The effects of the intestinal microbiota extend far beyond the intestine (Fig. 12.22). For example, several autoimmune diseases are more frequent in germ-free animals. The germ-free state greatly increases the severity of symptoms in a genetic model of type 1 diabetes. The composition of the microbiota influences susceptibility to many different immunological diseases, metabolic disorders such as obesity, cancer, cardiovascular disease, and even psychiatric disorders. The basis for these associations is unclear and few individual commensal species have been identified in disease susceptibility. However, some affected individuals have unusual compositions of the major bacterial species that normally make up the microbiota, a form of dysbiosis, as we saw in Section 12-19. In experimental models, disease susceptibility can be conferred by transferring intestinal bacteria between affected and unaffected animals, supporting the idea that the change in microbiota is a causal factor, rather than being secondary to preexisting disease. This observation underlies the use of probiotics, which are particular mixtures of live bacteria and yeast that are considered beneficial. Their use may manipulate the intestinal microbiota to prevent disease and promote health, although much remains to be understood about their potential benefits.
Many different mechanisms are probably involved in the effects of the microbiota (Fig. 12.23). Ligation of TLRs and NLRs is undoubtedly important for many of the local effects on epithelial cells and myeloid cells. Flagellin present on many intestinal bacterial species can stimulate TLR-5 on mucosal CD11b-expressing dendritic cells, inducing the production of IL-6 and IL-23 and favoring TH17 and IgA responses. There are also examples of individual bacterial species that have specific effects on immune function. Colonization of mice with segmented filamentous bacteria (SFB) enhances IgA production, accumulation of IELs, and the number of intestinal effector TH17 T cells (see Fig. 12.23). Conversion of dietary tryptophan by lactobacilli into kynurenine metabolites can activate the AhR (see Section 12-14) and enhance IL-22 production by ILC3. Polysaccharide A (PSA) from Bacteroides fragilis drives the differentiation of Treg cells in a TLR-2-dependent manner. Also, several Clostridium species stimulate the preferential generation of FoxP3+ regulatory T cells in the colon, perhaps by promoting a TGF-β-rich environment and by producing SCFAs. The mechanism by which SCFAs directly alter immune cell function is currently unclear. As yet, few specific organisms have been identified to explain the effects of dysbiosis on human disease, although certain E coli species, collectively called enteroadherent Escherichia coli, have been found to be prevalent in patients with Crohn’s disease. Recent studies have also shown increased abundance of Prevotella copri in a number of patients with newly diagnosed rheumatoid arthritis, but much more work needs to be done to confirm these associations and to find if there are similar effects in other diseases.