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

Abstract

Abstract As a critical component in maintaining intestinal homeostasis, intestinal epithelial cells (IEC) are known to tune gut microbiota via antimicrobial peptides (AMP) production. In return, microbiota has been reported to regulate IEC expression of AMPs, including RegIIIg and certain defensins. The underlying mechanisms are, however, still not completely understood. The present study attempted to address the novel pathways by which gut microbiota regulates IEC expression of AMP as a way to contribute to intestinal homeostasis. We found that the mice with deficiency of GPR43, a receptor for short chain fatty acids (SCFA), the metabolites of gut microbiota, have lower expression of RegIIIg and b-defensins 1, 3, and 4 in IECs compared to that of WT mice. Oral feeding with SCFA promoted IEC production of both RegIIIg and defensins in mice. Moreover, ex-vivo culture of enteroid revealed that SCFA induction of IEC RegIIIg and b-defensins production is GPR43-dependent. Mechanistically, SCFA activated mTOR and STAT3 in IECs. Knockdown of either mTOR or STAT3 impaired SCFA-induced AMP production. Collectively, our data revealed that microbiota-derived SCFA promote IEC production of both RegIIIg and b-defensins, which is through GPR43 and mediated by mTOR and STAT3 pathways.