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

Yukihiro Furusawa, Yuuki Obata, Shinji Fukuda, Takaho A. Endo, Gaku Nakato, Daisuke Takahashi, Yumiko Nakanishi, Chikako Uetake, Keiko Kato, Tamotsu Kato, Masumi Takahashi, Noriko N. Fukuda, Shinnosuke Murakami, Eiji Miyauchi, Shingo Hino, Koji Atarashi, Satoshi Onawa, Yumiko Fujimura, Trevor Lockett, Julie M. ClarkeDavid L. Topping, Masaru Tomita, Shohei Hori, Osamu Ohara, Tatsuya Morita, Haruhiko Koseki, Jun Kikuchi, Kenya Honda, Kouji Hase, Hiroshi Ohno

Research output: Contribution to journalArticle

1418 Citations (Scopus)

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 (T reg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic T reg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic T reg 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 T reg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of T reg 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 T reg -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 T reg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.

Original languageEnglish
Pages (from-to)446-450
Number of pages5
JournalNature
Volume504
Issue number7480
DOIs
Publication statusPublished - 2013

Fingerprint

Butyrates
Regulatory T-Lymphocytes
Volatile Fatty Acids
T-Lymphocytes
Metabolome
Clostridium
Adoptive Transfer
Colitis
Acetylation
Histones
Fermentation
Immune System
Colon
Homeostasis

ASJC Scopus subject areas

  • General

Cite this

Furusawa, Y., Obata, Y., Fukuda, S., Endo, T. A., Nakato, G., Takahashi, D., ... Ohno, H. (2013). Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature, 504(7480), 446-450. https://doi.org/10.1038/nature12721

Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. / 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, Kouji; Ohno, Hiroshi.

In: Nature, Vol. 504, No. 7480, 2013, p. 446-450.

Research output: Contribution to journalArticle

Furusawa, Y, Obata, Y, Fukuda, S, Endo, TA, Nakato, G, Takahashi, D, Nakanishi, Y, Uetake, C, Kato, K, Kato, T, Takahashi, M, Fukuda, NN, Murakami, S, Miyauchi, E, Hino, S, Atarashi, K, Onawa, S, Fujimura, Y, Lockett, T, Clarke, JM, Topping, DL, Tomita, M, Hori, S, Ohara, O, Morita, T, Koseki, H, Kikuchi, J, Honda, K, Hase, K & Ohno, H 2013, 'Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells', Nature, vol. 504, no. 7480, pp. 446-450. https://doi.org/10.1038/nature12721
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, Kouji ; Ohno, Hiroshi. / Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. In: Nature. 2013 ; Vol. 504, No. 7480. pp. 446-450.
@article{cc5f194d4941406aa5cf976f0fc2b1cb,
title = "Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells",
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 (T reg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic T reg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic T reg 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 T reg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of T reg 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 T reg -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 T reg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.",
author = "Yukihiro Furusawa and Yuuki Obata and Shinji Fukuda and Endo, {Takaho A.} and Gaku Nakato and Daisuke Takahashi and Yumiko Nakanishi and Chikako Uetake and Keiko Kato and Tamotsu Kato and Masumi Takahashi and Fukuda, {Noriko N.} and Shinnosuke Murakami and Eiji Miyauchi and Shingo Hino and Koji Atarashi and Satoshi Onawa and Yumiko Fujimura and Trevor Lockett and Clarke, {Julie M.} and Topping, {David L.} and Masaru Tomita and Shohei Hori and Osamu Ohara and Tatsuya Morita and Haruhiko Koseki and Jun Kikuchi and Kenya Honda and Kouji Hase and Hiroshi Ohno",
year = "2013",
doi = "10.1038/nature12721",
language = "English",
volume = "504",
pages = "446--450",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "7480",

}

TY - JOUR

T1 - Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells

AU - Furusawa, Yukihiro

AU - Obata, Yuuki

AU - Fukuda, Shinji

AU - Endo, Takaho A.

AU - Nakato, Gaku

AU - Takahashi, Daisuke

AU - Nakanishi, Yumiko

AU - Uetake, Chikako

AU - Kato, Keiko

AU - Kato, Tamotsu

AU - Takahashi, Masumi

AU - Fukuda, Noriko N.

AU - Murakami, Shinnosuke

AU - Miyauchi, Eiji

AU - Hino, Shingo

AU - Atarashi, Koji

AU - Onawa, Satoshi

AU - Fujimura, Yumiko

AU - Lockett, Trevor

AU - Clarke, Julie M.

AU - Topping, David L.

AU - Tomita, Masaru

AU - Hori, Shohei

AU - Ohara, Osamu

AU - Morita, Tatsuya

AU - Koseki, Haruhiko

AU - Kikuchi, Jun

AU - Honda, Kenya

AU - Hase, Kouji

AU - Ohno, Hiroshi

PY - 2013

Y1 - 2013

N2 - 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 (T reg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic T reg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic T reg 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 T reg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of T reg 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 T reg -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 T reg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.

AB - 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 (T reg) cells, which have a central role in the suppression of inflammatory and allergic responses. However, the molecular mechanisms by which commensal microbes induce colonic T reg cells have been unclear. Here we show that a large bowel microbial fermentation product, butyrate, induces the differentiation of colonic T reg 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 T reg cells in the colon. Among short-chain fatty acids, butyrate induced the differentiation of T reg 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 T reg -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 T reg cells. Our findings provide new insight into the mechanisms by which host-microbe interactions establish immunological homeostasis in the gut.

UR - http://www.scopus.com/inward/record.url?scp=84890564250&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84890564250&partnerID=8YFLogxK

U2 - 10.1038/nature12721

DO - 10.1038/nature12721

M3 - Article

C2 - 24226770

AN - SCOPUS:84890564250

VL - 504

SP - 446

EP - 450

JO - Nature Cell Biology

JF - Nature Cell Biology

SN - 1465-7392

IS - 7480

ER -