Article | Published:

Barrier function and epithelial cell biology

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

Mucosal Immunology volume 11, pages 752762 (2018) | Download Citation

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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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Acknowledgements

This work was supported by NIH grants DK098370, DK105585, and DK112436, and John Sealy Memorial Endowment Fund (to Y.C.). We appreciate Dr Linsey Yeager of The University of Texas Medical Branch for proofreading the manuscript.

Author information

Author notes

    • Ye Zhao
    •  & Feidi Chen

    These authors contributed equally to this work.

Affiliations

  1. Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    • Ye Zhao
  2. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA

    • Ye Zhao
    • , Wei Wu
    • , Mingming Sun
    • , Anthony J Bilotta
    • , Suxia Yao
    • , Yi Xiao
    • , Xiangsheng Huang
    • , Tonyia D Eaves-Pyles
    •  & Yingzi Cong
  3. Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA

    • Feidi Chen
    •  & Yingzi Cong
  4. Department of Gastroenterology, The Shanghai Tenth People’s Hospital, Shanghai, China

    • Wei Wu
    • , Mingming Sun
    •  & Zhanju Liu
  5. Institute of Animal Nutrition, Sichuan Agricultural University, Ya'an, China

    • Yi Xiao
  6. Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA

    • George Golovko
    •  & Yuriy Fofanov
  7. Amgen Inc., South San Francisco, CA, USA

    • Warren D'Souza
  8. Bristol-Myers Squibb, Princeton, NJ, USA

    • Qihong Zhao

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The authors declared no conflict of interest.

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Correspondence to Yingzi Cong.

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https://doi.org/10.1038/mi.2017.118

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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.

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