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 . Three predominant SCFAs, propionate, butyrate and acetate, are typically found in a proportion of 1:1:3 in the GI tract . 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 . Acetate is produced by most gut anaerobes, whereas propionate and butyrate are produced by different subsets of gut bacteria following distinct molecular pathways . 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 . In the human gut, propionate is mainly produced by Bacteroidetes, whereas the production of butyrate is dominated by Firmicutes . 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 . A. muciniphila is a key propionate producer specialised in mucin degradation. Propionate is primarily absorbed by the liver, whilst acetate is released into peripheral tissues. The role of SCFAs on human metabolism has recently been reviewed . Butyrate is known for its anti-inflammatory and anticancer activities. Butyrate is a particularly important energy source for colonocytes . 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. Butyrate can attenuate bacterial translocation and enhance gut barrier function by affecting tight-junction assembly and mucin synthesis. 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. SCFAs also play a role in regulating the immune system and inflammatory response . They influence the production of cytokines, for example, stimulating the production of IL-18, an interleukin involved in maintaining and repairing epithelial integrity . Butyrate and propionate are histone deacetylase inhibitors that epigenetically regulate gene expression. SCFAs have also been shown to modulate appetite regulation and energy intake via receptor-mediated mechanisms . Propionate has beneficial effects in humans acting on β-cell function and attenuating reward-based eating behaviour via striatal pathways . Microbial metabolites other than SCFAs have been reported to have an impact on intestinal barrier functions, epithelium proliferation and the immune system .
The GI microbiota is also crucial to the de novo synthesis of essential vitamins which the host is incapable of producing. Lactic acid bacteria are key organisms in the production of vitamin B12, which cannot be synthesised by either animals, plants or fungi . Bifidobacteria are main producers of folate, a vitamin involved in vital host metabolic processes including DNA synthesis and repair . Further vitamins, which gut microbiota have been shown to synthesise in humans, include vitamin K, riboflavin, biotin, nicotinic acid, panthotenic acid, pyridoxine and thiamine. Colonic bacteria can also metabolise bile acids that are not reabsorbed for biotransformation to secondary bile acids . 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 .
There are many lines of evidence in support of a role for the gut microbiota in influencing epithelial homeostasis . Germ-free mice exhibit impaired epithelial cell turnover which is reversible upon colonisation with microbiota . A role has been demonstrated for bacteria in promoting cell renewal and wound healing, for example, in the case of Lactobacilli rhamnosus GG . Furthermore, several species have been implicated in promoting epithelial integrity, such as A. muciniphila and Lactobacillus plantarum. 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 . B. thetaiotaomicron and F. prausnitzii have been implicated in the co-ordination of mucus production . R. gnavus E1, Lactobacillus casei DN-114 001 and B. thetaiotaomicron are able to remodel mucin glycosylation, for example, by modulating glycosyltransferase expression . 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 .
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. 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 . SFB, a class of anaerobic and clostridia-related spore-forming commensals present in the mammalian GI tract, actively interact with the immune system . 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. 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). A. muciniphila has been correlated with protection against several inflammatory diseases, suggesting that this strain possesses anti-inflammatory properties although the underlying mechanisms have not been completely elucidated. Individuals with CD display mucosal dysbiosis characterised by reduced diversity of core microbiota and lower abundance of F. prausnitzii. F. prausnitziimonitoring may therefore serve as a biomarker to assist in gut disease diagnostics. 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.
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. Antibiotics have a profound impact on the microbiota that alter the nutritional landscape of the gut and lead to the expansion of pathogenic populations. 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 . Enterohaemorrhagic E. coli has also been shown to access fucose or sialic acid liberated by the gut microbiota from mucins. 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 . 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 . The other mechanism by which the gut microbiota can limit pathogen overgrowth is by inducing mucosal SIgA . Induction of SIgAs directed against gut commensal bacteria occurs via an M-cell-mediated sampling mechanism . 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 . 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.
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 . 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, probiotics and psychobiotics) 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 such as lifestyle medicine 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.