Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells

Abstract

Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell. Clostridia, a dominant class of commensal microbe, can induce colonic regulatory T (Treg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic Treg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic Treg cells in mice. A comparative NMR-based metabolome analysis suggests that the luminal concentrations of short-chain fatty acids positively correlates with the number of Treg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of Treg cells in vitro and in vivo, and ameliorated the development of colitis induced by adoptive transfer of CD4(+) CD45RB(hi) T cells in Rag1(-/-) mice. Treatment of naive T cells under the Treg-cell-polarizing conditions with butyrate enhanced histone H3 acetylation in the promoter and conserved non-coding sequence regions of the Foxp3 locus, suggesting a possible mechanism for how microbial-derived butyrate regulates the differentiation of Treg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…Thus, PTEN deficiency in T Reg cells may drive loss of FOXP3 expression and effector cytokine production by enforcing glycolytic metabolism 79,80 . Short-chain fatty acids generated by commensal bacteria in the gut may induce FOXP3 expression and pT Reg cell polarization by supporting the T Reg cell meta bolic programme 98,99 . In addition to glucose or fatty acids, glutamine is an important biosynthetic precursor that tips the balance between T H 1 and T Reg cell polarization.…”

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

“…Induction of FOXP3 in response to food metabolites including short‐chain fatty acids is now well characterised at the molecular levels and is particularly relevant for induced Treg generation in the gut. Butyrate generated by commensals in the colon is able to activate the FOXP3 locus and promote a tolerogenic bias 81, 82. These mediators play a key role in differentiation of naïve T cells, but it is less clear whether they drive fate change in committed T‐cell subsets.…”

Western lifestyle and immunopathology of multiple sclerosis

“…SCFAs were recently found to ameliorate EAE, as well as other autoimmune diseases, such as type 1 diabetes, by expanding lamina propria–derived T reg cells through suppression of the JNK1 and p38 pathway 98, 125. In line with these studies, SFCAs also increase the number of colonic T reg cells in an experimental model of inflammatory bowel disease 126, 127. In addition to controlling JNK1 and p38 signaling, SCFA may also function as histone deacetylase inhibitors, thereby potentially controlling the acetylation of T reg ‐associated genes 128…”