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. 2013 Dec 19;504(7480):446-50.
doi: 10.1038/nature12721. Epub 2013 Nov 13.

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

Yukihiro Furusawa  1 , Yuuki Obata  2 , Shinji Fukuda  3 , Takaho A Endo  4 , Gaku Nakato  4 , Daisuke Takahashi  4 , Yumiko Nakanishi  5 , Chikako Uetake  4 , Keiko Kato  6 , Tamotsu Kato  4 , Masumi Takahashi  4 , Noriko N Fukuda  5 , Shinnosuke Murakami  5 , Eiji Miyauchi  4 , Shingo Hino  7 , Koji Atarashi  8 , Satoshi Onawa  4 , Yumiko Fujimura  9 , Trevor Lockett  10 , Julie M Clarke  10 , David L Topping  10 , Masaru Tomita  5 , Shohei Hori  4 , Osamu Ohara  4 , Tatsuya Morita  7 , Haruhiko Koseki  11 , Jun Kikuchi  12 , Kenya Honda  13 , Koji Hase  14 , Hiroshi Ohno  11
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Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells

Yukihiro Furusawa et al. Nature. .

Erratum in

  • Nature. 2014 Feb 13;506(7487):254

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.

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