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Nature. 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.

Author information

1
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].
2
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].
3
1] RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan [2] Institute for Advanced Biosciences, Keio University, Yamagata 997-0052, Japan [3].
4
RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan.
5
Institute for Advanced Biosciences, Keio University, Yamagata 997-0052, Japan.
6
1] RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan [2] Graduate School of Medical Life Science, Yokohama City University, Kanagawa 230-0045, Japan.
7
Faculty of Agriculture, Shizuoka University, Shizuoka 422-8529, Japan.
8
1] RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan [2] PRESTO, Japan Science and Technology Agency, Saitama 332-0012, Japan.
9
The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
10
Preventative Health National Research Flagship, CSIRO Food and Nutritional Sciences, South Australia 5000, Australia.
11
1] RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan [2] Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan [3] Graduate School of Medical Life Science, Yokohama City University, Kanagawa 230-0045, Japan.
12
1] Graduate School of Medical Life Science, Yokohama City University, Kanagawa 230-0045, Japan [2] RIKEN Center for Sustainable Resource Science, Kanagawa 230-0045, Japan.
13
1] RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan [2] CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan.
14
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] PRESTO, Japan Science and Technology Agency, Saitama 332-0012, Japan [4].

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.

PMID:
24226770
DOI:
10.1038/nature12721
[Indexed for MEDLINE]

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