Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells.
Furusawa, Yukihiro 1,2; Obata, Yuuki 1,2,3; Fukuda, Shinji 1,4; Endo, Takaho A. 1; Nakato, Gaku 1; Takahashi, Daisuke 1; Nakanishi, Yumiko 4; Uetake, Chikako 1; Kato, Keiko 1,5; Kato, Tamotsu 1; Takahashi, Masumi 1; Fukuda, Noriko N. 4; Murakami, Shinnosuke 4; Miyauchi, Eiji 1; Hino, Shingo 6; Atarashi, Koji 1,7; Onawa, Satoshi 1; Fujimura, Yumiko 2; Lockett, Trevor 8; Clarke, Julie M. 8; Topping, David L. 8; Tomita, Masaru 4; Hori, Shohei 1; Ohara, Osamu 1; Morita, Tatsuya 6; Koseki, Haruhiko 1,3,5; Kikuchi, Jun 5,9; Honda, Kenya 1,10; Hase, Koji 1,2,7; Ohno, Hiroshi 1,3,5
[Letter]
Nature.
504(7480):446-450, December 19, 2013.
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: Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell 1-5. 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 3. 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 CD45RBhi 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.
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