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

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 RegIII3 and certain defensins. However, the mechanisms involved are still not completely understood. In this report, we found that IEC expression levels of RegIII 3 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 RegIII 3 and defensins in mice. Furthermore, SCFA induced RegIII 3 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 RegIII 3 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.