Metabolites Produced by Commensal Bacteria Promote Peripheral Regulatory T-cell Generation

Nature. 2013 Dec 19;504(7480):451-5. doi: 10.1038/nature12726. Epub 2013 Nov 13.

Abstract

Intestinal microbes provide multicellular hosts with nutrients and confer resistance to infection. The delicate balance between pro- and anti-inflammatory mechanisms, essential for gut immune homeostasis, is affected by the composition of the commensal microbial community. Regulatory T cells (Treg cells) expressing transcription factor Foxp3 have a key role in limiting inflammatory responses in the intestine. Although specific members of the commensal microbial community have been found to potentiate the generation of anti-inflammatory Treg or pro-inflammatory T helper 17 (TH17) cells, the molecular cues driving this process remain elusive. Considering the vital metabolic function afforded by commensal microorganisms, we reasoned that their metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. We tested this hypothesis by exploring the effect of microbial metabolites on the generation of anti-inflammatory Treg cells. We found that in mice a short-chain fatty acid (SCFA), butyrate, produced by commensal microorganisms during starch fermentation, facilitated extrathymic generation of Treg cells. A boost in Treg-cell numbers after provision of butyrate was due to potentiation of extrathymic differentiation of Treg cells, as the observed phenomenon was dependent on intronic enhancer CNS1 (conserved non-coding sequence 1), essential for extrathymic but dispensable for thymic Treg-cell differentiation. In addition to butyrate, de novo Treg-cell generation in the periphery was potentiated by propionate, another SCFA of microbial origin capable of histone deacetylase (HDAC) inhibition, but not acetate, which lacks this HDAC-inhibitory activity. Our results suggest that bacterial metabolites mediate communication between the commensal microbiota and the immune system, affecting the balance between pro- and anti-inflammatory mechanisms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Butyrates / metabolism*
  • Cell Differentiation*
  • Cytokines / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Enhancer Elements, Genetic / genetics
  • Fermentation
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Histone Deacetylases / metabolism
  • Inflammation Mediators / metabolism
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / microbiology
  • Intestines / cytology
  • Intestines / immunology
  • Intestines / microbiology*
  • Introns / genetics
  • Lymphocyte Count
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Starch / metabolism
  • Symbiosis*
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*

Substances

  • Butyrates
  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Inflammation Mediators
  • Starch
  • Histone Deacetylases

Associated data

  • GEO/GSE51263