Microbiota metabolites short-chain fatty acid butyrate conditions intestinal epithelial cells to promote development of Treg cells and T cell IL-10 production

Abstract

Abstract Gut microbiota greatly impacts host immune response and intestinal homeostasis. However, the mechanisms are still largely unclear. Short chain fatty acids (SCFAs), the most abundant metabolites in intestines derived from gut bacterial fermentation of dietary fibers, either existing free in gut lumen or being absorbed into circulation, perform multiple functions in maintenance of intestinal epithelial integrity and immune homeostasis, and have been shown to directly induce Treg cells and ameliorate the colitis. However, the low concentration of SCFAs in bloodstream makes them hard to directly act on T cells in physiological condition. In this study, we investigated whether SCFAs regulate T cell development through interaction with intestinal epithelial cells (IECs), which are in constantly contact with high concentration of luminal SCFAs. We report here that treatment with SCFA butyrate induced IEC production of TGF-β in both primary IECs and cell line MSIE. We then cultured MSIE cells with or without butyrate for 24 and 48 hrs to generate condition media (CM). When added to T cell cultures under different polarization conditions, butyrate treated CM significantly enhanced the expression of Foxp3 under Treg conditions, and IL-10 production in Th1, Th17, and Treg cells. Furthermore, by using GPR43−/− IECs and the HDAC inhibitor, we found butyrate promotion of TGF-β production was partially mediated by its activity of HDAC inhibition but not through GPR43. Our study thus demonstrated that SCFA butyrate regulates host T cell responses through interaction with IECs. The trialogues of microbiota metabolites SCFAs, IECs, and T cells could play a crucial role in intestinal homeostasis.