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

Nature (2013) doi:10.1038/nature12721
Yukihiro Furusawa1,2*, Yuuki Obata1,2,3*, Shinji Fukuda1,4*, Takaho A. Endo1, Gaku Nakato1, Daisuke Takahashi1, Yumiko Nakanishi4, Chikako Uetake1, Keiko Kato1,5, Tamotsu Kato1, Masumi Takahashi1, Noriko N. Fukuda4, Shinnosuke Murakami4, Eiji Miyauchi1, Shingo Hino6, Koji Atarashi1,7, Satoshi Onawa1, Yumiko Fujimura2, Trevor Lockett8, Julie M. Clarke8, David L. Topping8, Masaru Tomita4, Shohei Hori1, Osamu Ohara1, Tatsuya Morita6, Haruhiko Koseki1,3,5, Jun Kikuchi5,9, Kenya Honda1,10, Koji Hase1,2,7* & Hiroshi Ohno1,3,5
1 RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan. 2 The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. 3 Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan. 4 Institute for Advanced Biosciences, Keio University, Yamagata 997-0052, Japan. 5 Graduate School of Medical Life Science, Yokohama City University, Kanagawa 230-0045, Japan. 6 Faculty of Agriculture, Shizuoka University, Shizuoka 422-8529, Japan. 7 PRESTO, Japan Science and Technology Agency, Saitama 332-0012, Japan. 8 Preventative Health National Research Flagship, CSIRO Food and Nutritional Sciences, South Australia 9 RIKEN Center for Sustainable Resource Science, Kanagawa 230-0045, Japan. 10 CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan.

Gut commensal microbes shape the mucosal immune system by regulating the differentiation and expansion of several types of T cell1, 2, 3, 4, 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 responses3. 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.