Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells.
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.
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].
Yukihiro
Y
Furusawa
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].
Yuuki
Y
Obata
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].
Shinji
S
Fukuda
RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan.
Takaho A
TA
Endo
RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan.
Gaku
G
Nakato
RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan.
Daisuke
D
Takahashi
Institute for Advanced Biosciences, Keio University, Yamagata 997-0052, Japan.
Yumiko
Y
Nakanishi
RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan.
Chikako
C
Uetake
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.
Keiko
K
Kato
RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan.
Tamotsu
T
Kato
RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan.
Masumi
M
Takahashi
Institute for Advanced Biosciences, Keio University, Yamagata 997-0052, Japan.
Noriko N
NN
Fukuda
Institute for Advanced Biosciences, Keio University, Yamagata 997-0052, Japan.
Shinnosuke
S
Murakami
RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan.
Eiji
E
Miyauchi
Faculty of Agriculture, Shizuoka University, Shizuoka 422-8529, Japan.
Shingo
S
Hino
1] RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan [2] PRESTO, Japan Science and Technology Agency, Saitama 332-0012, Japan.
Koji
K
Atarashi
RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan.
Satoshi
S
Onawa
The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Yumiko
Y
Fujimura
Preventative Health National Research Flagship, CSIRO Food and Nutritional Sciences, South Australia 5000, Australia.
Trevor
T
Lockett
Preventative Health National Research Flagship, CSIRO Food and Nutritional Sciences, South Australia 5000, Australia.
Julie M
JM
Clarke
Preventative Health National Research Flagship, CSIRO Food and Nutritional Sciences, South Australia 5000, Australia.
David L
DL
Topping
Institute for Advanced Biosciences, Keio University, Yamagata 997-0052, Japan.
Masaru
M
Tomita
RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan.
Shohei
S
Hori
RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan.
Osamu
O
Ohara
Faculty of Agriculture, Shizuoka University, Shizuoka 422-8529, Japan.
Tatsuya
T
Morita
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.
Haruhiko
H
Koseki
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.
Jun
J
Kikuchi
1] RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Kanagawa 230-0045, Japan [2] CREST, Japan Science and Technology Agency, Saitama 332-0012, Japan.
Kenya
K
Honda
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].
Koji
K
Hase
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.
Hiroshi
H
Ohno
D000107:Acetylation / Q000187:drug effects; D019264:Adoptive Transfer; D000818:Animals; D002087:Butyrates / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D003092:Colitis / Q000188:drug therapy / Q000473:pathology; D003106:Colon / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D017124:Conserved Sequence; D005260:Female; D005285:Fermentation; D051858:Forkhead Transcription Factors / Q000235:genetics; D005856:Germ-Free Life; D006657:Histones / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology; D018655:Lymphocyte Count; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055442:Metabolome; D051379:Mice; D011401:Promoter Regions, Genetic / Q000187:drug effects; D013559:Symbiosis; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects / Q000276:immunology
D002087:Butyrates; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006657:Histones