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

• Published in: Mucosal immunology Vol. 11; no. 3; pp. 752 - 762
• Main Authors: Zhao, Ye, Chen, Feidi, Wu, Wei, Sun, Mingming, Bilotta, Anthony J, Yao, Suxia, Xiao, Yi, Huang, Xiangsheng, Eaves-Pyles, Tonyia D, Golovko, George, Fofanov, Yuriy, D'Souza, Warren, Zhao, Qihong, Liu, Zhanju, Cong, Yingzi
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2018; Elsevier Limited
• Subjects: Allergology; Animals; Anti-Infective Agents - metabolism; Antibodies; Antimicrobial agents; Antimicrobial peptides; beta-Defensins - genetics; beta-Defensins - metabolism; Biomedical and Life Sciences; Biomedicine; Cell activation; Defensins; Epithelial cells; Fatty acids; Fatty Acids, Volatile - metabolism; Gastroenterology; Gastrointestinal Microbiome - physiology; Homeostasis; Immunity, Innate; Immunology; Intestinal microflora; Intestinal Mucosa - physiology; Intestine; Metabolites; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiota; Pancreatitis-Associated Proteins - genetics; Pancreatitis-Associated Proteins - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Stat3 protein; STAT3 Transcription Factor - metabolism; TOR protein; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1933-0219; 1935-3456
• DOI: 10.1038/mi.2017.118

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.