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

Nature volume 504, pages 446–450 (2013)Cite this article

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An Erratum to this article was published on 12 February 2014

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Abstract

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.

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Figure 1: Gut microbial metabolism is essential for the induction of colonic Treg cells.
Figure 2: Butyrate induces the differentiation of Treg cells in the colonic lamina propria.
Figure 3: Chromatin modification at the Foxp3 locus by butyrate.
Figure 4: Butyrate ameliorates T-cell-dependent experimental colitis.

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DDBJ/GenBank/EMBL

Gene Expression Omnibus

Data deposits

The microarray and ChIP-seq analysis data have been deposited at the Gene Expression Omnibus (GEO) under accession number GSE49655. The microbiome analysis data have been deposited at the DDBJ database (http://getentry.ddbj.nig.ac.jp/) under accession number DRA001105.

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Acknowledgements

We would like to thank P. Carninci, Y. Shinkai and M. Yoshida for discussion; Y. Chiba and S. Yamada for technical support; H. Sugahara for technical advice; and P. D. Burrows for critical reading and editing of the manuscript. This work was supported in part by grants from Japanese Ministry of Education, Culture, Sports, Science and Technology (24117524 to S.F.; 21022049 to K.Ha.; 20113003 to H.O.), The Japan Society for the Promotion of Science (24890293 to Y.F.; 252667 to Y.O.; 24380072 and 24658129 to S.F.; 22689017 to K.Ha.; 21390155 to H.O.), The Japan Science and Technology Agency (K.Ha., K.A. and K.Ho.), RIKEN President’s Special Research Grant (H.O.), RIKEN RCAI Young Chief Investigator program (K.Ha.), the Institute for Fermentation, Osaka (S.F.), the Mishima Kaiun Memorial Foundation (S.F.), The Takeda Science Foundation (S.F. and H.O.), The Mitsubishi Foundation (H.O.), and The Uehara Memorial Foundation (S.F. and K.Ha.).

Author information

Author notes

  1. Yukihiro Furusawa, Yuuki Obata, Shinji Fukuda and Koji Hase: These authors contributed equally to this work.

Authors and Affiliations

  1. RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan ,

    Yukihiro Furusawa, Yuuki Obata, Shinji Fukuda, Takaho A. Endo, Gaku Nakato, Daisuke Takahashi, Chikako Uetake, Keiko Kato, Tamotsu Kato, Masumi Takahashi, Eiji Miyauchi, Koji Atarashi, Satoshi Onawa, Shohei Hori, Osamu Ohara, Haruhiko Koseki, Kenya Honda, Koji Hase & Hiroshi Ohno

  2. The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan ,

    Yukihiro Furusawa, Yuuki Obata, Yumiko Fujimura & Koji Hase

  3. Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan ,

    Yuuki Obata, Haruhiko Koseki & Hiroshi Ohno

  4. Institute for Advanced Biosciences, Keio University, Yamagata 997-0052, Japan ,

    Shinji Fukuda, Yumiko Nakanishi, Noriko N. Fukuda, Shinnosuke Murakami & Masaru Tomita

  5. Graduate School of Medical Life Science, Yokohama City University, Kanagawa 230-0045, Japan ,

    Keiko Kato, Haruhiko Koseki, Jun Kikuchi & Hiroshi Ohno

  6. Faculty of Agriculture, Shizuoka University, Shizuoka 422-8529, Japan ,

    Shingo Hino & Tatsuya Morita

  7. PRESTO, Japan Science and Technology Agency, Saitama 332-0012, Japan ,

    Koji Atarashi & Koji Hase

  8. Preventative Health National Research Flagship, CSIRO Food and Nutritional Sciences, South Australia 5000, Australia ,

    Trevor Lockett, Julie M. Clarke & David L. Topping

  9. RIKEN Center for Sustainable Resource Science, Kanagawa 230-0045, Japan ,

    Jun Kikuchi

  10. CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan ,

    Kenya Honda

Authors
  1. Yukihiro Furusawa
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Contributions

S.F., K.Ha., D.L.T., T.M., K.Ho. and H.O. conceived the study; K.Ha. and S.F. designed the experiments and wrote the manuscript with Y.Fur., Y.O. and H.O.; Y. Fur. and Y.O conducted a large part of experiments together with S.F., G.N., D.T., C.U., K.K., T.K., M.Ta., E.M. and K.Ha; S.F, S.O. and K.Ha. prepared germ-free, CRB-associated and gnotobiotic mice. K.A. and K.Ho. were involved in data discussion. S.F., Y.N., C.U. and J.K. performed metabolome analysis. S.F., T.K., S.M. and M.To. performed microbiome analysis. T.A.E. performed bioinformatic analyses. S.Hi. and T.M. performed HPLC analysis. S.F. and N.N.F. performed GC–MS analysis. Y.Fuj. performed histological analysis. T.L., J.M.C., D.L.T. and S.Ho. provided essential materials and contributed to the design of experiments. Y.Fur. and H.K. contributed to the ChIP assay. H.O. directed the study and took primary responsibility for editing the manuscript.

Corresponding authors

Correspondence to Shinji Fukuda, Koji Hase or Hiroshi Ohno.

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The authors declare no competing financial interests.

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Furusawa, Y., Obata, Y., Fukuda, S. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013). https://doi.org/10.1038/nature12721

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