Project Summary
The mechanisms by which gut microbiota regulate intestinal homeostasis and the pathogenesis of inflammatory
bowel diseases (IBD) remain unclear. Emerging evidence suggests that the host immune system can sense gut
bacterial metabolites in addition to pathogen-associated molecular patterns (PAMP). The 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 (SCFA), such as acetate, propionate, and butyrate,
which are solely metabolized by gut bacteria from otherwise indigestible carbohydrates, i.e., from fiber-rich diets,
and have been shown to alleviate disease in animal models of colitis and allergic asthma. Furthermore, SCFAs
are associated with reduced risk of various diseases, including IBD, and dysbiosis in IBD patients has been
associated with altered SCFA fermentative pathways. However, the mechanisms involved are still largely
unknown. The intestinal epithelial cells (IECs) are the primary cell type in direct contact with stimuli from the
luminal microbiota and are critical players in microbe-host interactions. Although it has been shown that SCFA
can regulate T cell function, the majority of SCFA are absorbed by epithelial cells in the intestine. Only a small
portion of SCFA is available in the free form to directly act on T cells or other mucosal immune cells underneath
the epithelium in physiological conditions. Thus, how SCFA regulates mucosal immune cells to contribute to
intestinal homeostasis remains unclear. Our preliminary data demonstrated that SCFA has persistent effects on
T cell IL-10 production in vivo, which could mediate SCFA protection. The SCFA-induced long-lasting effect is
independent of gut microbiota. Interestingly, SCFA inhibits IEC expression of EZH2, a histone-modifying enzyme
methylating histone H3 lysine 27, and SCFA-treated IECs promote T cell IL-10 production. By employing
untargeted comparative metabolomic analyses, we identified that SCFA drives a significant shift in the levels of
IEC metabolites, which promote T cell IL-10 production, indicating a crucial role of IEC sensing SCFA in IEC-T
cell crosstalk and maintaining intestinal homeostasis. The central hypothesis of this project is that IEC sensing
of SCFA regulates T cell function through metabolic products, which leads to the preservation of intestinal
immune homeostasis and inhibition of IBD. We will test our hypothesis in this application to determine (1) how
SCFA epigenetically regulates IEC, the role of IEC EZH2 in T cell responses to microbiota, and the maintenance
of intestinal homeostasis; (2) which IEC metabolites induced by SCFA are required for promoting T cell IL-10
production and inhibition of colitis; and (3) the role of IEC metabolites in the prevention and treatment of colitis.
