Publication Date:
2013-11-15
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869884/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869884/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arpaia, Nicholas -- Campbell, Clarissa -- Fan, Xiying -- Dikiy, Stanislav -- van der Veeken, Joris -- deRoos, Paul -- Liu, Hui -- Cross, Justin R -- Pfeffer, Klaus -- Coffer, Paul J -- Rudensky, Alexander Y -- P30 CA008748/CA/NCI NIH HHS/ -- R37 AI034206/AI/NIAID NIH HHS/ -- R37AI034206/AI/NIAID NIH HHS/ -- T32 AI007621/AI/NIAID NIH HHS/ -- T32 CA009149/CA/NCI NIH HHS/ -- T32A1007621/PHS HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Dec 19;504(7480):451-5. doi: 10.1038/nature12726. Epub 2013 Nov 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; Institute of Medical Microbiology and Hospital Hygiene, Heinrich-Heine-University Duesseldorf, Duesseldorf 40225, Germany. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24226773" target="_blank"〉PubMed〈/a〉
Keywords:
Acetylation
;
Animals
;
Butyrates/*metabolism
;
*Cell Differentiation
;
Cytokines/metabolism
;
Dendritic Cells/immunology/metabolism
;
Enhancer Elements, Genetic/genetics
;
Fermentation
;
Forkhead Transcription Factors/genetics/metabolism
;
Histone Deacetylases/metabolism
;
Inflammation Mediators/metabolism
;
Intestinal Mucosa/cytology/immunology/metabolism/microbiology
;
Intestines/cytology/immunology/*metabolism/*microbiology
;
Introns/genetics
;
Lymphocyte Count
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Starch/metabolism
;
*Symbiosis
;
T-Lymphocytes, Regulatory/*cytology/immunology/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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