Microbiota metabolites SCFA promote intestinal epithelial repair and wound healing through promoting epithelial cell production of milk fat globule-EGF factor 8

Abstract

Abstract The mechanisms by which gut microbiota regulate intestinal homeostasis are still largely unknown. The short chain fatty acids (SCFA), mainly acetate, propionate, and butyrate, are bacterial metabolites produced from the fermentation of dietary fibers, which have been shown to regulate intestinal homeostasis. In this study, we investigated whether SCFAs promote intestinal epithelial repair and wound healing through promoting epithelial cell production of milk fat globulin E8 (MFG-E8), a known molecule promoting wound healing and cell migration via actin reorganization. Treatment with SCFAs enhanced intestinal epithelial cell (IEC) migration significantly, and promoted wound healing in both mouse and rat IEC in vitro. We then investigated how SCFAs regulated IEC gene expression by microarray. Microarray analysis showed 401 genes differentially expressed upon stimulation with butyrate, of which 196 were upregulated and 205 were downregulated. Among upregulated genes, MFG-E8 has been shown in several systems to promote IEC proliferation and tissue repair. We confirmed MFG-E8 upregulation by qRT-PCR for mRNA and Western blot for protein. Interestingly, SCFAs also upregulated several genes pertinent to actin reorganization including RhoA, Rho GTPase, and PAK1 as well as genes known to effect proliferation such as cyclin D2 and PKCδ, which are down stream of MFG-E8 signaling. Our study thus demonstrated that SCFAs promote intestinal epithelial cell tissue repair, possibly through upregulation of MFG-E8.