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

Yukihiro Furusawa, Yuuki Obata, Shinji Fukuda, Takaho A. Endo, Gaku Nakato, Daisuke Takahashi, Yumiko Nakanishi, Chikako Uetake, Keiko Kato, Tamotsu Kato, Masumi Takahashi, Noriko N. Fukuda, Shinnosuke Murakami, Eiji Miyauchi, Shingo Hino, Koji Atarashi, Satoshi Onawa, Yumiko Fujimura, Trevor Lockett, Julie M. ClarkeDavid L. Topping, Masaru Tomita, Shohei Hori, Osamu Ohara, Tatsuya Morita, Haruhiko Koseki, Jun Kikuchi, Kenya Honda, Koji Hase, Hiroshi Ohno

Research output: Contribution to journalArticle

1834 Citations (Scopus)

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 (T reg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic T reg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic T reg 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 T reg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of T reg 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 T reg -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 T reg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.

Original languageEnglish
Pages (from-to)446-450
Number of pages5
JournalNature
Volume504
Issue number7480
DOIs
Publication statusPublished - 2013

ASJC Scopus subject areas

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    Furusawa, Y., Obata, Y., Fukuda, S., Endo, T. A., Nakato, G., Takahashi, D., Nakanishi, Y., Uetake, C., Kato, K., Kato, T., Takahashi, M., Fukuda, N. N., Murakami, S., Miyauchi, E., Hino, S., Atarashi, K., Onawa, S., Fujimura, Y., Lockett, T., ... Ohno, H. (2013). Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature, 504(7480), 446-450. https://doi.org/10.1038/nature12721