Microbial Metabolites Orchestrate a Distinct Multi-Tiered Regulatory Network in the Intestinal Epithelium That Directs P-Glycoprotein Expression
Sage E. Foley, Michael J. Dente, Xuqiu Lei, Benjamin F. Sallis, Ethan B Loew, Mario Meza-Segura, Katherine A. Fitzgerald, Beth A. McCormick
Abstract
Preventing aberrant inflammation is essential to maintaining homeostasis in the mammalian intestine. Although P-glycoprotein (P-gp) expression in the intestine is critical for protecting the intestinal epithelium from toxins and damage due to neutrophil infiltration, its regulation in the intestine is poorly understood. Findings presented in our current study have now uncovered a sophisticated and heretofore unappreciated intracellular signaling network or "reactome" directed by intestinal microbial metabolites that orchestrate regulation of P-gp. Not only do we confirm the role of histone deacetylases (HDAC) inhibition and nuclear receptor activation in P-gp induction by butyrate and bile acids, but we also discovered new signaling pathways and transcription factors that are uniquely activated in response to the combination of microbial metabolites. Such findings shed new light into a multi-tiered network that maintains P-gp expression in the intestine in the context of the fluctuating commensal microbiome, to sustain a homeostatic tone in the absence of infection or insult.