TY - JOUR
AU - Steen, Tomoko Y
AB - Abstract The Chernobyl and Fukushima nuclear accidents have called forth a growing body of research on their biological aftermaths. A variety of wild organisms, including primates, birds, fish, insects, and worms are being studied in the affected areas, with emerging morphological, physiological, and genetic aberrations ascribed to ionizing radiation. Despite the effort in surveying Chernobyl and Fukushima wildlife, little is known about the microorganisms associated with these radiation-contaminated animals. The microbiota, especially the gut commensal, plays an important role in shaping the metabolic reservoir and immune system of the host, and is sensitive to a wide array of environmental factors, including ionizing radiation. Humans and limited numbers of laboratory species have been the main subjects of microbiome studies, however, a more practical insight on host–gut microbiota dynamics under environmental impact should be explored in natural habitats. In this analysis, we introduced a working model explaining possible mechanisms of ionizing radiation on the gut microbiota, with an evaluation of the gut microbiota as a potential biomarker for exposure to ionizing radiation. biodiversity, gut microbiota, inflammation, ionizing radiation, wildlife Biological Effects of Ionizing Radiation Post Nuclear Accidents—A General View Ionizing radiation has been known to cause biological consequences since the seminal discovery of X-rays in 1890s (Röntgen 1896; Walsh 1897). From the early 20th century, laboratory studies on drosophila showed that X-irradiation could lead to mutagenesis (Muller 1927). This Nobel-winning research, along with other early experimental work, has raised concerns of long-term health effects from radiation contaminants. In the event of a nuclear accident, for instance core melt-down of a nuclear reactor, massive release of radioactive materials such as Iodine-131, Cesium-134, Cesium-137, and Strontium-90 in the fallout could pose acute and chronic health effects on the local fauna and flora (Møller et al. 2013b; Mousseau and Møller 2014). The potential harm could also be extended to areas distant to the accident site due to fallout from contaminated clouds (Kortov and Ustyantsev 2013). A plethora of field and laboratory studies provided evidence to the exposure of postaccident ionizing radiation and its biological ramifications. Morphological abnormalities, physiological malfunctions, genetic aberrations, alterations in species richness, and abundance have been widely documented in areas influenced by Chernobyl and Fukushima nuclear accidents (Mousseau and Møller 2014; Møller and Mousseau 2015). In addition to those summarized in Mousseau and Møller (2014), onging projects are continuing to explore and monitor the biological effects of ionizing radiation on wild populations, including cloaca lesion of the Japanese bush warblers (Ishida et al. 2015), low blood cell counts in wild Japanese monkeys (Ochiai et al. 2014), DNA damage in earthworms (Fujita et al. 2014), chromosomal aberrations (dicentric) in wild mice (Kubota et al. 2015), and breeding rate declines in goshawks (Murase et al. 2015) and barn swallows (Bonisoli-Alquati et al. 2015). Significant health consequences are on the rise among wildlife with protracted radiation exposure in contaminated areas, leading to alarming prospects of biodiversity loss (Møller et al. 2012, 2013a, 2013b; Mousseau and Møller, 2012a, 2012b; Wehrden et al. 2012; Taira et al. 2014; Zaitsev et al. 2014). Long-term monitoring approach has been described for wild animal research in radio-contaminated areas (Ishida 2013), however an important aspect of biological effects from ionizing radiation has been underrepresented in current field studies: the gut microbiota associated with the animal host. With high-throughput molecular technology woven into every subject of life sciences in the new century, the blooming field of microbiomics has provided us with an unprecedented perspective of host–commensal interaction. Gut microbiota, in particular, has come under the spotlight for the wealth of research associating its diversity with host health. Dynamics of gut microbiota not only influence host nutrient intake and immune functions, but is also sensitive to assorted environmental factors including radiation exposure (Lam et al. 2012; Goudarzi et al. 2016). Because the health consequences of gut dysbiosis are pervasive, it is likely that radiation-induced pathology in part results from shifts in gut microbiota and its functional outcome. Gut Microbiota—Host Interaction The animal intestinal epithelium is colonized by a myriad of microorganisms, collectively referred to as the gut microbiota. The diversity and dynamics of this microbial consortium closely relate to, and in many cases reflect the health status of the host animal. Notably, the interaction of gut microbiota and the host intestinal epithelial cells (IECs) is critical in the maturation and maintenance of the mucosal immune functions (Cerf-Bensussan and Gaboriau-Routhiau 2010; Lathrop et al. 2011; Hooper et al. 2012; Molloy et al. 2012). For instance, studies comparing germ-free mice and conventional mice revealed the crucial role of gut microbiota in the development of innate and adaptive immune systems at the gut microbial–host interface by an altered production of interleukins and antimicrobial proteins (Satoh-Takayama et al. 2008; Vaishnava et al. 2008). In germ-free mice, gut morphology is substantially changed, including reduced mucus thickness, underdeveloped vascular network, immature Peyer’s patches and mesenteric lymph nodes (MLNs) (Sommer and Bäckhed 2013); the proliferative activity of crypt IECs and the migration of mature IECs along the crypt-villus axis are also markedly attenuated (Park et al. 2016). Therefore, alterations of gut microbiota can bring about local immune dysfunction and different types of enteropathy. Furthermore, mounting evidence is supporting a systemic role of the gut microbiota: dysbiosis not only has the potential of posing a proinflammatory tone in the intestine, but also triggers inflammation and autoimmunity in organs distal to the gut (Horai et al. 2015; Tai et al. 2016). The homeostatic gut milieu harbors trillions of commensal microorganisms, predominantly bacteria, who benefit from shared nutrients and immune protection from the host. Notably, the host–microbial interaction at the mucosal surface discriminate commensals from pathogens. It has been extensively studied that the mucin layers lining the epithelium, secretory IgA (sIgA), antimicrobial proteins (AMPs, such as defensins, cathelicidins, etc.), pattern recognition receptors (PRRs) expressed on the IECs, together with microvilli structure and tight junctions make up the physical and immunologic barriers between the host and the gut bacteria, the integrity of which is critical in promoting immune tolerance to commensals as well as mounting anti-microbial defense against invading pathogens (Shi and Walker 2015). Intestinal commensals enhance epithelium immune actions (stimulate IgA production, promote effector T cell differentiation, etc.) and discourage pathogen invasion by a variety of mechanisms, but the host immune system is usually hypo-responsive toward commensal-derived antigens. Specifically, PRR signaling in IECs is tuned down towards innocuous luminal antigens; commensal microbiota and its components (e.g., polysaccharide A (PSA) from the capsule of Bacteroides fragilis) or metabolites (e.g., secondary bile acids, and short-chain fatty acids [SCFAs] such as butyrate) actively dampen host immune response by inhibiting nuclear factor κB (NF-κB) inflammatory pathway or certain inflammasome, promoting the conversion of CD4+ T cells into Foxp3+ regulatory T cells (Tregs) and increasing the production of anti-inflammatory cytokines such as interleukin-10 (IL-10) (Guo et al. 2016; Rooks and Garrett 2016; Wahlström et al. 2016). It is noteworthy that besides mucosal immune cells, IECs are a direct source of cytokines and chemokines in response to microbial stimuli and environmental stressors (Stadnyk 2002). Commensalism, therefore, is a dynamic gut–microbial interaction orchestrated by a balance between pro- and anti-inflammatory signals that prevent bacterial dissemination while avoiding host tissue damage (Aymeric and Sansonetti 2015). In addition to modulating the host immune functions, the gut community is also an active participant in various aspects of the host metabolism, such as food digestion, nutrient acquisition, and energy balance. The host–diet–microbiota interplay is extensively studied, and the essential role of gut microbiota in breaking down dietary compounds and promoting nutrient absorption has been underscored in a wide range of metazoan species. For instance, termites forms partnership with gut symbionts to facilitate lignocellulose digestion (Brune 2014); in zebrafish, the intestinal commensals stimulate dietary fatty acid uptake in the intestinal epithelium and liver (Semova et al. 2012); foregut community analysis in wild sloths suggested that digesta microbiota mirrors diet specification (Dill-McFarland et al. 2016); and fecal microbiota of the wild black howlers displayed distinct patterns cross individuals with different energy and nutrition needs (Amato et al. 2014). While influencing immune functions and contributing to the metabolic profile of the animal host, the gut microbiota is sensitive to many factors, including host genetics, diet, health status, lifestyle, maternal effect, and environmental exposure to diverse situations including ionizing radiation (Turnbaugh et al. 2007; Ley et al. 2008; Spor et al. 2011; Goudarzi et al. 2016). The intestinal epithelium forms the largest interface between the host and the environment, so the microbial ecosystem in the gut is under constant challenge from the environmental intake (Shi and Walker 2015). The stability and resilience of the gut flora is still being explored; studies of human and mice supported a significant influence of diet (both current and past exposure) on the gut microbiota, however, diet oscillation doesn’t seem to override interindividual variations (Turnbaugh et al. 2009; David et al. 2014; Carmody et al. 2015; Walter 2015). Emerging research examining captive and wild nonmodel species is revealing a diversity of gut community dynamics—shift in intestinal microbiota as well as interindividual difference by season in Tibetan Macaques (Sun et al. 2016); interindividual gut microbial variations in cattle that cannot be attributed to breed, gender, diet, age, or weather (Durso et al. 2010); variations among neotropical birds explained by host taxonomy and environmental variables (Hird et al. 2015); habitat salinity, trophic level, and host phylogeny influence fish gut communities (Sullam et al. 2012); and a noted stability in the gut microbiota surveyed in some insects (Berasategui et al. 2016; Tinker and Ottesen 2016). Despite our limited knowledge regarding the gut microbial turnover in wild animals, it is plausible from current evidence that a healthy, diverse intestinal community is resilient to environmental stressors by certain degree: short-term perturbation such as diet alterations could cause reversible shifts in the gut microbial composition; acute disturbance or persistent environmental stressors may result in an incomplete recovery and a shift in the identity and functional profiles of the gut microbiota from the equilibrium prior to exposure (Lozupone et al. 2012; Walter 2015). Studying the patterns of such shift, therefore, has the potential of uncovering the effect of environmental variables on the host–gut microbiota interaction, and providing a measurable reference in evaluating the environmental effect, especially in natural habitats. Effects of Ionizing Radiation on the Gut Microbiota Ionizing radiation—one of the pronounced environmental stressors in the contaminated areas post nuclear accidents, is likely to account for a marked shift in the gut microbiota from a variety of animal hosts. In addition to studies on cancer radiotherapy, existing evidence of the effects of ionizing radiation on the gut microbiota has been mostly limited to controlled laboratory assays on rats and mice, with relatively high doses/dose-rates of X- or γ-irradiation (Chrom 1935; Furth et al. 1952; Kent et al. 1968; Lam et al. 2012; Goudarzi et al. 2016). These studies, including the earlier experiments from almost a century ago (summarized in Chrom 1935), substantiated the impacts of ionizing radiation on the intestine and the gut flora. Earlier work using culture-based methods demonstrated existence of gut-originated bacteria in blood or tissue samples post X-irradiation in mice and dogs (Chrom 1935; Furth et al. 1952). Modern experiments, benefitting from advanced molecular techniques, can obtain a more comprehensive profile of the intestinal microbiota and the metabolome through microarray, next-generation sequencing and mass spectrometry. These recent research (Lam et al. 2012; Goudarzi et al. 2016) revealed an alteration in 16S-based abundance of a number of gut microbial families such as Lactobacillaceae, Streptococcaceae, and Clostridiaceae, as well as statistically significant changes in microbial-derived metabolites pre- versus postirradiation. As summarized in the previous section, the gut microbiota forms a complex ecosystem and is closely interacting with the host immune system at the intestinal mucosal surface. The effect of ionizing radiation on the gut flora therefore is a combined outcome of the stress responses from the gut microbes, host cells, and the triangular interactions between the gut microbiota, host, and radiation. The intricacy of these relationships could be schematized into a tetrahedron, with the other influencing factors likewise included (Figure 1). An in-depth examination of the possible mechanisms underlying the radiation effects requires a careful parsing of the multivariate process while considering the potential difference in type and dose/dose-rate of ionizing radiation. The following discussion aims to generate a working model as a guideline to interpret the mechanisms of ionizing radiation on the gut microbiota post nuclear accidents. Figure 1. View largeDownload slide A tetrahedron network describing potential influencing factors involved in the host–radiation–gut microbiota interaction. There are multiple elements (subfactors) within each of the 3 factors, where a feedback arrow indicates possible interactions among the elements within the factor. The only bidirectional arrow is the one between animal host and gut microbiota. Dashes are only for the effect of a perspective view of the polyhedron. Figure 1. View largeDownload slide A tetrahedron network describing potential influencing factors involved in the host–radiation–gut microbiota interaction. There are multiple elements (subfactors) within each of the 3 factors, where a feedback arrow indicates possible interactions among the elements within the factor. The only bidirectional arrow is the one between animal host and gut microbiota. Dashes are only for the effect of a perspective view of the polyhedron. The working model (Figure 2) categorizes the effects of ionizing radiation on the diversity of gut microbiota and its functional profile into primary and secondary processes. The primary process involves the impacts of ionizing radiation immediately on the microbial cells and cellular activities, including direct and indirect actions—strand breaks, damaged bases, or tautomeric shifts of macromolecules (DNA, RNA, protein, and lipids) induced directly by radiation (Hutchinson 1985; Fielden et al. 1997; Reisz et al. 2014); formation of hydroxyl radical (•OH) and other reactive oxygen species (ROS) such as superoxide (O2•−) and hydrogen peroxide (H2O2) from water radiolysis, enhancing radiation-induced oxidative damage to the genome and the proteome (Daly 2009; Krisko and Radman 2010; Reisz et al. 2014; Sridharan et al. 2015); interruption of cell cycles, inhibition of DNA synthesis, or cell death (Frey and Pollard 1966; Haber 1972; Bernhard et al. 1995; Iliakis et al. 2003). Figure 2. View largeDownload slide A working model integrating the effects of ionizing radiation on the gut microbiota, exemplified in a mammalian colon. The model differentiates into primary and secondary processes. The primary process involves the impacts of ionizing radiation immediately on the genome and proteome of the microbial cells and host cells, from direct and indirect actions of ionizing radiation, leading to cell death or malfunction. In the figure these primary impacts from ionizing radiation are symbolized by black-and-yellow arrows crossing the cells. The secondary process describes cell–cell interactions under the influence of ionizing radiation, mediated by soluble stressors (ROS/RNS) released from the primary process and consequences from host/microbial cell loss and damage. With impaired epithelium and its compromised barrier function, the intestinal epithelial cells and innate immune cells such as macrophages and dendritic cells react to increasing oxidative stress and exposure to microbial antigens by releasing inflammatory cytokines and chemokines, through activated NF-κB signaling and inflammasome pathways, etc. Response mounted by immune cells, stimulated from damage- or microbe-associated molecular patterns, resulted in an enhanced production of cytokines and ROS/RNS, propagating the inflammatory signals. As the gut milieu is changing away from homeostasis, the shift in the microbial composition and metabolic profile is likely to ensue, and the protective, anti-inflammatory effects from the healthy commensals are likely to diminish, perpetuating inflammation and its influence on the gut microbiota. In such situation the chance of pathogen invading is also increased. Under some circumstances, cellular response post ionizing radiation may initiate the activities of damage repair and wound healing, again possibly mediated by the gut microbiota and mucosal environment. Radiation source and dose/dose-rate, host genetics, cell and tissue type, are among the many factors that could potentially influence the outcome of host cell–radiation–gut microbiota interactions in vitro and in vivo. Green arrows in the callout boxes represent “induction,” while “suppression” is indicated by a red “T” sign. M cell, microfold cell. Figure 2. View largeDownload slide A working model integrating the effects of ionizing radiation on the gut microbiota, exemplified in a mammalian colon. The model differentiates into primary and secondary processes. The primary process involves the impacts of ionizing radiation immediately on the genome and proteome of the microbial cells and host cells, from direct and indirect actions of ionizing radiation, leading to cell death or malfunction. In the figure these primary impacts from ionizing radiation are symbolized by black-and-yellow arrows crossing the cells. The secondary process describes cell–cell interactions under the influence of ionizing radiation, mediated by soluble stressors (ROS/RNS) released from the primary process and consequences from host/microbial cell loss and damage. With impaired epithelium and its compromised barrier function, the intestinal epithelial cells and innate immune cells such as macrophages and dendritic cells react to increasing oxidative stress and exposure to microbial antigens by releasing inflammatory cytokines and chemokines, through activated NF-κB signaling and inflammasome pathways, etc. Response mounted by immune cells, stimulated from damage- or microbe-associated molecular patterns, resulted in an enhanced production of cytokines and ROS/RNS, propagating the inflammatory signals. As the gut milieu is changing away from homeostasis, the shift in the microbial composition and metabolic profile is likely to ensue, and the protective, anti-inflammatory effects from the healthy commensals are likely to diminish, perpetuating inflammation and its influence on the gut microbiota. In such situation the chance of pathogen invading is also increased. Under some circumstances, cellular response post ionizing radiation may initiate the activities of damage repair and wound healing, again possibly mediated by the gut microbiota and mucosal environment. Radiation source and dose/dose-rate, host genetics, cell and tissue type, are among the many factors that could potentially influence the outcome of host cell–radiation–gut microbiota interactions in vitro and in vivo. Green arrows in the callout boxes represent “induction,” while “suppression” is indicated by a red “T” sign. M cell, microfold cell. It is noteworthy that in microbial studies, the disturbance of proteome functionality (protein carbonylation) from direct or indirect actions of ionizing radiation seem to outweigh genomic damage in predicting cell survival (Daly 2009; Krisko and Radman 2010, 2013). It is plausible that the integrity of proteins required for genomic repair and cell cycle regulation plays a key role in radiation resistance of the cell. A direct corollary of radiation-induced damage on the genome and proteome of the microbes is therefore the death of some members of commensals and shift of the gut community, as well as a likely altered metabolic profile from the microbiome. The extent of change depends partly on the dose/dose-rate and types of ionizing radiation. An observation in bacteria and some mammalian somatic and germ-line cells is the inverse dose-rate effects for mutagenesis by low-LET (linear energy transfer) radiation (X- or γ-irradiation), resulting in a parabolic response curve between DNA damage and radiation dose-rate (Brenner et al. 1996; Vilenchik and Knudson 2000; Min et al. 2003). A possible interpretation of the inverse dose-rate effects at low dose-rate exposure is radiation-induced cell cycle alteration. Among dividing cells, mitotic frequency is known to decrease with increasing radiation dose, and due to insufficient damage signal or other mechanisms that disable cell cycle arrest and DNA repair, the persistence of postirradiation cell division will produce nuclear imbalance with the imprints propagating in the progeny cells (Haber and Rothstein 1969; Haber 1972; Vilenchik and Knudson 2000; Min et al. 2003). Another related example is a study surveying expression profiles of genes involved in base excision repair in a human lymphoblastoid cell line, which concluded that repair enzymes known to process the majority of radiation-induced DNA lesions were not induced by low levels of ionizing radiation (Inoue et al. 2004). Although some bacterial and fungal species were found to be highly radio-resistant (Dadachova et al. 2007; Daly 2009), these observations suggest that microbial cells in the gut may subject to an extended cellular insult and genomic instability with continuous exposure at lower dose-rate of γ-irradiation, a scenario comparable to the radiation exposure in contaminated areas post nuclear accidents (Alexakhin et al. 2006; WHO 2012). It has also been noted that low-LET radiation affect cells mainly through indirect action—generating ROS and potentiating oxidative damage (Tsai et al. 2015). The major role of indirect damage by low-LET radiation via hydroxyl radicals and other ROS was supported in an abundance of microbial studies (Adler 1963; Frey and Pollard 1966; Frey and Pollard 1968; Samuni and Czapski 1978; Krisko and Radman 2010). Indirect effect of low-LET radiation is generally prominent in living biological materials because of the high water content in the cells, and a recent meta-analysis further demonstrated the ubiquity of oxidative damage by low-dose ionizing radiation among different species (Einor et al. 2016). This relates to the phenomenon where nontargeted, and/or delayed impacts of ionizing radiation were observed, such as genomic instability, bystander, and abscopal effects (Little 2003; Morgan 2003; Siva et al. 2015; Wang et al. 2015). There have been inconsistencies among evidence for nontargeted effects of ionizing radiation, where different end points were measured from a variety of cell types under different sources and doses of ionizing radiation. Nonetheless, common mechanisms underlying these nontargeted effects have been proposed, which highlight radiation-induced oxidative stress and a variety of inflammatory signals (Little 2003; Morgan 2003; Rugo and Schiestl 2004; Hei et al. 2008; Havaki et al. 2015). Studies involving in vivo exposure to ionizing radiation, in particular, indicated the potential role of reactive oxygen/nitrogen species (ROS/RNS), cytokines and immune cells in mediating and proliferating nontargeted effects (Coates et al. 2008; Lorimore et al. 2001, 2008; Mukherjee et al. 2011; Rastogi et al. 2011); increasing discussion has also been seen in the literature linking postradiation effects with inflammation-related mechanisms (Mukherjee et al. 2014; Schaue et al. 2015). The secondary process of the working model, inspired from the commonalities of these nontargeted phenomena, concerns the effects of ionizing radiation on cell–cell communications and the gut microbial ecosystem as a whole. Extensive research have been performed on mammalian and human cells, leading to notable progress on the development of a unifying model for nontargeted effects of ionizing radiation (Hei et al. 2008; Havaki et al. 2015). Although the cellular machinery and signaling mechanisms are different between eukaryotes and prokaryotes, there are appreciable amounts of radiation-induced stressors and molecular pathways shared between the two, especially in the context of gut microbiota–host interactions. With protracted exposure to ionizing radiation, both host cells (e.g., IECs) and gut microbial cells are influenced by direct and indirect actions of radiation. Besides potential damage to the genome and proteome of the cells, radiolytic products such as ROS and RNS can be transmitted extracellularly and trigger response in an autocrine or paracrine manner. These soluble stressors are among the key factors in modifying host immune response and amplifying the effects of ionizing radiation. First of all, redox state is the central regulator of cellular stress response both in prokaryotes and eukaryotes (Hidalgo et al. 1997; Zheng et al. 1998; Nishi et al. 2002). In prokaryotes, antioxidant defense systems involving transcription factors such as OxyR and SoxR are induced in response to ROS (Hidalgo et al. 1997; Zheng et al. 1998). In eukaryotes, NF-κB signaling and inflammasome pathways could be activated both in epithelial cells and innate immune cells at elevated level of ROS, protecting cells from apoptosis and initiating inflammatory response (Gloire et al. 2006; Schroder and Tschopp 2010; Peterson and Artis 2014). The activation of NF-κB transcription factor by ROS and other ionizing radiation-induced factors has been extensively studied in different cell and tissue models under different conditions of radiation exposure; there occurs to be variations in the outcomes from radiation-induced NF-κB signaling cascades, but a predominant scenario in immune cells seem to be the up-regulation of inflammatory cytokines and chemokines such as tumor necrosis factor-α (TNFα), IL-1β, IL-6, IL-18, CXCL8 (Gloire et al. 2006; Hellweg 2015). These soluble factors are potent autocrine or paracrine (and potentially endocrine) agents, which can perpetuate the inflammatory response. Especially in phagocytes such as macrophages and neutrophils, the immune-stimulating NF-κB signaling from microbe- or damage-associated molecular patterns (MAMPs/DAMPs) have the potential to amplify the production of ROS/RNS via phagocytotic activities (François et al. 2013). Of the innate immune system, inflammasome activation is also thought to partially involve NF-κB pathways (Bauernfeind et al. 2009). In addition to MAMPs/DAMPs, ROS is considered another possible agonist, leading to inflammasome assemblage, activated caspase-1, maturation and secretion of proinflammatory cytokines (e.g., IL-1β and IL-18) from myeloid cells and IECs (Schroder and Tschopp 2010; Guo et al. 2015; Levy et al. 2015). The stimulation of NLRP3 inflammasome, for example, usually needs to be “primed”—a classic case being lipopolysaccharide (LPS) from the outer membrane of Gram-negative bacteria binding to Toll-like receptor-4 (TLR-4) on macrophages, dendritic cells (DCs) or IECs, leading to the formation of the inflammasome complex (pathway summarized in Guo et al. 2015). In a gut milieu that is undergoing dysbiosis postirradiation, with an increasing contact between commensal/pathogen with IECs and innate immune cells due to damaged epithelium barrier, such “priming” could readily occur and end up enhancing the inflammatory response. Interestingly, circumstantial evidence has indicated an increase in caspase-1 activity independent of NLRP3 in murine immune cells post low-LET irradiation (Stoecklein et al. 2015). This may due to a lack of “priming” in the experimental scenario, or because radiation may have induced double strand breaks (DSBs), and instead of NLRP3, inflammasome pathway AIM2 was dominantly stimulated by directly binding to cytosolic dsDNA segments (Fernandes-Alnemri et al. 2009). Another inflammasome, NLRP6, is thought to be predominately expressed in IECs, which has an indispensable role in regulating gut homeostasis mediated by the intestinal microbiota and its metabolites (Elinav et al. 2011; Levy et al. 2015). Recently, NLRP6 was also shown to be a critical orchestrator of goblet cell mucin granule exocytosis; malfunction of NLRP6 pathway abrogated mucin secretion and intestinal protection against pathogens (Wlodarska et al. 2014). In addition, there is evidence that sensing of intestinal tissue damage or microbial ligands by NLRP3/NLRP6 inflammasomes regulates the level of IL-22, a cytokine key to the processes of intestinal tissue repair and tumorigenesis in the colon (Huber et al. 2012). The above discussion pointed out the importance of IECs and immune cells such as macrophages and DCs in sensing and responding to the “danger signals” from radiation-induced damage and to altered signals from the gut microbiota and its metabolites post radiation. Empirical data from radiation research, in particular, highlighted the role of macrophages in mediating stress response and propagating inflammation signals. Macrophages obtained from γ-irradiated murine bone marrow were able to induce genome instability via secreted factors such as ROS/RNS and TNFα (Lorimore et al. 2008). It was also indicated that macrophage activation (measured by increased nitrotyrosine formation) as well as neutrophil infiltration after γ-irradiation were mainly a result of recognition and clearance of apoptotic cells (Lorimore et al. 2001). Although it is uncertain to what extent could we generalize these findings, most in vivo studies have supported the important role of macrophages in radiation-induced bystander effect, especially in driving inflammatory response by producing cytokines (e.g., IL-1β, IL-6, TNFα, IL-12, IL-18) and ROS/RNS (Shan et al. 2007; Havaki et al. 2015). These processes change the gut milieu to various extent and likely contribute to the shift from the homeostatic commensal profile. Proinflammatory cytokines produced by phagocytes such as TNFα and IL-1β can also impair tight junction barrier and increase paracellular permeability in IECs (Ma et al. 2004; Al-Sadi et al. 2008). This would intensify the outcome of a “leaky” mucosa from damage and loss of the radio-sensitive enterocytes by ionizing radiation (Somosy et al. 2002; François et al. 2013), exposing mucosa immune cells to luminal antigens and amplify the inflammatory cascades via PRR signaling. Besides, the aforementioned SCFAs such as butyrate produced by gut commensals in the steady state have the potential to decrease IEC permeability and enhance intestinal barrier function (Suzuki et al. 2008); however, due to the potential influence of radiation-induced dysbiosis and dysregulation of the microbial metabolism, the protective effects from these SCFAs including anti-inflammation can be greatly diminished. While discussing gut microbiota–host interaction, we have provided extensive evidence depicting the layers of mechanisms by which commensals dampen host immune activation while maintaining protection against pathobionts and pathogens. When gut homeostasis is lost due to ionizing radiation, the chance of pathogen invasion is greatly increased, and besides reacting to the damage signals directly induced from radiation, as the host immune system is vigorously responding to pathogens, the resulting action may be more detrimental to the commensals than to the pathogens, leading to a further dysbiotic state. For instance, reactions involving ROS in the inflamed gut produce tetrathionate, an electron acceptor of Salmonella typhimurium, giving this pathogen a growing advantage over luminal commensals (Winter et al. 2010). Microbes that are capable of surviving the oxidative stress may also grow to dominate the gut community (Ferreira et al. 2014). In addition, some entero-invasive bacteria directly induce the production of RNS and chemokines in IECs, potentiating the inflammatory reactions in the mucosa immune system (Witthöft et al. 1998) which likely to worsen dysbiosis. Despite the abundance of research centering around the impact of ionizing radiation on immune cells, there have been limited empirical evidence on the combined effects of radiation and microbes on host immune activation. A notable example is an observation that the release of TNFα via LPS signaling is enhanced if macrophages have been X-irradiated, indicating a possibility that ionizing radiation “primes” immune cells for proinflammatory TLR signaling (Schaue et al. 2015). However, the order of irradiation and TLR-agonist signaling seem to make a difference in the outcome of stimulation. Indeed, stressor molecules such as ROS/RNS and inflammatory cytokines could be both radiation-induced and microbiota-induced; the interaction between the effects from radiation and the effects from microbiota on host mucosa immune response is ultimately a complex and dynamic process, depending on spatial and temporal parameters of the in vivo scenario, unique ensemble of cytokines and other signaling factors in the milieu, radiation type and intensity, host genetics, and other potential external and internal factors (Figure 1). There have been reviews on cytokines associated with biological response to radiation, reflecting the complexity of integrated cellular responses with mutually reinforcing or antagonistic cytokines along temporal and spatial axes, and with different dose/type of radiation (Barcellos-Hoff 1998; Schaue et al. 2012). Notably, a thought-provoking study compared gene expression profiles from high-dose (1 Gy) and low-dose (0.05 Gy) X-irradiated human peripheral blood samples and found that low-dose irradiation showed enrichment of inflammatory cytokines and chemokines, while high-dose irradiation was more associated with p53 signaling, apoptosis, DNA damage, and repair (El-Saghire et al. 2013).The same research team also showed that the immune-stimulatory response under low-dose (0.05 Gy) X-irradiation in human monocytes involved up-regulation of TLRs, mitogen-activated protein kinases (MAPKs), and NF-κB signaling pathway (El-Saghire et al. 2013). This might indicate different predominant responses under high- and low-dose ionizing radiation, and a careful examination of the complicated manifestation from cellular reactions at low-dose irradiation is thus suggested. In addition, under some circumstances, a cytokine should not be labeled simply as “proinflammatory”, or “anti-inflammatory”, in response to ionizing radiation; different “primers” or co-stimulating factors of these cytokines could lead to divergent pathways, as in the case of the pleiotropic transforming growth factor-β (TGFβ) (Ehrhart et al. 1997; Kirshner et al. 2006; Gervaz et al. 2009; Chai et al. 2013). The influence of host genetics on the immune response toward ionizing radiation, on the other hand, was studied intensively using model species of different genetic background, with a classic case being the genotype-dependent murine macrophage polarization to either M1 or M2 activities post in vivo γ-irradiation (Coates et al. 2008); the different outcome could pose contrasting effects to the microbes interacting with these immune cells. Counting host genetic effects on the gut microbiome in the context of radiation exposure is therefore a complex issue, and the genetic mutations result directly or indirectly from ionizing radiation add to the possibility of an altering gut microbiota, especially when such mutations are involved in digestive or immune functions. Genetic association with the gut microbiome has been explored mostly in humans and laboratory species (Bonder et al. 2016; Dąbrowska and Witkiewicz 2016; Goodrich et al. 2016; Wang et al. 2016). Due to the difference of immune system and metabolic profiles between species, it is crucial to pair gut microbiome data with well-recorded sample information, to help with cross-species and case/control comparisons. Dissection of the genetic effects, subsequently, should be facilitated by laboratory studies. Confounding factors such as host genetics and other environmental variables recapitulate the dimensions of consideration one should envisage in examining the effects of ionizing radiation on the gut microbiota—and many of the edges and vertexes of the tetrahedron are waiting to be explored, for every species under study. Evaluation of Gut Microbiota as a Biomarker for Radiation Exposure The exigencies of effective biomarkers for evaluating radiation injury and developing radiation countermeasures have brought forth a thriving field of radiation biodosimetry. Biomarker doesn’t imply causality; it is a signature that may reflect absorbed radiation dose and could potentially be used to infer the health status of the irradiated subject, especially in cases other than acute radiation syndrome (ARS). Biomarker does relate to the mechanism of the acting agent, and the development of many radiation biomarkers are components of the physiological reacting processes, with measurable change in values to radiation exposure. Proinflammatory cytokines and acute-phase proteins, peripheral blood counts, chromosomal aberrations, metabolic products such as citrulline have been proposed as candidate biomarkers for assessing absorbed doses of ionizing radiation (Singh et al. 2016). Recent advance in microbiome study has led to the perspective of using intestinal microbiota as a novel biomarker for radiation exposure (Goudarzi et al. 2016; Lam et al. 2012; Singh et al. 2016). The potential problem associated with the gut microbial imprints, similar to some other physiological markers, is how to dissect the impact of ionizing radiation from the complex host–radiation–microbiota interaction network, because the influence of postirradiation host health status on the gut community is largely unknown. As discussed in the previous sections, the gut microbiota is sensitive to a number of factors; although existing studies accumulated an enormous amount of data, it remains challenging to identify biological signals from the noisy background. In addition, microbiome research procedures are still waiting to be standardized, and disparities between laboratory and field studies need to be better understood. Despite the challenges in microbiome research, there are many advantages of using the gut flora as a potential radiation biomarker—we have emphasized its sensitivity to ionizing radiation, thus radiation-induced gut microbial alteration might be able to reveal hidden health consequences of the host animal; a good representation of the gut community could be noninvasively sampled from the animal feces, promoting its application in the field studies; automation of sample processing and analyses can be achieved, and the potential implementation of a portable, real-time sequencer would further benefit field research (Ma et al. 2017). Recent field survey in Fukushima and Chernobyl areas have reported variations of radio-sensitivity among different species, judged mainly from the abundance profiles of the animal populations (Møller et al. 2012, 2013; Mousseau and Møller 2012). The exploration of the mechanisms of radiation resistance has been focusing on the animal host. However, the addition of host-associated microbiome and metabolome profiles will be helpful in elucidating the interspecies and interindividual variations in radio-sensitivity, and explaining the phenotypic manifestation and population dynamics post nuclear accidents. For instance, in a recent study on barn swallows from contaminated areas in Fukushima, the researchers found that genetic damage to nestlings did not explain the population decline of barn swallows (Bonisoli-Alquati et al. 2015). Breeding birds require marked energy input and fat storage for egg production (Witter and Cuthill 1993; Kunz and Orrell 2004); since the gut microbiota could influence fat storage and energy balance of the host animal (Bäckhed et al. 2004; Krajmalnik-Brown et al. 2012), it is likely that radiation-induced shifts in the gut microbial community play a role in the decreasing reproduction rate of the Fukushima barn swallows. Accumulating knowledge in the mechanisms of host–radiation–gut microbiota interplay also has great potential in developing alternative treatment methods for radiation injury, for example, fecal transplantation or administration of probiotics/prebiotics, such as those microbial interventions being explored in cases of inflammatory bowel disease (IBD) (Sanders et al. 2013; Colman and Rubin 2014). Proposal Increasing effort has been made in field and laboratory studies with the goal of evaluating biological impacts of ionizing radiation post nuclear accidents. A central theme of these studies is “biodiversity”—the variability among all living organisms (plants, animals, environmental microbes, and commensals) in the levels of genes, species, ecosystems, and their interactions (Haahtela et al. 2013). The impacts on biodiversity due to disasters such as nuclear accidents are likely to pose a long-term influence on the well-being of species inhabiting these contaminated areas. Studies on human and mice, in particular, have led to the conjecture that loss of environmental and commensal microbial diversity greatly influence the occurrence of immune disorders such as atopy and IBD (Hanski et al. 2012; Haahtela et al. 2013). Given the complexity of the interplay between the environment, host animals and their microbiota, it is imperative to examine the compositional and functional changes of wildlife-associated microbial communities in the irradiated zones, which may serve as a key approach to identify the mechanisms of radiation-induced impacts on host–microbiota homeostasis underlying potential disease development. Such studies might help to devise countermeasures with the goal of reducing radiation damage and sustaining individual health and ecological functions after exposure to ionizing radiation. Conflict of Interest The authors declare no conflict of interests. 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TI - Gut Microbiomics—A Solution to Unloose the Gordian Knot of Biological Effects of Ionizing Radiation
JF - Journal of Heredity
DO - 10.1093/jhered/esx059
DA - 2018-03-01
UR - https://www.deepdyve.com/lp/oxford-university-press/gut-microbiomics-a-solution-to-unloose-the-gordian-knot-of-biological-vTrxtvZ7xC
SP - 212
EP - 221
VL - 109
IS - 2
DP - DeepDyve
ER -