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The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.

ABSTRACT: Regulatory T cells (Tregs) that express the transcription factor Foxp3 are critical for regulating intestinal inflammation. Candidate microbe approaches have identified bacterial species and strain-specific molecules that can affect intestinal immune responses, including species that modulate Treg responses. Because neither all humans nor mice harbor the same bacterial strains, we posited that more prevalent factors exist that regulate the number and function of colonic Tregs. We determined that short-chain fatty acids, gut microbiota-derived bacterial fermentation products, regulate the size and function of the colonic Treg pool and protect against colitis in a Ffar2-dependent manner in mice. Our study reveals that a class of abundant microbial metabolites underlies adaptive immune microbiota coadaptation and promotes colonic homeostasis and health.

SUBMITTER: Smith PM

PROVIDER: S-EPMC3807819 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.

Smith Patrick M PM Howitt Michael R MR Panikov Nicolai N Michaud Monia M Gallini Carey Ann CA Bohlooly-Y Mohammad M Glickman Jonathan N JN Garrett Wendy S WS

Science (New York, N.Y.) 20130704 6145

Regulatory T cells (Tregs) that express the transcription factor Foxp3 are critical for regulating intestinal inflammation. Candidate microbe approaches have identified bacterial species and strain-specific molecules that can affect intestinal immune responses, including species that modulate Treg responses. Because neither all humans nor mice harbor the same bacterial strains, we posited that more prevalent factors exist that regulate the number and function of colonic Tregs. We determined that ...[more]

PMID: 23828891

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Project description:BackgroundShort-chain fatty acids derived from gut microbial fermentation of dietary fiber have been shown to suppress autoimmunity through mechanisms that include enhanced regulation by T regulatory cells (Tregs).MethodsUsing a murine kidney transplantation model, we examined the effects on alloimmunity of a high-fiber diet or supplementation with the short-chain fatty acid acetate. Kidney transplants were performed from BALB/c(H2d) to B6(H2b) mice as allografts in wild-type and recipient mice lacking the G protein-coupled receptor GPR43 (the metabolite-sensing receptor of acetate). Allograft mice received normal chow, a high-fiber diet, or normal chow supplemented with sodium acetate. We assessed rejection at days 14 (acute) and 100 (chronic), and used 16S rRNA sequencing to determine gut microbiota composition pretransplantation and post-transplantation.ResultsWild-type mice fed normal chow exhibited dysbiosis after receiving a kidney allograft but not an isograft, despite the avoidance of antibiotics and immunosuppression for the latter. A high-fiber diet prevented dysbiosis in allograft recipients, who demonstrated prolonged survival and reduced evidence of rejection compared with mice fed normal chow. Allograft mice receiving supplemental sodium acetate exhibited similar protection from rejection, and subsequently demonstrated donor-specific tolerance. Depletion of CD25+ Tregs or absence of the short-chain fatty acid receptor GPR43 abolished this survival advantage.ConclusionsManipulation of the microbiome by a high-fiber diet or supplementation with sodium acetate modified alloimmunity in a kidney transplant model, generating tolerance dependent on Tregs and GPR43. Diet-based therapy to induce changes in the gut microbiome can alter systemic alloimmunity in mice, in part through the production of short-chain fatty acids leading to Treg cell development, and merits study as a potential clinical strategy to facilitate transplant acceptance.

Dataset Information

The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.

Publications

The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.

Similar Datasets

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