanasiou, H. Ashrafian, J. Nicholson (2011)
Understanding the role of gut microbiome-host metabolic signal disruption in health and disease.
Trends in microbiology, 19 7
L. Chien, N.‐F. Chi, C.‐J. Hu, H. Chiou (2013)
Central nervous system infections and stroke – a population‐based analysis
Acta Neurologica Scandinavica, 128
A. Bull (2003)
Microbial Diversity and Bioprospecting
E. Bruzzese, M. Callegari, V. Raia, Sara Viscovo, R. Scotto, S. Ferrari, L. Morelli, V. Buccigrossi, A. Vecchio, Eliana Ruberto, A. Guarino (2014)
Disrupted Intestinal Microbiota and Intestinal Inflammation in Children with Cystic Fibrosis and Its Restoration with Lactobacillus GG: A Randomised Clinical Trial
PLoS ONE, 9
M. Jepson, M. Clark (1998)
Studying M cells and their role in infection.
Trends in microbiology, 6 9
S. Bakhtiar, J. LeBlanc, E. Salvucci, Amjad Ali, R. Martín, P. Langella, J. Chatel, A. Miyoshi, L. Bermúdez-Humarán, V. Azevedo (2013)
Implications of the human microbiome in inflammatory bowel diseases.
FEMS microbiology letters, 342 1
T. Abrahamsson, Hedvig Jakobsson, Anders Andersson, Bengt Björkstén, Lars Engstrand, M. Jenmalm (2012)
Low diversity of the gut microbiota in infants with atopic eczema.
The Journal of allergy and clinical immunology, 129 2
John McArdle1, Laurie Whittaker2 (2009)
Cystic Fibrosis
Semin Respir Crit Care Med, 30
G. Mukamolova, N. Yanopolskaya, D. Kell, A. Kaprelyants (1998)
On resuscitation from the dormant state of Micrococcus luteus
Antonie van Leeuwenhoek, 73
David Luckey, A. Gomez, J. Murray, B. White, V. Taneja (2013)
Bugs & us: The role of the gut in autoimmunity
The Indian Journal of Medical Research, 138
Houeto Jean-Luc (2022)
[Parkinson's disease].
La Revue du praticien, 55 10
L. Lysak, E. Lapygina, I. Konova, D. Zvyagintsev (2010)
Quantity and taxonomic composition of ultramicrobacteria in soils
Microbiology, 79
R. Krishna (1966)
Proliferation
India Quarterly, 22
G. Tedeschi, A. Bondi, M. Paparelli, G. Sprovieri (1978)
Electron microscopical evidence of the evolution of corynebacteria-like microorganisms within human erythrocytes
Experientia, 34
R. Berg (1990)
Bacterial translocation from the gastrointestinal tract.
Trends in microbiology, 3 4
J. Macfie (2004)
Current status of bacterial translocation as a cause of surgical sepsis.
British medical bulletin, 71
C. Bingham, Malini Moni (2013)
Periodontal disease and rheumatoid arthritis: the evidence accumulates for complex pathobiologic interactions
Current Opinion in Rheumatology, 25
Zhiwei Wang, Lijuan Zhang, Zhi-rui Guo, Lei Liu, J. Ji, Jia-nian Zhang, Xue-hua Chen, Bing-ya Liu, Jun Zhang, Q. Ding, Xuefeng Wang, Wei Zhao, Zhenggang Zhu, Yingyan Yu (2012)
A Unique Feature of Iron Loss via Close Adhesion of Helicobacter pylori to Host Erythrocytes
PLoS ONE, 7
R. Hotchkiss, L. Moldawer, S. Opal, K. Reinhart, Isaiah Turnbull, J. Vincent (2016)
Sepsis and septic shock
Nature Reviews Disease Primers, 2
P. Degnan, M. Taga, A. Goodman (2014)
Vitamin B12 as a modulator of gut microbial ecology.
Cell metabolism, 20 5
C. Manichanh, N. Borruel, F. Casellas, F. Guarner (2012)
The gut microbiota in IBD
Nature Reviews Gastroenterology &Hepatology, 9
Etienne Maisonneuve, Manuela Castro-Camargo, K. Gerdes (2013)
RETRACTED: (p)ppGpp Controls Bacterial Persistence by Stochastic Induction of Toxin-Antitoxin Activity
Cell, 154
J. Clemente, L. Ursell, L. Parfrey, R. Knight (2012)
The Impact of the Gut Microbiota on Human Health: An Integrative View
Cell, 148
S. West, A. Buckling (2003)
Cooperation, virulence and siderophore production in bacterial parasites
Proceedings of the Royal Society of London. Series B: Biological Sciences, 270
L. Hooper, D. Littman, A. Macpherson (2012)
Interactions Between the Microbiota and the Immune System
Science, 336
D. Munteanu, A. Negru, M. Rădulescu, R. Mihăilescu, Ș. Aramă, V. Aramă (2014)
Evaluation of bacterial translocation in patients with chronic HCV infection.
Romanian journal of internal medicine = Revue roumaine de medecine interne, 52 2
N. Mancini, S. Carletti, N. Ghidoli, P. Cichero, R. Burioni, M. Clementi (2010)
The Era of Molecular and Other Non-Culture-Based Methods in Diagnosis of Sepsis
Clinical Microbiology Reviews, 23
C. Owyang, Gary Wu (2014)
The gut microbiome in health and disease.
Gastroenterology, 146 6
C. Lozupone, Jesse Stombaugh, J. Gordon, J. Jansson, R. Knight (2012)
Diversity, stability and resilience of the human gut microbiota
Nature, 489
M. Maiwald, A. Herbay, D. Fredricks, C. Ouverney, Jon Kosek, D. Relman (2003)
Cultivation of Tropheryma whipplei from cerebrospinal fluid.
The Journal of infectious diseases, 188 6
H. Minasyan (2014)
Erythrocyte and blood antibacterial defense.
European journal of microbiology & immunology, 4 2
G. Mandell, J. Bennett, R. Dolin (1995)
Mandell, Douglas and Bennett's principles and practice of infectious diseases. Volumes 1 and 2. Fourth edition.
E. Pretorius, J. Bester, N. Vermeulen, B. Lipinski, G. Gericke, D. Kell (2014)
Profound Morphological Changes in the Erythrocytes and Fibrin Networks of Patients with Hemochromatosis or with Hyperferritinemia, and Their Normalization by Iron Chelators and Other Agents
PLoS ONE, 9
T. Williams, Peter Foster, C. Cox, T. Embley (2013)
An archaeal origin of eukaryotes supports only two primary domains of life
Nature, 504
Byron Chu, R. Otten, K. Krewulak, F. Mulder, H. Vogel (2014)
The Solution Structure, Binding Properties, and Dynamics of the Bacterial Siderophore-binding Protein FepB*
The Journal of Biological Chemistry, 289
M. Frémont, D. Coomans, S. Massart, K. Meirleir (2013)
High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis/chronic fatigue syndrome patients.
Anaerobe, 22
L. Pearce (2016)
Non-alcoholic fatty liver disease.
Nursing standard (Royal College of Nursing (Great Britain) : 1987), 30 52
G. Domingue, H. Woody (1997)
Bacterial persistence and expression of disease
Clinical Microbiology Reviews, 10
Jennifer Owen, M. Mohamadzadeh (2013)
Microbial activation of gut dendritic cells and the control of mucosal immunity.
Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 33 11
A. Grau, C. Urbanek, F. Palm (2010)
Common infections and the risk of stroke
Nature Reviews Neurology, 6
F. Gich, K. Schubert, A. Bruns, Herbert Hoffelner, J. Overmann (2005)
Specific Detection, Isolation, and Characterization of Selected, Previously Uncultured Members of the Freshwater Bacterioplankton Community
Applied and Environmental Microbiology, 71
K. Grif, M. Fille, R. Würzner, G. Weiss, I. Lorenz, Gottfried Gruber, S. Eschertzhuber, D. Nachbaur, C. Lass‐Flörl, D. Orth (2012)
Rapid detection of bloodstream pathogens by real-time PCR in patients with sepsis
Wiener klinische Wochenschrift, 124
S. Mani, Hao Li (2014)
Symbiotic Bacterial Metabolites Regulate Gastrointestinal Barrier Function via the Xenobiotic Sensor PXR and Toll‐like Receptor 4
The FASEB Journal, 29
J. LeBlanc, C. Milani, G. Giori, F. Sesma, D. Sinderen, M. Ventura (2013)
Bacteria as vitamin suppliers to their host: a gut microbiota perspective.
Current opinion in biotechnology, 24 2
P. Almenoff, A. Johnson, M. Lesser, L. Mattman, L. Mattman (1996)
Growth of acid fast L forms from the blood of patients with sarcoidosis.
Thorax, 51
A. Dostal, J. Baumgartner, N. Riesen, C. Chassard, C. Smuts, M. Zimmermann, C. Lacroix (2014)
Effects of iron supplementation on dominant bacterial groups in the gut, faecal SCFA and gut inflammation: a randomised, placebo-controlled intervention trial in South African children
British Journal of Nutrition, 112
J. Detert, N. Pischon, G. Burmester, F. Buttgereit (2010)
The association between rheumatoid arthritis and periodontal disease
Arthritis Research & Therapy, 12
Allyson Sia, Benjamin Allred, K. Raymond (2012)
Siderocalins: Siderophore binding proteins evolved for primary pathogen host defense
Current Opinion in Chemical Biology, 17
A. Sabatino, G. Regolisti, I. Brusasco, A. Cabassi, S. Morabito, E. Fiaccadori (2015)
Alterations of intestinal barrier and microbiota in chronic kidney disease.
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 30 6
J. Cavanagh, Erik Hjerde, M. Holden, Tim Kahlke, C. Klingenberg, T. Flægstad, J. Parkhill, S. Bentley, J. Sollid (2014)
Whole-genome sequencing reveals clonal expansion of multiresistant Staphylococcus haemolyticus in European hospitals
Journal of Antimicrobial Chemotherapy, 69
P. Hopkins (2013)
Molecular biology of atherosclerosis.
Physiological reviews, 93 3
Wei Jiang, M. Lederman, P. Hunt, S. Sieg, K. Haley, B. Rodriguez, A. Landay, Jeffrey Martin, E. Sinclair, A. Asher, S. Deeks, D. Douek, J. Brenchley (2009)
Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection.
The Journal of infectious diseases, 199 8
G. Mukamolova, O. Turapov, K. Kazarian, M. Telkov, A. Kaprelyants, D. Kell, M. Young (2002)
The rpf gene of Micrococcus luteus encodes an essential secreted growth factor
Molecular Microbiology, 46
S. Nikkari, I. McLaughlin, Wanli Bi, D. Dodge, D. Relman (2001)
Does Blood of Healthy Subjects Contain Bacterial Ribosomal DNA?
Journal of Clinical Microbiology, 39
E. Nagata, A. Toledo, Takahiko Oho (2011)
Invasion of human aortic endothelial cells by oral viridans group streptococci and induction of inflammatory cytokine production.
Molecular oral microbiology, 26 1
M. Blaser, P. Bork, C. Fraser, R. Knight, Jun Wang (2013)
The microbiome explored: recent insights and future challenges
Nature Reviews Microbiology, 11
Zhong-Wei Wang, Yan Li, Li Huang, Q. Guan, D. Xu, Wenke Zhou, Xin Zhang (2012)
Helicobacter pylori infection contributes to high risk of ischemic stroke: evidence from a meta-analysis
Journal of Neurology, 259
E. Montassier, E. Batard, T. Gastinne, G. Potel, M. Cochetière (2013)
Recent changes in bacteremia in patients with cancer: a systematic review of epidemiology and antibiotic resistance
European Journal of Clinical Microbiology & Infectious Diseases, 32
David Fredricks (2013)
The Human Microbiota: How Microbial Communities Affect Health and Disease
E. Page, M. Nelson, P. Kelleher (2011)
HIV and hepatitis C coinfection: pathogenesis and microbial translocation.
Current opinion in HIV and AIDS, 6 6
S. Anghelescu (1980)
[Bacterial L forms].
Revista de igiena, bacteriologie, virusologie, parazitologie, epidemiologie, pneumoftiziologie. Bacteriologia, virusologia, parazitologia, epidemiologia, 25 3
D. Touati (2000)
Iron and oxidative stress in bacteria.
Archives of biochemistry and biophysics, 373 1
A. Catrina, K. Deane, J. Scher (2014)
Gene, environment, microbiome and mucosal immune tolerance in rheumatoid arthritis.
Rheumatology, 55 3
L. Desbonnet, L. Garrett, G. Clarke, J. Bienenstock, T. Dinan (2008)
The probiotic Bifidobacteria infantis: An assessment of potential antidepressant properties in the rat.
Journal of psychiatric research, 43 2
E. Kussell, R. Kishony, N. Balaban, S. Leibler (2005)
Bacterial Persistence
Genetics, 169
(2011)
The mind-body-microbial continuum
Dialogues in Clinical Neuroscience, 13
M. Ogrendik (2009)
Efficacy of roxithromycin in adult patients with rheumatoid arthritis who had not received disease-modifying antirheumatic drugs: a 3-month, randomized, double-blind, placebo-controlled trial.
Clinical therapeutics, 31 8
R. Wiest (2016)
The intestinal microbiota
M. Cénit, V. Matzaraki, E. Tigchelaar, A. Zhernakova (2014)
Rapidly expanding knowledge on the role of the gut microbiome in health and disease.
Biochimica et biophysica acta, 1842 10
A. Shreiner, J. Kao, V. Young (2015)
The gut microbiome in health and in disease
Current Opinion in Gastroenterology, 31
M. Yamaguchi, Y. Terao, Yuka Mori-Yamaguchi, H. Domon, Yuuki Sakaue, T. Yagi, K. Nishino, A. Yamaguchi, V. Nizet, S. Kawabata (2013)
Streptococcus pneumoniae Invades Erythrocytes and Utilizes Them to Evade Human Innate Immunity
PLoS ONE, 8
J. Vizcarra, H. Wilson-Pérez, A. Espay (2015)
The power in numbers: Gut microbiota in Parkinson's disease
Movement Disorders, 30
D. Kell (2006)
Metabolomics, modelling and machine learning in systems biology – towards an understanding of the languages of cells
The FEBS Journal, 273
N. Loman, C. Constantinidou, J. Chan, M. Halachev, M. Sergeant, C. Penn, E. Robinson, M. Pallen (2012)
High-throughput bacterial genome sequencing: an embarrassment of choice, a world of opportunity
Nature Reviews Microbiology, 10
Samuel Brusca, S. Abramson, J. Scher (2014)
Microbiome and mucosal inflammation as extra-articular triggers for rheumatoid arthritis and autoimmunity
Current Opinion in Rheumatology, 26
G. Cooke, J. Behan, M. Costello (2006)
Newly identified vitamin K-producing bacteria isolated from the neonatal faecal flora
Microbial Ecology in Health and Disease, 18
J. Lagier, Perrine Hugon, S. Khelaifia, P. Fournier, B. Scola, D. Raoult (2015)
The Rebirth of Culture in Microbiology through the Example of Culturomics To Study Human Gut Microbiota
Clinical Microbiology Reviews, 28
A. Kaprelyants, J. Gottschal, Douglas Kell (1993)
Dormancy in non-sporulating bacteria.
FEMS microbiology reviews, 10 3-4
E. Pretorius, N. Vermeulen, J. Bester, B. Lipinski, D. Kell (2013)
A novel method for assessing the role of iron and its functional chelation in fibrin fibril formation: the use of scanning electron microscopy
Toxicology Mechanisms and Methods, 23
Antigone Kotsaki, E. Giamarellos‐Bourboulis (2012)
Emerging drugs for the treatment of sepsis
Expert Opinion on Emerging Drugs, 17
O. Koren, A. Spor, Jenny Felin, F. Fåk, Jesse Stombaugh, V. Tremaroli, C. Behre, R. Knight, B. Fagerberg, R. Ley, F. Bäckhed (2010)
Human oral, gut, and plaque microbiota in patients with atherosclerosis
Proceedings of the National Academy of Sciences, 108
D. Kell, H. Ryder, A. Kaprelyants, H. Westerhoff (1991)
Quantifying heterogeneity: flow cytometry of bacterial cultures
Antonie van Leeuwenhoek, 60
J. Ochoa-Repáraz, D. Mielcarz, Sakhina Haque, L. Kasper (2011)
Gut, bugs, and brain: Role of commensal bacteria in the control of central nervous system disease
Annals of Neurology, 69
A. Kaprelyants, G. Mukamolova, H. Davey, D. Kell (1996)
Quantitative Analysis of the Physiological Heterogeneity within Starved Cultures of Micrococcus luteus by Flow Cytometry and Cell Sorting
Applied and Environmental Microbiology, 62
Junko Sato, A. Kanazawa, F. Ikeda, T. Yoshihara, Hiromasa Goto, Hiroko Abe, Koji Komiya, Minako Kawaguchi, Tomoaki Shimizu, T. Ogihara, Y. Tamura, Yuko Sakurai, Risako Yamamoto, T. Mita, Y. Fujitani, H. Fukuda, K. Nomoto, Takuya Takahashi, T. Asahara, T. Hirose, S. Nagata, Y. Yamashiro, H. Watada (2014)
Gut Dysbiosis and Detection of “Live Gut Bacteria” in Blood of Japanese Patients With Type 2 Diabetes
Diabetes Care, 37
J. Vincent, J. Rello, J. Marshall, Eliézer Silva, A. Anzueto, Claude Martin, R. Moreno, J. Lipman, C. Gomersall, Y. Sakr, K. Reinhart (2009)
International study of the prevalence and outcomes of infection in intensive care units.
JAMA, 302 21
D. Kell, A. Kaprelyants, A. Grafen (1995)
Pheromones, social behaviour and the functions of secondary metabolism in bacteria.
Trends in ecology & evolution, 10 3
Yijun Zhu, E. Jameson, M. Crosatti, H. Schäfer, K. Rajakumar, T. Bugg, Yin Chen (2014)
Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota
Proceedings of the National Academy of Sciences, 111
D. Kell, A. Kaprelyants, D. Weichart, C. Harwood, M. Barer (1998)
Viability and activity in readily culturable bacteria: a review and discussion of the practical issues
Antonie van Leeuwenhoek, 73
G. Flores, J. Caporaso, Jessica Henley, J. Rideout, Daniel Domogala, John Chase, J. Leff, Y. Vázquez-Baeza, Antonio Gonzalez, R. Knight, R. Dunn, N. Fierer (2010)
Additional file 7
Nurten Seringeç, G. Guncu, O. Arıhan, N. Avcu, N. Dikmenoğlu (2015)
Investigation of hemorheological parameters in periodontal diseases.
Clinical hemorheology and microcirculation, 61 1
M. Conte, S. Schippa, Ileana Zamboni, M. Penta, F. Chiarini, L. Seganti, J. Osborn, P. Falconieri, O. Borrelli, S. Cucchiara (2006)
Gut-associated bacterial microbiota in paediatric patients with inflammatory bowel disease
Gut, 55
Zhenzhen Guo, Pu Wang, Zhi-hui Yi, Zhi-yin Huang, Cheng-Wei Tang (2014)
The crosstalk between gut inflammation and gastrointestinal disorders during acute pancreatitis.
Current pharmaceutical design, 20 7
L. Geurts, A. Neyrinck, N. Delzenne, C. Knauf, Patrice Cani (2014)
Gut microbiota controls adipose tissue expansion, gut barrier and glucose metabolism: novel insights into molecular targets and interventions using prebiotics.
Beneficial microbes, 5 1
Susan Power, P. O’Toole, C. Stanton, R. Ross, G. Fitzgerald (2013)
Intestinal microbiota, diet and health
British Journal of Nutrition, 111
K. Kocan, J. Fuente, E. Blouin, J. Garcia-Garcia (2004)
Anaplasma marginale (Rickettsiales: Anaplasmataceae): recent advances in defining host–pathogen adaptations of a tick-borne rickettsia
Parasitology, 129
J. Renko, P. Lepp, N. Oksala, S. Nikkari, S. Nikkari (2008)
Bacterial signatures in atherosclerotic lesions represent human commensals and pathogens.
Atherosclerosis, 201 1
N. Delzenne, Patrice Cani (2011)
Interaction between obesity and the gut microbiota: relevance in nutrition.
Annual review of nutrition, 31
Christian Rinke, P. Schwientek, A. Sczyrba, Natalia Ivanova, I. Anderson, Jan-Fang Cheng, A. Darling, S. Malfatti, B. Swan, E. Gies, J. Dodsworth, B. Hedlund, G. Tsiamis, S. Sievert, Wen-Tso Liu, J. Eisen, S. Hallam, N. Kyrpides, R. Stepanauskas, E. Rubin, P. Hugenholtz, T. Woyke (2013)
Insights into the phylogeny and coding potential of microbial dark matter
Nature, 499
G. Mandell, R. Douglas, J. Bennett (1979)
Principles and practice of infectious diseases. Vols 1 and 2.
Michael Wilson, M Weinstein (1994)
General principles in the laboratory detection of bacteremia and fungemia.
Clinics in laboratory medicine, 14 1
S. Allen (2014)
Gastrointestinal complications and cardiac surgery.
The journal of extra-corporeal technology, 46 2
P. Vajro, Giulia Paolella, A. Fasano (2013)
Microbiota and Gut–Liver Axis: Their Influences on Obesity and Obesity-Related Liver Disease
Journal of Pediatric Gastroenterology and Nutrition, 56
J. Amar, M. Serino, C. Lange, C. Chabo, J. Iacovoni, S. Mondot, P. Lepage, C. Klopp, J. Mariette, O. Bouchez, L. Perez, M. Courtney, M. Marre, P. Klopp, O. Lantieri, J. Doré, M. Charles, B. Balkau, R. Burcelin, F. Group (2011)
Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept
Diabetologia, 54
(1969)
Death in Microbes and Macrobes
A. Puddu, R. Sanguineti, F. Montecucco, G. Viviani (2014)
Evidence for the Gut Microbiota Short-Chain Fatty Acids as Key Pathophysiological Molecules Improving Diabetes
Mediators of Inflammation, 2014
(1987)
The variability and individuality of the bacterium
A. Kaprelyants, D. Kell (1993)
Dormancy in Stationary-Phase Cultures of Micrococcus luteus: Flow Cytometric Analysis of Starvation and Resuscitation
Applied and Environmental Microbiology, 59
Nabeetha Nagalingam, S. Lynch (2012)
Role of the microbiota in inflammatory bowel diseases.
Inflammatory bowel diseases, 18 5
Wenyu Lin, E. Weinberg, R. Chung (2013)
Pathogenesis of accelerated fibrosis in HIV/HCV co-infection.
The Journal of infectious diseases, 207 Suppl 1
A. Butte, Null Null (2014)
The Integrative Human Microbiome Project: Dynamic Analysis of Microbiome-Host Omics Profiles during Periods of Human Health and Disease
Cell host & microbe, 16
G. Hold, Megan Smith, C. Grange, E. Watt, E. El-Omar, I. Mukhopadhya (2014)
Role of the gut microbiota in inflammatory bowel disease pathogenesis: what have we learnt in the past 10 years?
World journal of gastroenterology, 20 5
I. Mchardy, Xiaoxiao Li, M. Tong, Paul Ruegger, Jonathan Jacobs, J. Borneman, P. Anton, J. Braun (2013)
HIV Infection is associated with compositional and functional shifts in the rectal mucosal microbiota
Microbiome, 1
P Renesto, N Crapoulet, H Ogata (2003)
Genome-based design of a cell-free culture medium for Tropheryma whipplei
Lancet, 362
B. Sharma (2007)
Infection in patients with severe burns: causes and prevention thereof.
Infectious disease clinics of North America, 21 3
M. Schulz, Ç. Atay, J. Heringer, Franziska Romrig, S. Schwitalla, B. Aydin, Paul Ziegler, J. Varga, W. Reindl, C. Pommerenke, G. Salinas-Riester, A. Böck, C. Alpert, M. Blaut, Sara Polson, L. Brandl, T. Kirchner, F. Greten, Shawn Polson, M. Arkan (2014)
High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity
Nature, 514
A. Cowman, B. Crabb (2006)
Invasion of Red Blood Cells by Malaria Parasites
Cell, 124
A. Vila-Córcoles, O. Ochoa-Gondar, T. Rodríguez-Blanco, C. Diego-Cabanes, E. Satué-Gracia, Á. Vila-Rovira, Cristina Fraga (2014)
Evaluating clinical effectiveness of pneumococcal vaccination in preventing stroke: the CAPAMIS Study, 3-year follow-up.
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 23 6
A. Ebringer, T. Rashid (2014)
Rheumatoid arthritis is caused by a Proteus urinary tract infection
APMIS, 122
S. Salipante, D. Roach, J. Kitzman, M. Snyder, B. Stackhouse, S. Butler-Wu, Choli Lee, B. Cookson, J. Shendure (2015)
Large-scale genomic sequencing of extraintestinal pathogenic Escherichia coli strains
Genome Research, 25
Tanya Yatsunenko, F. Rey, M. Manary, Indi Trehan, M. Dominguez-Bello, M. Contreras, M. Magris, G. Hidalgo, R. Baldassano, A. Anokhin, A. Heath, B. Warner, Jens Reeder, Justin Kuczynski, J. Caporaso, C. Lozupone, C. Lauber, J. Clemente, D. Knights, R. Knight, J. Gordon (2012)
Human gut microbiome viewed across age and geography
Nature, 486
K. Devine (2012)
Bacterial L‐forms on tap: an improved methodology to generate Bacillus subtilis L‐forms heralds a new era of research
Molecular Microbiology, 83
Ray Zhang, N. Lahens, Heather Ballance, M. Hughes, J. Hogenesch (2014)
A circadian gene expression atlas in mammals: Implications for biology and medicine
Proceedings of the National Academy of Sciences, 111
E. Pretorius, D. Kell (2014)
Diagnostic morphology: biophysical indicators for iron-driven inflammatory diseases.
Integrative biology : quantitative biosciences from nano to macro, 6 5
S. Salipante, D. Sengupta, C. Rosenthal, G. Costa, Jessica Spangler, Elizabeth Sims, M. Jacobs, Samuel Miller, Daniel Hoogestraat, B. Cookson, C. McCoy, Frederick IV, J. Shendure, Clarence Lee, T. Harkins, N. Hoffman (2013)
Rapid 16S rRNA Next-Generation Sequencing of Polymicrobial Clinical Samples for Diagnosis of Complex Bacterial Infections
PLoS ONE, 8
M. Ogrendik (2009)
Rheumatoid arthritis is linked to oral bacteria: etiological association
Modern Rheumatology, 19
J. Kozieł, P. Mydel, J. Potempa (2014)
The Link Between Periodontal Disease and Rheumatoid Arthritis: An Updated Review
Current Rheumatology Reports, 16
C. Flurey, M. Morris, P. Richards, R. Hughes, S. Hewlett (2013)
It’s like a juggling act: rheumatoid arthritis patient perspectives on daily life and flare while on current treatment regimes
Rheumatology (Oxford, England), 53
L. Bakken, R. Olsen (1987)
The relationship between cell size and viability of soil bacteria
Microbial Ecology, 13
C. Erridge (2008)
The roles of pathogen-associated molecular patterns in atherosclerosis.
Trends in cardiovascular medicine, 18 2
M. Macdonell, M. Hood (1982)
Isolation and Characterization of Ultramicrobacteria from a Gulf Coast Estuary
Applied and Environmental Microbiology, 43
N. Klatt, N. Funderburg, J. Brenchley (2013)
Microbial translocation, immune activation, and HIV disease.
Trends in microbiology, 21 1
P. Muñoz, A. Cruz, M. Rodrı́guez-Créixems, E. Bouza (2008)
Gram-negative bloodstream infections.
International journal of antimicrobial agents, 32 Suppl 1
E. Severance, R. Yolken, W. Eaton (2016)
Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling
Schizophrenia Research, 176
T. Abrahamsson, R. Wu, M. Jenmalm (2015)
Gut microbiota and allergy: the importance of the pregnancy period
Pediatric Research, 77
H. Lelouard, S. Henri, B. Bovis, B. Mugnier, A. Chollat-Namy, B. Malissen, S. Méresse, J. Gorvel (2010)
Pathogenic bacteria and dead cells are internalized by a unique subset of Peyer's patch dendritic cells that express lysozyme.
Gastroenterology, 138 1
B Lipinski, E Pretorius (2013)
The role of iron-induced fibrin in the pathogenesis of Alzheimer's disease and the protective role of magnesium
Front Hum Neurosci, 7
M. Weinstein (1996)
Current blood culture methods and systems: clinical concepts, technology, and interpretation of results.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 23 1
H. Minuk (2005)
Metabolic syndrome.
Journal of insurance medicine, 37 2
A. French, C. Evans, D. Agniel, Mardge Cohen, M. Peters, A. Landay, Seema Desai (2013)
Microbial translocation and liver disease progression in women coinfected with HIV and hepatitis C virus.
The Journal of infectious diseases, 208 4
V. Taneja (2014)
Arthritis susceptibility and the gut microbiome
FEBS Letters, 588
A. Proal, Paul Albert, T. Marshall (2010)
Autoimmune Disease and the Human Metagenome
Metagenomics of the Human Body
Robert Koeth, Zeneng Wang, B. Levison, J. Buffa, E. Org, Brendan Sheehy, Earl Britt, Xiaoming Fu, Yuping Wu, Lin Li, D. Jonathan, Smith, J. DiDonato, Jun Chen, Hongzhe Li, Gary Wu, James Lewis, M. Warrier, J. Brown, R. Krauss, W. Tang, D. Frederic, Bushman, A. Lusis, Stanley Hazen (2013)
Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis
Nature medicine, 19
Katrin Groebel, K. Hoelzle, M. Wittenbrink, U. Ziegler, L. Hoelzle (2008)
Mycoplasma suis Invades Porcine Erythrocytes
Infection and Immunity, 77
Sudhir Singh, C. Eldin, M. Kowalczewska, D. Raoult (2013)
Axenic culture of fastidious and intracellular bacteria.
Trends in microbiology, 21 2
J. Steingrub (2009)
International study of the prevalence and outcomes of infection in intensive care units
B. Marshall, J. Warren (1984)
UNIDENTIFIED CURVED BACILLI IN THE STOMACH OF PATIENTS WITH GASTRITIS AND PEPTIC ULCERATION
The Lancet, 323
S. Finegold, S. Dowd, V. Gontcharova, Chengxu Liu, Kathleen Henley, R. Wolcott, Eunseog Youn, P. Summanen, D. Granpeesheh, Dennis Dixon, Minghsun Liu, D. Molitoris, John Green (2010)
Pyrosequencing study of fecal microflora of autistic and control children.
Anaerobe, 16 4
K. Berer, M. Mues, Michail Koutrolos, Z. Rasbi, M. Boziki, C. Johner, H. Wekerle, G. Krishnamoorthy (2011)
Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination
Nature, 479
H.H. Nielsen, Jiaheng Qiu, S. Friis, L. Wermuth, B. Ritz (2012)
Treatment for Helicobacter pylori infection and risk of parkinson’s disease in Denmark
European Journal of Neurology, 19
Christian Leli, A. Cardaccia, M. Ferranti, A. Cesarini, F. D'Alo', C. Ferri, E. Cenci, A. Mencacci (2014)
Procalcitonin better than C-reactive protein, erythrocyte sedimentation rate, and white blood cell count in predicting DNAemia in patients with sepsis
Scandinavian Journal of Infectious Diseases, 46
Jacques Merwe, T. Prysliak, J. Perez-Casal (2010)
Invasion of Bovine Peripheral Blood Mononuclear Cells and Erythrocytes by Mycoplasma bovis
Infection and Immunity, 78
J. Duynhoven, E. Vaughan, D. Jacobs, Robèr Kemperman, E. Velzen, G. Gross, L. Roger, S. Possemiers, A. Smilde, J. Dore, J. Westerhuis, T. Wiele (2010)
Metabolic fate of polyphenols in the human superorganism
Proceedings of the National Academy of Sciences, 108
V. Giannelli, V. Gregorio, V. Iebba, M. Giusto, S. Schippa, M. Merli, U. Thalheimer (2014)
Microbiota and the gut-liver axis: bacterial translocation, inflammation and infection in cirrhosis.
World journal of gastroenterology, 20 45
Tomasz Prajsnar, Ruth Hamilton, J. García‐Lara, Gareth McVicker, Alexander Williams, M. Boots, S. Foster, S. Renshaw (2012)
A privileged intraphagocyte niche is responsible for disseminated infection of Staphylococcus aureus in a zebrafish model
Cellular Microbiology, 14
Christoph Thaiss, D. Zeevi, M. Levy, Gili Zilberman-Schapira, Jotham Suez, A. Tengeler, Lior Abramson, Meirav Katz, Tal Korem, N. Zmora, Y. Kuperman, I. Biton, S. Gilad, A. Harmelin, H. Shapiro, Z. Halpern, E. Segal, E. Elinav (2014)
Transkingdom Control of Microbiota Diurnal Oscillations Promotes Metabolic Homeostasis
Cell, 159
(2014)
Allergic disease: bacterial translocation during pregnancy
P. Scanlan, A. Buckling, Weidong Kong, Y. Wild, S. Lynch, F. Harrison (2012)
Gut dysbiosis in cystic fibrosis.
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, 11 5
(1942)
What is ‘Sterile Blood’?
Brit Med J, 2
J. Qin, Yingrui Li, Z. Cai, Shenghui Li, Jianfeng Zhu, Fan Zhang, Suisha Liang, Wenwei Zhang, Yuanlin Guan, Dongqian Shen, Yangqing Peng, Dongya Zhang, Zhuye Jie, Wenxian Wu, Youwen Qin, Wenbin Xue, Junhua Li, Lingchuan Han, Dong-hui Lu, Peixian Wu, Yali Dai, Xiaojuan Sun, Zesong Li, A. Tang, S. Zhong, Xiaoping Li, Weineng Chen, Ran Xu, Mingbang Wang, Q. Feng, Meihua Gong, Jing Yu, Yanyan Zhang, Ming Zhang, T. Hansen, G. Sanchez, J. Raes, G. Falony, Shujiro Okuda, Mathieu Almeida, Emmanuelle LeChatelier, P. Renault, N. Pons, Jean-Michel Batto, Zhaoxi Zhang, Hua Chen, Ruifu Yang, Wei-Mou Zheng, Songgang Li, Huanming Yang, Jian Wang, S. Ehrlich, R. Nielsen, O. Pedersen, O. Pedersen, K. Kristiansen, Jun Wang (2012)
A metagenome-wide association study of gut microbiota in type 2 diabetes
Nature, 490
K. Nelson (2011)
Metagenomics of the human body
R. Ross, S. Mills, C. Hill, G. Fitzgerald, C. Stanton (2010)
Specific metabolite production by gut microbiota as a basis for probiotic function.
International Dairy Journal, 20
R. Bishop, A. Musoke, S. Morzaria, M. Gardner, V. Nene (2004)
Theileria: intracellular protozoan parasites of wild and domestic ruminants transmitted by ixodid ticks
Parasitology, 129
C. Mason, G. Hamer, J. Bryers (1986)
The death and lysis of microorganisms in environmental processes
Fems Microbiology Letters, 39
K. Kogure, U. Simidu, N. Taga (1979)
A tentative direct microscopic method for counting living marine bacteria.
Canadian journal of microbiology, 25 3
Jennifer Parla, M. Kramer, W. McCombie (2011)
High-Throughput Sequencing
(1996)
Sepsis due to surgery
J. Postgate (1967)
Viability Measurements and the Survival of Microbes Under Minimum Stress
Advances in Microbial Physiology, 1
G. Weinstock (2012)
Genomic approaches to studying the human microbiota
Nature, 489
E. Severance, K. Gressitt, C. Stallings, A. Origoni, S. Khushalani, F. Leweke, Faith Dickerson, R. Yolken (2013)
Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia
Schizophrenia Research, 148
N. Balaban, J. Merrin, R. Chait, Lukasz Kowalik, S. Leibler (2004)
Bacterial Persistence as a Phenotypic Switch
Science, 305
C. Woese, G. Fox (1977)
Phylogenetic structure of the prokaryotic domain: The primary kingdoms
Proceedings of the National Academy of Sciences of the United States of America, 74
Ilseung Cho, M. Blaser (2012)
The human microbiome: at the interface of health and disease
Nature Reviews Genetics, 13
M. Rosenfeld, Lee Campbell (2011)
Pathogens and atherosclerosis: Update on the potential contribution of multiple infectious organisms to the pathogenesis of atherosclerosis
Thrombosis and Haemostasis, 106
A. Kau, Philip Ahern, Nicholas Griffin, A. Goodman, J. Gordon (2011)
Human nutrition, the gut microbiome and the immune system
Nature, 474
Z. Szallasi, J. Stelling, V. Periwal (2006)
System Modeling in Cellular Biology: From Concepts to Nuts and Bolts
(2013)
IgE-associated eczema
E. Szigethy, L. McLafferty, A. Goyal (2011)
Inflammatory bowel disease.
Pediatric clinics of North America, 58 4
M. Demoruelle, K. Deane, V. Holers (2014)
When and where does inflammation begin in rheumatoid arthritis?
Current Opinion in Rheumatology, 26
D. Kell (2008)
Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases
BMC Medical Genomics, 2
C. McMahon, S. Hopkins, A. Vail, A. King, Debi Smith, K. Illingworth, Simon Clark, N. Rothwell, P. Tyrrell (2012)
Inflammation as a predictor for delayed cerebral ischemia after aneurysmal subarachnoid haemorrhage
Journal of Neurointerventional Surgery, 5
Daphne Odjig (2009)
Rebirth of a Culture
H. Davey, D. Kell (1996)
Flow cytometry and cell sorting of heterogeneous microbial populations: the importance of single-cell analyses.
Microbiological reviews, 60 4
N. Larsen, F. Vogensen, F. Berg, D. Nielsen, A. Andreasen, B. Pedersen, W. Al-Soud, S. Sørensen, L. Hansen, M. Jakobsen (2010)
Gut Microbiota in Human Adults with Type 2 Diabetes Differs from Non-Diabetic Adults
PLoS ONE, 5
H. Gest (2008)
The Modern Myth of “Unculturable” Bacteria/ Scotoma of contemporary microbiology
E. Stewart (2012)
Growing Unculturable Bacteria
Journal of Bacteriology, 194
G. Domingue (2010)
Demystifying pleomorphic forms in persistence and expression of disease: Are they bacteria, and is peptidoglycan the solution?
Discovery medicine, 10 52
V. Bieghs, C. Trautwein (2014)
Innate immune signaling and gut-liver interactions in non-alcoholic fatty liver disease.
Hepatobiliary surgery and nutrition, 3 6
B. Williams, M. Hornig, T. Buie, M. Bauman, Myunghee Paik, Ivan Wick, Ashlee Bennett, O. Jabado, D. Hirschberg, W. Lipkin, S. Jacobson (2011)
Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances
PLoS ONE, 6
A. Walker, S. Duncan, P. Louis, H. Flint (2014)
Phylogeny, culturing, and metagenomics of the human gut microbiota.
Trends in microbiology, 22 5
A. Proal, Paul Albert, T. Marshall, Greg Blaney, Inge Lindseth (2013)
Immunostimulation in the treatment for chronic fatigue syndrome/myalgic encephalomyelitis
Immunologic Research, 56
C. Hill, R. Ross, C. Stanton, P. O’Toole (2016)
The Human Microbiome in Health and Disease
M. Shaw (2003)
Cell invasion by Theileria sporozoites.
Trends in parasitology, 19 1
Michael Dalager-Pedersen, Mette Søgaard, H. Schønheyder, Henrik Nielsen, R. Thomsen (2014)
Risk for Myocardial Infarction and Stroke After Community-Acquired Bacteremia: A 20-Year Population-Based Cohort Study
Circulation, 129
J. Fugate, J. Lyons, K. Thakur, Bryan Smith, E. Hedley‐Whyte, F. Mateen (2014)
Infectious causes of stroke.
The Lancet. Infectious diseases, 14 9
F. Porter (1942)
What is “Sterile Blood”?
British Medical Journal, 2
A. Mathias, Bruno Pais, L. Favre, J. Benyacoub, B. Corthésy (2014)
Role of secretory IgA in the mucosal sensing of commensal bacteria
Gut Microbes, 5
J. Postgate (1969)
Chapter XVIII Viable counts and Viability
Methods in Microbiology, 1
A. D’Onofrio, J. Crawford, E. Stewart, K. Witt, E. Gavrish, S. Epstein, J. Clardy, K. Lewis (2010)
Siderophores from neighboring organisms promote the growth of uncultured bacteria.
Chemistry & biology, 17 3
M. ElRakaiby, B. Dutilh, Mariam Rizkallah, A. Boleij, J. Cole, R. Aziz (2014)
Pharmacomicrobiomics: the impact of human microbiome variations on systems pharmacology and personalized therapeutics.
Omics : a journal of integrative biology, 18 7
R. Anthony, T. Brown, G. French (2000)
Rapid Diagnosis of Bacteremia by Universal Amplification of 23S Ribosomal DNA Followed by Hybridization to an Oligonucleotide Array
Journal of Clinical Microbiology, 38
Smaranda Crăciun, E. Balskus (2012)
Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme
Proceedings of the National Academy of Sciences, 109
Stephanie Amato, Mehmet Orman, M. Brynildsen (2013)
Metabolic control of persister formation in Escherichia coli.
Molecular cell, 50 4
Cheol-Young Park, H. Yoo (2004)
Inflammation and Obesity
Endocrinology and Metabolism, 19
Etienne Maisonneuve, K. Gerdes (2014)
Molecular Mechanisms Underlying Bacterial Persisters
Cell, 157
Ellrodt Ag (1986)
Sepsis and septic shock.
Emergency medicine clinics of North America, 4 4
Y. Aboelatta, A. Abd-Elsalam, A. Omar, M. Abdelaal, A. Farid (2013)
Selective digestive decontamination (SDD) as a tool in the management of bacterial translocation following major burns.
Annals of burns and fire disasters, 26 4
S. Joyce, John Macsharry, P. Casey, M. Kinsella, E. Murphy, F. Shanahan, C. Hill, C. Gahan (2014)
Regulation of host weight gain and lipid metabolism by bacterial bile acid modification in the gut
Proceedings of the National Academy of Sciences, 111
(2003)
2014) and available (D’Onofrio et al. 2010), probably behaving in a social manner (Kell
Tao Ding, P. Schloss (2014)
Dynamics and associations of microbial community types across the human body
Nature, 509
I. Puspita, Moe Uehara, Taiki Katayama, Y. Kikuchi, W. Kitagawa, Y. Kamagata, Kozo Asano, C. Nakatsu, Michiko Tanaka (2012)
Resuscitation Promoting Factor (Rpf) from Tomitella biformata AHU 1821T Promotes Growth and Resuscitates Non-Dividing Cells
Microbes and Environments, 28
S. Radajewski, P. Ineson, N. Parekh, J. Murrell (2000)
Stable-isotope probing as a tool in microbial ecology
Nature, 403
Brian Bennett, Thomas Vallim, Zeneng Wang, D. Shih, Yonghong Meng, J. Gregory, H. Allayee, Richard Lee, M. Graham, R. Crooke, P. Edwards, S. Hazen, A. Lusis (2013)
Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation.
Cell metabolism, 17 1
GE Flores, JG Caporaso, JB Henley (2014)
Temporal variability is a personalized feature of the human microbiome
Genome Biol, 15
J. Caporaso, C. Lauber, E. Costello, Donna berg-Lyons, Antonio Gonzalez, Jesse Stombaugh, D. Knights, P. Gajer, J. Ravel, N. Fierer, N. Fierer, J. Gordon, Rob Knight, Rob Knight (2011)
Moving pictures of the human microbiome
Genome Biology, 12
Karin Kraft (2010)
[Type-2 diabetes].
MMW Fortschritte der Medizin, 152 13
H. Emsley, P. Tyrrell (2002)
Inflammation and Infection in Clinical Stroke
Journal of Cerebral Blood Flow & Metabolism, 22
H. Faras, Nahed Ateeqi, L. Tidmarsh (2010)
Autism spectrum disorders
Annals of Saudi Medicine, 30
J. Amar, C. Lange, Gaëlle Payros, C. Garret, C. Chabo, O. Lantieri, M. Courtney, M. Marre, M. Charles, B. Balkau, R. Burcelin (2013)
Blood Microbiota Dysbiosis Is Associated with the Onset of Cardiovascular Events in a Large General Population: The D.E.S.I.R. Study
PLoS ONE, 8
S. Dedysh (2011)
Cultivating Uncultured Bacteria from Northern Wetlands: Knowledge Gained and Remaining Gaps
Frontiers in Microbiology, 2
Bobbi Xayarath, N. Freitag (2012)
Optimizing the balance between host and environmental survival skills: lessons learned from Listeria monocytogenes.
Future microbiology, 7 7
D. Kell, E. Pretorius (2014)
Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells.
Metallomics : integrated biometal science, 6 4
Simone Eicher, C. Dehio (2012)
Bartonella entry mechanisms into mammalian host cells
Cellular Microbiology, 14
D. Perazzo, J. Brigante (1955)
[Systemic lupus erythematosus].
Prensa medica argentina, 42 13
P. Sacchi, S. Cima, M. Corbella, G. Comolli, A. Chiesa, F. Baldanti, C. Klersy, S. Novati, Patrizia Mulatto, M. Mariconti, C. Bazzocchi, M. Puoti, L. Pagani, G. Filice, R. Bruno (2015)
Liver fibrosis, microbial translocation and immune activation markers in HIV and HCV infections and in HIV/HCV co-infection.
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, 47 3
Ivan Vujkovic-Cvijin, R. Dunham, S. Iwai, M. Maher, Rebecca Albright, M. Broadhurst, Ryan Hernandez, M. Lederman, Yong Huang, M. Somsouk, S. Deeks, P. Hunt, S. Lynch, J. McCune (2013)
Dysbiosis of the Gut Microbiota Is Associated with HIV Disease Progression and Tryptophan Catabolism
Science Translational Medicine, 5
Iris Keren, Devang Shah, A. Spoering, N. Kaldalu, K. Lewis (2004)
Specialized Persister Cells and the Mechanism of Multidrug Tolerance in Escherichia coli
Journal of Bacteriology, 186
J. Patterson (2012)
The Commensal Microbiota
K. Lewis (2010)
Persister cells.
Annual review of microbiology, 64
(2014)
Sánchez-Calvo et al
F. Harrison, A. Buckling (2009)
Cooperative production of siderophores by Pseudomonas aeruginosa.
Frontiers in bioscience, 14
S. Kishino, M. Takeuchi, Si‐Bum Park, A. Hirata, N. Kitamura, J. Kunisawa, H. Kiyono, R. Iwamoto, Yosuke Isobe, M. Arita, H. Arai, K. Ueda, J. Shima, Satomi Takahashi, K. Yokozeki, S. Shimizu, J. Ogawa (2013)
Polyunsaturated fatty acid saturation by gut lactic acid bacteria affecting host lipid composition
Proceedings of the National Academy of Sciences, 110
W. Wikoff, A. Anfora, Jun Liu, P. Schultz, S. Lesley, E. Peters, G. Siuzdak (2009)
Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites
Proceedings of the National Academy of Sciences, 106
J. Syrjänen, V. Valtonen, M. Iivanainen, M. Kaste, J. Huttunen (1988)
Preceding infection as an important risk factor for ischaemic brain infarction in young and middle aged patients
British Medical Journal (Clinical research ed.), 296
Dominica Nichols, N. Cahoon, E. Trakhtenberg, Ly Pham, A. Mehta, A. Bélanger, T. Kanigan, K. Lewis, S. Epstein (2010)
Use of Ichip for High-Throughput In Situ Cultivation of “Uncultivable” Microbial Species
Applied and Environmental Microbiology, 76
Beatrice Claudi, Petra Sproete, A. Chirkova, Nicolas Personnic, Janine Zankl, Nura Schürmann, A. Schmidt, D. Bumann (2014)
Phenotypic Variation of Salmonella in Host Tissues Delays Eradication by Antimicrobial Chemotherapy
Cell, 158
S. Mariotti, M. Pardini, M. Gagliardi, R. Teloni, F. Giannoni, M. Fraziano, F. Lozupone, S. Meschini, R. Nisini (2013)
Dormant Mycobacterium tuberculosis Fails To Block Phagosome Maturation and Shows Unexpected Capacity To Stimulate Specific Human T Lymphocytes
The Journal of Immunology, 191
S. Epstein (2013)
The phenomenon of microbial uncultivability.
Current opinion in microbiology, 16 5
J. Clegg (2001)
Cryptobiosis--a peculiar state of biological organization.
Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology, 128 4
A. Everard, S. Matamoros, L. Geurts, N. Delzenne, Patrice Cani (2014)
Saccharomyces boulardii Administration Changes Gut Microbiota and Reduces Hepatic Steatosis, Low-Grade Inflammation, and Fat Mass in Obese and Type 2 Diabetic db/db Mice
mBio, 5
I. Kimura, K. Ozawa, D. Inoue, Takeshi Imamura, K. Kimura, Takeshi Maeda, Kazuya Terasawa, Daiji Kashihara, Kanako Hirano, T. Tani, Tomoyuki Takahashi, Satoshi Miyauchi, G. Shioi, H. Inoue, G. Tsujimoto (2013)
The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43
Nature Communications, 4
L. Marín, E. Miguélez, C. Villar, F. Lombó (2015)
Bioavailability of Dietary Polyphenols and Gut Microbiota Metabolism: Antimicrobial Properties
BioMed Research International, 2015
W. Bergen (2015)
Small-intestinal or colonic microbiota as a potential amino acid source in animals
Amino Acids, 47
T. Votyakova, A. Kaprelyants, D. Kell (1994)
Influence of Viable Cells on the Resuscitation of Dormant Cells in Micrococcus luteus Cultures Held in an Extended Stationary Phase: the Population Effect
Applied and Environmental Microbiology, 60
B. Schnabl, D. Brenner (2014)
Interactions between the intestinal microbiome and liver diseases.
Gastroenterology, 146 6
Sonntag Cb (2000)
HIV/AIDS infection.
Journal of The Canadian Dental Association, 66
E. Kozarov, D. Sweier, C. Shelburne, A. Progulske-Fox, D. Lopatin (2006)
Detection of bacterial DNA in atheromatous plaques by quantitative PCR.
Microbes and infection, 8 3
(1999)
Intercellular signalling and the multiplication of prokaryotes: bacterial cytokines
H. Anders, Kirstin Andersen, B. Stecher (2013)
The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease.
Kidney international, 83 6
R. Tojo, Adolfo Suárez, M. Clemente, C. Reyes-Gavilán, A. Margolles, M. Gueimonde, P. Ruas-Madiedo (2014)
Intestinal microbiota in health and disease: role of bifidobacteria in gut homeostasis.
World journal of gastroenterology, 20 41
P. Ding, Lijian Jin (2014)
The role of lipopolysaccharide-binding protein in innate immunity: a revisit and its relevance to oral/periodontal health.
Journal of periodontal research, 49 1
P. Gérard (2013)
Metabolism of Cholesterol and Bile Acids by the Gut Microbiota
Pathogens, 3
Yair Neuman (2006)
Cryptobiosis: a new theoretical perspective.
Progress in biophysics and molecular biology, 92 2
S. Salter, M. Cox, E. Turek, S. Calus, W. Cookson, M. Moffatt, P. Turner, J. Parkhill, N. Loman, A. Walker (2014)
Reagent and laboratory contamination can critically impact sequence-based microbiome analyses
BMC Biology, 12
M. Goffau, S. Fuentes, B. Bogert, H. Honkanen, W. Vos, G. Welling, H. Hyöty, H. Harmsen (2014)
Aberrant gut microbiota composition at the onset of type 1 diabetes in young children
Diabetologia, 57
F. Scheperjans, V. Aho, P. Pereira, K. Koskinen, L. Paulin, E. Pekkonen, E. Haapaniemi, S. Kaakkola, J. Eerola‐Rautio, M. Pohja, E. Kinnunen, K. Murros, P. Auvinen (2015)
Gut microbiota are related to Parkinson's disease and clinical phenotype
Movement Disorders, 30
H. Emsley, Craig Smith, C. Gavin, R. Georgiou, A. Vail, E. Barberan, J. Hallenbeck, G. Zoppo, N. Rothwell, P. Tyrrell, S. Hopkins (2003)
An early and sustained peripheral inflammatory response in acute ischaemic stroke: relationships with infection and atherosclerosis
Journal of Neuroimmunology, 139
Ying Zhang, W. Yew, M. Barer (2012)
Targeting Persisters for Tuberculosis Control
Antimicrobial Agents and Chemotherapy, 56
M. Hill (1997)
Intestinal flora and endogenous vitamin synthesis
European Journal of Cancer Prevention, 6
Dargaze Kibru, B. Gelaw, Agersew Alemu, Zelalem Addis (2014)
Helicobacter pyloriinfection and its association with anemia among adult dyspeptic patients attending Butajira Hospital, Ethiopia
BMC Infectious Diseases, 14
M. Faure, C. Mettraux, D. Moennoz, J. Godin, J. Vuichoud, F. Rochat, D. Breuillé, C. Obled, I. Corthésy-theulaz (2006)
Specific amino acids increase mucin synthesis and microbiota in dextran sulfate sodium-treated rats.
The Journal of nutrition, 136 6
J. Sánchez-Calvo, M. Garcia-Castillo, A. Lamas, M. Rodríguez-Baños, L. Máiz, L. Suárez, F. Baquero, R. Cantón, R. Campo (2008)
Gut microbiota composition in cystic fibrosis patients: molecular approach and classical culture
Journal of Cystic Fibrosis, 7
P. Turnbaugh, R. Ley, M. Mahowald, V. Magrini, E. Mardis, J. Gordon (2006)
An obesity-associated gut microbiome with increased capacity for energy harvest
Nature, 444
D. Kell, G. Mukamolova, Christopher Finan, Hongjuan Zhao, R. Goodacre, A. Kaprelyants, M. Young (2004)
Resuscitation of “Uncultured” Microorganisms
C. Ronco (2014)
Endotoxin Removal: History of a Mission
Blood Purification, 37
O. Vaarala (2013)
Human Intestinal Microbiota and Type 1 Diabetes
Current Diabetes Reports, 13
(2014)
Arrows in each micrograph
M. Ogrendik (2013)
Antibiotics for the treatment of rheumatoid arthritis
International Journal of General Medicine, 7
J. Bravo, P. Forsythe, Marianne Chew, Emily Escaravage, H. Savignac, T. Dinan, J. Bienenstock, J. Cryan (2011)
Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve
Proceedings of the National Academy of Sciences, 108
Vasudevan Dinakaran, A. Rathinavel, M. Pushpanathan, Ramamoorthy Sivakumar, P. Gunasekaran, J. Rajendhran (2014)
Elevated Levels of Circulating DNA in Cardiovascular Disease Patients: Metagenomic Profiling of Microbiome in the Circulation
PLoS ONE, 9
Dae-Wook Kang, Jin Park, Z. Ilhan, G. Wallstrom, J. LaBaer, J. Adams, R. Krajmalnik-Brown (2013)
Reduced Incidence of Prevotella and Other Fermenters in Intestinal Microflora of Autistic Children
PLoS ONE, 8
M. Ogrendik (2013)
Rheumatoid arthritis is an autoimmune disease caused by periodontal pathogens
International Journal of General Medicine, 6
(2013)
Short-chain fatty acids (SCFAs
R. Mercier, Y. Kawai, J. Errington (2014)
General principles for the formation and proliferation of a wall-free (L-form) state in bacteria
eLife, 3
V. Soina, L. Lysak, I. Konova, E. Lapygina, D. Zvyagintsev (2012)
Study of ultramicrobacteria (Nanoforms) in soils and subsoil deposits by electron microscopy
Eurasian Soil Science, 45
O. Koren, D. Knights, Antonio Gonzalez, L. Waldron, N. Segata, R. Knight, C. Huttenhower, R. Ley (2013)
A Guide to Enterotypes across the Human Body: Meta-Analysis of Microbial Community Structures in Human Microbiome Datasets
PLoS Computational Biology, 9
S. Karri, V. Acosta‐Martínez, Gopal Coimbatore (2010)
Effect of dihydrotestosterone on gastrointestinal tract of male Alzheimer's disease transgenic mice.
Indian journal of experimental biology, 48 5
Y. Kamagata, H. Tamaki (2005)
Cultivation of Uncultured Fastidious Microbes
Microbes and Environments, 20
A. Balakrishnan, S. Marathe, M. Joglekar, D. Chakravortty (2013)
Bactericidal/permeability increasing protein: A multifaceted protein with functions beyond LPS neutralization
Innate Immunity, 19
R. Wiest, G. Garcia‐Tsao (2005)
Bacterial translocation (BT) in cirrhosis
Hepatology, 41
N. Sandler, D. Douek (2012)
Microbial translocation in HIV infection: causes, consequences and treatment opportunities
Nature Reviews Microbiology, 10
H. Eilers, J. Pernthaler, F. Glöckner, R. Amann (2000)
Culturability and In Situ Abundance of Pelagic Bacteria from the North Sea
Applied and Environmental Microbiology, 66
S. Devaraj, P. Hemarajata, J. Versalovic (2013)
The human gut microbiome and body metabolism: implications for obesity and diabetes.
Clinical chemistry, 59 4
E. Allen-Vercoe (2013)
Bringing the gut microbiota into focus through microbial culture: recent progress and future perspective.
Current opinion in microbiology, 16 5
A. Kaprelyants, G. Mukamolova, D. Kell (1994)
Estimation of dormant Micrococcus luteus cells by penicillin lysis and by resuscitation in cell-free spent culture medium at high dilution
Fems Microbiology Letters, 115
R. Lasken, J. McLean (2014)
Recent advances in genomic DNA sequencing of microbial species from single cells
Nature Reviews Genetics, 15
N. Kyrpides, P. Hugenholtz, J. Eisen, T. Woyke, M. Göker, C. Parker, R. Amann, B. Beck, P. Chain, J. Chun, R. Colwell, A. Danchin, P. Dawyndt, T. Dedeurwaerdere, E. Delong, J. Detter, P. Vos, T. Donohue, Xiuzhu Dong, D. Ehrlich, C. Fraser, R. Gibbs, J. Gilbert, P. Gilna, F. Glöckner, J. Jansson, J. Keasling, R. Knight, D. Labeda, A. Lapidus, Jung-Sook Lee, Wenjun Li, Juncai Ma, V. Markowitz, E. Moore, M. Morrison, Folker Meyer, K. Nelson, M. Ohkuma, C. Ouzounis, N. Pace, J. Parkhill, N. Qin, R. Rosselló-Móra, J. Sikorski, David Smith, M. Sogin, Rick Stevens, U. Stingl, Ken-ichiro Suzuki, D. Taylor, J. Tiedje, B. Tindall, M. Wagner, G. Weinstock, J. Weissenbach, O. White, Jun Wang, Lixin Zhang, Yuguang Zhou, D. Field, W. Whitman, G. Garrity, H. Klenk (2014)
Genomic Encyclopedia of Bacteria and Archaea: Sequencing a Myriad of Type Strains
PLoS Biology, 12
A. Fernández-Cruz, M. Marín, M. Kestler, L. Alcalá, M. Rodrı́guez-Créixems, E. Bouza (2013)
The Value of Combining Blood Culture and SeptiFast Data for Predicting Complicated Bloodstream Infections Caused by Gram-Positive Bacteria or Candida Species
Journal of Clinical Microbiology, 51
Atsushi Saito, '. Rolfe, P. Edelstein, S. Finegold (1981)
Comparison of liquid growth media for Legionella pneumophila
Journal of Clinical Microbiology, 14
S. Epstein, Jianhui Zhu, Amir Najafi, M. Burnett (2009)
Insights Into the Role of Infection in Atherogenesis and in Plaque Rupture
Circulation, 119
M. Arrieta, L. Bistritz, J. Meddings (2006)
ALTERATIONS IN INTESTINAL
F. Wallet, C. Loïez, Stéphanie Herwegh, R. Courcol (2011)
Usefulness of real-time PCR for the diagnosis of sepsis in ICU-acquired infections.
Infectious disorders drug targets, 11 4
G. Mukamolova, S. Kormer, D. Kell, A. Kaprelyants (1999)
Stimulation of the multiplication of Micrococcus luteus by an autocrine growth factor
Archives of Microbiology, 172
(2002)
Cultivating the uncultured
Proceedings of the National Academy of Sciences of the United States of America, 99
B. Stevenson, S. Eichorst, John Wertz, T. Schmidt, J. Breznak (2004)
New Strategies for Cultivation and Detection of Previously Uncultured Microbes
Applied and Environmental Microbiology, 70
R. McLaughlin, H. Vali, P. Lau, R. Palfree, A. Ciccio, M. Sirois, Darakhshan Ahmad, R. Villemur, M. Desrosiers, E. Chan (2002)
Are There Naturally Occurring Pleomorphic Bacteria in the Blood of Healthy Humans?
Journal of Clinical Microbiology, 40
EJ Allan, C Hoischen, J Gumpert (2009)
Bacterial L-forms
Adv Appl Microbiol, 68
Elsa Germain, Daniel Castro-Roa, N. Zenkin, K. Gerdes (2013)
Molecular mechanism of bacterial persistence by HipA.
Molecular cell, 52 2
Indun Puspita, Yoichi Kamagata, Michiko Tanaka, Kozo Asano, C. Nakatsu (2012)
Are Uncultivated Bacteria Really Uncultivable ?
(2009b)
Rheumatoid arthritis is linked to oral bacteria: etiological association
Mod Rheumatol, 19
M. Clark, M Jepson (2003)
Intestinal M cells and their role in bacterial infection.
International journal of medical microbiology : IJMM, 293 1
K. Maslowski, A. Vieira, Aylwin Ng, J. Kranich, F. Sierro, Di Yu, H. Schilter, M. Rolph, F. Mackay, D. Artis, R. Xavier, M. Teixeira, C. Mackay (2009)
Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43
Nature, 461
Shintaro Sato, H. Kiyono, K. Fujihashi (2014)
Mucosal Immunosenescence in the Gastrointestinal Tract: A Mini-Review
Gerontology, 61
Trevor Glaros, S. Chang, Elizabeth Gilliam, Urmila Maitra, H. Deng, Liwu Li (2013)
Causes and consequences of low grade endotoxemia and inflammatory diseases.
Frontiers in bioscience, 5
V. Duda, N. Suzina, V. Polivtseva, A. Boronin (2012)
Ultramicrobacteria: Formation of the concept and contribution of ultramicrobacteria to biology
Microbiology, 81
F. Cardona, C. Andrés-Lacueva, S. Tulipani, F. Tinahones, M. Queipo-Ortuño (2013)
Benefits of polyphenols on gut microbiota and implications in human health.
The Journal of nutritional biochemistry, 24 8
J. Mylotte, A. Tayara (2000)
Blood Cultures: Clinical Aspects and Controversies
European Journal of Clinical Microbiology and Infectious Diseases, 19
Ramadass Balamurugan, R. Mary, Sucharita Chittaranjan, Hepsiba Jancy, R. Devi, B. Ramakrishna (2010)
Low levels of faecal lactobacilli in women with iron-deficiency anaemia in south India
British Journal of Nutrition, 104
J. Scher, S. Abramson (2011)
The microbiome and rheumatoid arthritis
Nature Reviews Rheumatology, 7
Gwen Duytschaever, G. Huys, Maarten Bekaert, L. Boulanger, K. Boeck, P. Vandamme (2013)
Dysbiosis of bifidobacteria and Clostridium cluster XIVa in the cystic fibrosis fecal microbiota.
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, 12 3
R. Wiest, Heiko Rath (2003)
Bacterial translocation in the gut
Best Practice & Research in Clinical Gastroenterology, 17
G. Rogler, G. Rosano (2014)
The heart and the gut.
European heart journal, 35 7
(2015)
Microbiology. Persisters unmasked
Science, 347
A. Koch (1971)
The adaptive responses of Escherichia coli to a feast and famine existence.
Advances in microbial physiology, 6
TR Abrahamsson, HE Jakobsson, AF Andersson (2014)
Low gut microbiota diversity in early infancy precedes asthma at school age
Clin Exp Allergy, 44
A. Gombart (1960)
Immunity and Disease
Scottish Medical Journal, 5
M. Klotz (2000)
HIV/AIDS infection.
Journal, 66 3
L. Ling, T. Schneider, Aaron Peoples, A. Spoering, I. Engels, Brian Conlon, A. Mueller, T. Schäberle, D. Hughes, S. Epstein, Michael Jones, L. Lazarides, Victoria Steadman, Douglas Cohen, Cintia Felix, K. Fetterman, W. Millett, Anthony Nitti, Ashley Zullo, Chao Chen, K. Lewis (2015)
A new antibiotic kills pathogens without detectable resistance
Nature, 517
Husen Zhang, X. Liao, Joshua Sparks, Xin Luo (2014)
Dynamics of Gut Microbiota in Autoimmune Lupus
Applied and Environmental Microbiology, 80
A. Oláh, L. Romics (2014)
Enteral nutrition in acute pancreatitis: a review of the current evidence.
World journal of gastroenterology, 20 43
S. Vartoukian, R. Palmer, W. Wade (2010)
Strategies for culture of 'unculturable' bacteria.
FEMS microbiology letters, 309 1
Stephen Epstein, Y. Zhou, Jianhui Zhu (1999)
Infection and atherosclerosis: emerging mechanistic paradigms.
Circulation, 100 4
M. Zimmermann, C. Chassard, F. Rohner, E. N'Goran, C. Nindjin, A. Dostal, J. Utzinger, H. Ghattas, C. Lacroix, R. Hurrell (2010)
The effects of iron fortification on the gut microbiota in African children: a randomized controlled trial in Cote d'Ivoire.
The American journal of clinical nutrition, 92 6
Jorge Ramírez, Jorge Ramírez, Beatriz Parra, Sonia Gutierrez, R. Arce, Adriana Jaramillo, Y. Ariza, Adolfo Contreras (2014)
Biomarkers of cardiovascular disease are increased in untreated chronic periodontitis: a case control study.
Australian dental journal, 59 1
M. Keller, K. Zengler (2004)
Tapping into microbial diversity
Nature Reviews Microbiology, 2
Hong-Di Ma, Yin-Hu Wang, Christopher Chang, M. Gershwin, Zhe‐Xiong Lian (2015)
The intestinal microbiota and microenvironment in liver.
Autoimmunity reviews, 14 3
K. Gerdes, Etienne Maisonneuve (2012)
Bacterial persistence and toxin-antitoxin loci.
Annual review of microbiology, 66
Genta Kakiyama, W. Pandak, P. Gillevet, P. Hylemon, D. Heuman, Kalyani Daita, H. Takei, Akina Muto, H. Nittono, Jason Ridlon, Melanie White, Nicole Noble, Pamela Monteith, M. Fuchs, L. Thacker, M. Sikaroodi, J. Bajaj (2013)
Modulation of the fecal bile acid profile by gut microbiota in cirrhosis.
Journal of hepatology, 58 5
Zeneng Wang, Elizabeth Klipfell, Brian Bennett, Robert Koeth, B. Levison, Brandon Dugar, Ariel Feldstein, Earl Britt, Xiaoming Fu, Yoon-Mi Chung, Yuping Wu, P. Schauer, Jonathan Smith, H. Allayee, W. Tang, J. DiDonato, A. Lusis, Stanley Hazen (2011)
Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease
Nature, 472
I. Martínez, G. Wallace, Chaomei Zhang, Ryan Legge, A. Benson, T. Carr, E. Moriyama, J. Walter (2009)
Diet-Induced Metabolic Improvements in a Hamster Model of Hypercholesterolemia Are Strongly Linked to Alterations of the Gut Microbiota
Applied and Environmental Microbiology, 75
J. Bester, A. Buys, B. Lipinski, D. Kell, E. Pretorius (2013)
High ferritin levels have major effects on the morphology of erythrocytes in Alzheimer's disease
Frontiers in Aging Neuroscience, 5
J. Sheedy, R. Wettenhall, D. Scanlon, P. Gooley, Donald Lewis, N. McGregor, D. Stapleton, H. Butt, K. Meirleir (2009)
Increased d-lactic Acid intestinal bacteria in patients with chronic fatigue syndrome.
In vivo, 23 4
H. Primas (1981)
Chemistry, Quantum Mechanics and Reductionism
J. Feeley, G. Gorman, R. Weaver, D. Mackel, H. Smith (1978)
Primary isolation media for Legionnaires disease bacterium
Journal of Clinical Microbiology, 8
R. Burcelin, M. Serino, C. Chabo, L. Garidou, Céline Pomié, M. Courtney, J. Amar, A. Bouloumié (2013)
Metagenome and metabolism: the tissue microbiota hypothesis
Diabetes, 15
S. Fukuda, K. Hase, H. Ohno (2011)
Application of a mouse ligated Peyer’s patch intestinal loop assay to evaluate bacterial uptake by M cells.
Journal of visualized experiments : JoVE, 58
T. Narihiro, Y. Kamagata (2013)
Cultivating Yet-to-be Cultivated Microbes: The Challenge Continues
Microbes and Environments, 28
G. Malaguarnera, M. Giordano, G. Nunnari, G. Bertino, M. Malaguarnera (2014)
Gut microbiota in alcoholic liver disease: pathogenetic role and therapeutic perspectives.
World journal of gastroenterology, 20 44
S. Dowd, Yan Sun, P. Secor, D. Rhoads, B. Wolcott, G. James, R. Wolcott (2008)
Survey of bacterial diversity in chronic wounds using Pyrosequencing, DGGE, and full ribosome shotgun sequencing
BMC Microbiology, 8
S. Kernéis, A. Bogdanova, J. Kraehenbuhl, E. Pringault (1997)
Conversion by Peyer's patch lymphocytes of human enterocytes into M cells that transport bacteria.
Science, 277 5328
Marie-Alice Vitry, Delphine Mambres, Michaël Deghelt, K. Hack, Arnaud Machelart, F. Lhommé, J. Vanderwinden, M. Vermeersch, C. Trez, D. Perez-Morga, J. Letesson, E. Muraille (2014)
Brucella melitensis Invades Murine Erythrocytes during Infection
Infection and Immunity, 82
M. Maiwald, D. Relman (2001)
Whipple's disease and Tropheryma whippelii: secrets slowly revealed.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 32 3
D. Jun, Kyung Kim, O. Lee, J. Chae, B. Son, Seong Kim, Y. Jo, Young Park (2010)
Association Between Small Intestinal Bacterial Overgrowth and Peripheral Bacterial DNA in Cirrhotic Patients
Digestive Diseases and Sciences, 55
S. Corr, C. Gahan, C. Hill (2008)
M-cells: origin, morphology and role in mucosal immunity and microbial pathogenesis.
FEMS immunology and medical microbiology, 52 1
G. Mukamolova, A. Kaprelyants, D. Young, M. Young, D. Kell (1998)
A bacterial cytokine.
Proceedings of the National Academy of Sciences of the United States of America, 95 15
R. Pattman, M. Snow, P. Handy, K. Sankar, B. Elawad (2005)
Hepatitis C virus (HCV) infection
Sherry Coleman, M. Minnick (2001)
Establishing a Direct Role for the Bartonella bacilliformis Invasion-Associated Locus B (IalB) Protein in Human Erythrocyte Parasitism
Infection and Immunity, 69
Peng Chen, B. Schnabl (2014)
Host-Microbiome Interactions in Alcoholic Liver Disease
Gut and Liver, 8
J. Heitman (2000)
Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases
Mycopathologia, 149
S. Varani, M. Stanzani, M. Paolucci, F. Melchionda, G. Castellani, L. Nardi, M. Landini, M. Baccarani, A. Pession, V. Sambri (2009)
Diagnosis of bloodstream infections in immunocompromised patients by real-time PCR.
The Journal of infection, 58 5
R. Lasken (2012)
Genomic sequencing of uncultured microorganisms from single cells
Nature Reviews Microbiology, 10
J. Rolain, M. Maurin, M. Mallet, D. Parzy, D. Raoult (2003)
Culture and Antibiotic Susceptibility of Bartonella quintana in Human Erythrocytes
Antimicrobial Agents and Chemotherapy, 47
A. Balagopal, Frances Philp, J. Astemborski, T. Block, A. Mehta, R. Long, G. Kirk, S. Mehta, A. Cox, David Thomas, S. Ray (2008)
Human immunodeficiency virus-related microbial translocation and progression of hepatitis C.
Gastroenterology, 135 1
S. O'Mahony, G. Clarke, Y. Borre, T. Dinan, J. Cryan (2015)
Serotonin, tryptophan metabolism and the brain-gut-microbiome axis
Behavioural Brain Research, 277
X. Morgan, C. Huttenhower (2014)
Meta'omic analytic techniques for studying the intestinal microbiome.
Gastroenterology, 146 6
B. Lanter, K. Sauer, D. Davies (2014)
Bacteria Present in Carotid Arterial Plaques Are Found as Biofilm Deposits Which May Contribute to Enhanced Risk of Plaque Rupture
mBio, 5
Patrice Cani, M. Osto, L. Geurts, A. Everard (2012)
Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity
Gut Microbes, 3
(2014)
Neurotransmitters Serotonin, melatonin
A. Mifkovič, J. Škultéty, D. Pindak, J. Pechán (2009)
Specific aspects of acute pancreatitis.
Bratislavske lekarske listy, 110 9
Kirsty Brown, Daniella DeCoffe, Erin Molcan, D. Gibson (2012)
Diet-Induced Dysbiosis of the Intestinal Microbiota and the Effects on Immunity and Disease
Nutrients, 4
W. Fricke, D. Rasko (2013)
Bacterial genome sequencing in the clinic: bioinformatic challenges and solutions
Nature Reviews Genetics, 15
(2014)
Symptomatic atherosclerosis/stroke
M. Clifton, Colin Corrent, R. Strong (2009)
Siderocalins: siderophore-binding proteins of the innate immune system
BioMetals, 22
M. Kinoshita, K. Takeda (2014)
Microbial and dietary factors modulating intestinal regulatory T cell homeostasis
FEBS Letters, 588
W. Tang, Zeneng Wang, B. Levison, Robert Koeth, Earl Britt, Xiaoming Fu, Yuping Wu, S. Hazen (2013)
Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk.
The New England journal of medicine, 368 17
J. Casadesús (2007)
Bacterial L‐forms require peptidoglycan synthesis for cell division
BioEssays, 29
H. Emsley, S. Hopkins (2008)
Acute ischaemic stroke and infection: recent and emerging concepts
The Lancet Neurology, 7
Y. Sanz, Á. Moya-Pérez (2014)
Microbiota, inflammation and obesity.
Advances in experimental medicine and biology, 817
M. Trøseid, I. Manner, K. Pedersen, Judith Haissman, D. Kvale, S. Nielsen (2014)
Microbial translocation and cardiometabolic risk factors in HIV infection.
AIDS research and human retroviruses, 30 6
P Seksik, L Rigottier-Gois, G Gramet (2003)
Alterations of the dominant faecal bacterial groups in patients with Crohn's disease of the colon
Gut, 52
E. Deitch (2012)
Gut-origin sepsis: evolution of a concept.
The surgeon : journal of the Royal Colleges of Surgeons of Edinburgh and Ireland, 10 6
F. Neidhardt, J. Ingraham (1987)
Escherichia Coli and Salmonella: Typhimurium Cellular and Molecular Biology
ScienceDirect (1993)
FEMS microbiology reviews
F. Tomás-Barberán, R. García-Villalba, A. Quartieri, S. Raimondi, Alberto Amaretti, Alan Leonardi, M. Rossi (2014)
In vitro transformation of chlorogenic acid by human gut microbiota.
Molecular nutrition & food research, 58 5
D. Festi, R. Schiumerini, L. Eusebi, G. Marasco, Martina Taddia, A. Colecchia (2014)
Gut microbiota and metabolic syndrome.
World journal of gastroenterology, 20 43
P. Calcott, T. Calvert (1981)
Characterization of 3': 5' -cyclic AMP phosphodiesterase in Klebsiella aerogenes and its role in substrate-accelerated death.
Journal of general microbiology, 122 2
J. Schroeter, I. Wilkemeyer, Reinhold Schiller, A. Pruß (2012)
Validation of the Microbiological Testing of Tissue Preparations Using the BACTECTM Blood Culture System
Transfusion Medicine and Hemotherapy, 39
G. Mukamolova, O. Turapov, D. Young, A. Kaprelyants, D. Kell, M. Young (2002)
A family of autocrine growth factors in Mycobacterium tuberculosis
Molecular Microbiology, 46
W. Eisenreich, T. Dandekar, J. Heesemann, W. Goebel (2010)
Carbon metabolism of intracellular bacterial pathogens and possible links to virulence
Nature Reviews Microbiology, 8
M. Angelis, M. Piccolo, L. Vannini, S. Siragusa, Andrea Giacomo, Diana Serrazzanetti, F. Cristofori, M. Guerzoni, M. Gobbetti, R. Francavilla (2013)
Fecal Microbiota and Metabolome of Children with Autism and Pervasive Developmental Disorder Not Otherwise Specified
PLoS ONE, 8
Tomohiro Tanaka, K. Kawasaki, Serina Daimon, W. Kitagawa, Kyosuke Yamamoto, H. Tamaki, Michiko Tanaka, C. Nakatsu, Y. Kamagata (2014)
A Hidden Pitfall in the Preparation of Agar Media Undermines Microorganism Cultivability
Applied and Environmental Microbiology, 80
R. Isberg (1991)
Discrimination between intracellular uptake and surface adhesion of bacterial pathogens.
Science, 252 5008
A. Mifkovič, J. Škultéty, P. Sýkora, A. Prochotský, R. Okoličány (2013)
Intra-abdominal hypertension and acute pancreatitis.
Bratislavske lekarske listy, 114 3
R. Wiest, H. Rath (2003)
Gastrointestinal disorders of the critically ill. Bacterial translocation in the gut.
Best practice & research. Clinical gastroenterology, 17 3
J. Leslie, V. Young (2015)
The rest of the story: the microbiome and gastrointestinal infections.
Current opinion in microbiology, 23
S. Steinberg (2003)
Bacterial translocation: what it is and what it is not.
American journal of surgery, 186 3
M. Alam, Q. Alam, M. Kamal, Adel Abuzenadah, A. Haque (2014)
A possible link of gut microbiota alteration in type 2 diabetes and Alzheimer's disease pathogenicity: an update.
CNS & neurological disorders drug targets, 13 3
P. Gaibani, M. Mariconti, G. Bua, S. Bonora, D. Sassera, M. Landini, Patrizia Mulatto, S. Novati, C. Bandi, V. Sambri (2013)
Development of a Broad-Range 23S rDNA Real-Time PCR Assay for the Detection and Quantification of Pathogenic Bacteria in Human Whole Blood and Plasma Specimens
BioMed Research International, 2013
D. Macintire, T. Bellhorn (2002)
Bacterial translocation: clinical implications and prevention.
The Veterinary clinics of North America. Small animal practice, 32 5
N. Sahin, J. Gonzalez, T. Iizuka, J. Hill (2010)
Characterization of two aerobic ultramicrobacteria isolated from urban soil and a description of Oxalicibacterium solurbis sp. nov.
FEMS microbiology letters, 307 1
M. Blaser (2014)
The microbiome revolution.
The Journal of clinical investigation, 124 10
T. Eleftheriadis, Liakopoulos, K. Leivaditis, G. Antoniadi, I. Stefanidis (2011)
Infections in hemodialysis: a concise review - Part 1: bacteremia and respiratory infections.
Hippokratia, 15 1
A. Dostal, C. Chassard, F. Hilty, M. Zimmermann, Tanja Jaeggi, S. Rossi, C. Lacroix (2012)
Iron depletion and repletion with ferrous sulfate or electrolytic iron modifies the composition and metabolic activity of the gut microbiota in rats.
The Journal of nutrition, 142 2
D. Young, J. Stark, D. Kirschner (2008)
Systems biology of persistent infection: tuberculosis as a case study
Nature Reviews Microbiology, 6
J. Adams, L. Johansen, L. Powell, D. Quig, R. Rubin (2011)
Gastrointestinal flora and gastrointestinal status in children with autism -- comparisons to typical children and correlation with autism severity
BMC Gastroenterology, 11
P. Hugenholtz (2002)
Exploring prokaryotic diversity in the genomic era
Genome Biology, 3
J. Ochoa-Repáraz, D. Mielcarz, Lauren Ditrio, A. Burroughs, D. Foureau, Sakhina Haque-Begum, L. Kasper (2009)
Role of Gut Commensal Microflora in the Development of Experimental Autoimmune Encephalomyelitis1
The Journal of Immunology, 183
A. McDermott, G. Huffnagle (2014)
The microbiome and regulation of mucosal immunity
Immunology, 142
B. Marshall (2006)
Helicobacter Connections
ChemMedChem, 1
B Kwiatkowska, M Maślińska (2012)
Macrolide therapy in chronic inflammatory diseases
Mediat Inflamm, 2012
P. Yarza, C. Spröer, J. Swiderski, N. Mrotzek, S. Spring, B. Tindall, S. Gronow, R. Pukall, H. Klenk, E. Lang, S. Verbarg, Audra Crouch, T. Lilburn, B. Beck, Christel Unosson, Sofia Cardew, E. Moore, M. Gomila, Y. Nakagawa, D. Janssens, P. Vos, Jindrich Peiren, Timo Suttels, D. Clermont, C. Bizet, M. Sakamoto, T. Iida, T. Kudo, Y. Kosako, Yumi Oshida, M. Ohkuma, David Arahal, E. Spieck, Andreas Roeser, M. Figge, D. Park, P. Buchanan, A. Cifuentes, Raúl Muñoz, J. Euzéby, K. Schleifer, W. Ludwig, R. Amann, F. Glöckner, R. Rosselló-Móra (2013)
Sequencing orphan species initiative (SOS): Filling the gaps in the 16S rRNA gene sequence database for all species with validly published names.
Systematic and applied microbiology, 36 1
F. Martin, M. Dumas, Yulan Wang, C. Legido-Quigley, I. Yap, Huiru Tang, S. Zirah, G. Murphy, O. Cloarec, J. Lindon, N. Sprenger, L. Fay, S. Kochhar, P. Bladeren, E. Holmes, J. Nicholson (2007)
A top-down systems biology view of microbiome-mammalian metabolic interactions in a mouse model
Molecular Systems Biology, 3
H. Emsley, Á. Chamorro (2010)
Stroke bugs: current and emerging concepts relevant to infection in cerebrovascular disease.
Infectious disorders drug targets, 10 2

Publisher: Oxford University Press
Copyright: Copyright © 2022 Federation of European Microbiological Societies
ISSN: 0168-6445
eISSN: 1574-6976
DOI: 10.1093/femsre/fuv013
pmid: 25940667
Publisher site: See Article on Publisher Site

Abstract

Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 FEMS Microbiology Reviews, fuv013, 39, 2015, 567–591 doi: 10.1093/femsre/fuv013 Advance Access Publication Date: 4 May 2015 Review Article REVIEW ARTICLE The dormant blood microbiome in chronic, inflammatory diseases 1 1 2,∗ 1 Marnie Potgieter , Janette Bester ,DouglasB.Kell and Etheresia Pretorius Department of Physiology, Faculty of Health Sciences, University of Pretoria, Arcadia 0007, South Africa and School of Chemistry and The Manchester Institute of Biotechnology, The University of Manchester, 131, Princess St, Manchester M1 7DN, Lancs, UK Corresponding author: School of Chemistry and The Manchester Institute of Biotechnology, The University of Manchester, 131, Princess St, Manchester M1 7DN, Lancs, UK. Tel: (+44)161 306 4492; E-mail: dbk@manchester.ac.uk One sentence summary: Atopobiosis of microbes (the term describing microbes that appear in places other than where they should be), as well as the products of their metabolism, seems to correlate with, and may contribute to, the dynamics of a variety of inflammatory diseases. Editor: Prof. Antoine Danchin ABSTRACT Blood in healthy organisms is seen as a ‘sterile’ environment: it lacks proliferating microbes. Dormant or not-immediately-culturable forms are not absent, however, as intracellular dormancy is well established. We highlight here that a great many pathogens can survive in blood and inside erythrocytes. ‘Non-culturability’, reflected by discrepancies between plate counts and total counts, is commonplace in environmental microbiology. It is overcome by improved culturing methods, and we asked how common this would be in blood. A number of recent, sequence-based and ultramicroscopic studies have uncovered an authentic blood microbiome in a number of non-communicable diseases. The chief origin of these microbes is the gut microbiome (especially when it shifts composition to a pathogenic state, known as ‘dysbiosis’). Another source is microbes translocated from the oral cavity. ‘Dysbiosis’ is also used to describe translocation of cells into blood or other tissues. To avoid ambiguity, we here use the term ‘atopobiosis’ for microbes that appear in places other than their normal location. Atopobiosis may contribute to the dynamics of a variety of inflammatory diseases. Overall, it seems that many more chronic, non-communicable, inflammatory diseases may have a microbial component than are presently considered, and may be treatable using bactericidal antibiotics or vaccines. Keywords: ‘sterile’ blood microbiome; culturability; dormancy; dysbiosis; atopobiosis; Parkinson’s disease; Alzheimer disease INTRODUCTION (Marshall and Warren 1984) being a particularly well-known ex- ample. There have also been hints for a microbial component to ‘Overall, it seems inevitable that the availability of these meth- many other non-communicable diseases, but culturing the rele- ods will cause the catalog of disease states recognized as having vant organisms has rarely been successful. However, there is in- a microbial contribution to their etiology to expand enormously creasing recognition that microbes may be present in forms that in the short term, particularly as improved methods for resusci- are not easily culturable, and a number of recent articles have tation of small cell numbers are found’ (Davey and Kell 1996). brought these possibilities more sharply into focus. Our aim is to Over the years, a variety of diseases that were previously con- review these developments. The manuscript structure is shown sidered non-communicable have been found to have a micro- in Fig. 1. bial component, the role of Helicobacter pylori in ulcerogenesis Received: 26 January 2015; Accepted: 2 March 2015 FEMS 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 567 Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 568 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 Figure 1. An overview figure summarizing the contents of this manuscript. Table 1. Operational definitions of viable, non-viable and dormant A note on terminology: viable, culturable, dormant and microbes. These are the three terms we consider best suited to de- sterile scribe the macroscopic physiological states of microbes as regards their ability to replicate. We note that the terms ‘not immediately In this field, much confusion has arisen historically because of culturable’ (NIC) and ‘active but not culturable’ (ABNC) can also have a failure to recognize that most microbes reproduce by binary some utility (Kell et al. 1998), while dormant cells are sometimes fission and that this reproduction must be a minimal property referred to as ‘persisters’. Other variants of ‘dormancy’ that have or hallmark of a microbial cell that possesses ‘life’ or is ‘alive’ been used include ‘anabiosis’ (Keilin 1959) and ‘cryptobiosis’ (e.g. (Proal, Albert and Marshall 2011). Thus, as with Schroding ¨ er’s cat Clegg 2001;Neuman 2006); all these terms imply a reversible state between the appearance of being living and non-living in differ- (e.g. Primas 1981; Gribbin 1985), we cannot say that an individ- ent circumstances. This definition of dormancy also likely includes ual microbial cell ‘is’ alive, only (if true) that it ‘was’ alive, since cells that may operationally be ‘injured’, and possibly wall-less L- it will by then have become two cells. This implies that being forms (Domingue and Woody 1997; Mattman 2001; Allan, Hoischen alive is not best treated as though it were an innate property of a and Gumpert 2009;Dom´ınguez-Cuevas et al. 2012; Errington 2013; cell, but the definition must be operational, and include both the Mercier, Kawai and Errington 2013, 2014) provided they are or may cell and the ‘environment’ (experiment) used to detect the status become culturable. ‘Sterile’ refers to an absence of operationally vi- able organisms as defined in this table. a posteriori (Kell et al. 1998). Thus, as with Postgate (e.g. Postgate 1967, 1969, 1976), we equate viability with culturability, and stress that culturability— Term Properties the ability to reproduce—is to be determined operationally. Other methods that do not determine culturability are not tests Viable Capable of observable replication, i.e. of viability per se, but merely measure what they measure (e.g. culturable, by any stated means. the content of a chemical such as ATP, membrane permeability Non-viable Incapable of observable replication by any to a dye, enzymatic activity, macromolecular sequences and so stated means normally capable of effecting on). In addition, it is impossible in principle to (cor)relate macro- replication in the relevant organism. scopic measurements of a culture with the ability of individual Dormant Not viable in the sense of not being more or cells to divide (Kell et al. 1991; Davey and Kell 1996). In other less immediately culturable, but may be words, if the macroscopic ATP content of say a starving culture returned to a state of viability or culturability were to decrease by 50%, we would not know if all of the cells by preincubation under suitable conditions. had lost half their ATP or half of the cells had lost all of their ATP (or anything in between). The culturability of the former would likely be 50% and of the latter 100%, despite the same macro- scopic ATP content. scathing about the term ‘unculturable’ (Gest 2008), noting that A lack of culturability may mean that a cell is non-viable one just needs to try harder to culture organisms. Table 1 shows under the circumstances tested, but viability or non-viability the three terms best suited to discuss these issues, while Fig. 2 are not the only two possible states here. An apparent non- shows a diagrammatic representation of the macroscopic phys- culturability of a surviving cell also admits another possibility, iological microbial states we mostly consider. for which the natural term is ‘dormant’ (Kaprelyants, Gottschal The assessment of replication potential (culturability) of in- and Kell 1993;Epstein 2013). This is that the cell is not presently dividual cells may be done microscopically (e.g. by microscopic culturable (viable), but it is not ‘dead’ (in the sense of an oper- counts) or macroscopically (e.g. via colony formation on an agar ationally irreversible loss of viability) in that it may be induced plate or through the ‘most probable number’ technique). The to return to a state of culturability (by a process or processes latter has the advantage of potentially assessing dormancy in typically referred to as ‘resuscitation’). This also means that the the absence of any contaminating culturable cells that might term ‘viable-but-non-culturable’, while quite common in use, is proliferate during the assay (Kaprelyants, Mukamolova and Kell in fact an oxymoron that is to be discouraged (Kell et al. 1998). 1994; Votyakova, Kaprelyants and Kell 1994;Kell et al. 1998). For The eminent microbial physiologist Howard Gest is similarly assessing culturability (=viability), we do not therefore include Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 569 Figure 2. A diagrammatic representation of the major macroscopic physiological states of microbes and their interrelationships. other strategies in which cells do not actually divide, such as the diseased humans and from 7% of supposedly healthy humans, so-called direct viable count of Kogure, Simidu and Taga (1979). when RBCs were lysed (Domingue and Schlegel 1977). A year Thus, we here highlight the point that the possibility of micro- later, corynebacteria-like microorganisms developing in hemo- bial dormancy means that a system that appears to be devoid cultures were shown within RBCs (Tedeschi et al. 1978), and in of culturable microbes may still contain dormant cells or forms 2001 it was found that even ‘healthy’ blood specimens can con- that may become culturable. tain bacterial 16S ribosomal DNA (Nikkari et al. 2001). Domingue and Woody (1997) and Domingue (2010) summarizes much of this earlier literature. L-forms are bacterial variants that lack The ‘sterile’ blood microbiome brought into question some or all of a cell wall. Nonetheless they can divide, especially in osmotically stabilized media, by processes that variously in- The circulation is a closed system and the blood in healthy or- volve membrane blebbing, tubulation, vesiculation and fission ganisms was first believed to be a sterile environment (Drennan (Allan, Hoischen and Gumpert 2009; Errington 2013; Mercier, 1942; Proal, Albert and Marshall 2014). This definition is used Kawai and Errington 2014). While it remains unclear whether in the most usual sense of an absence of culturable microbes, what was seen in these earlier studies (Domingue and Woody since blood can of course provide a suitable growth medium 1997; Domingue 2010) may have been L-forms (Mattman 2001), for microbes (as in blood culture; Wilson and Weinstein 1994; that could in time revert to normal bacteria under the correct Weinstein 1996; Schroeter et al. 2012; cf. Valencia-Shelton and conditions (Casadesus ´ 2007), L-forms are becoming a topic of Loeffelholz 2014), and any bacteraemia or sepsis, even at 1– −1 considerable current research (Devine 2012;Dom´ınguez-Cuevas 10 cells mL (Murray 2015), is potentially life-threatening (e.g. et al. 2012; Mercier, Kawai and Errington 2013, 2014). Vincent et al. 2009; Eleftheriadis et al. 2011; Havey, Fowler and The presence of a blood bacterial microbiome has also been Daneman 2011; Montassier et al. 2013). However, the principle associated with a variety of infectious, as well as non-infectious of the presence of truly sterile blood in healthy humans has disease states (Huang et al. 2006; Thwaites and Gant 2011; been challenged, as operationally it does not mean that dormant Nielsen et al. 2012; Prajsnar et al. 2012;Wang et al. 2012a; Ki- or non-culturable forms of organisms are absent (Kaprelyants, bru et al. 2014;Sato et al. 2014). It is, for example, known that Gottschal and Kell 1993;Kell et al. 1998; McLaughlin et al. 2002) H. pylori can exist not only in the gastric mucosa but also in (see Table 1). Nearly 50 years ago, the existence of a novel bacte- peripheral blood, where it could cause bacteremia (Huang et al. riological system was noted in 71% of blood samples taken from Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 570 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 2006), and could contribute to Parkinson’s disease (PD) or related (II) A second argument is that the morphological type of organ- pathologies that precede motor symptoms (Nielsen et al. 2012). ism (e.g. coccus versus bacillus) seems to be characteristic Helicobacter pylori was also previously implicated in the develop- of particular diseases. ment of anemia (Wang et al. 2012b; Kibru et al. 2014). Staphylo- (III) A third argument is that in many cases (see below) relevant coccus aureus can also use neutrophils as ‘Trojan horses’ to dis- organisms lurk intracellularly, which is hard to explain by seminate infection (Thwaites and Gant 2011; Prajsnar et al. 2012), contamination. while many other pathogens, such as Listeria monocytogenes (Xa- (IV) A fourth argument is that there are just too many diseases yarath and Freitag 2012), Salmonella typhimurium (Eisenreich et al. where bacteria have been found to play a role in the patho- 2010; Claudi et al. 2014; Holden 2015)and Yersinia pestis (Isberg genesis, that all of them may be caused by contamination. 1991), are well known to persist intracellularly; Gest (2008)gives (V) Finally, the actual numbers of cells involved seem far too other historical examples. The same is true for viruses, which great to be explicable by contamination; given that blood 9 −1 are not discussed here. contains more than 10 erythrocytes mL , if there was The presence of an aberrant blood microbiota (as assessed by just one bacterial cell per 100 000 erythrocytes (see below 4 −1 sequencing) has been implicated in type II diabetes and cardio- and Amar et al. 2011), this will equate to 10 bacteria mL . vascular disease (Amar et al. 2011, 2013;Sato et al. 2014). There These are not small numbers. is also growing evidence that periodontal disease and gingivi- It is important to point out that molecular methods have been tis are closely linked to cardiovascular disease (Yang et al. 2013; used frequently to detect active sepsis. These selfsame meth- Ram´ırez et al. 2014). Oral bacterial translocation into the blood ods are also used in environmental biology (as we pointed has been implicated in the development of periodontal disease- out in this review), without undue concern about the poten- induced endocarditis and myocardial and/or cerebral infarction, tial for contamination. Contamination will always be a concern, especially in patients with heart valve dysfunction (Koren et al. of course, as noted by Nikkari et al. (2001), but many papers 2011; Amar and Engelke 2014;Seringec et al. 2014). since 2001 have documented strategies for detecting prokaryotic We will argue in the next sections that the existence of poten- DNA in blood and serum using appropriate and careful controls tially viable (but possibly non-proliferating) pleomorphic bac- (Anthony et al. 2000; Mylotte and Tayara 2000;Jiang et al. 2009; teria in the blood of healthy humans (McLaughlin et al. 2002) Varani et al. 2009;Mancini et al. 2010; Chang et al. 2011; Grif et al. may therefore be of some significance in pathology. If such a 2012a;Fernandez-Cruz ´ et al. 2013;Gaibani et al. 2013). Also, de- microbiome can disrupt homeostasis, it can ultimately play a tecting bacteria in blood cultures during sepsis is considered the fundamental role in disease development and progression. It standard diagnostic tool for blood stream infections (Munoz ˜ et al. has therefore been proposed that the blood microbiota might 2008; Varani et al. 2009), and some laboratories consider that e.g. therefore represent or contribute to the first step in the kinetics PCR testing should always be a complement for the traditional of atherosclerosis (Sato et al. 2014), cardiovascular disease and blood culture test (Grif et al. 2012b). type II diabetes (Amar et al. 2011), and therefore ultimately serve as biomarkers for cardiovascular disease risk (Amar et al. 2013). Theroleofdormancy However, in the quest to use the blood microbiota as biomarkers, the question of detectability and cultivability are key concepts. Dormancy in microbiology is of course well known, even for non- In particular, the existence of a blood microbiome is only sporulating bacteria, and has been defined as a stable but re- really meaningful and of scientific interest if it represents an versible nonreplicating state (Mariotti et al. 2013; see also Table 1 undisturbed state, and is not, for instance, an artefact caused and Kaprelyants, Gottschal and Kell 1993;Kell et al. 1998, 2003). by the external introduction of microbes through human in- The importance of dormant or non-cultured (as opposed to ‘non- tervention, reagent contamination (Schroeter et al. 2012;Salter culturable’) organisms has long been recognized in environmen- et al. 2014) and so forth. We therefore rehearse the evidence tal microbiology (e.g. Mason, Hamer and Bryers 1986; Amann, that while such artefacts are certainly possible, and must be Ludwig and Schleifer 1995; Eilers et al. 2000; Hugenholtz 2002; excluded rigorously, the phenomenon of a human blood micro- Keller and Zengler 2004; Pham and Kim 2012;Epstein 2013), be- biome cannot be dismissed as such an artefact in toto. cause of the 100-fold or greater difference between microscopi- cally observable cells and those capable of forming a colony on Evidence that these observations are not due to an agar plate (‘the great plate count anomaly’, see below). contamination Of the four main possibilities, what we do not know in gen- eral is whether the ‘missing’ cells While contamination from reagents (e.g. Schroeter et al. 2012; Salter et al. 2014), or simply poor sterile technique with nee- (i) are incapable of growth on the enrichment/isolation media, dles and so on, can lead to an artefactual appearance of a blood (ii) are killed by the enrichment/isolation media (e.g. Tanaka microbiome, we consider that the following arguments, taken et al. 2014), together, exclude the thought that the entire (and consider- (iii) have lost viability irreversibly (i.e. are operationally dead) or able) literature on a blood microbiome can be explained via (iv) are in a dormant or not-immediately-culturable state from contamination. which we might resuscitate them (to effect culturability) if only we knew how. The fact that typical isolation media and incubation conditions (I) The first argument is that there are significant differences do not admit the measurable growth of all strains is certainly between the blood microbiomes of individuals harboring well known (indeed it is the basis for selective isolation media!), disease states and nominally healthy controls, despite the and it took a good while to learn how to culture pathogens such fact that samples are treated identically (see later). Some as H. pylori (Marshall and Warren 1984; Marshall 2006), Legionella similar arguments apply to the assessment of drug trans- pneumophila (Feeley et al. 1978;Saito et al. 1981;Meyer 1983), porters under different conditions (Kell and Oliver 2014). Tropheryma whipplei (Maiwald and Relman 2001;Maiwald et al. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 571 2003; Renesto et al. 2003) and so on (Singh et al. 2013). The major- The development of sequence-based methods for microbes ity of bacteria that persist in a ‘non-culturable’ form in wounds (and especially non-eukaryotes) owes much to the pioneering (e.g. Dowd et al. 2008;Percival et al. 2012), or in diseases such work of Carl Woese and colleagues, who recognized the util- as cystic fibrosis (Lewis 2010) or tuberculosis (Young, Stark and ity of small subunit ribosomal RNA (based on both its essen- Kirschner 2008; Zhang, Yew and Barer 2012), and even simply tiality and the small but significant sequence variations) and in conventional cultures of Escherichia coli (e.g. Koch 1987;Bal- applied it with great effect in molecular phylogenetics (Woese aban et al. 2004; Keren et al. 2004a,b; Gerdes and Maisonneuve and Fox 1977; Woese, Kandler and Wheelis 1990). Notwithstand- 2012; Amato, Orman and Brynildsen 2013; Germain et al. 2013; ing modern reinterpretations of the taxonomic details derived Maisonneuve, Castro-Camargo and Gerdes 2013; Maisonneuve therefrom (e.g. Williams et al. 2013), there can be little doubt and Gerdes 2014; Holden 2015), where phenotypic culture dif- that this work drew the attention of microbiologists to the po- ferentiation is well established (Koch 1971), are also ‘normally tential of sequence-based methods for detecting microbes that culturable’ by established means. Thus, the existence of oper- were then invisible to methods based solely on culture, e.g. in ationally ‘non-culturable’ forms of only moderately fastidious clinical microbiology (Didelot et al. 2012; Loman et al. 2012;Proal bacteria is very well established, and more and more bacteria et al. 2013; Fricke and Rasko 2014). rRNA remains a widely used previously thought ‘unculturable’ are being brought into culture strategy for detecting specific microbes. This has of course led to (e.g. Zengler et al. 2002; Keller and Zengler 2004; Stevenson et al. metagenomics, the large-scale sequencing of macromolecules 2004; Gich et al. 2005; Kamagata and Tamaki 2005; D’Onofrio et al. and indeed (statistically) entire genomes from complex (non- 2010; Nichols et al. 2010; Vartoukian, Palmer and Wade 2010; axenic) environments, increasing the requirement for a full set Dedysh 2011; Pham and Kim 2012; Puspita et al. 2012, 2013; Stew- of complete reference sequences (Kyrpides et al. 2014) and not art 2012; Allen-Vercoe 2013; Narihiro and Kamagata 2013;Singh just those of 16S rRNA (Yarza et al. 2013). Even the coupling of et al. 2013;Walker et al. 2014;Lagier et al. 2015a,b;Ling et al. 2015). sequences to activities has now become possible (e.g. Radajew- In environmental microbiology, some bacteria pass through ski et al. 2000;Wang et al. 2012c). the usual 0.2 μm filters, and have been referred to as ‘ultrami- crobacteria’ (Macdonell and Hood 1982; Morita 1997). It was pro- Microbiome analyses: latest technologies employed posed (Kaprelyants, Gottschal and Kell 1993) that rather than More recently, gut metagenomics has been systematized with being small (starved) forms of normal bacteria they were more likely to be normal forms of small bacteria, and this seems to NIH’s Human Microbiome project (HMP) and the European MetaHIT project aiming to deciphering the structure and func- have been accepted (Lysak et al. 2010;Sahin et al. 2010; Duda et al. tion of the human gut microbiota (Fredricks 2013; Robles-Alonso 2012;Soina et al. 2012). and Guarner 2014). The HMP has developed a reference collec- The ability to culture certain kinds of soil bacteria by prein- tion of 16S ribosomal RNA gene sequences collected from sites cubation in weak broth is also well established (e.g. Bakken and across the human body (Koren et al. 2013; Ding and Schloss 2014). Olsen 1987; Kaprelyants, Gottschal and Kell 1993), and our own This information can be used to associate changes in the micro- experiments showed very high levels of resuscitability of dor- biome with changes in health, and particularly also the blood mant cells of Micrococcus luteus (e.g. Kaprelyants and Kell 1993; microbiome. The Integrative Human Microbiome Project (iHMP, Kaprelyants, Mukamolova and Kell 1994; Kaprelyants et al. 1996, http://hmp2.org), the second phase of the NIH HMP, aims to 1999;Kell et al. 1998, 2003; Mukamolova et al. 1998a,b, 1999, study the interactions by analyzing microbiome and host ac- 2002a,b). In a similar way, substrate-accelerated death of non- or slowly growing microorganisms has been known for decades tivities in longitudinal studies of disease-specific cohorts and by creating integrated data sets of microbiome and host func- (Postgate 1967; Calcott and Postgate 1972; Calcott and Calvert 1981). tional properties (The Integrative HMP (iHMP) Research Network Consortium 2014), ultimately allowing us to analyze host and Thus, any of several well-established mechanisms may con- microbial DNA (genome) and RNA (transcriptome) sequences tribute to the (often) large differences observable between mi- (Morgan and Huttenhower 2014). However, in the HMP study, croscopic counts and the number of operationally culturable the main anatomic sites where samples are collected are skin, microbes, with the greatest likelihood being that we simply mouth, nose, colon and vagina (ElRakaiby et al. 2014). So far as we have to develop more and better methods to bring these strains are aware, these projects do not focus on the blood microbiome back into culture, i.e. to resuscitate them. In particular, however, (which is probably unsurprising when most commentators as- this ‘great plate count anomaly’ has, of course, been brought sume that it does not exist). into much sharper focus because of the advent of culture- independent, sequence-based means for detecting and (to a cer- The gut microbiome is by far the largest numerically, and our purpose here is not to review it in any detail, since this has been tain extent) enumerating microbes (though not, of course, of as- sessing their culturability). done very well in terms of Sequence-based methods for detecting (i) its constitution (Lozupone et al. 2012;Weinstock 2012), non-proliferating microbes (ii) temporal variation (Caporaso et al. 2011;Flores et al. 2014; Thaiss et al. 2014), The vast majority of microbial species remain uncultivated and, (iii) changes associated with diet (Muegge et al. 2011), until recently, about half of all known bacterial phyla were iden- (iv) obesity (Turnbaugh et al. 2006, 2009), tified only from their 16S ribosomal RNA gene sequence (Lasken (v) age and geography (Delzenne and Cani 2011; Delzenne and McLean 2014). Also, single-cell genomics is a powerful tool et al. 2011; Yatsunenko et al. 2012), for accessing genetic information from uncultivated microor- (vi) inflammation (Cani et al. 2008, 2012), ganisms (Lasken 2012;Rinke et al. 2013;Cavanagh et al. 2014; (vii) the immune system (Kau et al. 2011; McDermott and Huff- Clingenpeel et al. 2014). Bacterial single-cell genome sequenc- nagle 2014) ing and bioinformatics are, however, challenging (Pallen, Loman (viii) and various pathologies (Pflughoeft and Versalovic 2012; and Penn 2010;Didelot et al. 2012; Loman et al. 2012;Frickeand Schulz et al. 2014). Rasko 2014). Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 572 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 It was implied that a better understanding of microbiome- inflammation leading to tissue injury, organ failure, etc. (Stein- encoded pathways for xenobiotic metabolism might also have berg 2003; Wiest and Rath 2003;Balzan et al. 2007). We stress implications for improving the efficacy of pharmacologic inter- that they may be found in both infectious and non-infectious ventions with neuromodulatory agents (Gonzalez et al. 2011), diseases as well as being translocated during surgery, and and that the exploration of microbiome and metagenome might that atopobiosis of bacteria originating in the oral cavity, e.g. give us insightful new perspectives regarding human genet- in periodontal disease, may also be significant in rheumatoid ics and how the microbiota contribute to immunity, as well as arthritis, for instance (see below). Fig. 3 provides a schematic to metabolic and inflammatory diseases (Cho and Blaser 2012; representation of dysbiosis, bacterial translocation and Blaser et al. 2013; Blaser 2014; Leslie and Young 2015). This atopobiosis. is because it is assumed in such studies that it is the small- molecule products of the gut microbiome that can appear in How do gut bacteria escape into blood? the human serum metabolome, and thus influence the rest of If the gut microbiome is seen as the main source of the blood the human body (e.g. Wikoff et al. 2009; Holmes et al. 2011; microbiome, it is necessary to establish which kinds of condi- Le Chatelier et al. 2013, and see Table 2). Here we also need tions might permit this in the absence of real physical damage to mention lipopolysaccharide (LPS), a main constituent of the (as may, for instance, be caused by surgery) leading to micro- Gram-negative outer membrane that induces the production of bial translocation. Wiest, Lawson and Geuking (2014) mention cytokines and/or chemokines, which in turn regulate inflamma- three possible points of entrance for bacteria into the surround- tory and innate and subsequent adaptive immune responses ing (sterile) tissue: (Glaros et al. 2013;Rhee 2014; Ronco 2014). The release of LPS may therefore change gut homeostasis, may play a role in e.g. (i) by dendritic cells via processes between epithelial cells, not inflammatory bowel disease and necrotizing enterocolitis (Rhee 2014), and may certainly act as an acute phase protein in sepsis affecting tight junction function, (ii) via injured/inflamed epithelium with dysfunctional epithe- (Ding and Jin 2014). By contrast, our theme here is that it is additionally the mi- lial barrier, crobes themselves that can pass from the gut (and other ‘exter- (iii) and via M cells overlying Peyer’s patches as specialized cells providing access of microbial products to antigen- nal’ surfaces) into the human body, a phenomenon sometimes known as ‘dysbiosis’, albeit this term is more commonly used presenting cells. with another meaning. We here need to discriminate a changed (pathologic) microbiota in the place of origin from the results of a We discuss bacterial translocation in this context in the fol- translocation of microbiota to other areas of the body. In the fol- lowing sections. lowing sections, we use the term dysbiosis to describe changes in a microbiome in its main origin (typically the gut), and we The role of M cells and Peyer’s patches in gut microbial coin the term ‘atopobiosis’ to describe microbes that appear in translocation and atopobiosis places other than where they should be. While the gut epithelium represents the largest mucosal tissue, the mechanisms underlying the interaction between the micro- The origin of detectable but non-proliferating microbes biome and the epithelial cells remain poorly understood (Math- appears to be mainly via ‘atopobiosis’ of the gut ias et al. 2014). Although this is a vast and complex field that microbiome warrants a review of its own, we briefly argue that gut dysbio- Dysbiosis, also known as dysbacteriosis, particularly referring to sis results in an atypical interaction of both the microbiota, as microbial imbalance in the digestive tract, has been widely dis- well as their secretory products, with the gut epithelial layer. cussed (e.g. Scher and Abramson 2011;Scanlan et al. 2012; Amar This results in an altered barrier function, which may also lead et al. 2013; Bested, Logan and Selhub 2013; Duytschaever et al. to changed mucosal immunity and ultimately to atopobiosis. 2013; Vaarala 2013). Core to this literature is the idea that factors The gut epithelium is necessarily normally quite impermeable that lead to significant changes in the gut microbiota composi- to microbes, but there is increasing evidence that direct chem- tion (dysbiosis) ultimately result in pathology (Larsen et al. 2010; ical communication between the microbiota and the epithelial Amar et al. 2011, 2013; Bested, Logan and Selhub 2013; Burcelin cells regulates mucosal integrity (Venkatesh et al. 2014). A pos- et al. 2013; De Angelis et al. 2013; Fremont et al. 2013; Lanter, Sauer sible point of entry is by direct cellular uptake, and there is and Davies 2014; Petriz et al. 2014;Power et al. 2014; Tojo et al. one type of cell that can take up microbes, and these are the 2014). Table 3 gives a list of diseases, largely inflammatory dis- M cells overlaying the Peyer’s patches (Kerneis ´ et al. 1997;Jep- eases, which have been associated with gut dysbiosis. son and Clark 1998; Clark and Jepson 2003; Corr, Gahan and In addition, we argue here that as well as gut dysbiosis, a Hill 2008; Lelouard et al. 2010; Fukuda, Hase and Ohno 2011). derangement of the gut microbiome, what we are seeing here, Peyer’s patches are seen as the ‘immune sensors’ of the gut ep- often called ‘translocation’ in the context of surgery (Swank ithelium. Considerable evidence exists that they provide a pri- and Deitch 1996;MacFie 2004) and various diseases (Berg 1995) mary route for the limited translocation of microbes between (see Table 4 that lists diseases and conditions where bacterial the gut epithelium and the blood system (Jung, Hugot and Bar- translocation is specifically implicated), is what might better be reau 2010). These interactions with the cells of the gut may called atopobiosis (Greek ατ ¨ oπoς or atopos, in the wrong place), suggest that changes in the intestinal microbiota also influ- i.e. an appearance of members of the gut (or other) microbiome ence mucosal immunity (Sato, Kiyono and Fujihashi et al. 2014). in the wrong place. Bacterial translocation is therefore discussed This is indeed the case, and gut dysbiosis has been shown to in the context of the movement of gut origin microbes [that play a significant role in the development of autoimmune dis- changed from normal (dysbiosis)] that moved across the ‘intact’ eases, in particular inflammatory bowel diseases (Clemente et al. gastrointestinal tract into normally sterile tissues, including 2012; Morgan et al. 2012; Hold et al. 2014; Kostic, Xavier and blood, where the organisms may then directly cause infection or Gevers 2014;Owyangand Wu 2014;Ma et al. 2015). It was also Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 573 Table 2. Some examples of small molecule gut metabolites whose secretion has been implicated in various disease states. Role in health and Metabolite Intermediates/products Synthesis disease References Amino acids The gut microbiota is not itself an important source Faure et al. (2006); Devaraj, of amino acids during periods of adequate protein Hemarajata and Versalovic intake. Some commensal members produce biolog- (2013); Bergen (2014) ically active components from amino acids. Amino acid supplementation in a mouse model of ulcerative colitis has been shown to promote overall growth of commensal microbiota. The effect was considered to be mediated via the stimulatory effect on mucin pro- duction by amino acid supplementation. Benzoates Benzoic acid, hippurate, Gut microbiota in mice with active colitis displayed Rechner et al. (2002); 2-hydroxyhippurate enrichment for genes involved in benzoate degrada- Aronov et al. (2011); De tion. Hippurate derives from plant food polyphenols Preter and Verbeke (2013); and is a conjugate of benzoic acid with glycine. In Rooks et al. (2014) humans a large portion of hippurate is believed to be derived from precursors absorbed in the small in- testines. It is reliably decreased in IBD. Bile acids Bile acids are synthesized from cholesterol in the Martin et al. (2007); Bennett liver and further metabolized into secondary bile et al. (2013); Ger ´ ard (2013); acids by the gut microbiota. The amino acid sides Kakiyama et al. (2013); chain of glyco- and tauro-conjugated bile acids are Mart´ınez et al. (2013); Sayin cleaved by bacterial bile salt hydrolase (BSH) enzyme et al. (2013); Joyce et al. to yield unconjugated bile acids (cholic and chen- (2014) odeoxycholic acids). These products will then be fur- ther modified by gut bacteria to produce secondary bile acids. A decrease in this conversion is positively correlated with liver cirrhosis. Bile acids can mod- ulate the composition of the microbiota in the gut, where they function as signaling molecules and may constitute a mechanism of quorum sensing. In turn, the microbiota strongly affect bile acid metabolism by promoting deconjugation, dehydrogenation and dehydroxylation. It can also inhibit bile acid synthe- sis in the liver by alleviation of farnesoid X receptor inhibition in the ileum. Bile acids can induce FMO3 expression by an FXR-dependent mechanism. Lipids Cholesterol The gut microbiota impact on the host systemic lipid Martin et al. (2007); metabolism. When administered as probiotics Bifi- Mart´ınez et al. (2009, 2013); dobacteria and Lactobacillus can enhance dyslipidemia Yu et al. (2013); Joyce et al. and insulin resistance. Microbiota have an influence (2014 on cholesterol metabolism and weight gain in the host via the bacterial BSH mechanism. Methylamines and Methylamine, Cleavage of choline and phosphatidylcholine (PC) by Wang et al. (2011); Craciun products of choline dimethylamine, the gut microbiota via the enzyme choline TMA-lyase and Balskus (2012); Koeth metabolism dimethylglycine, produces TMA. Oxidation of TMA by hepatic flavin- et al. (2013); Tang et al. trimethylamine (TMA) and containing monooxygenase 3 (FMO3) forms TMAO. (2013); Zhu et al. (2014) trimethylamine N-oxide Microbial metabolism of L-carnitine also produces (TMAO) TMA via a novel Rieske-type protein. Risk for major adverse cardiovascular events coincides with higher levels of TMAO. Neurotransmitters Serotonin, melatonin, It was recently discovered that gut microbiota pro- Desbonnet et al. (2008); glutamate, GABA, duce tryptophan decarboxylase, the enzyme respon- Bravo et al. (2011); Rooks noradrenaline, dopamine sible for decarboxylasing tryptophan to tryptamine. et al. (2014); Williams et al. and acetylcholine Tryptamine promotes the release of serotonin by en- (2014); O’Mahony et al. terochromaffincells.Inaratmodelitwas shownthat (2015) Bifidobacteria treatment resulted in increased tryp- tophan and kynurenic acid levels. Another study in mice showed the potential of Lactobacillus rhamnosus to modulate the GABAergic system. Decreased levels of dopamine were measured in fecal samples from active colitis mice. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 574 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 Table 2. (Continued.) Role in health and Metabolite Intermediates/products Synthesis disease References Phytochemicals, Chlorogenic acids, A significant amount of polyphenols reaches the Tomas-Barberan et al. particularly hydrolysable tannins and colon and is believed to contribute to gut health (2014); Kahle et al. (2006); polyphenolic flavonoids by promoting the growth of some commen- Aronov et al. (2011); van compounds sals. Polyphenolic bioconversion by microbiota Duynhoven et al. (2011); is paramount in the production of a large range Cardona et al. (2013); Mar´ın of bioactive molecules. The exact roles of these et al. (2015) molecules in health and disease are yet to be fully understood. Nonetheless epidemiological stud- ies have tied polyphenols to health benefits such as antioxidative, anticarinogenic, antiadipogenic, antidiabetic and neuroprotective properties. Gut microbiota can also convert dietary polyphenols to benzoate. Polyunsaturated Omega3and 6 L. plantarum has genes encoding for the enzyme in- Kishino et al. (2013) fatty acids (PUFA) volved in saturation metabolism of PUFA. Short-chain fatty Most abundant acetate, The SCFAs are produced from bacterial fermentation Bergman (1990); Maslowski acids (SCFAs) propionate, butyrate; to a of non-digestible polysaccharides. They play a role in et al. (2009); den Besten et al. lesser extent—formate, metabolic syndrome prevention and treatment. Evi- (2013); Kimura et al. (2013); fumarate, malonate, dence point to their potential to promote metabolic Natarajan and Pluznick succinate, caproate and control in type 2 diabetes. SCFAs are a major source (2014); Puddu et al. (2014) valerate of energy for colonocytes and also contribute up to 10% of the host’s daily caloric requirements. They are further involved in the control of energy utiliza- tion and maintenance of metabolic homeostasis via the G Protein coupled Receptor 43 (GPR43) receptor. SCFA products also dampen inflammatory response through this receptor. SCFAs have also been shown to affect cell proliferation and apoptosis (in cancer cells), and in epigenetic machinery such as histone acetylation by butyrate. Vitamins B-group vitamins, vitamin It is well established that the gut microbiota synthe- Hill (1997); Cooke, Behan B12; vitamin C, biotin, size a large number of vitamins de novo.Thisisim- and Costello (2006); vitamin K portant since humans lack biosynthetic pathways for Arumugam et al. (2011); vitamins. The deleterious effects of vitamin deficien- LeBlanc et al. (2013); cies are well known. It has only recently been sug- Degnan, Taga and gested that vitamin B12 may also contribute to shap- Goodman (2014) ing the structure and function of microbial commu- nities in the human gut. Other noteworthy bioactives Conjugated linoleic acid (CLA), bacteriocin CLA is associated with a diverse array of biological Bowdish, Davidson and activities, and predominantly associated with acti- Hancock (2005); Ross et al. vation of peroxisome proliferator activated receptors (2010) (PPARs) and the associated switching on and off of genes. Some Bifidobacteria and Lactobacillus species have been shown to produce CLA. Bacteriocins are peptides synthesized by bacteria and have narrow (same species) or broad (across genera) spectrum ac- tivity against other bacteria. A large number of ar- chaea and bacteria are believed to produce at least one bacteriocin. Tetrathionate and nitric oxide Tetrathionate and nitric oxide are produced in an in- Winter et al. (2010); Bergen flammatory environment and are central to the fit- (2014); Rooks et al. (2014) ness of several Enterobacteriaceae. Tetrathionate uti- lization positively correlated with active colitis in a mouse model. Bacterial growth depends on the pres- ence of nitrogen. Synthesis of amino acids by the mi- crobiome depends on the recycling of nitrogen back into gastrointestinal organs. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 575 Table 3. Various pathologies that have been associated with dysbiosis of the gut. Condition References Asthma Abrahamsson et al. (2014) AD Karri, Martinez and Coimbatore (2010); Alam et al. (2014) Atherosclerosis Koren et al. (2011) Autism spectrum disorders Parracho et al. (2005); Finegold et al. (2010); Adams et al. (2011); Williams et al. (2011, 2012); De Angelis et al. (2013); Kang et al. (2013) β-Cell autoimmunity de Goffau et al. (2014) Cardiovascular disease Amar et al. (2011) Crohn’s disease Seksik et al. (2003) Chronic fatigue syndrome Sheedy et al. (2009); Proal et al. (2013) Cystic fibrosis Scanlan et al. (2012); Bruzzese et al. (2014);Sanc ´ hez-Calvo et al. (2008); Duytschaever et al. (2011, 2013); Madan et al. (2012) HIV/AIDS Lozupone et al. (2013); McHardy et al. (2013); Vujkovic-Cvijin et al. (2013) IgE-associated eczema Abrahamsson et al. (2012) Inflammation Cani et al. (2008, 2012); Delzenne and Cani (2011); Delzenne et al. (2011) Inflammatory bowel disease Conte et al. (2006); Clemente et al. (2012); Manichanh et al. (2012); Morgan et al. (2012); Nagalingam and Lynch (2012); Bakhtiar et al. (2013) Iron deficiency Balamurugan et al. (2010); Zimmermann et al. (2010); Dostal et al. (2012, 2014) Liver disease Schnabl and Brenner (2014) Multiple sclerosis Berer et al. (2011) Obesity Delzenne and Cani (2011); Geurts et al. (2014) Rheumatoid arthritis Detert et al. (2010); Berer et al. (2011); Scher and Abramson (2011); Bingham and Moni (2013); Brusca, Abramson and Scher (2014); Catrina, Deane and Scher (2014); Cenit ´ et al. (2014); Demoruelle, Deane and Holers (2014); Taneja (2014) Parkinson’s Disease Scheperjans et al. (2015); Vizcarra et al. (2015) Sarcoidosis Almenoff et al. (1996) Systemic lupus erythematosus Hevia et al. (2014); Zhang et al. (2014a) Symptomatic atherosclerosis/stroke Karlsson et al. (2012) Type 1 diabetes Brown et al. (2012); Owen and Mohamadzadeh (2013); Petersen and Round (2014) Type 2 diabetes Larsen et al. (2010); Brown et al. (2012); Qin et al. (2012); Karlsson et al. (2013); Everard et al. (2014) Table 4. Diseases and conditions where bacterial translocation (of gut or oral origin) and consequent chronic infection are specifically implicated Diseases and conditions where translocation of bacteria are present References Communicable diseases Fibrosis stage in HIV/HCV coinfection Balagopal et al. (2008); Montes-de-Oca et al. (2011); Page, Nelson and Kelleher (2011); Lin, Weinberg and Chung (2013); Sacchi et al. (2015) Hepatitis C virus (HCV) infection French et al. (2013); Munteanu et al. (2014) HIV/AIDS infection Sandler and Douek (2012); Klatt, Funderburg and Brenchley (2013); Vazquez-Castellanos et al. (2014) Pneumonia in immunocompromised Sawa (2014) patients Diseases usually seen as non-communicable Abdominal compartment syndrome Mifkovic et al. (2013) Alcoholic liver disease Chen and Schnabl (2014); Malaguarnera et al. (2014) Allergic disease: bacterial translocation Abrahamsson Wu and Jenmalm (2015) during pregnancy Atherosclerosis Epstein, Zhou and Zhu (1999); Kozarov et al. (2006); Erridge (2008); Renko et al. (2008); Epstein et al. (2009); Nagata, de Toledo and Oho (2011); Rosenfeld and Campbell (2011); Hopkins (2013); Dinakaran et al. (2014); Rogler and Rosano (2014); Trøseid et al. (2014) Burn wounds Macintire and Bellhorn (2002); Sharma (2007); Aboelatta et al. (2013) Cirrhosis Wiest and Garcia-Tsao (2005); Jun et al. (2010); Giannelli et al. (2014); Wiest, Lawson and Geuking (2014) Chronic kidney disease Anders, Andersen and Stecher (2013); Sabatino et al. (2014) Metabolic syndrome Festi et al. (2014) Non-alcoholic fatty liver disease Bieghs and Trautwein (2014) Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 576 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 Table 4. (Continued.) Diseases and conditions where translocation of bacteria are present References Obesity Vajro, Paolella and Fasano (2013); Sanz and Moya-Per ´ ez (2014) Pancreatitis Mifkovic et al. (2009); Guo et al. (2014); Olah ´ and Romics (2014) Rheumatoid arthritis Ogrendik (2009b, 2013b); Ebringer and Rashid (2014); Koziel, Mydel and Potempa (2014) Schizophrenia Severance et al. (2013); Severance, Yolken and Eaton (2014) Sepsis and Septic shock Tsujimoto, Ono and Mochizuki (2009); Wallet et al. (2011); Deitch (2012); Leli et al. (2014) Stroke Syrjanen ¨ et al. (1988); Emsley and Tyrrell (2002); Emsley et al. (2003); Emsley and Hopkins (2008); McColl, Allan and Rothwell (2009); Emsley and Chamorro (2010); Grau, Urbanek and Palm (2010); Wang et al. (2012a); Chien et al. (2013); Dalager-Pedersen et al. (2014); Fugate et al. (2014) Surgical procedures Bariatric surgery Festi et al. (2014) Cardiac surgery Allen (2014) Multiple organ failure (MOF) Swank and Deitch (1996) Sepsis due to surgery MacFie (2004); Puleo et al. (2011) ‘Sepsis’ is widely used to imply living microbes, but as is now well known it can also occur in the absence of any culturable microbes, including those incapable of proliferation due to antibiotic activity. Sepsis may commonly result simply from the effects of molecules such as LPS on the generation of inflammator y cytokines (Kotsaki and Giamarellos-Bourboulis 2012; Balakrishnan et al. 2013). suggested that a changed gut microbiota represents the initial well as other microorganisms can reside inside RBCs (e.g. Mi- site of autoimmunity generation, and might be a critical epige- nasyan 2014), and thus able to cross the RBC membrane some- netic factor in autoimmune diseases such as rheumatoid arthri- how (see Table 5). Transmission electron microscopy (TEM) anal- tis (Scher and Abramson 2011; Luckey et al. 2013; Brusca, Abram- ysis showing bacteria inside cells would also tend to imply that son and Scher 2014; Catrina, Deane and Scher 2014;Cenit ´ et al. the bacteria were not externally introduced artefactually during 2014; Taneja 2014). There is also evidence that regulatory T cells the preparation of the samples. in the gut are influenced by microbial factors, and that a changed For the current paper, we have revisited our AD and PD microbiota (dysbiosis) may influence the induction and suppres- samples and figures from Pretorius et al. (2014a) and Lipinski sor functions of these cells, in turn leading to a changed gut mu- and Pretorius (2013) and noted the prevalence of bacteria in al- cosal immunity (Kinoshita and Takeda 2014). most all of the AD and PD samples, in numbers much in ex- We have earlier reviewed the literature that suggests that cess of those seen in our database of thousands micrographs dysbiosis can cause gut epithelial barrier dysfunction, and from healthy individuals. Here we show additional micrographs thereby provide a point of entry into the body, including the from the previously published samples (see Figs 5 and 6). In blood, resulting in atopobiosis. This is supported by recent re- both conditions (see Figs 5AD and 6PD), microbes were noted search that has suggested that blood microbiota might be impli- in close proximity to RBCs, and in some cases RBCs extended cated in various (cardiovascular and other) diseases. Sequence- pseudopodia-like projections towards the microbiota. SEM anal- based techniques provided evidence for the presence of such ysis of AD whole blood (Fig. 5) shows that mostly coccus-shaped a blood microbiome. The question now arises as to whether bacteria are present. White blood cells are seen in close proxim- such a microbiome’s presence can be directly measured by e.g. ity to these bacteria in AD patients (see Fig. 5A–C). SEM anal- ultrastructural (microscopic) methods, since a consequence of yses of PD patients (Fig. 6) show both coccus- and bacillus- any translocation of microbes between the gut microbiome and shaped bacteria in close proximity to RBCs. We also observed blood is that they should then be observable in blood. The next that RBCs extend pseudopodia towards these bacteria and this sections will provide visual evidence of the presence of such might be part of the mechanism by which the bacteria en- a microbiota in Alzheimer’s disease (AD) and PD. As shown in ter the RBCs (see Fig. 6C–F). We also note possibly dividing Table 3, these conditions are known to be associated with the coccus-shaped bacteria in both these conditions, indicated with presence of dysbiosis. blue arrows on Fig. 5A (AD patient) and Fig. 6D (PD patient). This might suggest that these bacteria may be(come) cultur- able under appropriate conditions (see also Soina et al. 2012; Direct measurement by ultrastructural (microscopic) Epstein 2013). methods TEM analysis of the samples from Lipinski and Pretorius Direct measurement by ultrastructural (microscopic) methods of (2013) and Pretorius et al. (2014a) showed the presence in- side RBCs of cells that appeared to be microbial in nature analysis shows that microbes are in fact common constituents of blood in inflammatory diseases [previously seen in PD—Fig. 8 (unpublished data). These internalized cells further provide evidence for a sustained presence of such a blood micro- in (Pretorius et al. 2014a and in AD—Fig. 2 in (Lipinski and Pre- biota (and one hardly explained by contamination) (see Fig. 7A torius 2013). We show and annotate selected micrographs from and B: AD and C and D: PD). Bacteria are shown with ar- these papers in Fig. 4]. An important concern that needs to be rows in the micrographs. No bacterial membrane was noted; addressed, as is also the case with sequence-based methods, is therefore, the bacteria may be L-forms. There seems to be whether the presence of microbiota in whole blood is indeed bacterial species selectivity for a given disease, as our pre- not the result of introduced external contamination. There is liminary observations suggest a prevalence for bacillus-type in fact considerable evidence in the literature that bacteria as Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 577 Figure 3. Schematic representation of dysbiosis, bacterial translocation and atopobiosis. (A) When intestinal microbiota are associated with dysbiosis,(B) the gut barrier (1 and 2) becomes compromised; this leads to (C), a route of entry via the gut epithelia causing (D) bacterial translocation. Bacterial translocation is also associated with a compromised systemic immune system barrier (3). Therefore, intestinal microbiota dysbiosis (A) followed by bacterial translocation (D) results in (E) atopobiosis. (F) The results of bacterial translocation are seen in various conditions (see Table 4). bacteria in AD, but both coccus- and bacillus-shaped bacteria however, dormancy and viability versus non-viability issues per- in PD patients. tain (as discussed above). Our observations suggest that the presence of bacteria in We found a definite association between RBCs and bacteria, these two diseases occurs in only a small fraction of the RBC with RBCs (see Figs 6 and 7) forming pseudopodia-like extension, population, which is why we had not really noted them in our as if in the process of engulfing bacteria. Both coccoid (round) previous studies (e.g. Bester et al. 2013; Pretorius et al. 2013, and bacillary (elongated) bacteria were found in PD whole blood 2014a,b; Pretorius and Kell 2014), and SEM and TEM analysis con- SEM micrographs, but only coccoid forms in AD whole blood firms this observation. We have never (or not yet) found bacte- SEM micrographs. Samples from 25 diagnosed AD patients were ria inside RBCs from healthy controls (these without overt, diag- studied and bacteria were detected in 14 individuals from this nosed diseases) when studying blood smears using TEM analy- AD sample, while samples from 30 PD patients were studied, sis. The microscopy preparation methods involve a washing pro- in 21 of whom we detected bacteria. Obviously, the type of bac- cess, and this may wash away some of the bacteria, or RBCs and teria cannot be identified from ultrastructural observations. As white blood cells associated with bacteria. Therefore, the actual with the timeline of established cases such as the role of H. quantification of the bacteria can only be done by other means; pylori in ulcers and colon cancer, the next tasks are to bring Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 578 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 these microscopically observed bacteria into culture and to carry out sequence-based studies to establish their role (if any) in non-communicable diseases. However, to illustrate that the bac- teria may indeed be engulfed by the RBCs, and to confirm that the phenomenon is not due to external contamination, we show TEM micrographs from both of the studied diseases (see Fig. 7, AD and PD). CONCLUDING REMARKS AND PROSPECTIVE EXPERIMENTS ‘Non-culturable’ (which should be called ‘not-easily-culturable’ or ‘not-yet-cultured’) microbes are commonplace in the ‘envi- ronmental microbiology’ of soil and water, and the blood cer- tainly represents an ‘environment’. As we show here, there is a large and scattered literature, increasing in size, to the effect that there might be a (mainly dormant) microbial component Figure 4. Micrographs taken from previously published manuscripts. (A–C)Bac- in a variety of chronic diseases that are normally considered to terial presence in PD, originally shown in Fig. 8A, C and G in Pretorius et al. (2014a). (D) Bacterial presence in AD, originally shown in Fig. 2 in Lipinski and be non-microbial or non-communicable in nature, even when Pretorius (2013). microbes appear absent by culturability criteria. Our previous Table 5. Some microorganisms that are known to invade red blood cells. Pathogen Type of microorganism Mechanism of invasion References Anaplasma marginale A tick-borne pathogen that causes Via major surface protein 1a (MSP1a) Kocan et al. the disease anaplasmosis in cattle. (2004) Bartonella bacilliformis Bartonella species are fastidious The Trw T4SS mediates attachment of Bartonella to Iwaki-Egawa and B.quintana Gram-negative bacteria, which red blood cells in Bartonella lineage 4. Bartonella is Ihler (1997); belong to the alpha group of the collected in pits and trenches that form as a result Coleman and domain Proteobacteria. of deformation factor. Invaginations supposedly Minnick (2001); pinch off to carry the content in a vacuole structure Rolain et al. to the cytoplasm of the red blood cell where the (2003); Eicher organism persists. and Dehio (2012) Brucella melitensis Facultative intracellular Invasion shown in mouse erythrocytes. Mechanism Vitry et al. (2014) Gram-negative coccobacilli. to be identified. Francisella tularensis Highly infectious bacterium, Via serum complement-dependent and Conlan (2011); which can cause severe disease independent mechanisms. Horzempa et al. tularemia with an infection of (2011) fewer than 10 bacteria Mycoplasma suis A member or the hemotrophic Invasion occurs in a similar manner to that of P. Groebel et al. mycoplasma group that parasitize falciparum and B. bacilliformis. Attachment via MSG1 (2009); Zhang erythrocytes in pigs. (GAPDH) protein. et al. (2014c) M. bovis Small cell wall-less bacterium that Undetermined. van der Merwe, contributes to a number of chronic Prysliak and inflammatory diseases in dairy Perez-Casal and feedlot cattle. (2010) M. gallisepticum Mycoplasmas are small cell Not known. Vogl et al. (2008) wall-less prokaryotes. Plasmodium falciparum The main malaria parasite, part of Recognition of surface receptors precedes a Cowman and whose life cycle involves reorientation where the apical end is adjusted to Crabb (2006) inhabiting RBCs. the erythrocyte. A tight junction that involves high-affinity ligand receptor interactions is formed. The tight junction moves from the apical to posterior pole and is powered by the actin-myosin motor of the parasite. The adhesive proteins at the junction are proteolytically removed when the posterior pole is reached, most likely by a rhomboid resident protease in a process that facilitates membrane resealing. The invasion process produces a parasitophorous vacuole containing the merozoite. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 579 Table 5. (Continued.) Pathogen Type of microorganism Mechanism of invasion References Streptococcus pneumoniae Gram-positive bacterium which LPXTG motif-containing pneumococcal proteins, Yamaguchi et al. causes infection-related diseases. erythrocyte lipid rafts and erythrocyte actin (2013) remodeling are involved in the invasion mechanism. Theileria sporozites Intracellular protozoan Occurs in a similar manner to sporozoite entry. Shaw (2003); transmitted by ixodid ticks. Infect Bishop et al. wild and domesticated ruminants. (2004) Phylogenetically most closely related to Babesia. Figure 6. RBCs with microbiota from patients with diagnosed PD (additional mi- crographs from sample used in Pretorius et al. 2014a). These micrographs are rep- Figure 5. RBCs with microbiota from patients with diagnosed AD (additional mi- resentative of bacteria found in smears of 21 of the 30 PD individuals. (A) A col- crographs from sample used in Lipinski and Pretorius 2013). These micrographs lection of coccus- and bacillus-shaped bacteria; (B) coccus- and bacillus-shaped are representative of bacteria found in smears of 14 of the 30 AD individuals. bacteria associated with erythrocyte; (C) bacillus-shaped bacteria in close prox- (A and B) coccus-shaped bacteria associated with white blood cell; (B) coccus- imity with erythrocyte. Erythrocyte forms extensions towards bacteria; (D and E) shaped bacteria associated with an erythrocyte and white blood cell; (C)two bacillus-shaped bacteria associated with elongated erythrocytes; (F) coccus- and white blood cells associated with coccus-shaped bacteria; (D) a string of cocci- bacillus-shaped bacteria close to erythrocyte that extends pseudopodia towards blue arrow shows possibly dividing coccoid bacteria; (E) an erythrocyte associ- the bacteria. Coccus-shaped bacteria shown with pink arrows; bacillus-shaped ated with coccus-shaped bacteria; (F) a high machine magnification of a coccus- bacteria shown with white arrows. Dividing coccus-shaped bacteria shown with shaped bacteria associated with a dense matted fibrin deposit. Scale bar: 1 μm. blue arrow. Scale bar: 1 μm. work (e.g. Bester et al. 2013; Pretorius et al. 2013, 2014a;Kelland Pretorius 2014, 2015; Pretorius and Kell 2014) has implied iron dysregulation as a regular accompaniment to, and probable con- We have here pointed up the likelihood of a steady crop tributory factor for, a variety of similar diseases, all of which of effectively dormant microbes being a feature of blood bi- have an inflammatory component. We argue here that there is ology in chronically diseased humans, including those with also a microbial contribution to this in the blood, and it is not un- non-communicable diseases. As with any complex system, the reasonable that the microbial requirement for iron means that, magnitude of any component is affected by the kinetics of every despite the oxidative stress it can entail (Touati 2000;Kell 2009, relevant step; while the precise nature of all the interactions is 2010), microbes may be anticipated to increase in prevalence uncertain, Fig. 8 describes the general network—the first step in when iron is free (e.g. Ratledge 2007; Clifton, Corrent and Strong any systems analysis (Kell 2006; Kell and Knowles 2006). 2009; Sia, Allred and Raymond 2013; Chu et al. 2014) and avail- Consequently, we recognize that the analysis above has able (D’Onofrio et al. 2010), probably behaving in a social manner largely been qualitative (the ‘presence’ of a microbial compo- (Kell, Kaprelyants and Grafen 1995; West and Buckling 2003;Dig- nent in a specific disease is a qualitative statement). However, gle et al. 2007; Harrison and Buckling 2009). chronic, non-communicable diseases are very far from being Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 580 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 tectable blood microbiome in this and other diseases that show such flares. As with H. pylori and stomach ulcers (and cancer), the simple prediction is that bactericidal antibiotics should be of value in the treatment of such supposedly non-communicable diseases. Indeed, this prediction is borne out for diseases such as rheumatoid arthritis (Ogrendik 2009a, 2013a; Kwiatkowska and Masli ´ nska ´ 2012) and multiple sclerosis (Ochoa-Repar ´ az et al. 2009; 2011), while antipneumococcal vaccination has shown ef- ficacy in preventing stroke (Vila-Corcoles et al. 2014). Of course, events such as heart attacks and strokes (and see Table 4)may also be seen as sudden increases in severity of an underlying condition, and in some cases (such as the much increased like- lihood of strokes after subarachnoid haemorrhages; McMahon et al. 2013), analysis of changes in the blood microbiome might prove predictive. The obvious next tasks are thus to relate the number and nature of blood microbes observed in cases such as the above to microbial sequences and antigens that can be detected in aliquots of the same samples (e.g. Salipante et al. 2013, 2015), to determine the physiological state of the various microbes (in- Figure 7. TEM confirming the presence of bacteria inside erythrocytes of ( A and cluding e.g. whether they are L-forms), and to establish methods B)AD,(C and D) PD. (Additional micrographs from sample used in Lipinski and to bring them (back) into culture. Since microbes, inflammation Pretorius (2013) and Pretorius et al. (2014a). Arrows in each micrograph show the and various syndromes are such common co-occurrences (as presence of cellular inclusions, without visible membranes. Inclusions are not typically noted in erythrocytes. We suggest that these inclusions are bacteria, are coagulopathies; Kell and Pretorius 2015), longitudinal stud- possibly as L-forms. Scale bar = 1 μm (A, C, D); 200 nm (D). ies will have a specially important role, as they will both show the dynamics and be able to help discriminate cause and ef- fect during the time evolution of chronic, non-communicable diseases in ageing populations. The immunogenicity of per- static (and thousands of human genes change their expression sisters, and their ability to induce various kinds of inflamma- at least 2-fold even on a diurnal basis; Zhang et al. 2014b). Thus, a tion, must be rather different from that of replicating organ- clear further issue is to seek to understand how the blood micro- isms, and this must be investigated. Armed with such collec- biome may co-vary with the day-to-day dynamics of chronic dis- tive knowledge, we might be better placed to develop thera- eases. For example, rheumatoid arthritis has circadian rhythms peutics such as pre- and probiotics and bactericidal antibiotics (Straub and Cutolo 2007) and is well known to provide signifi- for use in such cases previously thought to lack a microbial cant variations (‘flares’; Flurey et al. 2014) in severity at different contribution. times. A reasonable strategy is thus to look for changes in a de- Figure 8. Relationships between a dormant blood microbiome and chronic disease dyamics. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 581 FUNDING Phylogenetics: a discipline of evolutionary biology that stud- ies the relationships between organisms based on how closely We thank the Biotechnology and Biological Sciences Research similar some of their macromolecular sequences are. Council (grant BB/L025752/1) as well as the National Re- Pleomorphic: possessing the ability to change shape or size search Foundation (NRF) of South Africa for supporting this in response to environmental stimuli. collaboration. Resuscitation: induction of apparently non-culturable cells to a state of culturability. Conflict of interest. None declared. Sterile: refers to an absence of operationally viable organ- isms. Viable: capable of observable replication, i.e. culturable, by any stated means. GLOSSARY 16S ribosomal RNA: a component of the 30S small subunit of REFERENCES prokaryotic ribosomes. The 16S rRNA gene is found in all bacte- Aboelatta YA, Abd-Elsalam AM, Omar AH, et al. Selective diges- ria and archaea and consists of nine short hypervariable regions tive decontamination (SDD) as a tool in the management of that may be used to distinguish bacterial taxa. bacterial translocation following major burns. Ann Burns Fire Anabiosis: when an organism is in a state of very low Disasters 2013;26:182–8. metabolic activity to the extent where it is hardly measurable Abrahamsson TR, Jakobsson HE, Andersson AF, et al. Low diver- and in some cases come to a standstill. The physiological and sity of the gut microbiota in infants with atopic eczema. J biochemical processes are arrested for different periods of time Allergy Clin Immun 2012;129:434–40,440 e431–32. but can be reversed. Abrahamsson TR, Jakobsson HE, Andersson AF, et al. Low gut mi- Atopobiosis (Greek ατooπoς or atopos) appearance of the gut crobiota diversity in early infancy precedes asthma at school or other microbiome in the wrong place. age. Clin Exp Allergy 2014;44:842–50. Bacterial translocation: the passage of viable resident bac- Abrahamsson TR, Wu RY, Jenmalm MC. Gut microbiota and al- teria from the gastrointestinal tract to normally sterile tissues lergy: the importance of the pregnancy period. Pediatr Res such as the mesenteric lymph nodes and the other internal 2015;77:214–9. organs. Adams JB, Johansen LJ, Powell LD, et al. Gastrointestinal Cryptobiosis: refers to latent life or a state where an organism flora and gastrointestinal status in children with autism— lacks any visible signs of life but is not dead in that it may revert comparisons to typical children and correlation with autism to a state of aliveness as usually defined. Its metabolic activity severity. BMC Gastroenterol 2011;11:22. becomes hardly measurable, or comes reversibly to a standstill. Alam MZ, Alam Q, Kamal MA, et al. A possible link of gut micro- Culturability: the ability of a cell to reproduce. biota alteration in type 2 diabetes and Alzheimer’s disease Direct viable count: the original method comprises incuba- pathogenicity: an update. CNS Neurol Disord-Dr 2014;13:383– tion of samples with nutrients (yeast extract) and a single an- timicrobial agent that specifically inhibits DNA synthesis but not Allan EJ, Hoischen C, Gumpert J. Bacterial L-forms. Adv Appl Mi- RNA synthesis (nalidixic acid). Cell division ceases as a result crobiol 2009;68:1–39. of DNA synthesis inhibition but other cellular metabolic activ- Allen SJ. Gastrointestinal complications and cardiac surgery. J ities remain unaffected and therefore cells continue to metab- Extra-Corp Technol 2014;46:142–9. olize nutrients and grow in size, which allows their detection Allen-Vercoe E. Bringing the gut microbiota into focus through microscopically in situ. microbial culture: recent progress and future perspective. Dormant: notviableinthe senseofnotbeingmoreorlessim- Curr Opin Microbiol 2013;16:625–9. mediately culturable, but may be returned to a state of viability Almenoff PL, Johnson A, Lesser M, et al. Growth of acid fast L or culturability by preincubation under suitable conditions. forms from the blood of patients with sarcoidosis. Thorax Dysbiosis: derangement of the species distribution in the 1996;51:530–3. normal microbiome. Amann RI, Ludwig W, Schleifer KH. Phylogenetic identification L-forms: these bacteria are cell wall-deficient forms of nor- and in situ detection of individual microbial cells without mal bacteria. They are able to proliferate as sphaeroplasts or cultivation. Microbiol Rev 1995;59:143–69. protoplasts under certain conditions. Amar J, Lange C, Payros G, et al. Blood microbiota dysbiosis Metagenomics: direct genetic analysis of a collection of is associated with the onset of cardiovascular events in genomes contained in an environmental sample. a large general population: the D.E.S.I.R. study. PLoS One Microbiome: the genetic sum of the ecological community 2013;8:e54461. of commensal, symbiotic and pathogenic microorganisms that Amar J, Serino M, Lange C, et al. Involvement of tissue bacteria lives on and inside our bodies. in the onset of diabetes in humans: evidence for a concept. ‘Most Probable Number’ technique: is a method used to Diabetologia 2011;54:3055–61. quantify the concentration of viable microorganisms in a sam- Amar S, Engelke M. Periodontal innate immune mecha- ple. It involves replicate liquid broth growth in 10-fold dilutions. nisms relevant to atherosclerosis. Mol Oral Microbiol 2014, When a dilution lacks growth, it is assumed not to have any or- DOI:10.1111/omi.12087. ganisms. Back-calculation via a Poissonian distribution leads to Amato SM, Orman MA, Brynildsen MP. Metabolic control of the ‘most probable number’ in the original sample persister formation in Escherichia coli. Mol Cell 2013;50: Non-axenic culture: contains more than one species, variety 475–87. or strain of organism. Anders HJ, Andersen K, Stecher B. The intestinal microbiota, a Non-viable: incapable of observable replication by any stated leaky gut, and abnormal immunity in kidney disease. Kidney means normally capable of effecting replication in the relevant Int 2013;83:1010–6. organism. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 582 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 Anthony RM, Brown TJ, French GL. Rapid diagnosis of bacteremia Bowdish DM, Davidson DJ, Hancock R. A re-evaluation of the role by universal amplification of 23S ribosomal DNA followed of host defence peptides in mammalian immunity. Curr Pro- by hybridization to an oligonucleotide array. J Clin Microbiol tein Pept Sc 2005;6:35–51. 2000;38:781–8. Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus Aronov PA, Luo FJ, Plummer NS, et al. Colonic contribution to strain regulates emotional behavior and central GABA recep- uremic solutes. J Am Soc Nephrol 2011;22:1769–76. tor expression in a mouse via the vagus nerve. P Natl Acad Sci Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human 2011;108:16050–5. gut microbiome. Nature 2011;473:174–80. Brown K, DeCoffe D, Molcan E, et al. Diet-induced dysbiosis of Bakhtiar SM, LeBlanc JG, Salvucci E, et al. Implications of the hu- the intestinal microbiota and the effects on immunity and man microbiome in inflammatory bowel diseases. FEMS Mi- disease. Nutrients 2012;4:1095–119. crobiol Lett 2013;342:10–7. Brusca SB, Abramson SB, Scher JU. Microbiome and mucosal in- Bakken LR, Olsen RA. The relationship between cell size and vi- flammation as extra-articular triggers for rheumatoid arthri- ability of soil bacteria. Microb Ecol 1987;13:103–14. tis and autoimmunity. Curr Opin Rheumatol 2014;26:101–7. Balaban NQ, Merrin J, Chait R, et al. Bacterial persistence as a Bruzzese E, Callegari ML, Raia V, et al. Disrupted intestinal mi- phenotypic switch. Science 2004;305:1622–5. crobiota and intestinal inflammation in children with cys- Balagopal A, Philp FH, Astemborski J, et al. Human immunodefi- tic fibrosis and its restoration with Lactobacillus GG: a ran- ciency virus-related microbial translocation and progression domised clinical trial. PLoS One 2014;9:e87796. of hepatitis C. Gastroenterology 2008;135:226–33. Burcelin R, Serino M, Chabo C, et al. Metagenome and Balakrishnan A, Marathe SA, Joglekar M, et al. Bacterici- metabolism: the tissue microbiota hypothesis. Diabetes Obes dal/permeability increasing protein: a multifaceted protein Metab 2013;15 (Suppl 3):61–70. with functions beyond LPS neutralization. Innate Immun Calcott PH, Calvert TJ. Characterization of 3’: 5’ -cyclic 2013;19:339–47. AMP phosphodiesterase in Klebsiella aerogenes and its role Balamurugan R, Mary RR, Chittaranjan S, et al. Low levels of fae- in substrate-accelerated death. J Gen Microbiol 1981;122: cal lactobacilli in women with iron-deficiency anaemia in 313–21. south India. Brit J Nutr 2010;104:931–4. Calcott PH, Postgate JR. On substrate-accelerated death in Kleb- Balzan S, de Almeida Quadros C, de Cleva R, et al. Bacterial siella aerogenes. J Gen Microbiol 1972;70:115–22. translocation: overview of mechanisms and clinical impact. Cani PD, Bibiloni R, Knauf C, et al. Changes in gut micro- J Gastroen Hepatol 2007;22:464–71. biota control metabolic endotoxemia-induced inflammation Bennett BJ, de Aguiar Vallim TQ, Wang Z, et al. Trimethylamine- in high-fat diet-induced obesity and diabetes in mice. Dia- N-oxide, a metabolite associated with atherosclerosis, ex- betes 2008;57:1470–81. hibits complex genetic and dietary regulation. Cell Metab Cani PD, Osto M, Geurts L, et al. Involvement of gut microbiota 2013;17:49–60. in the development of low-grade inflammation and type 2 BererK,MuesM,KoutrolosM, et al. Commensal microbiota and diabetes associated with obesity. Gut Microbes 2012;3:279–88. myelin autoantigen cooperate to trigger autoimmune de- Caporaso JG, Lauber CL, Costello EK, et al. Moving pictures of the myelination. Nature 2011;479:538–41. human microbiome. Genome Biol 2011;12:R50. Berg RD. Bacterial translocation from the gastrointestinal tract. Cardona F, Andres-Lacueva C, Tulipani S, et al. Benefits of Trends Microbiol 1995;3:149–54. polyphenols on gut microbiota and implications in human Bergen WG. Small-intestinal or colonic microbiota as a potential health. J Nutr Biochem 2013;24:1415–22. amino acid source in animals. Amino Acids 2014;47:251–8. Casadesus ´ J. Bacterial L-forms require peptidoglycan synthesis Bergman E. Energy contributions of volatile fatty acids from for cell division. Bioessays 2007;29:1189–91. the gastrointestinal tract in various species. Physiol Rev Catrina AI, Deane KD, Scher JU. Gene, environment, micro- 1990;70:567–90. biome and mucosal immune tolerance in rheumatoid arthri- Bested AC, Logan AC, Selhub EM. Intestinal microbiota, probi- tis. Rheumatology 2014, DOI:10.1093/rheumatology/keu469. otics and mental health: from Metchnikoff to modern ad- Cavanagh JP, Hjerde E, Holden MT, et al. Whole-genome se- vances: part III - convergence toward clinical trials. Gut Pathog quencing reveals clonal expansion of multiresistant Staphy- 2013;5:4. lococcus haemolyticus in European hospitals. J Antimicrob Bester J, Buys AV, Lipinski B, et al. High ferritin levels have ma- Chemoth 2014;69:2920–7. jor effects on the morphology of erythrocytes in Alzheimer’s Cenit ´ MC, Matzaraki V, Tigchelaar EF, et al. Rapidly expanding disease. Front Aging Neurosci 2013;5:00088. knowledge on the role of the gut microbiome in health and Bieghs V, Trautwein C. Innate immune signaling and gut-liver disease. Biochim Biophys Acta 2014;1842:1981–92. interactions in non-alcoholic fatty liver disease. Hepatobiliary Chang SS, Hsu HL, Cheng JC, et al. An efficient strategy for Surg Nutr 2014;3:377–85. broad-range detection of low abundance bacteria without Bingham CO III,Moni M. Periodontal disease and rheuma- DNA decontamination of PCR reagents. PLoS One 2011;6: toid arthritis: the evidence accumulates for complex e20303. pathobiologic interactions. Curr Opin Rheumatol 2013;25: Chen P, Schnabl B. Host-microbiome interactions in alcoholic 345–53. liver disease. Gut Liver 2014;8:237–41. Bishop R, Musoke A, Morzaria S, et al. Theileria: intracellular pro- Chien LN, Chi NF, Hu CJ, et al. Central nervous system infections tozoan parasites of wild and domestic ruminants transmit- and stroke—a population-based analysis. Acta Neurol Scand ted by ixodid ticks. Parasitology 2004;129:S271–83. 2013;128:241–8. Blaser M, Bork P, Fraser C, et al. The microbiome explored: recent Cho I, Blaser MJ. The human microbiome: at the interface of insights and future challenges. Nat Rev Microbiol 2013;11:213– health and disease. Nat Rev Genet 2012;13:260–70. 7. Chu BC, Otten R, Krewulak KD, et al. The solution structure, bind- Blaser MJ. The microbiome revolution. J Clin Invest 2014;124: ing properties, and dynamics of the bacterial siderophore- 4162–5. binding protein FepB. J Biol Chem 2014;289:29219–34. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 583 Clark MA, Jepson MA. Intestinal M cells and their role in bacterial Delzenne NM, Neyrinck AM, Bac ¨ khed F, et al. Targeting gut mi- infection. Int J Med Microbiol 2003;293:17–39. crobiota in obesity: effects of prebiotics and probiotics. Nat Claudi B, Sprote P, Chirkova A, et al. Phenotypic variation of Rev Endocrinol 2011;7:639–46. Salmonella in host tissues delays eradication by antimicro- Demoruelle MK, Deane KD, Holers VM. When and where does in- bial chemotherapy. Cell 2014;158:722–33. flammation begin in rheumatoid arthritis? Curr Opin Rheuma- Clegg JS. Cryptobiosis—a peculiar state of biological organiza- tol 2014;26:64–71. tion. Comp Biochem Phys B 2001;128:613–24. den Besten G, van Eunen K, Groen AK, et al. The role of short- Clemente JC, Ursell LK, Parfrey LW, et al. The impact of the chain fatty acids in the interplay between diet, gut micro- gut microbiota on human health: an integrative view. Cell biota, and host energy metabolism. J Lipid Res 2013;54:2325– 2012;148:1258–70. 40. Clifton MC, Corrent C, Strong RK. Siderocalins: siderophore- Desbonnet L, Garrett L, Clarke G, et al. The probiotic Bifidobacte- binding proteins of the innate immune system. Biometals ria infantis: an assessment of potential antidepressant prop- 2009;22:557–64. erties in the rat. J Psychiatr Res 2008;43:164–74. Clingenpeel S, Schwientek P, Hugenholtz P, et al. Effects of sam- Detert J, Pischon N, Burmester GR, et al. The association between ple treatments on genome recovery via single-cell genomics. rheumatoid arthritis and periodontal disease. Arthritis Res ISME J 2014;8:2546–9. Ther 2010;12:218. Coleman SA, Minnick MF. Establishing a direct role for the Devaraj S, Hemarajata P, Versalovic J. The human gut micro- Bartonella bacilliformis invasion-associated locus B (IalB) biome and body metabolism: implications for obesity and di- protein in human erythrocyte parasitism. Infect Immun abetes. Clin Chem 2013;59:617–28. 2001;69:4373–81. Devine KM. Bacterial L-forms on tap: an improved methodology Conlan JW. Francisella tularensis: a red-blooded pathogen. JInfect to generate Bacillus subtilis L-forms heralds a new era of re- Dis 2011;204:6–8. search. Mol Microbiol 2012;83:10–3. Conte MP, Schippa S, Zamboni I, et al. Gut-associated bacterial Didelot X, Bowden R, Wilson DJ, et al. Transforming clinical mi- microbiota in paediatric patients with inflammatory bowel crobiology with bacterial genome sequencing. Nat Rev Genet disease. Gut 2006;55:1760–7. 2012;13:601–12. Cooke G, Behan J, Costello M. Newly identified vitamin K- Diggle SP, Griffin AS, Campbell GS, et al. Cooperation and producing bacteria isolated from the neonatal faecal flora. conflict in quorum-sensing bacterial populations. Nature Microb Ecol Health D 2006;18:133–8. 2007;450:411–4. Corr SC, Gahan CC, Hill C. M-cells: origin, morphology and role Dinakaran V, Rathinavel A, Pushpanathan M, et al. Elevated lev- in mucosal immunity and microbial pathogenesis. FEMS Im- els of circulating DNA in cardiovascular disease patients: munol Med Mic 2008;52:2–12. metagenomic profiling of microbiome in the circulation. PLoS Cowman AF, Crabb BS. Invasion of red blood cells by malaria par- One 2014;9:e105221. asites. Cell 2006;124:755–66. Ding PH, Jin LJ. The role of lipopolysaccharide-binding pro- Craciun S, Balskus EP. Microbial conversion of choline to tein in innate immunity: a revisit and its relevance to trimethylamine requires a glycyl radical enzyme. P Natl Acad oral/periodontal health. J Periodontal Res 2014;49:1–9. Sci USA 2012;109:21307–12. Ding T, Schloss PD. Dynamics and associations of micro- Dalager-Pedersen M, Sogaard M, Schonheyder HC, et al. Risk for bial community types across the human body. Nature myocardial infarction and stroke after community-acquired 2014;509:357–60. bacteremia: a 20-year population-based cohort study. Circu- Domingue GJ. Demystifying pleomorphic forms in persistence lation 2014;129:1387–96. and expression of disease: Are they bacteria, and is peptido- Davey HM, Kell DB. Flow cytometry and cell sorting of heteroge- glycan the solution? Discov Med 2010;10:234–46. neous microbial populations: the importance of single-cell Domingue GJ, Schlegel JU. Novel bacterial structures in human analyses. Microbiol Rev 1996;60:641–96. blood: cultural isolation. Infect Immun 1977;15:621–7. De Angelis M, Piccolo M, Vannini L, et al. Fecal microbiota Domingue GJ, Sr, Woody HB. Bacterial persistence and expres- and metabolome of children with autism and pervasive sion of disease. Clin Microbiol Rev 1997;10:320–44. developmental disorder not otherwise specified. PLoS One Dom´ınguez-Cuevas P, Mercier R, Leaver M, et al. The rod to L- 2013;8:e76993. form transition of Bacillus subtilis is limited by a requirement de Goffau MC, Fuentes S, van den Bogert B, et al. Aberrant gut mi- for the protoplast to escape from the cell wall sacculus. Mol crobiota composition at the onset of type 1 diabetes in young Microbiol 2012;83:52–66. children. Diabetologia 2014;57:1569–77. D’Onofrio A, Crawford JM, Stewart EJ, et al. Siderophores from De Preter V, Verbeke K. Metabolomics as a diagnostic tool in gas- neighboring organisms promote the growth of uncultured troenterology. World J Gastrointest Pharmacol Ther 2013;4:97– bacteria. Chem Biol 2010;17:254–64. 107. Dostal A, Baumgartner J, Riesen N, et al. Effects of iron sup- Dedysh SN. Cultivating uncultured bacteria from northern wet- plementation on dominant bacterial groups in the gut, fae- lands: knowledge gained and remaining gaps. Front Microbiol cal SCFA and gut inflammation: a randomised, placebo- 2011;2:184. controlled intervention trial in South African children. Brit Degnan PH, Taga ME, Goodman AL. Vitamin B as a mod- JNutr 2014;112:547–56. ulator of gut microbial ecology. Cell Metab 2014;20: Dostal A, Chassard C, Hilty FM, et al. Iron depletion and repletion 769–78. with ferrous sulfate or electrolytic iron modifies the compo- Deitch EA. Gut-origin sepsis: evolution of a concept. Surgeon sition and metabolic activity of the gut microbiota in rats. J 2012;10:350–6. Nutr 2012;142:271–7. Delzenne NM, Cani PD. Interaction between obesity and the gut Dowd SE, Sun Y, Secor PR, et al. Survey of bacterial diversity in microbiota: relevance in nutrition. Annu Rev Nutr 2011;31:15– chronic wounds using pyrosequencing, DGGE, and full ribo- 31. some shotgun sequencing. BMC Microbiol 2008;8:43. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 584 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 Drennan M. What is ‘Sterile Blood’? Brit Med J 1942;2:526. plicated bloodstream infections caused by Gram-positive Duda VI, Suzina NE, Polivtseva VN, et al. Ultramicrobacteria: for- bacteria or Candida species. J Clin Microbiol 2013;51:1130–6. mation of the concept and contribution of ultramicrobacteria FestiD,SchiumeriniR,EusebiLH, et al. Gut microbiota and to biology. Mikrobiologiia 2012;81:415–27. metabolic syndrome. World J Gastroenterol 2014;20:16079–94. Duytschaever G, Huys G, Bekaert M, et al. Cross-sectional and Finegold SM, Dowd SE, Gontcharova V, et al. Pyrosequencing longitudinal comparisons of the predominant fecal micro- study of fecal microflora of autistic and control children. biota compositions of a group of pediatric patients with cys- Anaerobe 2010;16:444–53. tic fibrosis and their healthy siblings. Appl Environ Microb Flores GE, Caporaso JG, Henley JB, et al. Temporal variability is a 2011;77:8015–24. personalized feature of the human microbiome. Genome Biol Duytschaever G, Huys G, Bekaert M, et al. Dysbiosis of bifidobac- 2014;15:531. teria and Clostridium cluster XIVa in the cystic fibrosis fecal Flurey CA, Morris M, Richards P, et al. It’s like a juggling microbiota. JCystFibros 2013;12:206–15. act: rheumatoid arthritis patient perspectives on daily life Ebringer A, Rashid T. Rheumatoid arthritis is caused by a Proteus and flare while on current treatment regimes. Rheumatology urinary tract infection. APMIS 2014;122:363–8. 2014;53:696–703. Eicher SC, Dehio C. Bartonella entry mechanisms into mam- Fredricks DN. The Human Microbiota: How Microbial Communities malian host cells. Cell Microbiol 2012;14:1166–73. Affect Health and Disease. Hoboken, NJ: Wiley, 2013. Eilers H, Pernthaler J, Glockner FO, et al. Culturability and In situ Fremont M, Coomans D, Massart S, et al. High-throughput 16S abundance of pelagic bacteria from the North Sea. Appl Env- rRNA gene sequencing reveals alterations of intestinal mi- iron Microb 2000;66:3044–51. crobiota in myalgic encephalomyelitis/chronic fatigue syn- Eisenreich W, Dandekar T, Heesemann J, et al. Carbon drome patients. Anaerobe 2013;22:50–6. metabolism of intracellular bacterial pathogens and French AL, Evans CT, Agniel DM, et al. Microbial translocation possible links to virulence. Nat Rev Microbiol 2010;8: and liver disease progression in women coinfected with HIV 401–12. and hepatitis C virus. J Infect Dis 2013;208:679–89. Eleftheriadis T, Liakopoulos V, Leivaditis K, et al. Infections in Fricke WF, Rasko DA. Bacterial genome sequencing in the hemodialysis: a concise review—Part 1: bacteremia and res- clinic: bioinformatic challenges and solutions. Nat Rev Genet piratory infections. Hippokratia 2011;15:12–7. 2014;15:49–55. ElRakaiby M, Dutilh BE, Rizkallah MR, et al. Pharmacomicro- Fugate JE, Lyons JL, Thakur KT, et al. Infectious causes of stroke. biomics: the impact of human microbiome variations on sys- Lancet Infect Dis 2014;14:869–80. tems pharmacology and personalized therapeutics. Omics Fukuda S, Hase K, Ohno H. Application of a mouse ligated Peyer’s 2014;18:402–14. patch intestinal loop assay to evaluate bacterial uptake by M Emsley HC, Chamorro A. Stroke bugs: current and emerging con- cells. JVis Exp 2011;e3225–30. cepts relevant to infection in cerebrovascular disease. Infect Gaibani P, Mariconti M, Bua G, et al. Development of a broad- Disord Drug Targets 2010;10:65–6. range 23S rDNA real-time PCR assay for the detection and Emsley HC, Hopkins SJ. Acute ischaemic stroke and infection: quantification of pathogenic bacteria in human whole blood recent and emerging concepts. Lancet Neurol 2008;7:341–53. and plasma specimens. Biomed Res Int 2013;2013:264651. Emsley HC, Smith CJ, Gavin CM, et al. An early and sustained pe- Gerard P. Metabolism of cholesterol and bile acids by the gut mi- ripheral inflammatory response in acute ischaemic stroke: crobiota. Pathogens 2013;3:14–24. relationships with infection and atherosclerosis. J Neuroim- Gerdes K, Maisonneuve E. Bacterial persistence and toxin- munol 2003;139:93–101. antitoxin loci. Annu Rev Microbiol 2012;66:103–23. Emsley HC, Tyrrell PJ. Inflammation and infection in clinical Germain E, Castro-Roa D, Zenkin N, et al. Molecular mech- stroke. J Cerebr Blood F Met 2002;22:1399–419. anism of bacterial persistence by HipA. Mol Cell 2013;52: Epstein SE, Zhou YF, Zhu J. Infection and atherosclerosis: emerg- 248–54. ing mechanistic paradigms. Circulation 1999;100:e20–8. Gest H. The Modern Myth of ‘Unculturable’ Bacteria: Scotoma of Con- Epstein SE, Zhu J, Najafi AH, et al. Insights into the role of in- temporary Microbiology. Faculty Research (Bloomington), 2008, fection in atherogenesis and in plaque rupture. Circulation http://hdl.handle.net/2022/3149 (19 March 2015, date last ac- 2009;119:3133–41. cessed). Epstein SS. The phenomenon of microbial uncultivability. Curr Geurts L, Neyrinck AM, Delzenne NM, et al. Gut microbiota Opin Microbiol 2013;16:636–42. controls adipose tissue expansion, gut barrier and glucose Erridge C. The roles of pathogen-associated molecular patterns metabolism: novel insights into molecular targets and inter- in atherosclerosis. Trends Cardiovas Med 2008;18:52–6. ventions using prebiotics. Benef Microbes 2014;5:3–17. Errington J. L-form bacteria, cell walls and the origins of life. Open Giannelli V, DiGregorio V, Iebba V, et al. Microbiota and the gut- Biol 2013;3:120143. liver axis: bacterial translocation, inflammation and infec- Everard A, Matamoros S, Geurts L, et al. Saccharomyces boulardii tion in cirrhosis. World J Gastroenterol 2014;20:16795–810. administration changes gut microbiota and reduces hepatic Gich F, Schubert K, Bruns A, et al. Specific detection, isola- steatosis, low-grade inflammation, and fat mass in obese tion, and characterization of selected, previously uncultured and type 2 diabetic db/db mice. MBio 2014;5:e01011–4. members of the freshwater bacterioplankton community. Faure M, Mettraux C, Moennoz D, et al. Specific amino acids in- Appl Environ Microb 2005;71:5908–19. crease mucin synthesis and microbiota in dextran sulfate Glaros TG, Chang S, Gilliam EA, et al. Causes and consequences sodium-treated rats. JNutr 2006;136:1558–64. of low grade endotoxemia and inflammatory diseases. Front Feeley JC, Gorman GW, Weaver RE, et al. Primary isolation Biosci 2013;5:754–65. media for Legionnaires disease bacterium. J Clin Microbiol Gonzalez A, Stombaugh J, Lozupone C, et al. The mind-body- 1978;8:320–5. microbial continuum. Dialogues Clin Neurosci 2011;13:55–62. Fernandez-Cruz ´ A, Marin M, Kestler M, et al. The value of com- Grau AJ, Urbanek C, Palm F. Common infections and the risk of bining blood culture and SeptiFast data for predicting com- stroke. Nat Rev Neurol 2010;6:681–94. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 585 Gribbin JR. In Search of Schrodinger’ ¨ s Cat: Quantum Physics and Re- Kahle K, Kraus M, Scheppach W, et al. Studies on apple and blue- ality. London: Bantam Books, 1985. berry fruit constituents: do the polyphenols reach the colon Grif K, Fille M, Wurzner ¨ R, et al. Rapid detection of bloodstream after ingestion? Mol Nutr Food Res 2006;50:418–23. pathogens by real-time PCR in patients with sepsis. Wien Klin Kakiyama G, Pandak WM, Gillevet PM, et al. Modulation of the Wochenschr 2012a;124:266–70. fecal bile acid profile by gut microbiota in cirrhosis. J Hepatol Grif K, Heller I, Prodinger WM, et al. Improvement of detection 2013;58:949–55. of bacterial pathogens in normally sterile body sites with Kamagata Y, Tamaki H. Cultivation of uncultured fastidious mi- a focus on orthopedic samples by use of a commercial 16S crobes. Microbes Environ 2005;20:85–91. rRNA broad-range PCR and sequence analysis. J Clin Microbiol Kang DW, Park JG, Ilhan ZE, et al. Reduced incidence of Prevotella 2012b;50:2250–4. and other fermenters in intestinal microflora of autistic chil- Groebel K, Hoelzle K, Wittenbrink MM, et al. Mycoplasma suis dren. PLoS One 2013;8:e68322. invades porcine erythrocytes. Infect Immun 2009;77:576–84. Kaprelyants AS, Gottschal JC, Kell DB. Dormancy in non- Guo ZZ, Wang P, Yi ZH, et al. The crosstalk between gut inflam- sporulating bacteria. FEMS Microbiol Rev 1993;10:271–85. mation and gastrointestinal disorders during acute pancre- Kaprelyants AS, Kell DB. Dormancy in stationary-phase cul- atitis. Curr Pharm Des 2014;20:1051–62. tures of Micrococcus luteus: flow cytometric analysis of Harrison F, Buckling A. Cooperative production of siderophores starvation and resuscitation. Appl Environ Microb 1993;59: by Pseudomonas aeruginosa. Front Biosci 2009;14:4113–26. 3187–96. Havey TC, Fowler RA, Daneman N. Duration of antibiotic therapy Kaprelyants AS, Mukamolova GV, Davey HM, et al. Quantitative for bacteremia: a systematic review and meta-analysis. Crit analysis of the physiological heterogeneity within starved Care 2011;15:R267. cultures of Micrococcus luteus by flow cytometry and cell Hevia A, Milani C, Lopez P, et al. Intestinal dysbiosis associated sorting. Appl Environ Microb 1996;62:1311–6. with systemic lupus erythematosus. MBio 2014;5:e01548–14. Kaprelyants AS, Mukamolova GV, Kell DB. Estimation of dor- Hill MJ. Intestinal flora and endogenous vitamin synthesis. Eur J mant Micrococcus luteus cells by penicillin lysis and by resus- Cancer Prev 1997;6 (Suppl 1):S43–5. citation in cell-free spent medium at high dilution. FEMS Mi- Hold GL, Smith M, Grange C, et al. Role of the gut microbiota crobiol Lett 1994;115:347–52. in inflammatory bowel disease pathogenesis: what have we Kaprelyants AS, Mukamolova GV, Kormer SS, et al. Intercellular learnt in the past 10 years? World J Gastroenterol 2014;20:1192– signalling and the multiplication of prokaryotes: bacterial cy- 210. tokines. Symp Soc Gen Microbi 1999;57:33–69. Holden DW. Microbiology. Persisters unmasked. Science Karlsson FH, Fak F, Nookaew I, et al. Symptomatic atherosclero- 2015;347:30–2. sis is associated with an altered gut metagenome. Nat Com- Holmes E, Li JV, Athanasiou T, et al. Understanding the role of mun 2012;3:1245. gut microbiome-host metabolic signal disruption in health Karlsson FH, Tremaroli V, Nookaew I, et al. Gut metagenome in and disease. Trends Microbiol 2011;19:349–59. European women with normal, impaired and diabetic glu- Hopkins PN. Molecular biology of atherosclerosis. Physiol Rev cose control. Nature 2013;498:99–103. 2013;93:1317–542. Karri S, Martinez VA, Coimbatore G. Effect of dihydrotestos- Horzempa J, O’Dee DM, Stolz DB, et al. Invasion of erythrocytes terone on gastrointestinal tract of male Alzheimer’s disease by Francisella tularensis. J Infect Dis 2011;204:51–9. transgenic mice. 2010;48:453–65. Huang Y, Fan XG, Tang ZS, et al. Detection of Helicobacter pylori Kau AL, Ahern PP, Griffin NW, et al. Human nutrition, the gut DNA in peripheral blood from patients with peptic ulcer or microbiome and the immune system. Nature 2011;474:327– gastritis. APMIS 2006;114:851–6. 36. Hugenholtz P. Exploring prokaryotic diversity in the genomic Keilin D. The problem of anabiosis or latent life: history and cur- era. Genome Biol 2002;3:0003.1–0003.8. rent concept. PRoy SocLondBBio 1959;150:149–91. Isberg RR. Discrimination between intracellular uptake and Kell DB. Metabolomics, modelling and machine learning in sys- surface adhesion of bacterial pathogens. Science 1991;252: tems biology: towards an understanding of the languages of 934–8. cells. The 2005 Theodor Buc ¨ her lecture. FEBS J 2006;273:873– Iwaki-Egawa S, Ihler GM. Comparison of the abilities of proteins 94. from Bartonella bacilliformis and Bartonella henselae to de- Kell DB. Iron behaving badly: inappropriate iron chelation as a form red cell membranes and to bind to red cell ghost pro- major contributor to the aetiology of vascular and other pro- teins. FEMS Microbiol Lett 1997;157:207–17. gressive inflammatory and degenerative diseases. BMC Med Jepson MA, Clark MA. Studying M cells and their role in infection. Genomics 2009;2:2. Trends Microbiol 1998;6:359–65. Kell DB. Towards a unifying, systems biology understanding of Jiang W, Lederman MM, Hunt P, et al. Plasma levels of bacterial large-scale cellular death and destruction caused by poorly DNA correlate with immune activation and the magnitude liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, pri- of immune restoration in persons with antiretroviral-treated ons, bactericides, chemical toxicology and others as exam- HIV infection. J Infect Dis 2009;199:1177–85. ples. Arch Toxicol 2010;84:825–89. Joyce SA, MacSharry J, Casey PG, et al. Regulation of host weight Kell DB, Kaprelyants AS, Grafen A. Pheromones, social behaviour gain and lipid metabolism by bacterial bile acid modification and the functions of secondary metabolism in bacteria. in the gut. P Natl Acad Sci USA 2014;111:7421–6. Trends Ecol Evol 1995;10:126–9. Jun DW, Kim KT, Lee OY, et al. Association between small in- Kell DB, Kaprelyants AS, Weichart DH, et al. Viability and activity testinal bacterial overgrowth and peripheral bacterial DNA in readily culturable bacteria: a review and discussion of the in cirrhotic patients. Dig Dis Sci 2010;55:1465–71. practical issues. Anton Leeuw 1998;73:169–87. Jung C, Hugot JP, Barreau F. Peyer’s patches: the immune sensors Kell DB, Knowles JD. The role of modeling in systems biology. of the intestine. Int J Inflam 2010;2010:823710. In: Szallasi Z, Stelling J, Periwal V (eds). System Modeling in Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 586 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 Cellular Biology: From Concepts to Nuts and Bolts. Cambridge: across the human body: meta-analysis of microbial commu- MIT Press, 2006, 3–18. nity structures in human microbiome datasets. PLoS Comput Kell DB, Mukamolova GV, Finan CL Resuscitation of ‘uncultured’ Biol 2013;9:e1002863. microorganisms. In: Bull AT, et al. (ed). Microbial Diversity and Koren O, Spor A, Felin J, et al. Human oral, gut, and plaque mi- Bioprospecting. Washington, DC: American Society for Micro- crobiota in patients with atherosclerosis. P Natl Acad Sci USA biology, 2003, 100–8. 2011;108:4592–8. Kell DB, Oliver SG. How drugs get into cells: tested and testable Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory predictions to help discriminate between transporter- bowel disease: current status and the future ahead. Gastroen- mediated uptake and lipoidal bilayer diffusion. Front Pharma- terology 2014;146:1489–99. col 2014;5:231. Kotsaki A, Giamarellos-Bourboulis EJ. Emerging drugs for the Kell DB, Pretorius E. Serum ferritin is an important inflamma- treatment of sepsis. Expert Opin Emerg Dr 2012;17:379–91. tory disease marker, as it is mainly a leakage product from Kozarov E, Sweier D, Shelburne C, et al. Detection of bacterial damaged cells. Metallomics 2014;4:748–73. DNA in atheromatous plaques by quantitative PCR. Microbes Kell DB, Pretorius E. The simultaneous occurrence of both hyper- Infect 2006;8:687–93. coagulability and hypofibrinolysis in blood and serum dur- Koziel J, Mydel P, Potempa J. The link between periodontal ing systemic inflammation, and the roles of iron and fib- disease and rheumatoid arthritis: an updated review. Curr rin(ogen). Integr Biol 2015;7:24–52. Rheumatol Rep 2014;16:408. Kell DB, Ryder HM, Kaprelyants AS, et al. Quantifying hetero- Kwiatkowska B, Masli ´ nska ´ M. Macrolide therapy in chronic in- geneity: flow cytometry of bacterial cultures. Anton Leeuw flammatory diseases. Mediat Inflamm 2012;2012:636157. 1991;60:145–58. Kyrpides NC, Hugenholtz P, Eisen JA, et al. Genomic encyclopedia Keller M, Zengler K. Tapping into microbial diversity. Nat Rev Mi- of bacteria and archaea: sequencing a myriad of type strains. crobiol 2004;2:141–50. PLoS Biol 2014;12:1001920. Keren I, Kaldalu N, Spoering A, et al. Persister cells and tolerance Lagier JC, Edouard S, Pagnier I, et al. Current and past strategies to antimicrobials. FEMS Microbiol Lett 2004a;230:13–8. for bacterial culture in clinical microbiology. Clin Microbiol Rev Keren I, Shah D, Spoering A, et al. Specialized persister cells and 2015a;28:208–36. the mechanism of multidrug tolerance in Escherichia coli. J Lagier JC, Hugon P, Khelaifia S, et al. The rebirth of culture in Bacteriol 2004b;186:8172–80. microbiology through the example of culturomics to study Kerneis ´ S, Bogdanova A, Kraehenbuhl JP, et al. Conversion by human gut microbiota. Clin Microbiol Rev 2015b;28:237–64. Peyer’s patch lymphocytes of human enterocytes into M cells Lanter BB, Sauer K, Davies DG. Bacteria present in carotid arterial that transport bacteria. Science 1997;277:949–52. plaques are found as biofilm deposits which may contribute Kibru D, Gelaw B, Alemu A, et al. Helicobacter pylori infection to enhanced risk of plaque rupture. MBio 2014;5:e01206–14. and its association with anemia among adult dyspeptic pa- Larsen N, Vogensen FK, van den Berg FW, et al. Gut microbiota in tients attending Butajira Hospital, Ethiopia. BMC Infect Dis human adults with type 2 diabetes differs from non-diabetic 2014;14:656. adults. PLoS One 2010;5:e9085. Kimura I, Ozawa K, Inoue D, et al. The gut microbiota suppresses Lasken RS. Genomic sequencing of uncultured microorganisms insulin-mediated fat accumulation via the short-chain fatty from single cells. Nat Rev Microbiol 2012;10:631–40. acid receptor GPR43. Nat Commun 2013;4:1829. Lasken RS, McLean JS. Recent advances in genomic DNA se- Kinoshita M, Takeda K. Microbial and dietary factors modu- quencing of microbial species from single cells. Nat Rev Genet lating intestinal regulatory T cell homeostasis. FEBS Lett 2014;15:577–84. 2014;588:4182–7. Le Chatelier E, Nielsen T, Qin J, et al. Richness of human Kishino S, Takeuchi M, Park S-B, et al. Polyunsaturated fatty acid gut microbiome correlates with metabolic markers. Nature saturation by gut lactic acid bacteria affecting host lipid com- 2013;500:541–6. position. P Natl Acad Sci USA 2013;110:17808–13. LeBlanc JG, Milani C, de Giori GS, et al. Bacteria as vitamin sup- Klatt NR, Funderburg NT, Brenchley JM. Microbial transloca- pliers to their host: a gut microbiota perspective. Curr Opin tion, immune activation, and HIV disease. Trends Microbiol Biotechnol 2013;24:160–8. 2013;21:6–13. Leli C, Cardaccia A, Ferranti M, et al. Procalcitonin better than C- Kocan KM, de la Fuente J, Blouin EF, et al. Anaplasma marginale reactive protein, erythrocyte sedimentation rate, and white (Rickettsiales: Anaplasmataceae): recent advances in defin- blood cell count in predicting DNAemia in patients with sep- ing host-pathogen adaptations of a tick-borne rickettsia. Par- sis. Scand J Infect Dis 2014;46:745–52. asitology 2004;129 (Suppl):285–300. Lelouard H, Henri S, De Bovis B, et al. Pathogenic bacteria and Koch AL. The adaptive responses of Escherichia coli to a feast and dead cells are internalized by a unique subset of Peyer’s famine existence. Adv Microb Physiol 1971;6:147–217. patch dendritic cells that express lysozyme. Gastroenterology Koch AL. The variability and individuality of the bacterium. In: 2010;138:173–84, e171–73. Neidhardt FC, et al. (eds). Escherichia coli and Salmonella Ty- Leslie JL, Young VB. The rest of the story: the microbiome and phimurium: Cellular and Molecular Biology. Washington, DC: gastrointestinal infections. Curr Opin Microbiol 2015;23c:121– American Society for Microbiology, 1987, 1606–14. 5. Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota Lewis K. Persister cells. Annu Rev Microbiol 2010;64:357–72. metabolism of L-carnitine, a nutrient in red meat, promotes Lin W, Weinberg EM, Chung RT. Pathogenesis of accelerated fi- atherosclerosis. Nat Med 2013;19:576–85. brosis in HIV/HCV co-infection. J Infect Dis 2013;207 (Suppl Kogure K, Simidu U, Taga N. A tentative direct microscopic 1):S13–8. method for counting living marine bacteria. Can J Microbiol Ling LL, Schneider T, Peoples AJ, et al. A new antibi- 1979;25:415–20. otic kills pathogens without detectable resistance. Nature Koren O, Knights D, Gonzalez A, et al. A guide to enterotypes 2015;517:455–9. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 587 Lipinski B, Pretorius E. The role of iron-induced fibrin in the Mar´ın L, Miguelez ´ EM, Villar CJ, et al. Bioavailability of dietary pathogenesis of Alzheimer’s disease and the protective role polyphenols and gut microbiota metabolism: antimicrobial of magnesium. Front Hum Neurosci 2013;7:735. properties. BioMed Res Int 2015;2015:905215. Loman NJ, Constantinidou C, Chan JZ, et al. High-throughput Mariotti S, Pardini M, Gagliardi MC, et al. Dormant Mycobac- bacterial genome sequencing: an embarrassment of choice, terium tuberculosis fails to block phagosome maturation and a world of opportunity. Nat Rev Microbiol 2012;10:599–606. shows unexpected capacity to stimulate specific human T Lozupone CA, Li M, Campbell TB, et al. Alterations in the gut lymphocytes. JImmunol 2013;191:274–82. microbiota associated with HIV-1 infection. Cell Host Microbe Marshall B. Helicobacter connections. ChemMedChem 2013;14:329–39. 2006;1:783–802. Lozupone CA, Stombaugh JI, Gordon JI, et al. Diversity, sta- Marshall BJ, Warren JR. Unidentified curved bacilli in the stom- bility and resilience of the human gut microbiota. Nature ach of patients with gastritis and peptic ulceration. Lancet 2012;489:220–30. 1984;1:1311–5. Luckey D, Gomez A, Murray J, et al. Bugs, us: the role of the gut Martin F-PJ, Dumas M-E, Wang Y, et al. A top-down systems biol- in autoimmunity. Indian J Med Res 2013;138:732–43. ogy view of microbiome-mammalian metabolic interactions Lysak LV, Lapygina EV, Konova IA, et al. Quantity and taxo- in a mouse model. Mol Syst Biol 2007;3:112. nomic composition of ultramicrobacteria in soils. Microbiol- Mart´ınez I, Perdicaro DJ, Brown AW, et al. Diet-induced alter- ogy 2010;79:408–12. ations of host cholesterol metabolism are likely to affect the Ma HD, Wang YH, Chang C, et al. The intestinal microbiota and gut microbiota composition in hamsters. Appl Environ Microb microenvironment in liver. Autoimmun Rev 2015;14:183–91. 2013;79:516–24. McColl BW, Allan SM, Rothwell NJ. Systemic infection, in- Mart´ınez I, Wallace G, Zhang C, et al. Diet-induced metabolic im- flammation and acute ischemic stroke. Neuroscience provements in a hamster model of hypercholesterolemia are 2009;158:1049–61. strongly linked to alterations of the gut microbiota. Appl En- McDermott AJ, Huffnagle GB. The microbiome and regulation of viron Microb 2009;75:4175–84. mucosal immunity. Immunology 2014;142:24–31. Maslowski KM, Vieira AT, Ng A, et al. Regulation of inflammatory Macdonell MT, Hood MA. Isolation and characterization of ultra- responses by gut microbiota and chemoattractant receptor microbacteria from a gulf coast estuary. Appl Environ Microb GPR43. Nature 2009;461:1282–6. 1982;43:566–71. Mason CA, Hamer G, Bryers JD. The death and lysis of mi- MacFie J. Current status of bacterial translocation as a cause of croorganisms in environmental processes. FEMS Microbiol Rev surgical sepsis. Brit Med Bull 2004;71:1–11. 1986;39:373–401. McHardy IH, Li X, Tong M, et al. HIV Infection is associated with MathiasA,PaisB,Favre L, et al. Role of secretory IgA in compositional and functional shifts in the rectal mucosal the mucosal sensing of commensal bacteria. Gut Microbes microbiota. Microbiome 2013;1:26. 2014;5:688–95. Macintire DK, Bellhorn TL. Bacterial translocation: clinical im- Mattman L. Cell Wall Deficient Forms: Stealth Pathogens . Boca Raton, plications and prevention. Vet Clin N Am-Small 2002;32: FL: CRC Press, 2001. 1165–78. Mercier R, Kawai Y, Errington J. Excess membrane synthe- McLaughlin RW, Vali H, Lau PCK, et al. Are there naturally occur- sis drives a primitive mode of cell proliferation. Cell ring pleomorphic bacteria in the blood of healthy humans? J 2013;152:997–1007. Clin Microbiol 2002;40:4771–5. Mercier R, Kawai Y, Errington J. General principles for the forma- McMahon CJ, Hopkins S, Vail A, et al. Inflammation as a predic- tion and proliferation of a wall-free (L-form) state in bacteria. tor for delayed cerebral ischemia after aneurysmal subarach- Elife 2014;3:e04629. noid haemorrhage. J Neurointerv Surg 2013;5:512–7. Meyer RD. Legionella infections: a review of five years of re- Madan JC, Koestler DC, Stanton BA, et al. Serial analysis of the search. Rev Infect Dis 1983;5:258–78. gut and respiratory microbiome in cystic fibrosis in infancy: Mifkovic A, Skultety J, Pindak D, et al. Specific aspects of acute interaction between intestinal and respiratory tracts and im- pancreatitis. Bratisl Lek Listy 2009;110:544–52. pact of nutritional exposures. MBio 2012;3:e00251–12. Mifkovic A, Skultety J, Sykora P, et al. Intra-abdominal hyperten- Maisonneuve E, Castro-Camargo M, Gerdes K. (p)ppGpp con- sion and acute pancreatitis. Bratisl Lek Listy 2013;114:166–71. trols bacterial persistence by stochastic induction of toxin- Minasyan H. Erythrocyte and blood antibacterial defense. Eur J antitoxin activity. Cell 2013;154:1140–50. Microbiol Immunol 2014;4:138–43. Maisonneuve E, Gerdes K. Molecular mechanisms underlying Montassier E, Batard E, Gastinne T, et al. Recent changes in bacterial persisters. Cell 2014;157:539–48. bacteremia in patients with cancer: a systematic review of Maiwald M, Relman DA. Whipple’s disease and Tropheryma epidemiology and antibiotic resistance. Eur J Clin Microbiol whippelii: secrets slowly revealed. Clin Infect Dis 2001;32:457– 2013;32:841–50. 63. Montes-de-Oca M, Blanco MJ, Marquez M, et al. Haemodynamic Maiwald M, von Herbay A, Fredricks DN, et al. Cultivation of derangement in human immunodeficiency virus-infected Tropheryma whipplei from cerebrospinal fluid. J Infect Dis patients with hepatitis C virus-related cirrhosis: the role of 2003;188:801–8. bacterial translocation. Liver Int 2011;31:850–8. Malaguarnera G, Giordano M, Nunnari G, et al. Gut microbiota Morgan XC, Huttenhower C. Meta’omic analytic techniques in alcoholic liver disease: pathogenetic role and therapeutic for studying the intestinal microbiome. Gastroenterology perspectives. World J Gastroenterol 2014;20:16639–48. 2014;146:1437–48. Mancini N, Carletti S, Ghidoli N, et al. The era of molecular and Morgan XC, Tickle TL, Sokol H, et al. Dysfunction of the intestinal other non-culture-based methods in diagnosis of sepsis. Clin microbiome in inflammatory bowel disease and treatment. Microbiol Rev 2010;23:235–51. Genome Biol 2012;13:R79. Manichanh C, Borruel N, Casellas F, et al. The gut microbiota in Morita RY. Bacteria in Oligotrophic Environments: Starvation-Survival IBD. Nat Rev Gastroentero 2012;9:599–608. Lifestyle. New York: Chapman and Hall, 1997. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 588 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 Muegge BD, Kuczynski J, Knights D, et al. Diet drives convergence ized, double-blind, placebo-controlled trial. Clin Ther in gut microbiome functions across mammalian phylogeny 2009a;31:1754–64. and within humans. Science 2011;332:970–4. Ogrendik M. Rheumatoid arthritis is linked to oral bacteria: eti- Mukamolova GV, Kaprelyants AS, Young DI, et al. A bacterial cy- ological association. Mod Rheumatol 2009b;19:453–6. tokine. P Natl Acad Sci USA 1998a;95:8916–21. Ogrendik M. Antibiotics for the treatment of rheumatoid arthri- Mukamolova GV, Kormer SS, Kell DB, et al. Stimulation of the tis. Int J Gen Med 2013a;7:43–7. multiplication of Micrococcus luteus by an autocrine growth Ogrendik M. Rheumatoid arthritis is an autoimmune disease factor. Arch Microbiol 1999;172:9–14. caused by periodontal pathogens. Int J Gen Med 2013b;6:383– Mukamolova GV, Turapov OA, Kazarian K, et al. The rpf gene of 6. Micrococcus luteus encodes an essential secreted growth fac- Olah A, Romics L, Jr. Enteral nutrition in acute pancreati- tor. Mol Microbiol 2002a;46:611–21. tis: a review of the current evidence. World J Gastroenterol Mukamolova GV, Turapov OA, Young DI, et al. A family of au- 2014;20:16123–31. tocrine growth factors in Mycobacterium tuberculosis. Mol Mi- Owen JL, Mohamadzadeh M. Microbial activation of gut dendritic crobiol 2002b;46:623–35. cells and the control of mucosal immunity. J Interf Cytok Res Mukamolova GV, Yanopolskaya ND, Kell DB, et al. On resuscita- 2013;33:619–31. tion from the dormant state of Micrococcus luteus. Anton Leeuw Owyang C, Wu GD. The gut microbiome in health and disease. 1998b;73:237–43. Gastroenterology 2014;146:1433–6. Munoz ˜ P, Cruz AF, Rodr´ıguez-Creixems ´ M, et al. Gram-negative Page EE, Nelson M, Kelleher P. HIV and hepatitis C coinfec- bloodstream infections. Int J Antimicrob Ag 2008;32 (Suppl tion: pathogenesis and microbial translocation. Curr Opin HIV 1):S10–14. AIDS 2011;6:472–7. Munteanu D, Negru A, Radulescu M, et al. Evaluation of bacterial Pallen MJ, Loman NJ, Penn CW. High-throughput sequencing translocation in patients with chronic HCV infection. Rom J and clinical microbiology: progress, opportunities and chal- Intern Med 2014;52:91–6. lenges. Curr Opin Microbiol 2010;13:625–31. Murray PR. The clinician and the microbiology laboratory. In: Parracho HM, Bingham MO, Gibson GR, et al. Differences between Bennett JE, Dolin R, Blaser MJ (eds). Mandell, Douglas and Ben- the gut microflora of children with autistic spectrum disor- nett’s Principles and Practice of Infectious Diseases. Philadelphia: ders and that of healthy children. J Med Microbiol 2005;54:987– Saunders Elsevier, 2015. 91. Mylotte JM, Tayara A. Blood cultures: clinical aspects and con- Percival SL, Hill KE, Williams DW, et al. A review of the scien- troversies. Eur J Clin Microbiol 2000;19:157–63. tific evidence for biofilms in wounds. Wound Repair Regen Nagalingam NA, Lynch SV. Role of the microbiota in inflamma- 2012;20:647–57. tory bowel diseases. Inflamm Bowel Dis 2012;18:968–84. Petersen C, Round JL. Defining dysbiosis and its influence on host Nagata E, de Toledo A, Oho T. Invasion of human aortic en- immunity and disease. Cell Microbiol 2014;16:1024–33. dothelial cells by oral viridans group streptococci and induc- Petriz BA, Castro AP, Almeida JA, et al. Exercise induction of gut tion of inflammatory cytokine production. Mol Oral Microbiol microbiota modifications in obese, non-obese and hyperten- 2011;26:78–88. sive rats. BMC Genomics 2014;15:511. Narihiro T, Kamagata Y. Cultivating yet-to-be cultivated Pflughoeft KJ, Versalovic J. Human microbiome in health and dis- microbes: the challenge continues. Microbes Environ ease. Annu Rev Pathol 2012;7:99–122. 2013;28:163–5. Pham VH, Kim J. Cultivation of unculturable soil bacteria. Trends Natarajan N, Pluznick JL. From microbe to man: the role of mi- Biotechnol 2012;30:475–84. crobial short chain fatty acid metabolites in host cell biology. Postgate JR. Viability measurements and the survival of mi- Am J Physiol-Cell Ph 2014;307:C979–85. crobes under minimum stress. Adv Microb Physiol 1967;1:1– Neuman Y. Cryptobiosis: a new theoretical perspective. Prog Bio- 23. phys Mol Bio 2006;92:258–67. Postgate JR. Viable counts and viability. Methods Microbiol Nichols D, Cahoon N, Trakhtenberg EM, et al. Useofichip for 1969;1:611–28. high-throughput in situ cultivation of ‘uncultivable’ micro- Postgate JR. Death in Microbes and Macrobes. Cambridge: Cam- bial species. Appl Environ Microb 2010;76:2445–50. bridge University Press, 1976. Nielsen HH, Qiu J, Friis S, et al. Treatment for Helicobacter pylori Power SE, O’Toole PW, Stanton C, et al. Intestinal microbiota, diet infection and risk of Parkinson’s disease in Denmark. Eur J and health. Brit J Nutr 2014;111:387–402. Neurol 2012;19:864–9. Prajsnar TK, Hamilton R, Garcia-Lara J, et al. A privileged in- Nikkari S, McLaughlin IJ, Bi W, et al. Does blood of healthy traphagocyte niche is responsible for disseminated infection subjects contain bacterial ribosomal DNA? J Clin Microbiol of Staphylococcus aureus in a zebrafish model. Cell Microbiol 2001;39:1956–9. 2012;14:1600–19. O’Mahony SM, Clarke G, Borre YE, et al. Serotonin, tryptophan Pretorius E, Bester J, Vermeulen N, et al. Profound morphological metabolism and the brain-gut-microbiome axis. Behav Brain changes in the erythrocytes and fibrin networks of patients Res 2015;277:32–48. with hemochromatosis or with hyperferritinemia, and their Ochoa-Repar ´ az J, Mielcarz DW, Begum-Haque S, et al. Gut, bugs, normalization by iron chelators and other agents. PlosOne and brain: role of commensal bacteria in the control of cen- 2014a;9:e85271. tral nervous system disease. Ann Neurol 2011;69:240–7. Pretorius E, Kell DB. Diagnostic morphology: biophysical in- Ochoa-Repar ´ az J, Mielcarz DW, Ditrio LE, et al. Role of gut com- dicators for iron-driven inflammatory diseases. Integr Biol mensal microflora in the development of experimental au- 2014;6:486–510. toimmune encephalomyelitis. JImmunol 2009;183:6041–50. Pretorius E, Swanepoel AC, Buys AV, et al. Eryptosis as a marker Ogrendik M. Efficacy of roxithromycin in adult patients with of Parkinson’s disease. Aging 2014b;6:788–818. rheumatoid arthritis who had not received disease- Pretorius E, Vermeulen N, Bester J, et al. A novel method for modifying antirheumatic drugs: a 3-month, random- assessing the role of iron and its functional chelation in Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 589 fibrin fibril formation: the use of scanning electron mi- Rosenfeld ME, Campbell LA. Pathogens and atherosclerosis: up- croscopy. Toxicol Mech Method 2013;23:352–9. date on the potential contribution of multiple infectious Primas H. Chemistry, Quantum Mechanics and Reductionism. Berlin: organisms to the pathogenesis of atherosclerosis. Thromb Springer, 1981. Haemostasis 2011;106:858–67. Proal AD, Albert PJ, Marshall TG. Autoimmune disease and the Ross R, Mills S, Hill C, et al. Specific metabolite production by human metagenome. In: Nelson KE (ed). Metagenomics of the gut microbiota as a basis for probiotic function. Int Dairy J Human Body. New York: Springer Science and Business Media, 2010;20:269–76. 2011. Sabatino A, Regolisti G, Brusasco I, et al. Alterations of intestinal Proal AD, Albert PJ, Marshall TG, et al. Immunostimulation in barrier and microbiota in chronic kidney disease. Nephrol Dial the treatment for chronic fatigue syndrome/myalgic en- Transpl 2014, DOI:10.1093/ndt/gfu287. cephalomyelitis. Immunol Res 2013;56:398–412. Sacchi P, Cima S, Corbella M, et al. Liver fibrosis, microbial Proal AD, Albert PJ, Marshall TG. Inflammatory disease and the translocation and immune activation markers in HIV and human microbiome. Discov Med 2014;17:257–65. HCV infections and in HIV/HCV co-infection. Dig Liver Dis Puddu A, Sanguineti R, Montecucco F, et al. Evidence for 2015;47:218–25. the gut microbiota short-chain fatty acids as key patho- Sahin N, Gonzalez JM, Iizuka T, et al. Characterization of two physiological molecules improving diabetes. Mediat Inflamm aerobic ultramicrobacteria isolated from urban soil and a de- 2014;2014:162021. scription of Oxalicibacterium solurbis sp. nov. FEMS Microbiol Puleo F, Arvanitakis M, Van Gossum A, et al. Gut failure in the Lett 2010;307:25–9. ICU. Semin Respir Crit Care 2011;32:626–38. Saito A, Rolfe RD, Edelstein PH, et al. Comparison of liquid Puspita DI, Kamagata Y, Tanaka M, et al. Are unculti- growth media for Legionella pneumophila. J Clin Microbiol vated bacteria really uncultivable? Microbes Environ 2012;27: 1981;14:623–7. 356–66. Salipante SJ, Roach DJ, Kitzman JO, et al. Large-scale ge- Puspita DI, Uehara M, Katayama T, et al. Resuscitation promoting nomic sequencing of extraintestinal pathogenic Escherichia factor (Rpf) from Tomitella biformata AHU 1821(T) promotes coli strains. Genome Res 2015;25:119–28. growth and resuscitates non-dividing cells. Microbes Environ Salipante SJ, Sengupta DJ, Rosenthal C, et al. Rapid 16S rRNA 2013;28:58–64. next-generation sequencing of polymicrobial clinical sam- QinJ,LiY,Cai Z, et al. A metagenome-wide association study of ples for diagnosis of complex bacterial infections. PLoS One gut microbiota in type 2 diabetes. Nature 2012;490:55–60. 2013;8:e65226. Radajewski S, Ineson P, Parekh NR, et al. Stable-isotope probing Salter SJ, Cox MJ, Turek EM, et al. Reagent and laboratory contam- as a tool in microbial ecology. Nature 2000;403:646–9. ination can critically impact sequence-based microbiome Ram´ırez JH, Parra B, Gutierrez S, et al. Biomarkers of cardiovascu- analyses. BMC Biol 2014;12:87. lar disease are increased in untreated chronic periodontitis: Sanc ´ hez-Calvo JM, Garc´ıa-Castillo M, Lamas A, et al. Gut mi- a case control study. Aust Dent J 2014;59:29–36. crobiota composition in cystic fibrosis patients: molecu- Ratledge C. Iron metabolism and infection. Food Nutr Bull lar approach and classical culture. JCystFibros 2008;7: 2007;28:S515–23. S50. Rechner AR, Kuhnle G, Hu H, et al. The metabolism of dietary Sandler NG, Douek DC. Microbial translocation in HIV infection: polyphenols and the relevance to circulating levels of conju- causes, consequences and treatment opportunities. Nat Rev gated metabolites. Free Radical Res 2002;36:1229–41. Microbiol 2012;10:655–66. Renesto P, Crapoulet N, Ogata H, et al. Genome-based design of Sanz Y, Moya-Per ´ ez A. Microbiota, inflammation and obesity. a cell-free culture medium for Tropheryma whipplei. Lancet Adv Exp Med Biol 2014;817:291–317. 2003;362:447–9. Sato J, Kanazawa A, Ikeda F, et al. Gut dysbiosis and detection of Renko J, Lepp PW, Oksala N, et al. Bacterial signatures in ‘live gut bacteria’ in blood of Japanese patients with type 2 atherosclerotic lesions represent human commensals and diabetes. Diabetes Care 2014;37:2343–50. pathogens. Atherosclerosis 2008;201:192–7. Sato S, Kiyono H, Fujihashi K. Mucosal immunosenescence in Rhee SH. Lipopolysaccharide: basic biochemistry, intracellular the gastrointestinal tract: a mini-review. Gerontology 2014. signaling, and physiological impacts in the gut. Intest Res Sawa T. The molecular mechanism of acute lung injury caused 2014;12:90–5. by Pseudomonas aeruginosa: from bacterial pathogenesis to Rinke C, Schwientek P, Sczyrba A, et al. Insights into the phy- host response. J Intensive Care 2014;2:10. logeny and coding potential of microbial dark matter. Nature Sayin SI, Wahlstrom A, Felin J, et al. Gut microbiota regulates 2013;499:431–7. bile acid metabolism by reducing the levels of tauro-beta- Robles-Alonso V, Guarner F. From basic to applied research: muricholic acid, a naturally occurring FXR antagonist. Cell lessons from the human microbiome projects. J Clin Gastroen- Metab 2013;17:225–35. terol 2014;48 (Suppl 1):S3–4. Scanlan PD, Buckling A, Kong W, et al. Gut dysbiosis in cystic Rogler G, Rosano G. The heart and the gut. Eur Heart J fibrosis. JCystFibros 2012;11:454–5. 2014;35:426–30. Scheperjans F, Aho V, Pereira PA, et al. Gut microbiota are related Rolain JM, Maurin M, Mallet MN, et al. Culture and antibiotic sus- to Parkinson’s disease and clinical phenotype. Movement Dis- ceptibility of Bartonella quintana in human erythrocytes. An- ord 2015;30:350–8. timicrob Agents Ch 2003;47:614–9. Scher JU, Abramson SB. The microbiome and rheumatoid arthri- Ronco C. Endotoxin removal: history of a mission. Blood Purif tis. Nat Rev Rheumatol 2011;7:569–78. 2014;37 (Suppl 1):5–8. Schnabl B, Brenner DA. Interactions between the intestinal mi- Rooks MG, Veiga P, Wardwell-Scott LH, et al. Gut microbiome crobiome and liver diseases. Gastroenterology 2014;146:1513– composition and function in experimental colitis during 24. active disease and treatment-induced remission. ISME J Schroeter J, Wilkemeyer I, Schiller RA, et al. Validation of 2014;8:1403–17. the microbiological testing of tissue preparations using the Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 590 FEMS Microbiology Reviews, 2015, Vol. 39, No. 4 BACTEC blood culture system. Transfus Med Hemoth 2012;39: The Integrative HMP (iHMP) Research Network Consortium. 387–90. The Integrative Human Microbiome Project: dynamic anal- Schulz MD, Atay C, Heringer J, et al. High-fat-diet-mediated dys- ysis of microbiome-host omics profiles during periods biosis promotes intestinal carcinogenesis independently of of human health and disease. Cell Host Microbe 2014;16: obesity. Nature 2014;514:508–12. 276–89. Seksik P, Rigottier-Gois L, Gramet G, et al. Alterations of the dom- Thwaites GE, Gant V. Are bloodstream leukocytes Trojan Horses inant faecal bacterial groups in patients with Crohn’s disease for the metastasis of Staphylococcus aureus? Nat Rev Microbiol of the colon. Gut 2003;52:237–42. 2011;9:215–22. Seringec N, Guncu G, Arihan O, et al. Investigation of hemorhe- Tojo R, Suar ´ ez A, Clemente MG, et al. Intestinal microbiota in ological parameters in periodontal diseases. Clin Hemorheol health and disease: role of bifidobacteria in gut homeosta- Micro 2014, DOI:10.3233/CH-141892. sis. World J Gastroenterol 2014;20:15163–76. Severance EG, Gressitt KL, Stallings CR, et al. Discordant pat- Tomas-Barberan F, Garcia-Villalba R, Quartieri A, et al. In vitro terns of bacterial translocation markers and implications for transformation of chlorogenic acid by human gut microbiota. innate immune imbalances in schizophrenia. Schizophr Res Mol Nutr Food Res 2014;58:1122–31. 2013;148:130–7. Touati D. Iron and oxidative stress in bacteria. Arch Biochem Bio- Severance EG, Yolken RH, Eaton WW. Autoimmune dis- phys 2000;373:1–6. eases, gastrointestinal disorders and the microbiome in Trøseid M, Manner IW, Pedersen KK, et al. Microbial translocation schizophrenia: more than a gut feeling. Schizophr Res 2014, and cardiometabolic risk factors in HIV infection. AIDS Res DOI:10.1016/j.schres.2014.06.027. Hum Retrov 2014;30:514–22. Sharma BR. Infection in patients with severe burns: causes and Tsujimoto H, Ono S, Mochizuki H. Role of translocation of prevention thereof. Infect Dis Clin N Am 2007;21:745–59. pathogen-associated molecular patterns in sepsis. Digest Shaw MK. Cell invasion by Theileria sporozoites. Trends Parasitol Surg 2009;26:100–9. 2003;19:2–6. Turnbaugh PJ, Hamady M, Yatsunenko T, et al. A core gut micro- Sheedy JR, Wettenhall RE, Scanlon D, et al. Increased d-lactic biome in obese and lean twins. Nature 2009;457:480–4. acid intestinal bacteria in patients with chronic fatigue syn- Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated drome. In Vivo 2009;23:621–8. gut microbiome with increased capacity for energy harvest. Sia AK, Allred BE, Raymond KN. Siderocalins: siderophore bind- Nature 2006;444:1027–131. ing proteins evolved for primary pathogen host defense. Curr Vaarala O. Human intestinal microbiota and type 1 diabetes. Curr Opin Chem Biol 2013;17:150–7. Diabetes Rep 2013;13:601–7. Singh S, Eldin C, Kowalczewska M, et al. Axenic culture of fas- Vajro P, Paolella G, Fasano A. Microbiota and gut-liver axis: their tidious and intracellular bacteria. Trends Microbiol 2013;21: influences on obesity and obesity-related liver disease. JPe- 92–9. diatr Gastr Nutr 2013;56:461–8. Soina VS, Lysak LV, Konova IA, et al. Study of ultramicrobacte- Valencia-Shelton F, Loeffelholz M. Nonculture techniques for ria (nanoforms) in soils and subsoil deposits by electron mi- the detection of bacteremia and fungemia. Future Microbiol croscopy. Eurasian Soil Sci 2012;45:1048–56. 2014;9:543–59. Steinberg SM. Bacterial translocation: what it is and what it is van der Merwe J, Prysliak T, Perez-Casal J. Invasion of bovine not. Am J Surg 2003;186:301–5. peripheral blood mononuclear cells and erythrocytes by My- Stevenson BS, Eichorst SA, Wertz JT, et al. New strategies for coplasma bovis. Infect Immun 2010;78:4570–8. cultivation and detection of previously uncultured microbes. van Duynhoven J, Vaughan EE, Jacobs DM, et al. Metabolic fate Appl Environ Microb 2004;70:4748–55. of polyphenols in the human superorganism. P Natl Acad Sci Stewart EJ. Growing unculturable bacteria. J Bacteriol USA 2011;108 (Suppl 1):4531–8. 2012;194:4151–60. Varani S, Stanzani M, Paolucci M, et al. Diagnosis of blood- Straub RH, Cutolo M. Circadian rhythms in rheumatoid arthritis: stream infections in immunocompromised patients by real- implications for pathophysiology and therapeutic manage- time PCR. JInfect 2009;58:346–51. ment. Arthritis Rheum 2007;56:399–408. Vartoukian SR, Palmer RM, Wade WG. Strategies for culture Swank GM, Deitch EA. Role of the gut in multiple organ fail- of ‘unculturable’ bacteria. FEMS Microbiol Lett 2010;309: ure: bacterial translocation and permeability changes. World 1–7. JSurg 1996;20:411–7. Vazquez-Castellanos ´ JF, Serrano-Villar S, Latorre A, et al. Al- Syrjanen ¨ J, Valtonen VV, Iivanainen M, et al. Preceding infection tered metabolism of gut microbiota contributes to chronic as an important risk factor for ischaemic brain infarction in immune activation in HIV-infected individuals. Mucosal Im- young and middle aged patients. Brit Med J 1988;296:1156–60. munol 2014, DOI:10.1038/mi.2014.107. Tanaka T, Kawasaki K, Daimon S, et al. Ahiddenpitfallinthe Venkatesh M, Mukherjee S, Wang H, et al. Symbiotic bacte- preparation of agar media undermines microorganism cul- rial metabolites regulate gastrointestinal barrier function via tivability. Appl Environ Microb 2014;80:7659–66. the xenobiotic sensor PXR and Toll-like receptor 4. Immunity Taneja V. Arthritis susceptibility and the gut microbiome. FEBS 2014;41:296–310. Lett 2014;588:4244–9. Vila-Corcoles A, Ochoa-Gondar O, Rodriguez-Blanco T, et al. Eval- Tang WH,WangZ,LevisonBS, et al. Intestinal microbial uating clinical effectiveness of pneumococcal vaccination in metabolism of phosphatidylcholine and cardiovascular risk. preventing stroke: the CAPAMIS Study 3-year follow-up. J New Engl J Med 2013;368:1575–84. Stroke Cerebrovasc 2014;23:1577–84. Tedeschi GG, Bondi A, Paparelli M, et al. Electron microscopical Vincent JL, Rello J, Marshall J, et al. International study of the evidence of the evolution of corynebacteria-like microorgan- prevalence and outcomes of infection in intensive care units. isms within human erythrocytes. Experientia 1978;34:458–60. JAMA 2009;302:2323–9. Thaiss CA, Zeevi D, Levy M, et al. Transkingdom control of micro- Vitry MA, Hanot Mambres D, Deghelt M, et al. Brucella melitensis biota diurnal oscillations promotes metabolic homeostasis. invades murine erythrocytes during infection. Infect Immun Cell 2014;159:514–29. 2014;82:3927–38. Downloaded from https://academic.oup.com/femsre/article/39/4/567/2467761 by DeepDyve user on 19 July 2022 Potgieter et al. 591 Vizcarra JA, Wilson-Perez HE, Espay AJ. The power in num- logenetic characterization of Sutterella species in intestinal bers: gut microbiota in Parkinson’s disease. Movement Disord biopsy samples from children with autism and gastrointesti- 2015;30:296–8. nal disturbances. MBio 2012;3:00261–11. Vogl G, Plaickner A, Szathmary S, et al. Mycoplasma gallisep- Williams TA, Foster PG, Cox CJ, et al. An archaeal origin of eu- ticum invades chicken erythrocytes during infection. Infect karyotes supports only two primary domains of life. Nature Immun 2008;76:71–7. 2013;504:231–6. Votyakova TV, Kaprelyants AS, Kell DB. Influence of vi- Wilson ML, Weinstein MP. General principles in the labora- able cells on the resuscitation of dormant cells in Mi- tory detection of bacteremia and fungemia. Clin Lab Med crococcus luteus cultures held in an extended stationary 1994;14:69–82. phase: the population effect. Appl Environ Microb 1994;60: Winter SE, Thiennimitr P, Winter MG, et al. Gut inflammation 3284–91. provides a respiratory electron acceptor for Salmonella. Na- Vujkovic-Cvijin I, Dunham RM, Iwai S, et al. Dysbiosis of the gut ture 2010;467:426–9. microbiota is associated with HIV disease progression and Woese CR, Fox GE. Phylogenetic structure of the prokary- tryptophan catabolism. Sci Transl Med 2013;5:193–1. otic domain: the primary kingdoms. P Natl Acad Sci USA Walker AW, Duncan SH, Louis P, et al. Phylogeny, culturing, and 1977;74:5088–90. metagenomics of the human gut microbiota. Trends Microbiol Woese CR, Kandler O, Wheelis ML. Towards a natural sys- 2014;22:267–74. tem of organisms: proposal for the domains Archaea, Wallet F, Loiez C, Herwegh S, et al. Usefulness of real-time PCR Bacteria, and Eucarya. P Natl Acad Sci USA 1990;87: for the diagnosis of sepsis in ICU-acquired infections. Infect 4576–79. Disord Drug Targets 2011;11:348–53. Xayarath B, Freitag NE. Optimizing the balance between host and Wang Y, Chen Y, Zhou Q, et al. A culture-independent approach environmental survival skills: lessons learned from Listeria to unravel uncultured bacteria and functional genes in a monocytogenes. Future Microbiol 2012;7:839–52. complex microbial community. PLoS One 2012c;7:e47530. Yamaguchi M, Terao Y, Mori-Yamaguchi Y, et al. Streptococcus Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of pneumoniae invades erythrocytes and utilizes them to evade phosphatidylcholine promotes cardiovascular disease. Na- human innate immunity. PLoS One 2013;8:e77282. ture 2011;472:57–63. Yang J, Feng L, Ren J, et al. Correlation between the severity of Wang Z, Zhang L, Guo Z, et al. A unique feature of iron loss via periodontitis and coronary artery stenosis in a Chinese pop- close adhesion of Helicobacter pylori to host erythrocytes. PLoS ulation. Aust Dent J 2013;58:333–8. One 2012b;7:e50314. Yarza P, Sproer ¨ C, Swiderski J, et al. Sequencing orphan species Wang ZW, Li Y, Huang LY, et al. Helicobacter pylori infection con- initiative (SOS): filling the gaps in the 16S rRNA gene tributes to high risk of ischemic stroke: evidence from a sequence database for all species with validly published meta-analysis. JNeurol 2012a;259:2527–37. names. Syst Appl Microbiol 2013;36:69–73. Weinstein MP. Current blood culture methods and systems: clin- Yatsunenko T, Rey FE, Manary MJ, et al. Human gut micro- ical concepts, technology, and interpretation of results. Clin biome viewed across age and geography. Nature 2012;486: Infect Dis 1996;23:40–6. 222–7. Weinstock GM. Genomic approaches to studying the human mi- Young D, Stark J, Kirschner D. Systems biology of persistent crobiota. Nature 2012;489:250–6. infection: tuberculosis as a case study. Nat Rev Microbiol West SA, Buckling A. Cooperation, virulence and siderophore 2008;6:520–8. production in bacterial parasites. Proc R Soc B 2003;270:37–44. Yu RQ, Yuan JL, Ma LY, et al. Probiotics improve obesity- Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis. associated dyslipidemia and insulin resistance in high-fat Hepatology 2005;41:422–33. diet-fed rats. Zhongguo Dang Dai Er Ke Za Zhi 2013;15:1123–7. Wiest R, Lawson M, Geuking M. Pathological bacterial transloca- Zengler K, Toledo G, Rappe M, et al. Cultivating the uncultured. tion in liver cirrhosis. J Hepatol 2014;60:197–209. P Natl Acad Sci USA 2002;99:15681–6. Wiest R, Rath HC. Gastrointestinal disorders of the critically Zhang H, Liao X, Sparks JB, et al. Dynamics of gut microbiota in ill. Bacterial translocation in the gut. Best Pract Res Cl Ga autoimmune lupus. Appl Environ Microb 2014a;80:7551–60. 2003;17:397–425. Zhang R, Lahens NF, Ballance HI, et al. A circadian gene ex- Wikoff WR, Anfora AT, Liu J, et al. Metabolomics anal- pression atlas in mammals: implications for biology and ysis reveals large effects of gut microflora on mam- medicine. P Natl Acad Sci USA 2014b;111:16219–24. malian blood metabolites. P Natl Acad Sci USA 2009;106: Zhang Y, Yew WW, Barer MR. Targeting persisters for tuberculo- 3698–703. sis control. Antimicrob Agents Ch 2012;56:2223–30. Williams BB, Van Benschoten AH, Cimermancic P, et al. Discov- Zhang Y, Zou Y, Ma P, et al. Identification of Mycoplasma suis ery and characterization of gut microbiota decarboxylases MSG1 interaction proteins on porcine erythrocytes. Arch Mi- that can produce the neurotransmitter tryptamine. Cell Host crobiol 2014c;80:7551–60. Microbe 2014;16:495–503. Zhu Y, Jameson E, Crosatti M, et al. Carnitine metabolism to Williams BL, Hornig M, Buie T, et al. Impaired carbohydrate trimethylamine by an unusual Rieske-type oxygenase from digestion and transport and mucosal dysbiosis in the in- human microbiota. P Natl Acad Sci USA 2014;111:4268–73. testines of children with autism and gastrointestinal distur- Zimmermann MB, Chassard C, Rohner F, et al. The effects of bances. PLoS One 2011;6:e24585. iron fortification on the gut microbiota in African children: Williams BL, Hornig M, Parekh T, et al. Application of novel a randomized controlled trial in Cote d’Ivoire. Am J Clin Nutr PCR-based methods for detection, quantitation, and phy- 2010;92:1406–15.

Journal

FEMS Microbiology Reviews – Oxford University Press

Published: Jul 1, 2015

Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

The dormant blood microbiome in chronic, inflammatory diseases

The dormant blood microbiome in chronic, inflammatory diseases

Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

The dormant blood microbiome in chronic, inflammatory diseases

The dormant blood microbiome in chronic, inflammatory diseases

References (512)

Abstract

Journal

Recommended Articles

There are no references for this article.

Our policy towards the use of cookies