Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR–S6K pathway

Abstract

Microbial metabolites such as short chain fatty acids (SCFAs) are highly produced in the intestine and potentially regulate the immune system. We studied the function of SCFAs in regulation of T cell differentiation into effector and regulatory T cells. We report that SCFAs can directly promote T cell differentiation into T cells producing IL-17, IFN-γ, and/or IL-10 depending on cytokine milieu. This effect of SCFAs on T cells is independent of GPR41- or GPR43 but dependent on direct histone deacetylase (HDAC) inhibitor activity. Inhibition of HDACs in T cells by SCFAs increased the acetylation of p70 S6 kinase and phosphorylation rS6, regulating the mTOR pathway required for generation of Th17, Th1, and IL-10+ T cells. Acetate (C2) administration enhanced the induction of Th1 and Th17 cells during C. rodentium infection but decreased anti-CD3-induced inflammation in an IL-10-dependent manner. Our results indicate that SCFAs promote T cell differentiation into both effector and regulatory T cells to promote either immunity or immune tolerance depending on immunological milieu.

Microbiota Metabolite Short Chain Fatty Acid Acetate Promotes Intestinal IgA Response to Microbiota which is Mediated by GPR43

“…As SCFA propionate also binds GPR43, even at a low affinity, we are actively investigating whether it also promotes intestinal IgA responses. Although it has been shown that SCFA inhibit histone deacetylases in a GPR41-and GPR43-independent manner, a recent report also suggested that HDAC activity could be regulated in a GPR43-dependent manner 20,46 . We are still unclear at this point as to whether HDAC inhibitory activity of acetate is involved in the regulation of the intestinal IgA responses.…”

T cell metabolism drives immunity

“…In agreement with this idea, lineage-specific cytokine-encoding genes that affect T cell differentiation undergo dynamic changes in microenvironmental factors influence T cell function will provide further insight into immune cell biology and could lead to new approaches to treating human diseases. produced by bacteria induce differentiation of colonic T reg cells (Furusawa et al, 2013;Smith et al, 2013) and also Th17 cells under certain conditions (Park et al, 2015). The vitamin A metabolite retinoic acid can synergize with TGF- to stimulate T reg conversion (Coombes et al, 2007;Denning et al, 2007;Mucida et al, 2007;Sun et al, 2007;Elias et al, 2008).…”

Antibiotic Overusage Causes Mitochondrial Dysfunction Which May Promote Tumorigenesis

“…Microbial co-metabolism can affect T-cell signaling pathways by production of amino-acids, fatty acids and butyrate especially production of proinflammatory Th17 and anti-inflammatory Tregs [10][11]. This co-metabolism can determine the result of immunotherapeutics and cancer cell survival [12][13][14].…”