Commensal Microbe-Derived Butyrate Induces the Differentiation of Colonic Regulatory T Cells

Nature. 2013 Dec 19;504(7480):446-50. doi: 10.1038/nature12721. Epub 2013 Nov 13.

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 (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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation / drug effects
  • Adoptive Transfer
  • Animals
  • Butyrates / analysis
  • Butyrates / metabolism*
  • Butyrates / pharmacology
  • Cell Differentiation* / drug effects
  • Colitis / drug therapy
  • Colitis / pathology
  • Colon / cytology
  • Colon / immunology*
  • Colon / metabolism
  • Colon / microbiology*
  • Conserved Sequence
  • Female
  • Fermentation*
  • Forkhead Transcription Factors / genetics
  • Germ-Free Life
  • Histones / metabolism
  • Homeostasis / drug effects
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / immunology
  • Lymphocyte Count
  • Magnetic Resonance Spectroscopy
  • Male
  • Metabolome
  • Mice
  • Promoter Regions, Genetic / drug effects
  • Symbiosis*
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology

Substances

  • Butyrates
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Histones

Associated data

  • GEO/GSE49655