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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Gene Expression Omnibus
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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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.).
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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