How gut microbiota regulates intestinal homeostasis and the pathogenesis of inflammatory bowel diseases remains unclear. Emerging evidence suggests that the host immune system can sense bacterial metabolites in addition to pathogen-associated molecular patterns and that recognition of these small molecules can influence the host immune response in the context of disease and inflammation in the gut and beyond. Of particular interest are short-chain fatty acids (SCFAs) such as acetate, n-propionate, and n-butyrate, which are solely metabolized by gut bacteria from otherwise indigestible carbohydrates, i.e., from fiber-rich diets. Moreover, SCFAs have been shown to ameliorate disease in models of inflammatory bowel disease (IBD) and allergic asthma. Further, SCFAs are associated with reduced risk of various diseases, including IBD, and dysbiosis in IBD patients was associated with altered SCFA fermentative pathways. However, the mechanisms involved are still largely unknown. Most notable among the SCFA targets is the mammalian G protein-coupled receptor pair of GPR41 and GPR43. Our hypothesis is that SCFAs promote Th1 and Th17 cell production of IL-10 through mTOR and Blimp-1 in a GPR43-dependent manner, which leads to preservation of intestinal immune homeostasis to microbiota and inhibition of IBD. Further, the diets supplemented with SCFAs will prevent as well as treat colitis, through regulation of gut microbiota compositions. We will investigate whether the mechanisms by which SCFAs promote T effector cell production of IL-10, and loss of GPR43 in microbiota antigen-specific T effector cells promoting the pathogenesis of colitis. Finally, we will define whether the diets supplemented with SCFAs prevent as well as treat colitis through regulation of gut microbiota compositions.
Lay Abstract Gut bacteria are important in regulation of intestinal homeostasis and the pathogenesis of inflammatory bowel disease, a chronic intestinal inflammation. However, how it is unclear how they do these. We will investigate whether SCFAs promotes T cell production of IL-10, an anti-inflammatory molecule, which leads to preservation of intestinal immune homeostasis and inhibition of inflammatory bowel disease.
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