Elsevier

Mucosal Immunology

Volume 11, Issue 3, May 2018, Pages 752-762
Mucosal Immunology

Article
GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3

https://doi.org/10.1038/mi.2017.118Get rights and content
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Abstract

The antimicrobial peptides (AMP) produced by intestinal epithelial cells (IEC) play crucial roles in the regulation of intestinal homeostasis by controlling microbiota. Gut microbiota has been shown to promote IEC expression of RegIIIγ and certain defensins. However, the mechanisms involved are still not completely understood. In this report, we found that IEC expression levels of RegIIIγ and β-defensins 1, 3, and 4 were lower in G protein-coupled receptor (GPR)43−/− mice compared to that of wild-type (WT) mice. Oral feeding with short-chain fatty acids (SCFA) promoted IEC production of RegIIIγ and defensins in mice. Furthermore, SCFA induced RegIIIγ and β-defensins in intestinal epithelial enteroids generated from WT but not GPR43−/− mice. Mechanistically, SCFA activated mTOR and STAT3 in IEC, and knockdown of mTOR and STAT3 impaired SCFA induction of AMP production. Our studies thus demonstrated that microbiota metabolites SCFA promoted IEC RegIIIγ and β-defensins in a GPR43-dependent manner. The data thereby provide a novel pathway by which microbiota regulates IEC expression of AMP and intestinal homeostasis.

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Published online: 7 February 2018

Author contributions Y.Z. and F.C. performed experiments, analyzed data, and wrote the manuscript. W.W., M.S., A.J.B., S.Y., Y.X., and X.H. performed part of experiments, analyzed data, and reviewed the manuscript. G.G., Y.X., and Y.F. performed and analyzed 16s rRNA pyrosequencing. T.D.E.-P., W.D., Q.Z., and Z.L. provided the reagents and revised the manuscript. Y.C. conceived the project, designed the experiments, and wrote the manuscript.

SUPPLEMENTARY MATERIAL is linked to the online version of the paper

Ye Zhao and Feidi Chen: These authors contributed equally to this work.

Supplementary information The online version of this article (doi:https://doi.org/10.1038/mi.2017.118) contains supplementary material, which is available to authorized users.