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

Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation.

Author information

1
1] Howard Hughes Medical Institute and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
2
Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
3
Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Duesseldorf, Duesseldorf 40225, Germany.
4
1] Howard Hughes Medical Institute and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [3] Department of Cell Biology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.

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.

PMID:
24226773
PMCID:
PMC3869884
DOI:
10.1038/nature12726
[Indexed for MEDLINE]
Free PMC Article

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