Publication Date:
2013-11-15
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Furusawa, Yukihiro -- Obata, Yuuki -- Fukuda, Shinji -- Endo, Takaho A -- Nakato, Gaku -- Takahashi, Daisuke -- Nakanishi, Yumiko -- Uetake, Chikako -- Kato, Keiko -- Kato, Tamotsu -- Takahashi, Masumi -- Fukuda, Noriko N -- Murakami, Shinnosuke -- Miyauchi, Eiji -- Hino, Shingo -- Atarashi, Koji -- Onawa, Satoshi -- Fujimura, Yumiko -- Lockett, Trevor -- Clarke, Julie M -- Topping, David L -- Tomita, Masaru -- Hori, Shohei -- Ohara, Osamu -- Morita, Tatsuya -- Koseki, Haruhiko -- Kikuchi, Jun -- Honda, Kenya -- Hase, Koji -- Ohno, Hiroshi -- England -- Nature. 2013 Dec 19;504(7480):446-50. doi: 10.1038/nature12721. Epub 2013 Nov 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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]. ; 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]. ; 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]. ; RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan. ; Institute for Advanced Biosciences, Keio University, Yamagata 997-0052, Japan. ; 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. ; Faculty of Agriculture, Shizuoka University, Shizuoka 422-8529, Japan. ; 1] RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan [2] PRESTO, Japan Science and Technology Agency, Saitama 332-0012, Japan. ; The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. ; Preventative Health National Research Flagship, CSIRO Food and Nutritional Sciences, South Australia 5000, Australia. ; 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. ; 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. ; 1] RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan [2] CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan. ; 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].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24226770" target="_blank"〉PubMed〈/a〉
Keywords:
Acetylation/drug effects
;
Adoptive Transfer
;
Animals
;
Butyrates/analysis/*metabolism/pharmacology
;
*Cell Differentiation/drug effects
;
Colitis/drug therapy/pathology
;
Colon/cytology/*immunology/metabolism/*microbiology
;
Conserved Sequence
;
Female
;
*Fermentation
;
Forkhead Transcription Factors/genetics
;
Germ-Free Life
;
Histones/metabolism
;
Homeostasis/drug effects
;
Intestinal Mucosa/cytology/immunology
;
Lymphocyte Count
;
Magnetic Resonance Spectroscopy
;
Male
;
Metabolome
;
Mice
;
Promoter Regions, Genetic/drug effects
;
*Symbiosis
;
T-Lymphocytes, Regulatory/*cytology/drug effects/immunology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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