Department of Microbiology and Physiological Systems; Program in Microbiome Dynamics; Graduate School of Nursing; Division of Gastroenterology, Department of Medicine
Amino Acids, Peptides, and Proteins | Digestive System Diseases | Gastroenterology | Microbiology
BACKGROUND: P-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.
RESULTS: We 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.
CONCLUSION: Overall, 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. Video abstract.
Endocannabinoid, Inflammation, Inflammatory bowel diseases, Intestinal epithelium, Microbiome, Multi-drug resistance transporter, P-glycoprotein, Secondary bile acids, Short-chain fatty acids, Ulcerative colitis
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DOI of Published Version
Foley SE, Tuohy C, Dunford M, Grey MJ, De Luca H, Cawley C, Szabady RL, Maldonado-Contreras A, Houghton JM, Ward DV, Mrsny RJ, McCormick BA. Gut microbiota regulation of P-glycoprotein in the intestinal epithelium in maintenance of homeostasis. Microbiome. 2021 Sep 7;9(1):183. doi: 10.1186/s40168-021-01137-3. PMID: 34493329; PMCID: PMC8425172. Link to article on publisher's site
Foley SE, Tuohy C, Dunford M, Grey MJ, De Luca H, Cawley C, Szabady RL, Maldonado-Contreras A, Houghton J, Ward DV, Mrsny RJ, McCormick BA. (2021). Gut microbiota regulation of P-glycoprotein in the intestinal epithelium in maintenance of homeostasis. Open Access Publications by UMass Chan Authors. https://doi.org/10.1186/s40168-021-01137-3. Retrieved from https://escholarship.umassmed.edu/oapubs/4917
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