The human gastrointestinal (GI) tract harbours a complex and dynamic population of microorganisms, the gut microbiota, which exert a marked influence on the host during homeostasis and disease. Multiple factors contribute to the establishment of the human gut microbiota during infancy. Diet is considered as one of the main drivers in shaping the gut microbiota across the life time. Intestinal bacteria play a crucial role in maintaining immune and metabolic homeostasis and protecting against pathogens. Altered gut bacterial composition (dysbiosis) has been associated with the pathogenesis of many inflammatory diseases and infections. The interpretation of these studies relies on a better understanding of inter-individual variations, heterogeneity of bacterial communities along and across the GI tract, functional redundancy and the need to distinguish cause from effect in states of dysbiosis. This review summarises our current understanding of the development and composition of the human GI microbiota, and its impact on gut integrity and host health, underlying the need for mechanistic studies focusing on host–microbe interactions.

Introduction

The human gastrointestinal (GI) tract represents one of the largest interfaces (250–400 m2) between the host, environmental factors and antigens in the human body. In an average life time, around 60 tonnes of food pass through the human GI tract, along with an abundance of microorganisms from the environment which impose a huge threat on gut integrity [1]. The collection of bacteria, archaea and eukarya colonising the GI tract is termed the ‘gut microbiota’ and has co-evolved with the host over thousands of years to form an intricate and mutually beneficial relationship [2,3]. The number of microorganisms inhabiting the GI tract has been estimated to exceed 1014, which encompasses ∼10 times more bacterial cells than the number of human cells and over 100 times the amount of genomic content (microbiome) as the human genome [2,4]. However, a recently revised estimate has suggested that the ratio of human:bacterial cells is actually closer to 1:1 [5]. As a result of the vast number of bacterial cells in the body, the host and the microorganisms inhabiting it are often referred to as a ‘superorganism’ [4,6].

The microbiota offers many benefits to the host, through a range of physiological functions such as strengthening gut integrity or shaping the intestinal epithelium [7], harvesting energy [8], protecting against pathogens [9] and regulating host immunity [10]. However, there is potential for these mechanisms to be disrupted as a result of an altered microbial composition, known as dysbiosis. With increasingly sophisticated methods to profile and characterise complex ecosystems being developed, a role for the microbiota in a large number of intestinal and extra-intestinal diseases has become steadily apparent [11,12]. This review summarises our current understanding of the development and composition of the human GI microbiota, and its impact on gut integrity and host health.

Composition and structure of the human GI microbiota

Around a decade ago, most knowledge about the adult human gut microbiota stemmed from labour-intensive culture-based methods [13]. Recently, our ability to survey the breadth of the gut microbiota has greatly improved due to the advent of culture-independent approaches such as high-throughput and low-cost sequencing methods. Targeting of the bacterial 16S ribosomal RNA (rRNA) gene is a popular approach [14,15], since this gene is present in all bacteria and archaea and contains nine highly variable regions (V1–V9), which allows species to be easily distinguished. Former techniques concentrated on sequencing the entire 16S rRNA gene. In an early study using this method, the extreme insensitivity and bias of culturing methods were highlighted, since 76% of the rRNA sequences obtained from an adult male faecal sample belonged to novel and uncharacterised species [16]. Recently, the focus of 16S rRNA sequencing has shifted to analysing shorter subregions of the gene in greater depth [15]; however, the utilisation of shorter read lengths can introduce errors [14]. More reliable estimates of microbiota composition and diversity may be provided by whole-genome shotgun metagenomics due to the higher resolution and sensitivity of these techniques [14]. Combined data from the MetaHit and the Human Microbiome Project have provided the most comprehensive view of the human-associated microbial repertoire to date [17,18]. Compiled data from these studies identified 2172 species isolated from human beings, classified into 12 different phyla, of which 93.5% belonged to Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes. Three of the 12 identified phyla contained only one species isolated from humans, including an intestinal species, Akkermansia muciniphila, the only known representative of the Verrucomicrobia phyla. In humans, 386 of the identified species are strictly anaerobic and hence will generally be found in mucosal regions such as the oral cavity and the GI tract [17].

The gut microbiota is not as diverse as the microbial communities from some other bodily sites and reveals a high degree of functional redundancy [1921]. An extensive catalogue of the functional capacity of the human gut microbiome was recently obtained, where 9 879 896 genes were identified through a combination of 249 newly sequenced and 1018 published samples [18]. The study identified the presence of country-specific microbial signatures, suggesting that gut microbiota composition is shaped by environmental factors, such as diet, and possibly also by host genetics [18]. However, it should also be noted that microbiotas that differ in terms of composition may share some degree of functional redundancy, yielding similar protein or metabolite profiles [22]. This information is crucial for developing therapeutic strategies to modify and shape the microbial community in disease.

Development of the human GI microbiota

The development of the microbiota is generally believed to begin from birth, although this dogma is challenged by a limited number of studies in which microbes were detected in womb tissues, such as the placenta [23,24]. After birth, the GI tract is rapidly colonised, with life events such as illness, antibiotic treatment and changes in diet causing chaotic shifts in the microbiota [24,25]. The mode of delivery also appears to affect the microbiota composition, with vaginally delivered infants' microbiota containing a high abundance of lactobacilli during the first few days, a reflection of the high load of lactobacilli in the vaginal flora [26,27]. In contrast, the microbiota of infants delivered by C-section is depleted and delayed in the colonisation of the Bacteroides genus, but colonised by facultative anaerobes such as Clostridium species [28,29]. Whilst the faecal microbiota of 72% of vaginally delivered infants resembles that of their mothers' faecal microbiota, in babies delivered by C-section, this percentage is reduced to only 41% [30]. In early stages of development, the microbiota is generally low in diversity and is dominated by two main phyla, Actinobacteria and Proteobacteria [24,31]. During the first year of life, the microbial diversity increases and the microbiota composition converges towards a distinct adult-like microbial profile with temporal patterns that are unique to each infant [32]. By around 2.5 years of age, the composition, diversity and functional capabilities of the infant microbiota resemble those of adult microbiota [24,25]. Although, in adulthood, the composition of the gut microbiota is relatively stable, it is still subject to perturbation by life events [33]. In individuals over the age of 65, the microbial community shifts, with an increased abundance of Bacteroidetes phyla and Clostridium cluster IV, in contrast with younger subjects where cluster XIVa is more prevalent [34]. In contrast, a separate study observed that the microbiota of a young cohort and an elderly population (70 years) were relatively comparable, whilst the diversity of the microbiota from a cohort of centenarians was significantly reduced [35]. The centenarian microbiota also exhibited group-specific differences such as an increase in the abundance of facultative anaerobes (e.g. Escherichia coli) and rearrangement of the profile of butyrate producers (e.g. decrease in Faecalibacterium prausnitzii) [35]. In the elderly population, a significant relationship has been identified between diversity and living arrangements, such as community dwelling or long-term residential care [36]. Overall, the capacity of the microbiota to carry out metabolic processes such as short-chain fatty acid (SCFA) production and amylolysis is reduced in the elderly, whilst proteolytic activity is increased [37]. Given the increasing evidence for the role of SCFAs as key metabolic and immune mediators (as reviewed below), it was postulated that the decrease in SCFAs may nurture the inflamm-ageing process in the intestine of aged people [38].

Biogeography of the human microbiota in the GI tract

Microbiota composition in the GI tract is reflective of the physiological properties in a given region and is stratified on both a transverse and longitudinal axis [39]. The density and composition of the microbiota are affected by chemical, nutritional and immunological gradients along the gut. In the small intestine, there are typically high levels of acids, oxygen and antimicrobials, and a short transit time [40]. These properties limit bacterial growth, such that only rapidly growing, facultative anaerobes with the ability to adhere to epithelia/mucus are thought to survive [40]. In mice, the small-intestine microbial community is largely dominated by Lactobacillaceae [41]. In contrast, colonic conditions support a dense and diverse community of bacteria, mainly anaerobes with the ability to utilise complex carbohydrates which are undigested in the small intestine. In the colon Prevotellaceae, Lachnospiraceae and Rikenellaceae have been shown to dominate [40,41].

In contrast with the differing microbiota composition between varying GI organs, the microbiota of different colorectal mucosal regions within the same individual is spatially conserved in terms of both composition and diversity [42,43]. This feature is apparent even during periods of localised inflammation [43]. On the other hand, the faecal/luminal and mucosal compositions are significantly different [42,43]. For example, the abundance of Bacteroidetes appears to be higher in faecal/luminal samples than in the mucosa [42,44]. In contrast, Firmicutes, specifically Clostridium cluster XIVa, are enriched in the mucus layer compared with the lumen [44]. Interestingly, recent experiments in mice colonised with a diverse specific pathogen-free microbiota showed that the outer mucus of the large intestine forms a unique microbial niche and that bacterial species present in the mucus show differential proliferation and resource utilisation compared with the same species in the intestinal lumen [45]. These observations highlight the need for careful consideration in choosing a sampling method when analysing the microbiota composition.

Inter-individual differences in the species and subspecies arrangement are proposed to outweigh differences in the community arrangement within an individual [42,46,47]. Suggestions have been made of the presence of a ‘core microbiota’, proposed to be a set of the same abundant organisms present in all individuals. However, more similarity can be observed in the repertoire of microbial genes present between individuals than the taxonomic profile, suggesting that the core microbiota may be better defined at a functional rather than organism level [46]. Recently, it has been possible to classify individual microbiota arrangements into ‘community types’ that can be predictive of each other and are associated with background [48]. Multi-dimensional analysis of 33 samples from different nationalities revealed the presence of three enterotypes identifiable by variations in the level of one of three genera: Bacteroides (enterotype 1), Prevotella (enterotype 2) and Ruminococcus (enterotype 3) [49]. However, evidence surrounding the existence and formation of these enterotypes is controversial, as thoroughly reviewed in [50].

Factors shaping the GI microbiota

The microbiota composition is subject to shaping by host and environmental selective pressures. To protect from injury and maintain homeostasis, the GI tract limits exposure of the host immune system to the microbiota by recruitment of a multifactorial and dynamic intestinal barrier. The barrier comprises several integrated components including physical (the epithelial and mucus layers), biochemical (enzymes and antimicrobial proteins) and immunological (IgA and epithelia-associated immune cells) factors [51]. An individual microbe's longevity is determined by whether it is contributing to the range of essential functions on which host fitness relies. It is proposed that organisms who do not contribute beneficial functions are controlled by, and may occasionally be purged during, for example, transferral of the microbiota to a new host [52,53].

Gut microbes must be adapted to a certain type of lifestyle due to the relatively fewer number of biochemical niches available in the gut, compared with other microbial-rich environments. In the gut, energy can generally be derived through processes such as fermentation and sulphate reduction of dietary and host carbohydrates. The organisms that can survive in the gut are therefore limited by their phenotypic traits [52].

Current research suggests that diet exerts a large effect on the gut microbiota [40]. Meta-transcriptomic studies revealed that the ileal microbiota is driven by the capacity of the microbial members to metabolise simple sugars, reflecting adaptation of the microbiota to the nutrient availability in the small intestine [54]. Shaping of the colonic microbiota is subject to the availability of microbiota-accessible carbohydrates (MACs) that are found in dietary fibre. Extreme ‘animal-based’ or ‘plant-based’ diets result in wide-ranging alterations of the gut microbiota in humans [55]. The influence of fibre was demonstrated in a crossover study showing that otherwise matched diets high in resistant starch or in non-starch polysaccharide fibre (wheat bran) resulted in the strong and reproducible enrichment of different bacterial species in the human gut [56]. Feeding methods can also affect the abundance of some bacterial groups in the gut microbiota of infants. For example, fucosylated oligosaccharides present in human milk can be utilised by Bifidobacterium longum and several species of Bacteroides allowing them to outcompete other bacteria such as E. coli and Clostridium perfringens [57,58]. Whilst the abundance of Bifidobacterium spp. in breast-fed infant microbiota is typically high [57], this is reduced in formula-fed infants [59]. Furthermore, formula-fed infant microbiota has an increased diversity and altered levels of other groups such as E. coli, Clostridium difficile, Bacteroides fragilis and lactobacilli [5961]. The microbiota of undernourished infants is immature, dysbiotic and contains greater numbers of enteropathogens, such as Enterobacteriaceae [62]. Infants from rural Africa, with a diet dominated by starch, fibre and plant polysaccharides, harbour a microbiota that is abundant in the Actinobacteria (10.1%) and Bacteroidetes (57.7%) phyla [63]. In contrast, in European children, whose diet is rich in sugar, starch and animal protein, the abundance of these groups is reduced to just 6.7 and 22.4% [63]. Some SCFA producers, such as Prevotella, were exclusive to the microbiota of African children [63]. This trend was also apparent in healthy individuals consuming high amounts of carbohydrates and simple sugars [64]. A decreased SCFA output is also evident in individuals consuming a low MAC diet, a notable effect since SCFAs play an important role in host health via, for example, anti-inflammatory mechanisms [65]. The abundance of MACs is substantially reduced in the Western diet. Administration of a low MAC diet to mice results in a reduction in microbial diversity [66]. Restoration of diversity requires administration of MACs in combination with the bacterial taxa that were missing [66]. Recent studies using gnotobiotic mice showed that certain microbial species can be used to restore growth impairments transmitted by microbiota from malnourished children, raising the possibility of using these species as a therapeutic intervention to counteract the negative effects of undernutrition [6769].

Intestinal mucus also provides a source of carbohydrates to the gut microbiota [70,71]. The intestinal mucus layers are built around the large highly glycosylated gel-forming mucin MUC2 (Muc2 in mouse) secreted by goblet cells [72]. The glycan structures present in mucins are diverse and complex and based on four core mucin-type O-glycans containing N-acetylgalactosamine, galactose and N-acetylglucosamine. These core structures are further elongated and frequently terminated by fucose and sialic acid sugar residues. Collectively, O-glycans account for up to 80% of the total molecular mass of Muc2/MUC2 [73]. Mucus is present throughout the GI tract and is thickest in the colon where it is crucial in mediating the host–microbiota relationship [74]. Normalisation of host intestinal mucus layers requires long-term microbial colonisation [75]. Colonic mucus is divided into two layers consisting of a dense and impermeable inner layer and a loose outer coating which is penetrable by bacteria [74]. Whilst the inner layer is virtually sterile, in the outer layer, the mucin proteins, which are decorated by a rich and diverse repertoire of O-glycans, provide an energy source and preferential binding sites for commensal bacteria [73,76,77]. The arrangement of the outer mucus layer provides a unique niche in which bacterial species display different patterns of proliferation and utilisation of resources compared with their counterparts in the lumen [45]. The type of mucin O-glycosylation is dependent on the glycosyltransferases expressed and where in the Golgi apparatus they are located [71], alterations of which affect the microbiota composition. For example, the presence (secretor) or absence (non-secretor) of H and ABO antigens in GI mucosa, determined by the FUT2 genotype (a gene expressing an α1,2-fucosyltransferase), affects the abundance of many bacterial groups [78]. Mucus and mucin glycosylation are therefore key in shaping the microbiota and allow for the selection of the most optimal microbial species to mediate host health [7981]. A depletion of MACs from the diet of mice can result in thinner mucus in the distal colon, increased proximity of microbes to the epithelium and heightened expression of the inflammatory marker REGIIIβ [82]. The erosion of the colonic mucus barrier under dietary fibre deficiency is associated with a switch of the gut microbiota towards the utilisation of secreted mucins as a nutrient source [83]. On the other hand, administration of a mucin degrader, A. muciniphila, to mice prevents the development of high-fat diet-induced obesity and ameliorates metabolic endotoxemia-induced inflammation through restoration of the gut barrier [84,85]. Some of these effects are the result of increased mucin secretion and intestinal tight-junction proteins, which highlight the dynamic role played by mucin degraders in their interaction with the host. The protective role of A. muciniphila could be recapitulated using A. muciniphila purified membrane protein or the pasteurised bacterium [86]. Recently, A. muciniphila supplementation was shown to significantly alleviate body weight gain and reduce fat mass in chow diet-fed mice by relieving metabolic inflammation [87]. These studies suggest the potential of A. muciniphila as a therapeutic option to target human obesity and associated disorders.

The capacity of gut bacteria to utilise dietary or mucin glycans is dictated by the repertoire of glycoside hydrolases (GHs) and polysaccharide lyases (PLs) encoded by their genomes [70]. Some species act as generalists able to degrade a wide range of polysaccharides, whilst others are specialists targeting specific glycans [88]. Bacteroidetes encode many more glycan-cleaving enzymes (137.1 GH and PL genes per genome) than Firmicutes members (39.6 GH and PL genes per genome) [89]. The Bacteroides thetaiotaomicron genome contains 260 GHs, in comparison with the 97 hydrolases encoded by humans [90]. The GH13 family, which contains enzymes involved in the breakdown of starch, is the most represented family in the gut microbiota [89]. Recently, the detailed biochemical and structural characterisation of the extensive degrading apparatus of prominent gut species such as B. thetaiotaomicron or Bacteroides ovatus revealed that the recognition and breakdown of complex carbohydrates, such as xylan, mannan, xyloglucan or starch, by the human gut microbiota is significantly more complex than previously suggested [9196]. Although less studied, members of Firmicutes also show some unique and complex features such as the recent discovery of amylosomes in the resistant starch-utilising bacterium Ruminococcus bromii [97].

Diversification of the microbial population can occur through, for example, mutation or lateral gene transfer [98,99]. The introduction of new bacterial functions promotes niche variation, creating a positive feedback loop in which more diversification can occur [100,101]. Co-operation between gut microbes also allows colonisation by a more diverse set of organisms, shaping the gut microbiota community. Microbial cross-feeding is one mechanism proposed to mediate this effect. Some carbohydrate fermentation products, including lactate, succinate and 1,2-propanediol, do not usually accumulate to high levels in the human colon of healthy adults, as they can serve as substrates for other bacteria, including propionate and butyrate producers [102]. For example, acetate produced by fermentation of resistant starch by R. bromii [103] or lactate produced by lactic acid bacteria such as lactobacilli and bifidobacteria provides substrate for other microbiota members such as Eubacterium hallii and Anaerostipes caccae which convert it into butyrate [104,105]. Recently, B. ovatus has been demonstrated to perform extracellular digestion of inulin at its own cost, but at an advantage to other species which provide reciprocal benefits [106]. Such co-operation is particularly apparent in the outer mucus layer where mucin-degrading bacteria provide mono- or oligosaccharides to bacteria without specialised mucolytic capability [45]. For example, the capacity of cleaving sialic acid off mucins is restricted to bacterial species encoding GH33 sialidases. Many bacteria, including pathogens such as Salmonella Typhimurium or C. difficile, lack a sialidase but harbour a ‘nan cluster’ dedicated to sialic acid metabolism, and thus rely on other members of the gut microbiota to provide them with this source of carbon [107]. Intramolecular trans-sialidase is a new class of sialidases recently identified in Ruminococcus gnavus strains that may play a role in the adaptation of gut commensal bacteria to the mucosal niche [70,108,109]. This activity may provide such bacteria with a competitive nutritional advantage over other species within the gut mucosal environment, specifically in inflammatory bowel diseases, which is rich in short, sialylated mucin glycans [70,110].

The availability of sulphated compounds in the colon, either of inorganic (e.g. sulphates and sulphites) or organic (e.g. dietary amino acids and host mucins) origin, can influence specific groups of bacteria such as sulphate-reducing bacteria, which are residents of the gut microbiota that have been implicated in the aetiology of intestinal disorders such as IBD, IBS or colorectal cancer [111].

The distribution of bile acids in the small and large intestine can also affect the bacterial community dynamics in the gut as thoroughly reviewed [112,113]. Primary bile acids, such as taurocholate, can provide homing signals to gut bacteria and promote germination of spores, and may also facilitate recovery of microbiota after dysbiosis induced by antibiotics or toxins [114]. Furthermore, reduced bile acid concentration in the gut may play an important role in allowing pro-inflammatory microbial taxa to expand [115]. These studies highlight the role of bile acids in shaping the GI microbiota.

The microbiota can also be shaped by the host immune system. This effect is mostly limited to stratification and compartmentalisation of bacteria to avoid opportunistic invasion of host tissue, whilst species-specific effects are less probable due to the high amount of functional redundancy within the microbiota [52,116119]. Both host-derived and administered antimicrobials play a key role in shaping the gut microbiota. In the GI tract, Paneth cells produce antimicrobials such as angiogenin 4, α-defensins, cathelicidins, collectins, histatins, lipopolysaccharide (LPS)-binding protein, lysozymes, secretory phospholipase A2 and lectins such as REGIIIα/γ [120]. These proteins are localised in the mucus layer and are virtually absent from the lumen, probably either due to poor diffusion through mucus or luminal degradation [51,121]. Many secreted antimicrobial proteins (AMPs) kill bacteria through direct interaction with, and disruption of the bacterial cell wall or inner membrane via enzymatic attack [51]. Reduced mucosal α-defensin expression has been demonstrated in patients with ileal Crohn's disease (CD), highlighting the importance of these proteins [122,123]. Secretory IgA (SIgA), another component of the immune system, co-localises with gut bacteria in the outer mucus layer and assists in limiting the exposure of the epithelial cell surface to bacteria [120,124]. SIgA is proposed to mediate bacterial biofilm formation via binding to SIgA receptors on bacteria [125]. The expression of SIgA receptors by bacteria is reduced in IgA-deficient individuals [126]. Dysbiosis of the microbiota, in particular an over-representation of segmented filamentous bacteria (SFB), occurs in mice deficient in IgA, an effect that may be particularly damaging to the host due to the ability of SFB to strongly adhere to the epithelium and activate the immune system [127].

Several environmental factors have been implicated in shaping the microbiota including geographical location, surgery, smoking, depression and living arrangements (urban or rural) [24,128130]. Xenobiotics, such as antibiotics but not host-targeted drugs, shape the physiology and gene expression of the active human gut microbiome [131]. Antibiotic treatment dramatically disrupts both short- and long-term microbial balance, including decreases in the richness and diversity of the community. Clindamycin [132], clarithromycin and metronidazole [47], and ciproflaxin [33] have all been demonstrated to affect the microbiota structure for varying lengths of time. The exact effects and the time for recovery of the microbiota following antibiotic administration appear to be individual-dependent, a likely effect of the inter-individual variation in the microbiota prior to treatment [33,47,132]. An explorative study in humans showed that the administration of β-lactam intravenous therapy consisting of ampicillin, sulbactam and cefazolin affects both the microbial ecology and the production of key metabolites, such as acetyl phosphate and acetyl-CoA, that are involved in major cellular functions [133]. Recent investigations in mice demonstrated that microbiota depletion by antibiotics affected secondary bile acid and serotonin metabolism in the colon, resulting in delayed GI motility [134]. Antibiotic-treated mice are also more susceptible to pathogenic infection by antibiotic-associated pathogens, S. Typhimurium and C. difficile, due to an alteration in mucosal carbohydrate availability favouring their expansion into the gut [135]. A better understanding of the mechanisms leading to the antibiotic-induced blooms of bacteria and the biochemical activities and metabolites affected will help develop complementary and/or alternative strategies required for maintaining human health.

Role of the GI microbiota in health

Owing to its large genomic content and metabolic complement, the gut microbiota provides a range of beneficial properties to the host. Some of the most important roles of these microbes are to help to maintain the integrity of the mucosal barrier, to provide nutrients such as vitamins or to protect against pathogens. In addition, the interaction between commensal microbiota and the mucosal immune system is crucial for proper immune function.

Colonic bacteria express carbohydrate-active enzymes, which endow them with the ability to ferment complex carbohydrates generating metabolites such as SCFAs [136]. Three predominant SCFAs, propionate, butyrate and acetate, are typically found in a proportion of 1:1:3 in the GI tract [137]. These SCFAs are rapidly absorbed by epithelial cells in the GI tract where they are involved in the regulation of cellular processes such as gene expression, chemotaxis, differentiation, proliferation and apoptosis [138]. Acetate is produced by most gut anaerobes, whereas propionate and butyrate are produced by different subsets of gut bacteria following distinct molecular pathways [102]. Butyrate is produced from carbohydrates via glycolysis and acetoacetyl-CoA, whereas two pathways, the succinate or propanediol pathway, are known for the formation of propionate, depending on the nature of the sugar [102]. In the human gut, propionate is mainly produced by Bacteroidetes, whereas the production of butyrate is dominated by Firmicutes [102,139,140]. For example, fermentation of starch by specialist Actinobacteria and Firmicutes, e.g. Eubacterium rectale or E. hallii, is thought to contribute significantly to butyrate production in the colon both directly and via metabolic cross-feeding [102]. A. muciniphila is a key propionate producer specialised in mucin degradation [141]. Propionate is primarily absorbed by the liver, whilst acetate is released into peripheral tissues [142]. The role of SCFAs on human metabolism has recently been reviewed [140,143]. Butyrate is known for its anti-inflammatory and anticancer activities [140,143]. Butyrate is a particularly important energy source for colonocytes [138]. A decreasing gradient of butyrate from lumen to crypt is suggested to control intestinal epithelial turnover and homeostasis by promoting colonocyte proliferation at the bottom of crypts, whilst increasing apoptosis and exfoliation of cells closer to the lumen [144]. Butyrate can attenuate bacterial translocation and enhance gut barrier function by affecting tight-junction assembly and mucin synthesis [140]. SCFAs also appear to regulate hepatic lipid and glucose homeostasis via complementary mechanisms. In the liver, propionate can activate gluconeogenesis, whilst acetate and butyrate are lipogenic [140]. SCFAs also play a role in regulating the immune system and inflammatory response [140]. They influence the production of cytokines, for example, stimulating the production of IL-18, an interleukin involved in maintaining and repairing epithelial integrity [138]. Butyrate and propionate are histone deacetylase inhibitors that epigenetically regulate gene expression [140,143]. SCFAs have also been shown to modulate appetite regulation and energy intake via receptor-mediated mechanisms [145]. Propionate has beneficial effects in humans acting on β-cell function [146] and attenuating reward-based eating behaviour via striatal pathways [147]. Microbial metabolites other than SCFAs have been reported to have an impact on intestinal barrier functions, epithelium proliferation and the immune system [148].

The GI microbiota is also crucial to the de novo synthesis of essential vitamins which the host is incapable of producing [149]. Lactic acid bacteria are key organisms in the production of vitamin B12, which cannot be synthesised by either animals, plants or fungi [149,150]. Bifidobacteria are main producers of folate, a vitamin involved in vital host metabolic processes including DNA synthesis and repair [151]. Further vitamins, which gut microbiota have been shown to synthesise in humans, include vitamin K, riboflavin, biotin, nicotinic acid, panthotenic acid, pyridoxine and thiamine [152]. Colonic bacteria can also metabolise bile acids that are not reabsorbed for biotransformation to secondary bile acids [113]. All of these factors will influence host health. For example, an alteration of the co-metabolism of bile acids, branched fatty acids, choline, vitamins (i.e. niacin), purines and phenolic compounds has been associated with the development of metabolic diseases such as obesity and type 2 diabetes [153].

There are many lines of evidence in support of a role for the gut microbiota in influencing epithelial homeostasis [7]. Germ-free mice exhibit impaired epithelial cell turnover which is reversible upon colonisation with microbiota [154]. A role has been demonstrated for bacteria in promoting cell renewal and wound healing, for example, in the case of Lactobacilli rhamnosus GG [155]. Furthermore, several species have been implicated in promoting epithelial integrity, such as A. muciniphila [156] and Lactobacillus plantarum [157]. In addition to modulating epithelial properties, bacteria are proposed to modulate mucus properties and turnover. Mice housed under germ-free conditions have an extremely thin adherent colonic mucus layer, but when exposed to bacterial products (peptidoglycan or LPS), the thickness of the adherent mucus layer can be restored to levels observed in conventionally reared mice [158]. B. thetaiotaomicron and F. prausnitzii have been implicated in the co-ordination of mucus production [159]. R. gnavus E1, Lactobacillus casei DN-114 001 and B. thetaiotaomicron are able to remodel mucin glycosylation, for example, by modulating glycosyltransferase expression [160162]. It is proposed that these functions mediate the ability of other commensals or pathogens to colonise, potentially giving some commensal species a competitive advantage in the gut [162].

The GI microbiota is also important for the development of both the intestinal mucosal and systemic immune system as demonstrated by the deficiency in several immune cell types and lymphoid structures exhibited by germ-free animals. A major immune deficiency exhibited by germ-free animals is the lack of expansion of CD4+ T-cell populations. This deficiency can be completely reversed by the treatment of GF mice with polysaccharide A from the capsule of B. fragilis [163]. This process is mainly performed via the pattern recognition receptors (PRRs) of epithelial cells, such as Toll-like or Nod-like receptors, which are able to recognise the molecular effectors that are produced by intestinal microbes. These effectors mediate processes that can ameliorate certain inflammatory gut disorders, discriminate between beneficial and pathogenic bacteria or increase the number of immune cells or PRRs [164]. SFB, a class of anaerobic and clostridia-related spore-forming commensals present in the mammalian GI tract, actively interact with the immune system [165]. Unlike other commensal bacteria, SFB are closely associated with the epithelial lining of the mammalian GI tract membrane, which stimulates epithelial cells to release serum amyloid A1 [148]. Colonisation with SFB may also direct post-natal maturation of the gut mucosal lymphoid tissue, trigger a potent and broad IgA response, stimulate the T-cell compartment and up-regulate intestinal innate defence mediators, suggesting immune-stimulatory capacities of SFB (as reviewed in [143]). A. muciniphila has been correlated with protection against several inflammatory diseases [84,87,166170], suggesting that this strain possesses anti-inflammatory properties although the underlying mechanisms have not been completely elucidated [171]. Individuals with CD display mucosal dysbiosis characterised by reduced diversity of core microbiota and lower abundance of F. prausnitzii [172]. F. prausnitzii monitoring may therefore serve as a biomarker to assist in gut disease diagnostics [173]. Recently, an anti-inflammatory protein from F. prausnitzii was shown to inhibit the NF-κB pathway in intestinal epithelial cells and prevent colitis in an animal model [174].

The physical presence of the microbiota in the GI tract also influences pathogen colonisation by, for example, competing for attachment sites or nutrient sources, and by producing antimicrobial substances [9]. Antibiotics have a profound impact on the microbiota that alter the nutritional landscape of the gut and lead to the expansion of pathogenic populations [175]. For example, S. Typhimurium and C. difficile utilise fucose and sialic acid liberated by the gut microbiota, and increasing sialic acid levels post-antibiotic treatment favour their expansion within the gut [135]. Enterohaemorrhagic E. coli has also been shown to access fucose or sialic acid liberated by the gut microbiota from mucins [176]. Dietary fibre deficiency, together with a fibre-deprived, mucus-eroding microbiota, promotes greater epithelial access and lethal colitis by the mucosal pathogen Citrobacter rodentium in mice [83]. The GI microbiota, via its structural components and metabolites, also stimulates the host to produce various antimicrobial compounds. These include AMPs such as cathelicidins, C-type lectins and (pro)defensins by the host Paneth cells via a PRR-mediated mechanism [51]. The other mechanism by which the gut microbiota can limit pathogen overgrowth is by inducing mucosal SIgA [177]. Induction of SIgAs directed against gut commensal bacteria occurs via an M-cell-mediated sampling mechanism [178]. SIgAs are then anchored in the outer layer of colonic mucus through combined interactions with mucins and gut bacteria, thus providing immune protection against pathogens whilst maintaining a mutually beneficial relationship with commensals [124]. PRR–MAMP (pattern recognition receptor–microbe-associated molecular patterns) cross-talk results in activation of several signalling pathways that are essential for promoting mucosal barrier function and production of AMPs, mucins and IgA, contributing to host protection against invading pathogens and preventing the overgrowth of the commensals themselves [179].

Conclusion

Given the close symbiotic relationship existing between the gut microbiota and the host, it is not surprising to observe a divergence from the normal microbiota composition (generally referred to as dysbiosis) in a plethora of disease states ranging from chronic GI diseases to neurodevelopmental disorders [12, 180]. The application of metabolomics approaches has greatly advanced our understanding of the mechanisms linking the gut microbiota composition and its activity to health and disease phenotypes. At a functional level, a potential way to describe a ‘dysbiotic microbiota’ might be one which fails to provide the host with the full complement of beneficial properties. Whether dysbiosis of the microbiota is a cause or a consequence of the disease is therefore likely to exacerbate the progression of the disease and affect the type of strategies needed to restore symbiosis. Depending on the type and stage of disease, these include the development of microbiome modulators (e.g. antimicrobials, diet, prebiotics or probiotics) mostly aimed at changing the composition of the host microbiota, or of microbial-based solutions to replace some of the defective microbes and their associated benefits (e.g. specific commensal strains, probiotics, defined microbial communities, microbial-derived signalling molecules or metabolites). Given the contribution of host genetics in many diseases associated with a dysbiotic microbiota, dual therapeutic strategies (e.g. combining immunotherapy and microbiota-targeted approaches) may also be required to restore the environment required to re-establish an effective communication between the host and the targeted microbiota. Success in these endeavours is dependent on our mechanistic understanding of how the microbiota affects and is affected by the host at a molecular and biochemical level.

Abbreviations

     
  • AMPs

    antimicrobial proteins

  •  
  • CD

    Crohn's disease

  •  
  • FUT2

    α1,2-fucosyltransferase

  •  
  • GHs

    glycoside hydrolases

  •  
  • GI

    gastrointestinal

  •  
  • IBD

    inflammatory bowel disease

  •  
  • IBS

    inflammatory bowel syndrome

  •  
  • IL-18

    interleukin

  •  
  • LPS

    lipopolysaccharide

  •  
  • MACs

    microbiota-accessible carbohydrates

  •  
  • PLs

    polysaccharide lyases

  •  
  • PRRs

    pattern recognition receptors

  •  
  • rRNA

    ribosomal RNA

  •  
  • SCFA

    short-chain fatty acid

  •  
  • SFB

    segmented filamentous bacteria

  •  
  • SIgA

    secretory IgA

Funding

This research was partly funded by the Biotechnology and Biological Sciences Research Council (BBSRC) Institute Strategic Programme for the Gut Health and Food Safety [BB/J004529/1] and the Norwich Research Park.

Acknowledgments

The authors gratefully acknowledge the support of the Biotechnology and Biological Sciences Research Council (BBSRC).

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

References

References
1
Bengmark
,
S.
(
1998
)
Ecological control of the gastrointestinal tract. The role of probiotic flora
.
Gut
42
,
2
7
doi:
2
Backhed
,
F.
(
2005
)
Host-bacterial mutualism in the human intestine
.
Science
307
,
1915
1920
doi:
3
Neish
,
A.S.
(
2009
)
Microbes in gastrointestinal health and disease
.
Gastroenterology
136
,
65
80
doi:
4
Gill
,
S.R.
,
Pop
,
M.
,
DeBoy
,
R.T.
,
Eckburg
,
P.B.
,
Turnbaugh
,
P.J.
,
Samuel
,
B.S.
et al. 
(
2006
)
Metagenomic analysis of the human distal gut microbiome
.
Science
312
,
1355
1359
doi:
5
Sender
,
R.
,
Fuchs
,
S.
and
Milo
,
R.
(
2016
)
Revised estimates for the number of human and bacteria cells in the body
.
bioRxiv
6
Luckey
,
T.D.
(
1972
)
Introduction to intestinal microecology
.
Am. J. Clin. Nutr.
25
,
1292
1294
7
Natividad
,
J.M.M.
and
Verdu
,
E.F.
(
2013
)
Modulation of intestinal barrier by intestinal microbiota: Pathological and therapeutic implications
.
Pharmacol. Res.
69
,
42
51
doi:
8
den Besten
,
G.
,
van Eunen
,
K.
,
Groen
,
A.K.
,
Venema
,
K.
,
Reijngoud
,
D.-J.
,
Bakker
,
B.M.
(
2013
)
The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism
.
J. Lipid Res.
54
,
2325
2340
doi:
9
Bäumler
,
A.J.
and
Sperandio
,
V.
(
2016
)
Interactions between the microbiota and pathogenic bacteria in the gut
.
Nature
535
,
85
93
doi:
10
Gensollen
,
T.
,
Iyer
,
S.S.
,
Kasper
,
D.L.
,
Blumberg
,
R.S.
(
2016
)
How colonization by microbiota in early life shapes the immune system
.
Science
352
,
539
544
doi:
11
Chang
,
C.
and
Lin
,
H.
(
2016
)
Dysbiosis in gastrointestinal disorders
.
Best Pract. Res. Clin. Gastroenterol.
30
,
3
15
doi:
12
Schroeder
,
B.O.
and
Bäckhed
,
F.
(
2016
)
Signals from the gut microbiota to distant organs in physiology and disease
.
Nat. Med.
22
,
1079
1089
doi:
13
Moore
,
W.E.C.
and
Holdeman
,
L.V.
(
1974
)
Human fecal flora - normal flora of 20 Japanese-hawaiians
.
Appl. Microbiol.
27
,
961
979
14
Poretsky
,
R.
,
Rodriguez-R
,
L.M.
,
Luo
,
C.
,
Tsementzi
,
D.
,
Konstantinidis
,
K.T.
,
Rodriguez-Valera
,
F.
(
2014
)
Strengths and limitations of 16S rRNA gene amplicon sequencing in revealing temporal microbial community dynamics
.
PLoS ONE
9
,
e93827
doi:
15
Mizrahi-Man
,
O.
,
Davenport
,
E.R.
,
Gilad
,
Y.
, and
White
,
B.A.
(
2013
)
Taxonomic classification of bacterial 16S rRNA genes using short sequencing reads: evaluation of effective study designs
.
PLoS ONE
8
,
e53608
doi:
16
Suau
,
A.
et al. 
(
1999
)
Direct analysis of genes encoding 16S rRNA from complex communities reveals many novel molecular species within the human gut
.
Appl. Environ. Microbiol.
65
,
4799
4807
17
Hugon
,
P.
,
Dufour
,
J.-C.
,
Colson
,
P.
,
Fournier
,
P.-E.
,
Sallah
,
K.
,
Raoult
,
D.
(
2015
)
A comprehensive repertoire of prokaryotic species identified in human beings
.
Lancet Infect. Dis.
15
,
1211
1219
doi:
18
Li
,
J.
,
Jia
,
H.
,
Cai
,
X.
,
Zhong
,
H.
,
Feng
,
Q.
,
Sunagawa
,
S.
et al. 
(
2014
)
An integrated catalog of reference genes in the human gut microbiome
.
Nat. Biotechnol.
32
,
834
841
doi:
19
Schluter
,
J.
,
Foster
,
K.R.
,
Ellner
,
S.P.
(
2012
)
The evolution of mutualism in gut microbiota via host epithelial selection
.
PLoS Biol.
10
,
e1001424
doi:
20
Costello
,
E.K.
,
Lauber
,
C.L.
,
Hamady
,
M.
,
Fierer
,
N.
,
Gordon
,
J.I.
,
Knight
,
R.
(
2009
)
Bacterial community variation in human body habitats across space and time
.
Science
326
,
1694
1697
doi:
21
Pérez-Cobas
,
A.E.
,
Gosalbes
,
M.J.
,
Friedrichs
,
A.
,
Knecht
,
H.
,
Artacho
,
A.
,
Eismann
,
K.
et al. 
(
2013
)
Gut microbiota disturbance during antibiotic therapy: a multi-omic approach
.
Gut
62
,
1591
1601
doi:
22
Moya
,
A.
and
Ferrer
,
M.
(
2016
)
Functional redundancy-Induced stability of Gut microbiota subjected to disturbance
.
Trends Microbiol.
24
,
402
413
doi:
23
Aagaard
,
K.
,
Ma
,
J.
,
Antony
,
K.M.
,
Ganu
,
R.
,
Petrosino
,
J.
,
Versalovic
,
J.
(
2014
)
The placenta harbors a unique microbiome
.
Sci. Transl. Med.
6
,
237ra65
doi:
24
Rodriguez
,
J.M.
et al. 
(
2015
)
The composition of the gut microbiota throughout life, with an emphasis on early life
.
Microb. Ecol. Health Dis.
26
,
26050
25
Koenig
,
J.E.
,
Spor
,
A.
,
Scalfone
,
N.
,
Fricker
,
A.D.
,
Stombaugh
,
J.
,
Knight
,
R.
et al. 
(
2011
)
Succession of microbial consortia in the developing infant gut microbiome
.
Proc. Natl. Acad. Sci. U.S.A.
108
(
Suppl 1
),
4578
4585
doi:
26
Avershina
,
E.
,
Storrø
,
O.
,
Øien
,
T.
,
Johnsen
,
R.
,
Pope
,
P.
,
Rudi
,
K.
(
2014
)
Major faecal microbiota shifts in composition and diversity with age in a geographically restricted cohort of mothers and their children
.
FEMS Microbiol. Ecol.
87
,
280
290
doi:
27
Aagaard
,
K.
,
Riehle
,
K.
,
Ma
,
J.
,
Segata
,
N.
,
Mistretta
,
T.-A.
,
Coarfa
,
C.
et al. 
(
2012
)
A metagenomic approach to characterization of the vaginal microbiome signature in pregnancy
.
PLoS ONE
7
,
e36466
doi:
28
Jakobsson
,
H.E.
,
Abrahamsson
,
T.R.
,
Jenmalm
,
M.C.
,
Harris
,
K.
,
Quince
,
C.
,
Jernberg
,
C.
et al. 
(
2014
)
Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by caesarean section
.
Gut
63
,
559
566
doi:
29
Salminen
,
S.
(
2004
)
Influence of mode of delivery on gut microbiota composition in seven year old children
.
Gut
53
,
1388
1389
doi:
30
Backhed
,
F.
,
Roswall
,
J.
,
Peng
,
Y.
,
Feng
,
Q.
,
Jia
,
H.
,
Kovatcheva-Datchary
,
P.
et al. 
(
2015
)
Dynamics and stabilization of the human gut microbiome during the first year of life
.
Cell Host Microbe
17
,
852
doi:
31
Bäckhed
,
F.
(
2011
)
Programming of host metabolism by the gut microbiota
.
Ann. Nutr. Metab.
58
(
Suppl 2
),
44
52
doi:
32
Palmer
,
C.
,
Bik
,
E.M.
,
DiGiulio
,
D.B.
,
Relman
,
D.A.
,
Brown
,
P.O.
,
Ruan
,
Y.
(
2007
)
Development of the human infant intestinal microbiota
.
PLoS Biol.
5
,
e177
doi:
33
Dethlefsen
,
L.
and
Relman
,
D.A.
(
2011
)
Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation
.
Proc. Natl. Acad. Sci. U.S.A.
108
,
4554
4561
doi:
34
Claesson
,
M.J.
,
Cusack
,
S.
,
O'Sullivan
,
O.
,
Greene-Diniz
,
R.
,
de Weerd
,
H.
,
Flannery
,
E.
et al. 
(
2011
)
Composition, variability, and temporal stability of the intestinal microbiota of the elderly
.
Proc. Natl. Acad. Sci. U.S.A.
108
(
Supplement 1
),
4586
4591
doi:
35
Biagi
,
E.
,
Nylund
,
L.
,
Candela
,
M.
,
Ostan
,
R.
,
Bucci
,
L.
,
Pini
,
E.
et al. 
(
2010
)
Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians
.
PLoS ONE
5
,
e10667
doi:
36
Claesson
,
M.J.
et al. 
(
2012
)
Gut microbiota composition correlates with diet and health in the elderly
.
Nature
488
,
178
+
37
Woodmansey
,
E.J.
,
McMurdo
,
M.E.T.
,
Macfarlane
,
G.T.
,
Macfarlane
,
S.
(
2004
)
Comparison of compositions and metabolic activities of fecal microbiotas in young adults and in antibiotic-treated and non-antibiotic-treated elderly subjects
.
Appl. Environ. Microbiol.
70
,
6113
6122
doi:
38
Biagi
,
E.
,
Candela
,
M.
,
Turroni
,
S.
,
Garagnani
,
P.
,
Franceschi
,
C.
,
Brigidi
,
P.
(
2013
)
Ageing and gut microbes: perspectives for health maintenance and longevity
.
Pharmacol. Res.
69
,
11
20
doi:
39
Macpherson
,
A.J.
and
McCoy
,
K.D.
(
2013
)
Stratification and compartmentalisation of immunoglobulin responses to commensal intestinal microbes
.
Semin. Immunol.
25
,
358
363
doi:
40
Donaldson
,
G.P.
,
Lee
,
S.M.
and
Mazmanian
,
S.K.
(
2015
)
Gut biogeography of the bacterial microbiota
.
Nat. Rev. Microbiol.
14
,
20
32
doi:
41
Gu
,
S.
,
Chen
,
D.
,
Zhang
,
J.-N.
,
Lv
,
X.
,
Wang
,
K.
,
Duan
,
L.-P.
et al. 
(
2013
)
Bacterial community mapping of the mouse gastrointestinal tract
.
PLoS ONE
8
,
e74957
doi:
42
Eckburg
,
P.B.
(
2005
)
Diversity of the human intestinal microbial flora
.
Science
308
,
1635
1638
doi:
43
Lavelle
,
A.
et al. 
(
2015
)
Spatial variation of the colonic microbiota in patients with ulcerative colitis and control volunteers
.
Gut
44
Van den Abbeele
,
P.
,
Belzer
,
C.
,
Goossens
,
M.
,
Kleerebezem
,
M.
,
De Vos
,
W.M.
,
Thas
,
O.
et al. 
(
2013
)
Butyrate-producing Clostridium cluster XIVa species specifically colonize mucins in an in vitro gut model
.
ISME J.
7
,
949
961
doi:
45
Li
,
H.
,
Limenitakis
,
J.P.
,
Fuhrer
,
T.
,
Geuking
,
M.B.
,
Lawson
,
M.A.
,
Wyss
,
M.
et al. 
(
2015
)
The outer mucus layer hosts a distinct intestinal microbial niche
.
Nat. Commun.
6
,
8292
doi:
46
Turnbaugh
,
P.J.
,
Hamady
,
M.
,
Yatsunenko
,
T.
,
Cantarel
,
B.L.
,
Duncan
,
A.
,
Ley
,
R.E.
et al. 
(
2009
)
A core gut microbiome in obese and lean twins
.
Nature
457
,
480
484
doi:
47
Jakobsson
,
H.E.
,
Jernberg
,
C.
,
Andersson
,
A.F.
,
Sjölund-Karlsson
,
M.
,
Jansson
,
J.K.
,
Engstrand
,
L.
et al. 
(
2010
)
Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome
.
PLoS ONE
5
doi:
48
Ding
,
T.
and
Schloss
,
P.D.
(
2014
)
Dynamics and associations of microbial community types across the human body
.
Nature
509
,
357
360
doi:
49
Arumugam
,
M.
,
Raes
,
J.
,
Pelletier
,
E.
,
Le Paslier
,
D.
,
Yamada
,
T.
,
Mende
,
D.R.
et al. 
(
2011
)
Enterotypes of the human gut microbiome
.
Nature
473
,
174
180
doi:
50
Jeffery
,
I.B.
,
Claesson
,
M.J.
,
O'Toole
,
P.W.
,
Shanahan
,
F.
(
2012
)
Categorization of the gut microbiota: enterotypes or gradients?
Nat. Rev. Microbiol.
10
,
591
592
doi:
51
Hooper
,
L.V.
and
Macpherson
,
A.J.
(
2010
)
Immune adaptations that maintain homeostasis with the intestinal microbiota
.
Nat. Rev. Immunol.
10
,
159
169
doi:
52
Ley
,
R.E.
,
Peterson
,
D.A.
and
Gordon
,
J.I.
(
2006
)
Ecological and evolutionary forces shaping microbial diversity in the human intestine
.
Cell
124
,
837
848
doi:
53
Travisano
,
M.
and
Velicer
,
G.J.
(
2004
)
Strategies of microbial cheater control
.
Trends Microbiol.
12
,
72
78
doi:
54
Zoetendal
,
E.G.
Raes
,
J.
,
van den Bogert
,
B.
,
Arumugam
,
M.
,
Booijink
,
C.C.G.M.
,
Troost
,
F.J.
et al. 
(
2012
)
The human small intestinal microbiota is driven by rapid uptake and conversion of simple carbohydrates
.
ISME J.
6
,
1415
1426
doi:
55
David
,
L.A.
,
Maurice
,
C.F.
,
Carmody
,
R.N.
,
Gootenberg
,
D.B.
,
Button
,
J.E.
,
Wolfe
,
B.E.
et al. 
(
2013
)
Diet rapidly and reproducibly alters the human gut microbiome
.
Nature
505
,
559
563
doi:
56
Walker
,
A.W.
,
Ince
,
J.
,
Duncan
,
S.H.
,
Webster
,
L.M.
,
Holtrop
,
G.
,
Ze
,
X.
et al. 
(
2011
)
Dominant and diet-responsive groups of bacteria within the human colonic microbiota
.
ISME J.
5
,
220
230
doi:
57
Yu
,
Z.T.
,
Chen
,
C.
,
Kling
,
D.E.
,
Liu
,
B.
,
McCoy
,
J.M.
,
Merighi
,
M.
et al. 
(
2013
)
The principal fucosylated oligosaccharides of human milk exhibit prebiotic properties on cultured infant microbiota
.
Glycobiology
23
,
169
177
doi:
58
Marcobal
,
A.
,
Barboza
,
M.
,
Sonnenburg
,
E.D.
,
Pudlo
,
N.
,
Martens
,
E.C.
,
Desai
,
P.
et al. 
(
2011
)
Bacteroides in the infant gut consume milk oligosaccharides via mucus-utilization pathways
.
Cell Host Microbe
10
,
507
514
doi:
59
Bezirtzoglou
,
E.
,
Tsiotsias
,
A.
and
Welling
,
G.W.
(
2011
)
Microbiota profile in feces of breast- and formula-fed newborns by using fluorescence in situ hybridization (FISH)
.
Anaerobe
17
,
478
482
doi:
60
Penders
,
J.
,
Thijs
,
C.
,
Vink
,
C.
,
Stelma
,
F.F.
,
Snijders
,
B.
,
Kummeling
,
I.
et al. 
(
2006
)
Factors influencing the composition of the intestinal microbiota in early infancy
.
Pediatrics
118
,
511
521
doi:
61
Favier
,
C.F.
,
Vaughan
,
E.E.
,
De Vos
,
W.M.
,
Akkermans
,
A.D.L.
(
2002
)
Molecular monitoring of succession of bacterial communities in human neonates
.
Appl. Environ. Microbiol.
68
,
219
226
doi:
62
Kau
,
A.L.
et al. 
(
2015
)
Functional characterization of IgA-targeted bacterial taxa from undernourished Malawian children that produce diet-dependent enteropathy
.
Sci. Transl. Med.
7
,
276ra24
63
De Filippo
,
C.
,
Cavalieri
,
D.
,
Di Paola
,
M.
,
Ramazzotti
,
M.
,
Poullet
,
J.B.
,
Massart
,
S.
et al. 
(
2010
)
Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa
.
Proc. Natl. Acad. Sci. U.S.A.
107
,
14691
14696
doi:
64
Wu
,
G.D.
,
Chen
,
J.
,
Hoffmann
,
C.
,
Bittinger
,
K.
,
Chen
,
Y.-Y.
,
Keilbaugh
,
S.A.
et al. 
(
2011
)
Linking long-term dietary patterns with gut microbial enterotypes
.
Science
334
,
105
108
doi:
65
Sonnenburg
,
E.D.
and
Sonnenburg
,
J.L.
(
2014
)
Starving our microbial self: the deleterious consequences of a diet deficient in microbiota-accessible carbohydrates
.
Cell Metab.
20
,
779
786
doi:
66
Sonnenburg
,
E.D.
,
Smits
,
S.A.
,
Tikhonov
,
M.
,
Higginbottom
,
S.K.
,
Wingreen
,
N.S.
,
Sonnenburg
,
J.L.
(
2016
)
Diet-induced extinctions in the gut microbiota compound over generations
.
Nature
529
,
212
215
doi:
67
Blanton
,
L.V.
,
Charbonneau
,
M.R.
,
Salih
,
T.
,
Barratt
,
M.J.
,
Venkatesh
,
S.
,
Ilkaveya
,
O.
et al. 
(
2016
)
Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children
.
Science
351
,
aad3311
doi:
68
Charbonneau
,
M.R.
,
O'Donnell
,
D.
,
Blanton
,
L.V.
,
Totten
,
S.M.
,
Davis
,
J.C.C.
,
Barratt
,
M.J.
et al. 
(
2016
)
Sialylated milk oligosaccharides promote microbiota-Dependent growth in models of infant undernutrition
.
Cell
164
,
859
871
doi:
69
Schwarzer
,
M.
,
Makki
,
K.
,
Storelli
,
G.
,
Machuca-Gayet
,
I.
,
Srutkova
,
D.
,
Hermanova
,
P.
et al. 
(
2016
)
Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition
.
Science
351
,
854
857
doi:
70
Tailford
,
L.E.
,
Owen
,
C.D.
,
Walshaw
,
J.
,
Crost
,
E.H.
,
Hardy-Goddard
,
J.
,
Le Gall
,
G.
et al. 
(
2015
)
Discovery of intramolecular trans-sialidases in human gut microbiota suggests novel mechanisms of mucosal adaptation
.
Nat. Commun.
6
,
7624
doi:
71
Arike
,
L.
and
Hansson
,
G.C.
(
2016
)
The densely O-glycosylated MUC2 mucin protects the intestine and provides food for the commensal bacteria
.
J. Mol. Biol
72
Ouwerkerk
,
J.P.
,
de Vos
,
W.M.
,
Belzer
,
B.
(
2013
)
Glycobiome: Bacteria and mucus at the epithelial interface
.
Best Pract. Res. Clin. Gastroenterol.
27
,
25
38
doi:
73
Johansson
,
M.E.V.
,
Larsson
,
J.M.H.
and
Hansson
,
G.C.
(
2011
)
The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions
.
Proc. Natl. Acad. Sci. U.S.A.
108
(
Suppl 1
),
4659
4665
doi:
74
Gustafsson
,
J.K.
,
Ermund
,
A.
,
Johansson
,
M.E.V.
,
Schutte
,
A.
,
Hansson
,
G.C.
,
Sjovall
,
H.
(
2012
)
An ex vivo method for studying mucus formation, properties, and thickness in human colonic biopsies and mouse small and large intestinal explants
.
Am. J. Physiol. Gastrointest. Liver Physiol.
302
,
G430
G438
doi:
75
Johansson
,
M.E.
,
Jakobsson
,
H.E.
,
Holmén-Larsson
,
J.
,
Schütte
,
A.
,
Ermund
,
A.
,
Rodríguez-Piñeiro
,
A.M.
et al. 
(
2015
)
Normalization of host intestinal mucus layers requires long-Term microbial colonization
.
Cell Host Microbe
18
,
582
592
doi:
76
Juge
,
N.
(
2012
)
Microbial adhesins to gastrointestinal mucus
.
Trends Microbiol.
20
,
30
39
doi:
77
Tailford
,
L.E.
,
Crost
,
E.H.
,
Kavanaugh
,
D.
,
Juge
,
N.
(
2015
)
Mucin glycan foraging in the human gut microbiome
.
Frontiers in Genetics.
6
,
131
doi:
78
Rausch
,
P.
,
Rehman
,
A.
,
Kunzel
,
S.
,
Hasler
,
R.
,
Ott
,
S.J.
,
Schreiber
,
S.
et al. 
(
2011
)
Colonic mucosa-associated microbiota is influenced by an interaction of crohn disease and FUT2 (Secretor) genotype
.
Proc Natl Acad Sci U.S.A.
108
,
19030
19035
doi:
79
Arpaia
,
N.
,
Campbell
,
C.
,
Fan
,
X.
,
Dikiy
,
S.
,
van der Veeken
,
J.
,
deRoos
,
P.
et al. 
(
2013
)
Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation
.
Nature.
504
,
451
455
doi:
80
Furusawa
,
Y.
,
Obata
,
Y.
,
Fukuda
,
S.
,
Endo
,
T.A.
,
Nakato
,
G.
,
Takahashi
,
D.
et al. 
(
2013
)
Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells
.
Nature.
504
,
446
450
doi:
81
Zarepour
,
M.
,
Bhullar
,
K.
,
Montero
,
M.
,
Ma
,
C.
,
Huang
,
T.
,
Velcich
,
A.
et al. 
(
2013
)
The mucin MUC2 limits pathogen burdens and epithelial barrier dysfunction during salmonella enterica serovar typhimurium colitis
.
Infect Immun.
81
,
3672
3683
doi:
82
Earle
,
K.A.
,
Billings
,
G.
,
Sigal
,
M.
,
Lichtman
,
J.S.
,
Hansson
,
G.C.
,
Elias
,
J.E.
et al. 
(
2015
)
Quantitative imaging of gut microbiota spatial organization
.
Cell Host Microbe
18
,
478
488
doi:
83
Desai
,
M.S.
,
Seekatz
,
A.M.
,
Koropatkin
,
N.M.
,
Kamada
,
N.
,
Hickey
,
C.A.
,
Wolter
,
M.
et al. 
(
2016
)
A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility
.
Cell.
167
,
1339
1353.e21
doi:
84
Everard
,
A.
,
Belzer
,
C.
,
Geurts
,
L.
,
Ouwerkerk
,
J.P.
,
Druart
,
C.
,
Bindels
,
L.B.
et al. 
(
2013
)
Cross-talk between akkermansia muciniphila and intestinal epithelium controls diet-induced obesity
.
Proc Natl Acad Sci U.S.A.
110
,
9066
9071
doi:
85
Li
,
J.
,
Lin
,
S.
,
Vanhoutte
,
P.M.
,
Woo
,
C.W.
,
Xu
,
A.
(
2016
)
Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia-induced inflammation in apoe-/- mice
.
Circulation.
133
,
2434
2446
doi:
86
Plovier
,
H.
,
Everard
,
A.
,
Druart
,
C.
,
Depommier
,
C.
,
Van Hul
,
M.
,
Geurts
,
L.
et al. 
(
2016
)
A purified membrane protein from akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice
.
Nat Med.
23
,
107
113
doi:
87
Zhao
,
S.
,
Liu
,
W.
,
Wang
,
J.
,
Shi
,
J.
,
Sun
,
Y.
,
Wang
,
W.
et al. 
(
2017
)
Akkermansia muciniphila improves metabolic profiles by reducing inflammation in chow diet-fed mice
.
J Mol Endocrinol.
58
,
1
14
doi:
88
Cockburn
,
D.W.
and
Koropatkin
,
N.M.
(
2016
)
Polysaccharide degradation by the intestinal microbiota and its influence on human health and disease
.
J Mol Biol.
428
,
3230
3252
doi:
89
El Kaoutari
,
A.
,
Armougom
,
F.
,
Gordon
,
J.I.
,
Raoult
,
D.
,
Henrissat
,
B.
(
2013
)
The abundance and variety of carbohydrate-active enzymes in the human gut microbiota
.
Nat Rev Microbiol.
11
,
497
504
doi:
90
Cantarel
,
B.L.
,
Lombard
,
V.
,
Henrissat
,
B.
and
Appanna
,
V.D.
(
2012
)
Complex carbohydrate utilization by the healthy human microbiome
.
PLoS One.
7
,
e28742
doi:
91
Larsbrink
,
J.
,
Rogers
,
T.E.
,
Hemsworth
,
G.R.
,
McKee
,
L.S.
,
Tauzin
,
A.S.
,
Spadiut
,
O.
et al. 
(
2014
)
A discrete genetic locus confers xyloglucan metabolism in select human gut bacteroidetes
.
Nature.
506
,
498
502
doi:
92
Rogowski
,
A.
,
Briggs
,
J.A.
,
Mortimer
,
J.C.
,
Tryfona
,
T.
,
Terrapon
,
N.
,
Lowe
,
E.C.
et al. 
(
2015
)
Glycan complexity dictates microbial resource allocation in the large intestine
.
Nat Commun.
6
,
7481
doi:
93
Cuskin
,
F.
,
Lowe
,
E.C.
,
Temple
,
M.J.
,
Zhu
,
Y.
,
Cameron
,
E.A.
,
Pudlo
,
N.A.
et al. 
(
2015
)
Human gut Bacteroidetes can utilize yeast mannan through a selfish mechanism
.
Nature.
517
,
165
169
doi:
94
Tauzin
,
A.S.
,
Kwiatkowski
,
K.J.
,
Orlovsky
,
N.I.
,
Smith
,
C.J.
,
Creagh
,
A.L.
,
Haynes
,
C.A.
et al. 
(
2016
)
Molecular dissection of xyloglucan recognition in a prominent human Gut symbiont
.
MBio.
7
,
e02134
15
doi:
95
Foley
,
M.H.
,
Cockburn
,
D.W.
and
Koropatkin
,
N.M.
(
2016
)
The Sus operon: a model system for starch uptake by the human gut bacteroidetes
.
Cell Mol Life Sci.
73
,
2603
2617
doi:
96
Glenwright
,
A.J.
,
Pothula
,
K.R.
,
Bhamidimarri
,
S.P.
,
Chorev
,
D.S.
,
Baslé
,
A.
,
Firbank
,
S.J.
et al. 
(
2017
)
Structural basis for nutrient acquisition by dominant members of the human gut microbiota
.
Nature.
541
,
407
411
doi:
97
Ze
,
X.
et al. 
(
2015
)
Unique organization of extracellular amylases into amylosomes in the resistant starch-utilizing human colonic firmicutes bacterium Ruminococcus bromii
.
MBio.
6
,
e01058
15
98
Bjedov
,
I.
(
2003
)
Stress-induced mutagenesis in bacteria
.
Science.
300
,
1404
1409
doi:
99
Xu
,
J.
et al. 
(
2007
)
Evolution of symbiotic bacteria in the distal human intestine
.
PLoS Biol.
5
,
1574
1586
100
Svanback
,
R.
and
Bolnick
,
D.I.
(
2007
)
Intraspecific competition drives increased resource use diversity within a natural population
.
Proceedings of the Royal Society B-Biological Sciences.
274
,
839
844
doi:
101
Emerson
,
B.C.
and
Kolm
,
N.
(
2005
)
Species diversity can drive speciation
.
Nature
434
,
1015
1017
doi:
102
Louis
,
P.
and
Flint
,
H.J.
(
2016
)
Formation of propionate and butyrate by the human colonic microbiota
.
Environ Microbiol
103
Ze
,
X.
,
Duncan
,
S.H.
,
Louis
,
P.
,
Flint
,
H.J.
(
2012
)
Ruminococcus bromii is a keystone species for the degradation of resistant starch in the human colon
.
ISME J
6
,
1535
1543
doi:
104
Louis
,
P.
,
Scott
,
K.P.
,
Duncan
,
S.H.
and
Flint
,
H.J.
(
2007
)
Understanding the effects of diet on bacterial metabolism in the large intestine
.
Journal of Applied Microbiology
102
,
1197
1208
doi:
105
Duncan
,
S.H.
,
Louis
,
P.
and
Flint
,
H.J.
(
2004
)
Lactate-utilizing bacteria, isolated from human feces, that produce butyrate as a major fermentation product
.
Appl Environ Microbiol
70
,
5810
5817
doi:
106
Rakoff-Nahoum
,
S.
,
Foster
,
K.R.
and
Comstock
,
L.E.
(
2016
)
The evolution of cooperation within the gut microbiota
.
Nature
533
,
255
259
doi:
107
Juge
,
N.
,
Tailford
,
L.
and
Owen
,
C.D.
(
2016
)
Sialidases from gut bacteria: a mini-review
.
Biochem Soc Trans
44
,
166
175
doi:
108
Crost
,
E.H.
,
Tailford
,
L.E.
,
Le Gall
,
G.
,
Fons
,
M.
,
Henrissat
,
B.
,
Juge
,
N.
et al. 
(
2013
)
Utilisation of mucin glycans by the human Gut symbiont ruminococcus gnavus Is strain-Dependent
.
PLoS One
8
,
e76341
doi:
109
Crost
,
E.H.
et al. 
(
2016
)
The mucin-degradation strategy of ruminococcus gnavus: The importance of intramolecular trans-sialidases
.
Gut Microbes
1
11
110
Larsson
,
J.M.H.
,
Karlsson
,
H.
,
Crespo
,
J.G.
,
Johansson
,
M.E.V.
,
Eklund
,
L.
,
Sjövall
,
H.
et al. 
(
2011
)
Altered o-glycosylation profile of MUC2 mucin occurs in active ulcerative colitis and is associated with increased inflammation
.
Inflamm Bowel Dis
17
,
2299
2307
doi:
111
Carbonero
,
F.
,
Benefiel
,
A.C.
,
Alizadeh-Ghamsari
,
A.H.
,
Gaskins
,
H.R.
(
2012
)
Microbial pathways in colonic sulfur metabolism and links with health and disease
.
Front Physiol
3
,
448
doi:
112
Ridlon
,
J.M.
,
Kang
,
D.J.
,
Hylemon
,
P.B.
,
Bajaj
,
J.S.
(
2014
)
Bile acids and the gut microbiome
.
Curr Opin Gastroenterol
30
,
332
338
doi:
113
Staley
,
C.
,
Weingarden
,
A.R.
,
Khoruts
,
A.
,
Sadowsky
,
M.J.
(
2017
)
Interaction of gut microbiota with bile acid metabolism and its influence on disease states
.
Appl Microbiol Biotechnol
101
,
47
64
doi:
114
Browne
,
H.P.
,
Forster
,
S.C.
,
Anonye
,
B.O.
,
Kumar
,
N.
,
Neville
,
B.A.
,
Stares
,
M.D.
et al. 
(
2016
)
Culturing of 'unculturable' human microbiota reveals novel taxa and extensive sporulation
.
Nature
533
,
543
546
doi:
115
Kakiyama
,
G.
,
Pandak
,
W.M.
,
Gillevet
,
P.M.
,
Hylemon
,
P.B.
,
Heuman
,
D.M.
,
Daita
,
K.
et al. 
(
2013
)
Modulation of the fecal bile acid profile by gut microbiota in cirrhosis
.
J Hepatol
58
,
949
955
doi:
116
Hooper
,
L.V.
,
Littman
,
D.R.
and
Macpherson
,
A.J.
(
2012
)
Interactions between the microbiota and the immune system
.
Science
336
,
1268
1273
doi:
117
Macpherson
,
A.J.
(
2000
)
A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria
.
Science
288
,
2222
2226
doi:
118
Macpherson
,
A.J.
and
Uhr
,
T.
(
2004
)
Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria
.
Science
303
,
1662
1665
doi:
119
Cash
,
H.L.
(
2006
)
Symbiotic bacteria direct expression of an intestinal bactericidal lectin
.
Science
313
,
1126
1130
doi:
120
McGuckin
,
M.A.
,
Lindén
,
S.K.
,
Sutton
,
P. and
Florin
,
T.H.
(
2011
)
Mucin dynamics and enteric pathogens
.
Nat Rev Microbiol
9
,
265
278
doi:
121
Meyer-Hoffert
,
U.
,
Hornef
,
M.W.
,
Henriques-Normark
,
B.
,
Axelsson
,
L.-G.
,
Midtvedt
,
T.
,
Putsep
,
K.
et al. 
(
2008
)
Secreted enteric antimicrobial activity localises to the mucus surface layer
.
Gut
57
,
764
771
doi:
122
Wehkamp
,
J.
(
2004
)
NOD2 (CARD15) mutations in crohn's disease are associated with diminished mucosal alpha-defensin expression
.
Gut
53
,
1658
1664
doi:
123
Wehkamp
,
J.
,
Salzman
,
N.H.
,
Porter
,
E.
,
Nuding
,
S.
,
Weichenthal
,
M.
,
Petras
,
R.E.
et al. 
(
2005
)
Reduced paneth cell alpha-defensins in ileal crohn's disease
.
Proc Natl Acad Sci U.S.A
102
,
18129
18134
doi:
124
Rogier
,
E.W.
,
Frantz
,
A.
,
Bruno
,
M. and
Kaetzel
,
C.
(
2014
)
Secretory IgA is concentrated in the outer layer of colonic mucus along with gut bacteria
.
Pathogens
3
,
390
403
doi:
125
Bollinger
,
R.R..
,
Everett
,
M.L.
,
Palestrant
,
D.
,
Love
,
S.D.
,
Lin
,
S.S. and
Parker
,
W.
(
2003
)
Human secretory immunoglobulin A May contribute to biofilm formation in the gut
.
Immunology
109
,
580
587
doi:
126
Friman
,
V.
et al. 
(
1996
)
Decreased expression of mannose-specific adhesins by Escherichia coli in the colonic microflora of immunoglobulin A-deficient individuals
.
Infect Immun
64
,
2794
2798
127
Suzuki
,
K.
,
Meek
,
B.
,
Doi
,
Y.
,
Muramatsu
,
M.
,
Chiba
,
T.
,
Honjo
,
T.
et al. 
(
2004
)
Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut
.
Proc Natl Acad Sci U.S.A.
101
,
1981
1986
doi:
128
Biedermann
,
L.
,
Zeitz
,
J.
,
Mwinyi
,
J.
,
Sutter-Minder
,
E.
,
Rehman
,
A.
,
Ott
,
S.J.
et al. 
(
2013
)
Smoking cessation induces profound changes in the composition of the intestinal microbiota in humans
.
PLoS One
8
,
e59260
doi:
129
Jiang
,
H.
,
Ling
,
Z.
,
Zhang
,
Y.
,
Mao
,
H.
,
Ma
,
Z.
,
Yin
,
Y.
et al. 
(
2015
)
Altered fecal microbiota composition in patients with major depressive disorder
.
Brain Behavior and Immunity
48
,
186
194
doi:
130
Tyakht
,
A.V.
,
Kostryukova
,
E.S.
,
Popenko
,
A.S.
,
Belenikin
,
M.S.
,
Pavlenko
,
A.V.
,
Larin
,
A.K.
et al. 
(
2013
)
Human gut microbiota community structures in urban and rural populations in russia
.
Nature Commun
4
,
2469
doi:
131
Maurice
,
C.F.
,
Haiser
,
H.J.
and
Turnbaugh
,
P.J.
(
2013
)
Xenobiotics shape the physiology and gene expression of the active human gut microbiome
.
Cell
152
,
39
50
doi:
132
Jernberg
,
C.
,
Löfmark
,
S.
,
Edlund
,
C. and
Jansson
,
J.K.
(
2007
)
Long-term ecological impacts of antibiotic administration on the human intestinal microbiota
.
ISME J
1
,
56
66
doi:
133
Ferrer
,
M.
,
Martins dos Santos
,
V.A.P.
,
Ott
,
S.J. and
Moya
,
A.
(
2014
)
Gut microbiota disturbance during antibiotic therapy: a multi-omic approach
.
Gut Microbes
5
,
64
70
doi:
134
Ge
,
X.
,
Ding
,
C.
,
Zhao
,
W.
,
Xu
,
L.
,
Tian
,
H.
,
Gong
,
J.
et al. 
(
2017
)
Antibiotics-induced depletion of mice microbiota induces changes in host serotonin biosynthesis and intestinal motility
.
J Transl Med
15
,
13
doi:
135
Ng
,
K.M.
,
Ferreyra
,
J.A.
,
Higginbottom
,
S.K.
,
Lynch
,
J.B.
,
Kashyap
,
P.C.
,
Gopinath
,
S.
et al. 
(
2013
)
Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens
.
Nature
502
,
96
99
doi:
136
Musso
,
G.
,
Gambino
,
R.
and
Cassader
,
M.
(
2010
)
Obesity, diabetes, and gut microbiota: The hygiene hypothesis expanded?
Diabetes Care
33
,
2277
2284
doi:
137
Louis
,
P.
,
Hold
,
G.L.
and
Flint
,
H.J.
(
2014
)
The gut microbiota, bacterial metabolites and colorectal cancer
.
Nat Rev Microbiol
12
,
661
672
doi:
138
Corrêa-Oliveira
,
R.
,
Fachi
,
J.L.
,
Vieira
,
A.
,
Sato
,
F.T. and
Vinolo
,
M.A.R.
(
2016
)
Regulation of immune cell function by short-chain fatty acids
.
Clin Transl Immunol
5
,
e73
doi:
139
Macfarlane
,
S.
and
Macfarlane
,
G.T.
(
2003
)
Regulation of short-chain fatty acid production
.
Proc Nutr Soc
62
,
67
72
doi:
140
Morrison
,
D.J.
and
Preston
,
T.
(
2016
)
Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism
.
Gut Microbes
7
,
189
200
doi:
141
Derrien
,
M.
(
2004
)
Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium
.
Int J Syst Evol Microbiol
54
(
Pt 5
),
1469
1476
doi:
142
Guarner
,
F.
and
Malagelada
,
J.R.
(
2003
)
Gut flora in health and disease
.
Lancet
361
,
512
519
doi:
143
Lin
,
L.
and
Zhang
,
J.
(
2017
)
Role of intestinal microbiota and metabolites on gut homeostasis and human diseases
.
BMC Immunol.
18
144
Donohoe
,
D.R.
,
Collins
,
L.B.
,
Wali
,
A.
,
Bigler
,
R.
,
Sun
,
W. and
Bultman
,
S.J.
(
2012
)
The warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation
.
Mol Cell.
48
,
612
626
doi:
145
Chambers
,
E.S.
,
Morrison
,
D.J.
and
Frost
,
G.
(
2015
)
Control of appetite and energy intake by SCFA: what are the potential underlying mechanisms?
Proc Nutr Soc.
74
,
328
336
doi:
146
Pingitore
,
A.
et al. 
(
2016
)
The diet-derived short chain fatty acid propionate improves beta-cell function in humans and stimulates insulin secretion from human islets in vitro
.
Diabetes Obes. Metab.
19
,
257
265
doi:
147
Byrne
,
C.S.
,
Chambers
,
E.S.
,
Alhabeeb
,
H.
,
Chhina
,
N.
,
Morrison
,
D.J.
,
Preston
,
T.
et al. 
(
2016
)
Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods
.
Am J Clin Nutr.
104
,
5
14
doi:
148
Nagai
,
M.
,
Obata
,
Y.
,
Takahashi
,
D. and
Hase
,
K.
(
2016
)
Fine-tuning of the mucosal barrier and metabolic systems using the diet-microbial metabolite axis
.
Int Immunopharmacol.
37
,
79
86
doi:
149
LeBlanc
,
J.G.
,
Milani
,
C.
,
de Giori
,
G.S.
,
Sesma
,
F.
,
van Sinderen
,
D. and
Ventura
,
M.
(
2013
)
Bacteria as vitamin suppliers to their host: a gut microbiota perspective
.
Current Opinion in Biotechnology.
24
,
160
168
doi:
150
Martens
,
J.H.
,
Barg
,
H.
,
Warren
,
M. and
Jahn
,
D.
(
2002
)
Microbial production of vitamin B-12
.
Applied Microbiology and Biotechnology.
58
,
275
285
doi:
151
Pompei
,
A.
,
Cordisco
,
L.
,
Amaretti
,
A.
,
Zanoni
,
S.
,
Matteuzzi
,
D. and
Rossi
,
M.
(
2007
)
Folate production by bifidobacteria as a potential probiotic property
.
Appl Environ Microbiol.
73
,
179
185
doi:
152
Hill
,
M.J.
(
1997
)
Intestinal flora and endogenous vitamin synthesis
.
European Journal of Cancer Prevention.
6
,
S43
S45
doi:
153
Palau-Rodriguez
,
M.
,
Tulipani
,
S.
,
Isabel Queipo-Ortuño
,
M.
,
Urpi-Sarda
,
M.
,
Tinahones
,
F.J. and
Andres-Lacueva
,
C.
(
2015
)
Metabolomic insights into the intricate gut microbial-host interaction in the development of obesity and type 2 diabetes
.
Front Microbiol.
6
,
1151
doi:
154
Smith
,
K.
,
McCoy
,
K.D.
and
Macpherson
,
A.J.
(
2007
)
Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota
.
Seminars in Immunology.
19
,
59
69
doi:
155
Swanson
, II,
P.A.
,
Kumar
,
A.
,
Samarin
,
S.
,
Vijay-Kumar
,
M.
,
Kundu
,
K.
,
Murthy
,
N.
et al. 
(
2011
)
Enteric commensal bacteria potentiate epithelial restitution via reactive oxygen species-mediated inactivation of focal adhesion kinase phosphatases
.
Proc Natl Acad Sci U.S.A.
108
,
8803
8808
doi:
156
Reunanen
,
J.
et al. 
(
2015
)
Akkermansia muciniphila adheres to enterocytes and strengthens the integrity of epithelial cell layer
.
Appl Environ Microbiol
157
Chen
,
H.Q.
,
Yang
,
J.
,
Zhang
,
M.
,
Zhou
,
Y.-K.
,
Shen
,
T.-Y.
,
Chu
,
Z.-X.
et al. 
(
2010
)
Lactobacillus plantarum ameliorates colonic epithelial barrier dysfunction by modulating the apical junctional complex and PepT1 in IL-10 knockout mice
.
Am J Physiol Gastrointest Liver Physiol.
299
,
G1287
G1297
doi:
158
Petersson
,
J.
,
Schreiber
,
O.
,
Hansson
,
G.C.
,
Gendler
,
S.J.
,
Velcich
,
A.
,
Lundberg
,
J.O.
et al. 
(
2011
)
Importance and regulation of the colonic mucus barrier in a mouse model of colitis
.
Am J Physiol Gastrointest Liver Physiol.
300
,
G327
G333
doi:
159
Wrzosek
,
L.
,
Miquel
,
S.
,
Noordine
,
M.-L.
,
Bouet
,
S.
,
Chevalier-Curt
,
M.
,
Robert
,
V.
et al. 
(
2013
)
Bacteroides thetaiotaomicron and faecalibacterium prausnitzii influence the production of mucus glycans and the development of goblet cells in the colonic epithelium of a gnotobiotic model rodent
.
BMC Biol.
11
,
61
doi:
160
Graziani
,
F.
,
Pujol
,
A.
,
Nicoletti
,
C.
,
Dou
,
S.
,
Maresca
,
M.
,
Giardina
,
T.
et al. 
(
2016
)
Ruminococcus gnavus E1 modulates mucin expression and intestinal glycosylation
.
J Appl Microbiol.
120
,
1403
1417
doi:
161
Varyukhina
,
S.
,
Freitas
,
M.
,
Bardin
,
S.
,
Robillard
,
E.
,
Tavan
,
E.
,
Sapin
,
C.
et al. 
(
2012
)
Glycan-modifying bacteria-derived soluble factors from bacteroides thetaiotaomicron and lactobacillus casei inhibit rotavirus infection in human intestinal cells
.
Microbes Infect.
14
,
273
278
doi:
162
Freitas
,
M.
,
Cayuela
,
C.
,
Antoine
,
J.-M.
,
Piller
,
F.
,
Sapin
,
C. and
Trugnan
,
G.
(
2001
)
A heat labile soluble factor from bacteroides thetaiotaomicron VPI-5482 specifically increases the galactosylation pattern of HT29-MTX cells
.
Cell Microbiol.
3
,
289
300
doi:
163
Mazmanian
,
S.K.
,
Liu
,
C.H.
,
Tzianabos
,
A.O. and
Kasper
,
D.L.
(
2005
)
An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system
.
Cell.
122
,
107
118
doi:
164
Hevia
,
A.
,
Delgado
,
S.
,
Sánchez
,
B. and
Margolles
,
A.
(
2015
)
Molecular players involved in the interaction between beneficial bacteria and the immune system
.
Front Microbiol.
6
,
1285
doi:
165
Schnupf
,
P.
,
Gaboriau-Routhiau
,
V.
,
Gros
,
M.
,
Friedman
,
R.
,
Moya-Nilges
,
M.
,
Nigro
,
G.
et al. 
(
2015
)
Growth and host interaction of mouse segmented filamentous bacteria in vitro
.
Nature.
520
,
99
103
doi:
166
Candela
,
M.
,
Biagi
,
E.
,
Maccaferri
,
S.
,
Turroni
,
S. and
Brigidi
,
P.
(
2012
)
Intestinal microbiota is a plastic factor responding to environmental changes
.
Trends Microbiol.
20
,
385
391
doi:
167
Ellekilde
,
M.
,
Krych
,
L.
,
Hansen
,
C.H.F.
,
Hufeldt
,
M.R.
,
Dahl
,
K.
,
Hansen
,
L.H.
et al. 
(
2014
)
Characterization of the gut microbiota in leptin deficient obese mice - correlation to inflammatory and diabetic parameters
.
Res Vet Sci.
96
,
241
250
doi:
168
Hansen
,
C.H.
,
Krych
,
L.
,
Nielsen
,
D.S.
,
Vogensen
,
F.K.
,
Hansen
,
L.H.
,
Sørensen
,
S.J.
et al. 
(
2012
)
Early life treatment with vancomycin propagates akkermansia muciniphila and reduces diabetes incidence in the NOD mouse
.
Diabetologia.
55
,
2285
2294
doi:
169
Le Chatelier
,
E.
,
Nielsen
,
T.
,
Qin
,
J.
,
Prifti
,
E.
,
Hildebrand
,
F.
,
Falony
,
G.
et al. 
(
2013
)
Richness of human gut microbiome correlates with metabolic markers
.
Nature.
500
,
541
546
doi:
170
Wang
,
L.
,
Christophersen
,
C.T.
,
Sorich
,
M.J.
,
Gerber
,
J.P.
,
Angley
,
M.T. and
Conlon
,
M.A.
(
2011
)
Low relative abundances of the mucolytic bacterium akkermansia muciniphila and bifidobacterium spp. in feces of children with autism
.
Appl Environ Microbiol.
77
,
6718
6721
doi:
171
Derrien
,
M.
,
Belzer
,
C.
and
de Vos
,
W.M.
(
2016
)
Akkermansia muciniphila and its role in regulating host functions
.
Microb. Pathog.
doi:
172
Sokol
,
H.
,
Seksik
,
P.
,
Furet
,
J.P.
,
Firmesse
,
O.
,
Nion-Larmurier
,
I.
,
Beaugerie
,
L.
et al. 
(
2009
)
Low counts of faecalibacterium prausnitzii in colitis microbiota
.
Inflamm Bowel Dis.
15
,
1183
1189
doi:
173
Lopez-Siles
,
M.
et al. 
(
2017
)
Faecalibacterium prausnitzii: from microbiology to diagnostics and prognostics
.
ISME J.
doi:
174
Quévrain
,
E.
,
Maubert
,
M.A.
,
Michon
,
C.
,
Chain
,
F.
,
Marquant
,
R.
,
Tailhades
,
J.
et al. 
(
2016
)
Identification of an anti-inflammatory protein from faecalibacterium prausnitzii, a commensal bacterium deficient in crohn's disease
.
Gut.
65
,
415
425
doi:
175
Ferreyra
,
J.A.
,
Wu
,
K.J.
,
Hryckowian
,
A.J.
,
Bouley
,
D.M.
,
Weimer
,
B.C.
,
Sonnenburg
,
J.L.
et al. 
(
2014
)
Gut microbiota-produced succinate promotes C. difficile infection after antibiotic treatment or motility disturbance
.
Cell Host Microbe
16
,
770
777
doi:
176
Huang
,
Y.L.
,
Chassard
,
C.
,
Hausmann
,
M.
,
von Itzstein
,
M. and
Hennet
,
T.
(
2015
)
Sialic acid catabolism drives intestinal inflammation and microbial dysbiosis in mice
.
Nat Commun.
6
,
8141
doi:
177
Mathias
,
A.
,
Pais
,
B.
,
Favre
,
L.
,
Benyacoub
,
J. and
Corthésy
,
B.
(
2014
)
Role of secretory IgA in the mucosal sensing of commensal bacteria
.
Gut Microbes.
5
,
688
695
doi:
178
Rios
,
D.
,
Wood
,
M.B.
,
Li
,
J.
,
Chassaing
,
B.
,
Gewirtz
,
A.T. and
Williams
,
I.R.
(
2016
)
Antigen sampling by intestinal M cells is the principal pathway initiating mucosal IgA production to commensal enteric bacteria
.
Mucosal Immunol.
9
,
907
916
doi:
179
Jandhyala
,
S.M.
(
2015
)
Role of the normal gut microbiota
.
World J Gastroenterol.
21
,
8787
8803
doi:
180
Guinane
,
C.M.
and
Cotter
,
P.D.
(
2013
)
Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ
.
Therap Adv Gastroenterol.
6
,
295
308
doi:
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