Gut microbiota regulation of P-glycoprotein in the intestinal epithelium in maintenance of homeostasis

Microbiome

Rose L. Szabady¹  Christine Tuohy²  Ana Maldonado-Contreras³  Sage E. Foley³  Beth A. McCormick³  Doyle V. Ward³  Caitlin Cawley³  Merran Dunford⁴  Randall J. Mrsny⁴  Michael J. Grey⁵  Heidi De Luca⁵  Jean Marie Houghton⁶ 

[1] Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 01605, Worcester, MA, USA;Ferring Pharmaceuticals, 92121, San Diego, CA, USA;Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 01605, Worcester, MA, USA;Graduate School of Nursing, University of Massachusetts Medical School, 01605, Worcester, MA, USA;Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, 01605, Worcester, MA, USA;Program in Microbiome Dynamics, University of Massachusetts Medical School, 01605, Worcester, MA, USA;Department of Pharmacy and Pharmacology, University of Bath, BA2 7AY, Bath, UK;Division of Gastroenterology and Nutrition, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, 02115, Boston, MA, USA;Division of Gastroenterology, Department of Medicine, University of Massachusetts Medical School, 01605, Worcester, MA, USA;

关键词: P-glycoprotein;    Multi-drug resistance transporter;    Endocannabinoid;    Inflammatory bowel diseases;    Ulcerative colitis;    Inflammation;    Intestinal epithelium;    Short-chain fatty acids;    Secondary bile acids;    Microbiome;   

DOI  :  10.1186/s40168-021-01137-3

来源: Springer

【 摘 要 】

BackgroundP-glycoprotein (P-gp) plays a critical role in protection of the intestinal epithelia by mediating efflux of drugs/xenobiotics from the intestinal mucosa into the gut lumen. Recent studies bring to light that P-gp also confers a critical link in communication between intestinal mucosal barrier function and the innate immune system. Yet, despite knowledge for over 10 years that P-gp plays a central role in gastrointestinal homeostasis, the precise molecular mechanism that controls its functional expression and regulation remains unclear. Here, we assessed how the intestinal microbiome drives P-gp expression and function.ResultsWe have identified a “functional core” microbiome of the intestinal gut community, specifically genera within the Clostridia and Bacilli classes, that is necessary and sufficient for P-gp induction in the intestinal epithelium in mouse models. Metagenomic analysis of this core microbial community revealed that short-chain fatty acid and secondary bile acid production positively associate with P-gp expression. We have further shown these two classes of microbiota-derived metabolites synergistically upregulate P-gp expression and function in vitro and in vivo. Moreover, in patients suffering from ulcerative colitis (UC), we find diminished P-gp expression coupled to the reduction of epithelial-derived anti-inflammatory endocannabinoids and luminal content (e.g., microbes or their metabolites) with a reduced capability to induce P-gp expression.ConclusionOverall, by means of both in vitro and in vivo studies as well as human subject sample analysis, we identify a mechanistic link between cooperative functional outputs of the complex microbial community and modulation of P-gp, an epithelial component, that functions to suppress overactive inflammation to maintain intestinal homeostasis. Hence, our data support a new cross-talk paradigm in microbiome regulation of mucosal inflammation.E5eiP3AkGcyQ2ZEhk_J1qbVideo abstract

【 授权许可】

CC BY