Abstract
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
Highlights
The human intestine is home to a continuous balancing act between the host immune response, a large community of resident bacteria, and a single-cell epithelial layer that functions to maintain a barrier between them
We previously discovered two ATP-binding cassette (ABC) transporter systems, multi-drug resistance protein 2 (MRP2) and Pglycoprotein (P-gp), that act in opposition at the epithelial surface to maintain intestinal homeostasis through regulation of neutrophil migration [1, 2]
This study provides a mechanistic link between metabolites produced by the healthy intestinal microbiome and suppression of neutrophil migration in ulcerative colitis (UC), via induction of functional protein (MRP2) and Pglycoprotein (P-gp) expression
Summary
The human intestine is home to a continuous balancing act between the host immune response, a large community of resident bacteria, and a single-cell epithelial layer that functions to maintain a barrier between them. Disruptions in this fine balance can lead to chronic and acute intestinal inflammation, which is a significant cause of morbidity and mortality worldwide. P-gpmediated epithelial export of N-acyl ethanolamine-type (NAE) endocannabinoids (eCB) suppresses this neutrophil transepithelial migration through eCB engagement with the neutrophilic cannabinoid receptor 2 (CB2) [2] These ABC transporters and their endogenous substrates play an underappreciated yet fundamental role in balancing immune-modulation at the intestinal mucosal surface. We assessed how the intestinal microbiome drives P-gp expression and function
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