Role Of The Gastrointestinal Microbiota In Humans

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Traditionally, the colon has been considered to largely be the human sewage system which, as well as storing and removing waste material from the GI tract, was capable of recycling water (i.e., absorption). However, we now recognize that the GI tract is one of the most metabolically and immunologically active organs of the human body. Indeed, the primary function of the microbiota is generally considered to be salvage of energy via fermentation of carbohydrates, such as indigestible dietary residues (plant cell walls, non-digestible fibers and oligosaccharides), mucin side-chains and sloughed-off epithelial cells (5,6,8,13,17). It has been estimated that between 20 and 60 grams of carbohydrate are available in the colon of healthy human adults per day, as well as 5-20 grams of protein. In addition to salvaging energy, principally through production of short-chain fatty acids (SCFAs) and their subsequent absorption and use by the host, microbial fermentation produces gases (principally hydrogen, carbon dioxide and methane) and increases biomass. These all impact upon gut physiology. Components of the gut microbiota also synthesize certain B and K vitamins, metabolize xenobiotics, contribute to amino acid homeostasis, may impact drug efficacy and are an integral part of the host defense (both through host-microbe and microbe-microbe interactions; including colonization resistance) (6,17,18). Recent observations, using molecular techniques and germ-free/ gnotobiotic animals, have also identified that intestinal bacteria can influence gene expression of epithelial cells (5,19). Taken together, the activity of the microbiota, or certain components thereof, may be more important to the homeostasis of the ecosystem than specific numerics. Although the combination of all these factors, as well as host and environmental factors, will ultimately determine the equilibrium of the colon.

Three main SCFAs are produced by microbial fermentation in the human colon: acetate, butyrate, and propionate (the approximate molar ratio for which is 70:10:20— although diet and microbiota composition influence the exact ratio) (5). SCFAs supply energy to cells (acetate, muscle; butyrate, colonocytes; propionate, liver), affect colonic metabolism, control epithelial cell proliferation and differentiation, and impact upon bowel motility and circulation (including water absorption and the hepatic regulation of lipids and sugars) (5,8,13).

Uptake and utilization of acetate is the primary method of the host salvaging energy from non-digestible dietary carbohydrates. Acetate may also play a role in lipogenesis by adipocytes and, together with propionate, may be involved in modulation of glucose metabolism (via the glycaemic index). Butyrate is estimated to provide between 40 and 70% of the required energy of the colonic mucosa (5,6). In vitro studies have demonstrated inhibition of proliferation of neoplastic cell lines by butyrate, suggesting a possible beneficial role of butyrate against the progression of colorectal carcinoma. Such work has also shown that butyrate stimulates cell differentiation, promoting reversion to non-neoplastic phenotypes.

In addition to carbohydrate fermentation, bacterial metabolism of amino acids may generate branched-chain fatty acids (such as isobutyrate, isovalerate, and 2-methyl butyrate), whilst microbial degradation of peptides and proteins forms potentially toxic compounds (including ammonia, amines, phenols, and indoles) (8,17).

The colonic microbiota impacts upon amino acid homeostasis, with 1-20% of circulating plasma lysine being derived from the activity of gut bacteria (18). In addition, microbial hydrolysis of urea to ammonia by the gut microbiota is important in the recycling of nitrogen in the intestine.

The protective effect of the gut microbiota against pathogenic microorganisms falls under two umbrellas: 1, colonization resistance and, 2, stimulation of immune function. In the healthy state, the resident microbiota effectively inhibits the establishment and/or overgrowth of harmful bacteria. A number of mechanisms appear to be responsible, including competition for adhesion sites, competition for nutrients, production of environmental conditions restrictive to pathogenic growth (pH, redox potential), production of anti-microbial compounds (either toxic metabolites or bacteriocins) and/or generation of signals which interact with gene expression of exogenous organisms (3,8,13). In addition, certain members of the intestinal microbiota are known to stimulate immune function (both locally and systemically) (17,20,21). Interactions between the mucosal barrier, the indigenous microbiota and the gut-associated lymphoid tissue (GALT) are paramount to the host defense against pathogenic invasion and infection. This three-component system is integral to the equilibrium of the GI tract ecosystem and defines the balance between oral tolerance and mounting an immune response.

Bacterial-host cell communications can also impact upon expression by host cells. One example of this is the ability of Bact. thetaiotaomicron to influence fucosylated glycoconjugate production by intestinal cells in relation to the availability of fucose

(a substrate for the organism) (5,19). In this manner, the bacteria can essentially order nutrients from the epithelial cells as necessary. Such microbial induced signals may also act in cell-cell communications between different bacterial species and play an important role in homeostasis of their environmental niche.

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