TY - JOUR
AU - Mansell, Thomas J
AB - Abstract The human gut is an ecosystem comprising trillions of microbes interacting with the host. The composition of the microbiota and their interactions play roles in different biological processes and in the development of human diseases. Close relationships between dietary modifications, microbiota composition and health status have been established. This review focuses on prebiotics, or compounds which selectively encourage the growth of beneficial bacteria, their mechanisms of action and benefits to human hosts. We also review advances in synthesis technology for human milk oligosaccharides, part of one of the most well-characterized prebiotic–probiotic relationships. Current and future research in this area points to greater use of prebiotics as tools to manipulate the microbial and metabolic diversity of the gut for the benefit of human health. Introduction The human gastrointestinal tract hosts an enormous population of microorganisms, bacteria, archaea, and eukarya [5], roughly 40 trillion cells [132, 133]. Although the gut microbiota has been explored for centuries, only recently have correlations been made between the population of the gut and human diseases [21], including Crohn’s disease [58], inflammatory bowel disease [77], cardiovascular disease [75, 139] and cancer [45, 144]. In addition to host genetics, the composition of the gut microbiome is influenced to a large extent by environmental factors including diet [14, 35, 54, 86, 96, 149, 167], especially in early life [175]. Given the connection between gut population dynamics and disease states, strategies to alter microbiome composition have been developed including fecal transplants [46, 68], introduction of consortia or single beneficial microorganisms (also known as probiotics) [30, 148] and purveyal of substrates to support growth of commensal microorganisms [9]. While it may not be surprising that the overall diet can affect the composition of the microbiome, certain compounds, known as prebiotics, have been found to uniquely influence the growth of particular beneficial microbes [53]. Prebiotic enrichment is not a new concept. The term “bifidus factor” was coined in the 1950s to account for the enrichment of beneficial Lactobacillus bifidus in infants [57]. Recently, a consensus definition was recently proposed by the International Scientific Association of Probiotics and Prebiotics (ISAPP) as “a substrate that is selectively utilized by host microorganisms conferring a health benefit” [50]. The mechanisms of the benefit of prebiotics are manifold, but are essentially either direct (e.g., carbohydrate structures similar to host glycans can block adhesion to host cells [78]) or downstream, encouraging the proliferation of bacteria whose metabolites directly affect the gut environment or host gene expression (e.g., the effect of short-chain fatty acids on both gut pH and modulation of immune function [156]). In this review, we describe the most common prebiotics, their role in manipulating the microbiome and their downstream effects on human health, as well as strategies for chemical and biotechnological synthesis of these important compounds. Carbohydrate prebiotics The accessibility of a carbon source is a major contributor to a microbe’s ability to produce biomass [108, 164]. It follows, then, that microbial populations might change in response to changing carbon sources based on each species’ ability to use those sources. Species from the two major bacterial phyla, Bacteroidetes and Firmicutes, have been identified that break down polysaccharides and complex oligosaccharides [126, 127] including Bacteroides thetaiotaomicron [90], Bacteroides cellulolyticus [91] and Roseburia intestinalis [39]. Other mechanisms besides carbohydrate utilization, like cross-feeding [150], allow homogeneous bacterial populations to give rise to more diverse populations where metabolites from one strain provide a niche for the other [7, 147]. Human milk oligosaccharides (HMOs) Evidence from as early as the 1930s showed lower risk of morbidity or mortality due to enteric disease in breast-fed infants [55]. In addition to lipids and sugars such as lactose that directly provide nutrition to infants, human breast milk is rich in biologically active compounds that exhibit antimicrobial and immunomodulatory activities [3]. It also contains human milk oligosaccharides (HMOs), carbohydrates which are not digestible by the infant but instead influence the gut microbiome, which will be the main focus of this review. The symbiotic relationship between human milk and beneficial bacteria is the result of 200 million years of co-evolution [174] and represents nature’s strategy for establishing a healthy human infant microbiome. With the growing evidence of the beneficial functions that HMOs offer to infants, various methods of synthesis have been devised. Before the advent of current synthesis technologies, alternative complex oligosaccharides such as fructans and galactans which can be sourced more readily and economically were derived from relatively abundant resources. The structures of prebiotics discussed in this review have been illustrated in Fig. 1. Beneficial outcomes from consumption of prebiotics are listed in Table 1. Fig. 1 Open in new tabDownload slide Structural diversity of carbohydrate prebiotics. a Fructans: inulin is composed of fructose units linked to each other by β-(2,1) bonds, found in many plants. b Galactans: GOS are composed of β-(1,6)-linked galactose residues with a terminal glucose or galactose at the reducing end that are produced by enzymatic transgalactosylation of glucose, galactose, or lactose. c Xylooligosaccharides, XOS are produced from xylan-rich lignocellulosic materials, consisting of xylose residues linked via β-(1,4) linkages. Side groups such as α‐d‐glucopyranosyl uronic acid, acetyl groups, or arabinofuranosyl residues leads to branched XOS. d Mannan-oligosaccharides, MOS are composed of β-(1,4)-linked mannose residues, derived from many plants and yeast cell walls. e HMO blueprint and simple HMOs, all composed of a lactose core at the reducing end. Lactose can be fucosylated or sialylated terminally or elongated by lacto-N-biose (β-(1,3)-linked, type I) or N-acetyllactosamine (β-(1,4)-linked, type II) structures. The structures pictured are (i) basic structure of HMOs, (ii) 2′-fucosyllactose, (iii) 3-fucosyllactose, (iv) 6′-sialyllactose, (v) lacto-N-tetraose, and (vi) lacto-N-neotetraose Prebiotics and their beneficial outcomes Prebiotic oligosaccharides . Benefit to host . Proposed responsible microorganism . References . HMO Anti-inflammatory effect, regulation of permeability of host cells, protection from diarrhea, necrotizing enterocolitis and respiratory tract infections, diabetes, prevent binding of pathogens like rotavirus and Campylobacter jejuni to host cells Bifidobacterium longum subsp. infantis, Bacteroides [12, 27, 99, 162, 165, 170, 171] FOS Anti-inflammatory effect, improved IBS symptoms, lower blood glucose level, anti-cancer, diarrhea treatment, reduces atopic dermatitis Bifidobacteria, Faecalibacterium prausnitzii, Bacteroidetes [83, 95, 105, 112, 171] Inulin Improved bowel function, increased bifidobacteria population, lower serum lipopolysaccharide level, immunomodulatory action, increased mineral absorption, cardiovascular effects, anti-cancer Bifidobacteria, Bacteroidetes [33, 36, 44, 73, 114, 146, 154, 157] GOS Immunomodulatory action, pathogen adherence inhibition, improved IBS symptoms, reduces atopic dermatitis Bifidobacteria, lactobacilli [44, 95, 116, 135] MOS Lower IBS symptoms, increased expression of proinflammatory mediators, lower proinflammatory cytokines, prevent binding of pathogens to host cells Lactobacilli [43, 102] XOS Immunomodulatory action, increased plasma HDL concentration, anti-inflammatory effect, reduction in triglycerides, lower dose requirement for clinical efficacy, anti-cancer Bifidobacteria, lactobacilli [59, 66, 117, 128, 163] Prebiotic oligosaccharides . Benefit to host . Proposed responsible microorganism . References . HMO Anti-inflammatory effect, regulation of permeability of host cells, protection from diarrhea, necrotizing enterocolitis and respiratory tract infections, diabetes, prevent binding of pathogens like rotavirus and Campylobacter jejuni to host cells Bifidobacterium longum subsp. infantis, Bacteroides [12, 27, 99, 162, 165, 170, 171] FOS Anti-inflammatory effect, improved IBS symptoms, lower blood glucose level, anti-cancer, diarrhea treatment, reduces atopic dermatitis Bifidobacteria, Faecalibacterium prausnitzii, Bacteroidetes [83, 95, 105, 112, 171] Inulin Improved bowel function, increased bifidobacteria population, lower serum lipopolysaccharide level, immunomodulatory action, increased mineral absorption, cardiovascular effects, anti-cancer Bifidobacteria, Bacteroidetes [33, 36, 44, 73, 114, 146, 154, 157] GOS Immunomodulatory action, pathogen adherence inhibition, improved IBS symptoms, reduces atopic dermatitis Bifidobacteria, lactobacilli [44, 95, 116, 135] MOS Lower IBS symptoms, increased expression of proinflammatory mediators, lower proinflammatory cytokines, prevent binding of pathogens to host cells Lactobacilli [43, 102] XOS Immunomodulatory action, increased plasma HDL concentration, anti-inflammatory effect, reduction in triglycerides, lower dose requirement for clinical efficacy, anti-cancer Bifidobacteria, lactobacilli [59, 66, 117, 128, 163] Open in new tab Prebiotics and their beneficial outcomes Prebiotic oligosaccharides . Benefit to host . Proposed responsible microorganism . References . HMO Anti-inflammatory effect, regulation of permeability of host cells, protection from diarrhea, necrotizing enterocolitis and respiratory tract infections, diabetes, prevent binding of pathogens like rotavirus and Campylobacter jejuni to host cells Bifidobacterium longum subsp. infantis, Bacteroides [12, 27, 99, 162, 165, 170, 171] FOS Anti-inflammatory effect, improved IBS symptoms, lower blood glucose level, anti-cancer, diarrhea treatment, reduces atopic dermatitis Bifidobacteria, Faecalibacterium prausnitzii, Bacteroidetes [83, 95, 105, 112, 171] Inulin Improved bowel function, increased bifidobacteria population, lower serum lipopolysaccharide level, immunomodulatory action, increased mineral absorption, cardiovascular effects, anti-cancer Bifidobacteria, Bacteroidetes [33, 36, 44, 73, 114, 146, 154, 157] GOS Immunomodulatory action, pathogen adherence inhibition, improved IBS symptoms, reduces atopic dermatitis Bifidobacteria, lactobacilli [44, 95, 116, 135] MOS Lower IBS symptoms, increased expression of proinflammatory mediators, lower proinflammatory cytokines, prevent binding of pathogens to host cells Lactobacilli [43, 102] XOS Immunomodulatory action, increased plasma HDL concentration, anti-inflammatory effect, reduction in triglycerides, lower dose requirement for clinical efficacy, anti-cancer Bifidobacteria, lactobacilli [59, 66, 117, 128, 163] Prebiotic oligosaccharides . Benefit to host . Proposed responsible microorganism . References . HMO Anti-inflammatory effect, regulation of permeability of host cells, protection from diarrhea, necrotizing enterocolitis and respiratory tract infections, diabetes, prevent binding of pathogens like rotavirus and Campylobacter jejuni to host cells Bifidobacterium longum subsp. infantis, Bacteroides [12, 27, 99, 162, 165, 170, 171] FOS Anti-inflammatory effect, improved IBS symptoms, lower blood glucose level, anti-cancer, diarrhea treatment, reduces atopic dermatitis Bifidobacteria, Faecalibacterium prausnitzii, Bacteroidetes [83, 95, 105, 112, 171] Inulin Improved bowel function, increased bifidobacteria population, lower serum lipopolysaccharide level, immunomodulatory action, increased mineral absorption, cardiovascular effects, anti-cancer Bifidobacteria, Bacteroidetes [33, 36, 44, 73, 114, 146, 154, 157] GOS Immunomodulatory action, pathogen adherence inhibition, improved IBS symptoms, reduces atopic dermatitis Bifidobacteria, lactobacilli [44, 95, 116, 135] MOS Lower IBS symptoms, increased expression of proinflammatory mediators, lower proinflammatory cytokines, prevent binding of pathogens to host cells Lactobacilli [43, 102] XOS Immunomodulatory action, increased plasma HDL concentration, anti-inflammatory effect, reduction in triglycerides, lower dose requirement for clinical efficacy, anti-cancer Bifidobacteria, lactobacilli [59, 66, 117, 128, 163] Open in new tab HMOs are the third most abundant component in human milk by dry weight, after lactose and lipids, and constitute a family of structurally diverse unconjugated glycans with a core lactose residue at the reducing end, a backbone of alternating N-acetyl glucosamine and galactose, and/or other moieties including fucose (α-1,2, α-1,3, or α-1,4 linked) or sialic acid (α-2,3 or α-2,6 linked) [12] (Fig. 1e). Human breast milk contains about 5–15 g/L of free oligosaccharides [12, 78]. Genome sequencing of bifidobacteria such as Bifidobacterium longum subsp. infantis and other isolates revealed gene clusters encoding glycosyl hydrolases and transporters [174] that allow them to consume HMOs as a primary carbon source [152]. B. longum subsp. infantis, B. longum subsp. longum, B. breve and B. pseudocatenulatum, internalize HMOs via ATP-binding cassette (ABC) transporters and hydrolyze these oligosaccharides using intracellular glycosyl hydrolases [88]. This strategy protects the infant by giving an ecological advantage to these bifidobacteria, preventing potential pathogens from colonizing the gut [23]. Other species including B. bifidum and Bacteroides species secrete extracellular hydrolases that break down oligosaccharides before the sugars are internalized. Sugars are fermented to acetate, which can be converted to butyrate by obligate anaerobes [93] and is found in higher concentrations in infants with healthy guts [153]. There are a few reported mechanisms by which the proliferation of bifidobacteria helps in protecting infants from diseases like diarrhea and necrotizing enterocolitis. Their unique mechanism of metabolizing HMOs is also accompanied by improved binding to the intestinal mucosal layer [27]. A recent metagenomic study, The Environmental Determinants of Diabetes in the Young (TEDDY), showed an overrepresentation of bifidobacteria and the presence of HMO utilization genes in breast-fed infants [155]. These data also supported the protective effects of short-chain fatty acids (SCFAs) in early-onset Type 1 diabetes (T1D), as was seen in mice [89]. A major challenge in developing and utilizing HMOs for therapeutic purposes is the limited supply of human milk and difficulty in isolation from other milk sources [13]. Thus, chemical and biotechnological synthesis of HMOs has become a field of great interest, as outlined below. Chemical synthesis The assembly of complex carbohydrates is challenging due to the combined demands of elaborate procedures for glycosyl donor and acceptor preparation and the requirements of regio- and stereoselectivity in glycosylation. They involve the preparation of selectively protected monosaccharide units, one with a strategically positioned free hydroxyl group (a nucleophilic acceptor) and one bearing a labile leaving group at the anomeric carbon that acts as a glycosyl donor in the ensuing glycosylation reaction. The remaining hydroxyl groups need to be protected (1) to tune the overall electronic properties of the donors and acceptors so that the donor–acceptor pair can be matched and (2) for further deprotection and glycosylation or functional-group modifications [161]. Chemoselective, orthogonal and iterative glycosylation strategies, which exploit differential reactivities of anomeric leaving groups, allow several selected glycosyl donors to react in a specific order resulting in a single oligosaccharide product [158]. Plante et al. devised a solid-phase synthesis method that allows automated synthesis by framing the repetitive glycosylation and deprotection into a coupling cycle [111]. By exposing the nucleophilic acceptor hydroxyl group on the solid support to the glycosylating agent in solution, support-bound oligosaccharides can be produced. Solid-phase synthesis eases purification but the complexity of protection–deprotection remains the same and is accompanied by steric hindrance [131]. One-pot synthesis methods have been developed that involve multistep reactions performed in a single setup, thus eliminating the need to isolate intermediates and shortening the experimental time frame. Wang et al. developed a highly regioselective, combinatorial, orthogonal and one-pot protection method that can aid in glycan synthesis using a single catalyst, which gives selectively one isomer at each step [161]. The complex and dynamic nature of the glycans makes their synthesis via traditional chemical methods challenging [109] and the numerous selective protection and deprotection steps makes it tedious. This is exacerbated by the formation of a mixture of anomers which would involve an additional separation step [34]. Enzymatic/chemoenzymatic synthesis Biocatalytic approaches avoid some of the challenges faced in chemical synthesis. The use of enzymes as catalysts means regioselectivity and stereospecificity are better controlled and there are fewer steps involved, making the process cost effective and less time consuming [34, 109]. Two different enzymatic approaches can be taken: (1) glycosyltransferase-catalyzed synthesis, which requires sugar nucleotides or sugar-1-phosphates as donors, and (2) glycosidase-catalyzed synthesis. These enzymatic methods for synthesis involve either isolation or recombinant production of the enzymes [62]. The substrates for the glycosyltransferases are nucleotide sugars (e.g., UDP-glucose) and require an acceptor for the transfer of the glycosyl residue. The glycosidase-catalyzed pathway involves the transfer of an enzyme-bound glycosyl residue to an acceptor (water, in the absence of an organic compound). Enzymatic solid-phase synthesis combines advantages of enzymatic synthesis with the ease of purification that comes with solid-phase methods [130]. One-pot synthesis methods require protection of groups only during building block synthesis which is in the order of increasing reactivity [173]. To build more complex HMO structures of varying lengths, linkages or branching, a chemoenzymatic strategy is more desirable, in which a chemically synthesized acceptor is further modified via enzymatic steps. A one-pot multienzyme approach was used to synthesize lacto-N-neotetraose in two steps via azido alkyl-lactoside using glycosyltransferases and this strategy was reiterated to synthesize sialyl- and fucosyl-derivatives [25]. Another approach is to synthesize an acceptor with a cleavable anomeric linker to allow for purification of reaction intermediates [115]. After the enzymatic extension is complete, the linker can be hydrolyzed to give oligosaccharides with a free reducing end. A solid-phase strategy was used to synthesize sialylated HMOs, which is generally challenging due to steric hindrance and reduced reactivity of the position. Fair et al. overcame this limitation using automated solid-phase assembly of the glycan backbone followed by enzymatic sialylation with an α-(2,3)-sialyltransferase, and obtained sialylated HMOs with high regio- and stereoselectivity [41]. Microbial synthesis New strategies for oligosaccharide production have been developed using metabolically engineered microbes. This approach has brought down the cost of synthesis of glycans significantly since they do not require the overproduction and isolation of the glycosyltransferases and expensive precursors and have high production titers [22]. Lactose has commonly been used as the sugar acceptor because of its abundance and its presence in all HMOs. Figure 2 exemplifies engineered metabolic pathways for synthesis of common HMOs. Fig. 2 Open in new tabDownload slide Engineered metabolic pathways for the production of fucosyllactose, sialyllactose and lacto-N-triose. Lactose, l-fucose and sialic acid are transported into the cell by specific permeases LacY, FucP and NanT. Glycerol serves as the carbon/energy source. Lactose serves as the substrate acceptor and in many cases the lacZ is deleted to prevent lactose from being metabolized. Molecules and enzymes have been abbreviated as: Glc d-glucose, Gal d-galactose, l-Fuc l-fucose, Neu5Ac sialic acid, Lac lactose, GDP-4k-6d-Man GDP-4-keto-6-deoxymannose, GDP-Man GDP-d-mannose, ManNAc N-acetylmannosamine, UDP-GlcNAc uridine diphosphate N-acetylglucosamine, 2′-FL 2′-fucosyllactose, 6′-SL 6′-sialyllactose, LNT2 lacto-N-triose II, LacY lactose permease, LacZ β-galactosidase, FucP fucose permease, WcaG GDP-fucose synthase, GlpF glycerol MIP channel, ManB phosphomannomutase, ManC mannose-1-phosphate guanylyltransferase, Gmd GDP-mannose 4,6-dehydratase, FutC α-1,2-fucosyltransferase, ST6Gal β-galactoside α-2,6-sialyltransferase, LgtA N-acetylglucosaminyltransferase, GlmS glutamine-fructose-6-phosphate aminotransferase, GlmM phosphoglucosamine mutase, GlmU N-acetylglucosamine 1-phosphate uridyltransferase, NeuC UDP-N-acetylglucosamine 2-epimerase, NeuB N-acetyl neuraminic acid synthetase, NeuA N-acylneuraminate cytidylyltransferase, NanT sialic acid transporter Several workhorse microbes have been used as hosts, mainly dependent on the commercial availability of the expression vector and the ease of manipulation. Escherichia coli has been the host of choice but the use of species that are naturally evolved to rapidly regenerate sugar nucleotides reduces a number of steps taken to genetically modify certain pathways. Saccharomyces cerevisiae, carrying plasmids expressing the human β-1,4-galactosyltransferase gene, was used to successfully produce LacNAc from GlcNAc and UDP-Gal [61]. Ruffing et al. successfully engineered Agrobacterium spp. to synthesize galactose-core oligosaccharides by exploiting the UDP-galactose regeneration system [124]. E. coli and Corynebacterium ammoniagenes strains have been used to synthesize N-acetyllactosamine, 3′-sialyllactose and Lewisx blood group antigen structures. E. coli strains overexpressing CMP-NeuAc synthetase and CTP synthetase genes were used to produce cytidine 5′ monophospho-N-acetylneuraminic acid (CMP-NeuAc). The production of this nucleotide sugar donor coupled with the overexpression of the α-(2,3)-sialyltransferase gene of Neisseria gonorrhoeae and coupling with C. ammoniagenes that forms UTP from orotic acid resulted in high titer production of 3′-sialyllactose [40]. 2′-Fucosyllactose (2′-FL) is the most abundant oligosaccharide in human milk [24] and has been shown to offer protection against pathogens including Campylobacter jejuni [125]. Scientists have developed different biosynthetic pathways in E. coli to produce 2′-FL [6, 81]. Baumgärtner et al. chromosomally integrated recombinant α-(1,2)-fucosyltransferase from Helicobacter pylori and genes from the GDP-l-fucose de novo pathway, which transforms mannose-6-phosphate to GDP-l-fucose, into E. coli [6]. With the addition of the salvage pathway, the intracellular GDP-l-fucose concentration was controlled via FucP using extracellularly added l-fucose. This resulted in a tenfold greater yield and a final 2′-FL concentration of 20 g/L. Earlier, another group produced 2′-FL using two expression plasmids where glycosylation was achieved by the Neisseria meningitidis lgtAB genes [37]. Recently, Yu et al. demonstrated production of 2′-FL in engineered S. cerevisiae via the salvage pathway to produce 2′-FL using l-fucose and lactose [169]. Although 3-FL can be synthesized by a similar approach using α-1,3-fucosyltransferase, its poor expression results in very low titers. Yu et al. engineered it by removing the membrane-binding region and elongating the heptad repeats to achieve a 10–20-fold increase in 3-FL titer [168]. Priem et al. expressed the β-1,3 N-acetylglucosaminyltransferase lgtA gene and the β-1,4 galactosyltransferase lgtB gene of N. meningitidis in E. coli and by sequential reactions produced lacto-N-triose (GlcNAcβ-1,3Galβ-1,4Glc) and lacto-N-neotetraose (Galβ-1,4GlcNAcβ-1,3Galβ-1,4Glc). They also produced 3′-sialyllactose by inactivating the nanA gene which encodes an aldolase and by exogenous addition of sialic acid [113]. More recently, Guo et al. demonstrated synthesis of 6′-sialyllactose, using a unique trans-sialidase to transfer a sialyl residue to lactose by transglycosylation, with high transglycosylation activity and strict regioselectivity [56]. In glycosidase-catalyzed synthesis, there is typically competition between transglycosylation and hydrolysis, which can be improved by employing higher acceptor/donor ratios that increase the probability of nucleophilic attack by the acceptor on the enzyme to form a glycosyl–enzyme intermediate. Zeuner et al. engineered an α-1,3/4-l-fucosidase to completely remove its hydrolytic activity and improved the transfucosylation activity to achieve threefold higher yields in their fucosylated product [172]. Excellent reviews covering the recent developments in synthesizing galactose-containing oligosaccharides [26] and regarding commercialization and regulatory framework [69] can be found at the aforementioned references. Fructans: inulin and fructooligosaccharide (FOS) Inulin, a polysaccharide abundant in commercial plant sources such as chicory and agave, is a polydisperse β-(2,1) fructan with the fructose units linked to each other by β-(2,1) bonds, with a degree of polymerization (DP) ranging from 2 to 60 [110] (Fig. 1a). Each fructose chain is capped by a terminal α-(1,2)-linked glucose molecule. Fructooligosaccharide (FOS) is composed of shorter chain oligomers, with a DP between 2 and 10, which can be produced by hydrolysis of inulin using endoinulinase. The prebiotic property of inulin is derived from its β-(2,1) linkages that remain indigestible. Their selective fermentation by bifidobacteria that produce an intracellular inulinase to hydrolyse the β-(2,1) fructose linkages, allows for the modulation of the composition of the gut microbiota [119]. Fructans are widely used as additives in food for their health boosting properties, especially in conjunction with probiotics, for a synergistic “synbiotic” effect [100]. Their physiological effects are dictated by their chain length, as shown by a study where FOS was fermented more rapidly and produced more butyrate compared to inulin [138]. In a simulated microbial environment seeded with fecal samples, supplementation of inulin resulted in increased Bacterioides uniformis or Bacterioides caccae [29]. Galactans: galactooligosaccharides (GOS) GOS are composed of galactose residues with a terminal glucose or galactose at the reducing end (Fig. 1b). Commercially, GOS are produced by enzymatic transgalactosylation of glucose, galactose, or lactose attached via β-(1, 2, 3, 4, or 6) linkages, with a DP of 2–8. GOS utilization is dependent on the linkage specificity of the β-galactosidases. Studies have shown a dose-dependent increase in fecal bifidobacteria in infants and increased SCFA levels upon fermentation [8, 42, 134]. GOS has been widely used in infant formula and other confectioneries and beverages [52, 151] and together with commercially available probiotic bifidobacteria and lactobacilli [143]. Xylooligosaccharides (XOS) XOS are produced from xylan-rich lignocellulosic materials, consisting of xylose residues linked via β-(1,4) linkages with a DP between 2 and 10 (Fig. 1c). Depending on the source, XOS are usually accompanied by other side groups such as α‐d‐glucopyranosyl uronic acid, acetyl groups, or arabinofuranosyl residues, whose presence results in branched structures [1]. Studies showed the selective ability of certain probiotic strains, Bifidobacterium adolescentis and Lactobacillus plantarum to utilize XOS owing to the presence of xylanolytic enzyme systems [76, 103]. Compared to other prebiotic substrates, including FOS, GOS and MOS, XOS produced the largest amount of SCFA upon degradation by fecal microbiota of pigs [136]. There is direct experimental evidence for the prebiotic efficacy of XOS in humans, including increased proportion of bifidobacteria [65] and SCFA levels [74]. Mannan-oligosaccharides (MOS) MOS are oligomers composed of mannose residues, linked together by β-1,4 glycosidic bonds, with a DP in the range 2–10 (Fig. 1d). Derived from yeast cell walls, MOS has been widely used to improve growth and health performance of livestock and aquaculture [94]. Supplementation of MOS to chicken feed reduced Clostridium perfringens and E. coli, and increased the relative population of Lactobacillus spp. [71]. Bacterial genera such as Bacteroides and Bacillus produce mannanases that can cleave β-1,4 mannopyranoside in mannan products. MOS has been shown to bind to mannose-specific lectins expressed in bacteria with fimbriae and hence, reduces bacterial adhesion to mannose-containing glycoprotein receptors on intestinal epithelial cells [102]. Mechanisms of action of prebiotics While prebiotics can manipulate the bacterial population, they can also benefit the host via gut environment through direct interactions with potential pathogens and/or the immune system. Figure 3 summarizes the proposed mechanisms of prebiotic action. Fig. 3 Open in new tabDownload slide Schematic diagram illustrating mechanisms by which prebiotics influence the gut microbiota. The effect of prebiotics is shown below the dashed line. (1) Selective colonization of probiotic bacteria (bifidobacteria and lactobacilli) by competition with pathogenic strains for prebiotics. (2) Production of short-chain fatty acids (SCFA), acetate, propionate and butyrate, resulting in reduction of pH. (3) Exclusion of pathogen binding to epithelial cells. (4) Enhanced intestinal barrier function by increased mucus. (5) Modulation of immune response Prebiotics are capable of interacting with the carbohydrate receptors on immune cells. Receptors on phagocytes and natural killer (NK) cells can be activated by binding of β-glucans which triggers neutrophil phagocytosis [122]. Glucans are a heterogeneous group of glucose polymers, composed of a backbone of β-(1,3)-linked β-d-glucopyranosyl units with β-(1,6)-linked side chains. Dectin-1, a NK-cell-receptor-like C-type lectin [16], was identified as a macrophage receptor for β-glucans, eliciting antitumor and antimicrobial activity [17]. Inulin-type fructans are also receptors for gut dendritic cells (DCs), via Toll-like receptors, C-type lectin receptors, and galectins, that induce anti-inflammatory cytokines [157]. The activity of HMOs against bacterial and viral infections can be explained by their absorption from the GI tract into the system and serving as receptors for bacterial or viral adhesion molecules [101]. Another mechanism by which prebiotics promote health is by promoting the production of metabolites, e.g., folate, indoles, secondary bile acids, trimethylamine-N-oxide (TMAO) and short-chain fatty acids (SCFAs), through fermentation of the prebiotic compounds [21]. The gut microbiota are endowed with plethora of glycoside hydrolases and polysaccharide lyases that are capable of breaking down the indigestible carbohydrates that traverse intact all the way to the distal gut [97]. It is the fermentation of these carbohydrates that produces SCFAs. These SCFAs can be transported across the intestine and into the systemic compartments, affecting the immune system. The SCFAs, acetate, propionate and butyrate in particular, showcase antimicrobial activity, lead to the lowering of pH in the gut, and heavily impacting the host metabolism and immunity, including from food and self-antigens [10, 49, 53, 140]. SCFAs also inhibit histone-deacetylase (HDAC) activity that affects gene transcription [137]. SCFAs can also bind to G-coupled protein receptors on leukocytes. Butyrate serves not only as a carbon source for colonic cells and hence helps to maintain a healthy gut barrier but also aids in maintaining the anaerobic conditions inside the gut [19, 20]. One study reported downregulation of inflammatory cytokines upon treatment with propionate but no effect with XOS indicating the indirect SCFA-mediated anti-inflammatory effect [59]. Another outcome of prebiotic treatment is the selective increase/decrease in specific intestinal bacteria that in turn, can induce health benefits. Early studies showed the growth advantage of bifidobacteria over E. coli and Clostridium spp. that cannot utilize XOS, leading to the predominance of bifidobacterial population [103]. Treatment with FOS was also associated with higher intestinal bifidobacteria counts in another study [66]. These bifidobacteria can digest XOS and FOS to produce lactate and SCFAs. One study showed that the gut microbial composition is a key player in energy homeostasis and hence dysbiosis can contribute towards obesity [84]. It was hypothesized that the Firmicutes-enriched cecal microbiota (relative to Bacteroidetes-enriched microbiota) promoted obesity by limiting energy uptake/storage. Role of prebiotics in human health The gut microbiota has been considered as functioning like an organ, constituting multitudes of cells and performing various functions in the human body. Prebiotics have a profound effect in modulating the gut microbiota, and hence a concomitant effect on human health. With increasing number of pre-clinical studies underway supporting the benefits of prebiotics, they are becoming an attractive therapeutic target for the prevention and treatment of human diseases. Immunomodulation Prebiotics may affect the immune system, either directly or indirectly via metabolites produced through fermentation or probiotic-mediated modulation of gene expression. β-Glucans interact with cell surface receptors to induce macrophages and NK cells which can also lead to inhibition of tumor growth in its promotion stage [2]. HMOs have shown to directly affect the development of the neonatal immune system. They stimulate production of cytokines and proliferation of immune cellular population [32]. In elderly adults, GOS was shown to increase phagocytosis, NK cell activity and production of anti-inflammatory cytokines and to decrease the production of proinflammatory cytokines [159]. HMOs containing sialic acid moieties were shown to inhibit the binding of rotavirus to host cells, directly affecting immune activity in rotavirus-infected neonates [31]. Several studies showed that mice exposed to inulin enriched with oligofructose, raffinose or FOS had enhanced production of cytokines [64, 98, 121]. HMOs also exhibit anti-adhesive properties against pathogenic bacteria and toxins, preventing attachment to epithelial cells [87]. Irritable bowel syndrome (IBS) Irritable bowel syndrome (IBS) is a common functional disorder characterized by abdominal discomfort and pain, bloating and an alteration in bowel habit [142]. Studies have shown that soluble fibers in partially hydrolyzed guar gum can alleviate abdominal pain and improve bowel habits [60]. Another study showed a decrease in digestive discomfort in patients given FOS [105]. GOS was also shown to significantly improve IBS symptoms [135]. Inflammatory bowel disease (IBD) The two main types of inflammatory bowel disease are ulcerative colitis and Crohn’s disease. Crohn’s disease usually affects the intestine and causes inflammation that affects the body’s ability to digest food, absorb nutrients and eliminate waste. Ulcerative colitis mainly affects the lining of the large intestine and rectum and chronic colitis can lead to colon cancer. IBD is associated with increased levels of the proinflammatory cytokines interleukin-1 (IL-1), IL-6, IL-8, and tumor necrosis factor α (TNF-α) [120]. Treatment with inulin and oligofructose was shown to reduce inflammation in rat models with colitis [63]. Reduced severity of DSS-induced colitis was also observed by another study on treatment with a combination of inulin/oligofructose and B. infantis [104]. Consumption of MOS also attenuated colitis symptoms in mice with DSS-induced colitis [43], presumably by altering the microbiota. Mental health and neurological disease The gut-brain axis has emerged as an exciting concept in microbial endocrinology. This crosstalk between the gut and brain is mediated by the vagus nerve [15]. There is evidence that shows the ability of the gut microbiota to communicate with the brain and modulate behavior by activating neural pathways and central nervous system (CNS) signaling systems [47]. Treatment with XOS was shown to reduce effects from pro-inflammatory cytokines in the brain [48]. Long-term consumption of XOS diminished activation of microglia and restored cognitive function in obese rats [28]. Chronic supplementation of FOS/GOS exhibited both antidepressant and anxiolytic effects and also reduced stress-induced corticosterone release by modifying gene expression in the hippocampus and hypothalamus in mice [18]. Similarly, significant decrease in anxiety was observed in animals treated with MOS [43]. Cardiovascular disease Cardiovascular diseases are associated with high levels of cholesterol and/or triglycerides [72]. Studies in rats with prebiotic fiber demonstrated a significant decrease in serum cholesterol levels [107]. Consumption of XOS by rats also showed a decline in the level of triglycerides [66]. Other studies have reported the reduction in cholesterol on consumption of FOS in diabetic subjects [166] and improvement in lipid profiles with inulin [118]. Propionate, produced by prebiotic fermentation, also lowers serum cholesterol levels and inhibits expression of the genes associated with intestinal cholesterol biosynthesis [4]. Cancer Numerous studies have identified prebiotics exhibiting anti-cancer properties [11, 51, 141]. Non-digestible polyphenols have the ability to alter the gut microbiota population, favoring strains capable of breaking down polyphenols, e.g., Bifidobacterium spp. and Lactobacillus spp., and producing simple phenolic metabolites. These metabolites can modulate enzyme and gene expression, e.g., phenolic residues like coumaric and caffeic acid produced by degradation of polyphenolics suppressed the histone-deacetylase activity in human colon cancer cells [160]. Butyrate was also reported to suppress cancer by inducing apoptosis in cancer cells and limiting histone-deacetylase activity [106]. Microbial metabolites of quercetin and caffeic acid lowered the DNA damage in human adenoma cells by regulating enzymes involved in detoxification and inflammation [92]. XOS and FOS were shown to inhibit colonic aberrant crypt foci in rats by lowering cecal pH and serum triglyceride levels [123]. It has also been proposed that absorption of micronutrients helped alleviate cancer risks. Consumption of inulin, FOS, and GOS was shown to increase the solubility of minerals and hence enhance their absorption [129]. Conclusion Significant progress has been made over the past few decades in recognizing the importance of gut microbiota to overall health. Going forward, armed with new tools and innovative approaches, opportunities still exist to allow researchers to further elucidate the mechanisms involved. Realization of the properties and benefits of prebiotics offer a new dimension for the development of functional foods and new treatment strategies for therapeutic targeting of the gut microbiota. However, further investigations are needed to elucidate the mechanisms involved in the treatment of diseases and confirmed with experimental models and clinical trials before prebiotics can be used as a potential therapeutic. In this review, we focused only on carbohydrate-based prebiotics but more recent studies have shown the prebiotic effects of other molecules including phytochemicals. Phytochemicals are bioactive non-nutrient plant compounds shown to exhibit selective stimulation of the gut microbiota [145]. Some polyphenols, for example, are not absorbed and reach the colon where they undergo metabolic transformations through the gut microbiota: fission of cyclic rings, deglycosylation, ester hydrolysis, and these metabolites are absorbed by the body [82]. These phytochemicals have been reported to lower risks of major chronic diseases, including hypertension, diabetes, neurodegenerative diseases and cancer [85]. Further studies need to be carried out to better understand their mechanisms and elucidate their benefits to host health. Engineering strategies to develop tools for the enrichment of the gut microbiota are evolving and custom-designed prebiotics is another area that needs further exploration, to better understand their effects on immunomodulation and interactions with pathogenic microbes. With current large-scale synthesis routes, elaborate biological investigations can be carried out. In addition, there is still a need to understand the effects all components of the microbiota including the spectrum of fungi, archaea, bacteriophages and viruses. The approach of coupling prebiotics and probiotics (as synbiotics), still has untapped capabilities toward influencing and improving human health. Another exciting development in this area is the creation of engineered bacteria capable of producing metabolites, peptides, or proteins that benefit the host, i.e., live biotherapeutics [38, 67, 79, 80]. As development of these engineered probiotic organisms continues, it follows that strategies for controlling their population dynamics will be essential for optimizing their efficacy. Two recent studies have approached this topic by creating orthogonal niches for bacteria via diet-based intervention [70, 133]. 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TI - Prebiotics: tools to manipulate the gut microbiome and metabolome
JF - Journal of Industrial Microbiology and Biotechnology
DO - 10.1007/s10295-019-02203-4
DA - 2019-10-01
UR - https://www.deepdyve.com/lp/oxford-university-press/prebiotics-tools-to-manipulate-the-gut-microbiome-and-metabolome-ExubVXtYsJ
SP - 1445
EP - 1459
VL - 46
IS - 9-10
DP - DeepDyve
ER -