Gut microbiota regulation of P-glycoprotein in the intestinal epithelium in maintenance of homeostasis.
Gut microbiota regulation of P-glycoprotein in the intestinal epithelium in maintenance of homeostasis.
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DOI：
10.1186/s40168-021-01137-3
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发表时间：
2021-09-07
期刊：
影响因子：
15.5
通讯作者：
McCormick BA
中科院分区：
文献类型：
--
作者：
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
P-糖蛋白（P-gp）通过介导药物/外源性物质从肠粘膜流出进入肠腔而在保护肠上皮中起关键作用。最近的研究表明，P-gp在肠粘膜屏障功能和先天免疫系统之间的沟通中也起着关键作用。然而，尽管10多年来人们都知道P-gp在胃肠道内稳态中起着重要作用，但控制其功能表达和调节的精确分子机制仍不清楚。在这里，我们评估了肠道微生物组如何驱动P-gp表达和功能。我们已经确定了肠肠道群落的“功能核心”微生物组，特别是梭菌和芽孢杆菌类中的属，其对于小鼠模型中肠上皮中的P-gp诱导是必要且充分的。该核心微生物群落的宏基因组学分析显示，短链脂肪酸和次级胆汁酸的产生与P-gp表达呈正相关。我们进一步表明，这两类微生物衍生的代谢产物在体外和体内协同上调P-gp表达和功能。此外，在患有溃疡性结肠炎（UC）的患者中，我们发现P-gp表达减少与上皮来源的抗炎内源性大麻素和管腔内容物（例如，微生物或其代谢物）诱导P-gp表达的能力降低。总体而言，通过体外和体内研究以及人类受试者样本分析，我们确定了复杂微生物群落的合作功能输出与P-gp（一种上皮成分）的调节之间的机制联系，P-gp的功能是抑制过度活跃的炎症以维持肠道稳态。因此，我们的数据支持在粘膜炎症的微生物组调节中的新的串扰范例。 视频摘要在线版本包含补充材料，可在10. 1186/s40168-021-01137-3。
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. 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. 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 The online version contains supplementary material available at 10.1186/s40168-021-01137-3.
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影响因子：
30.3
作者：
Kelly CJ;Zheng L;Campbell EL;Saeedi B;Scholz CC;Bayless AJ;Wilson KE;Glover LE;Kominsky DJ;Magnuson A;Weir TL;Ehrentraut SF;Pickel C;Kuhn KA;Lanis JM;Nguyen V;Taylor CT;Colgan SP
通讯作者：
Colgan SP
影响因子：
30.3
作者：
Jacobson A;Lam L;Rajendram M;Tamburini F;Honeycutt J;Pham T;Van Treuren W;Pruss K;Stabler SR;Lugo K;Bouley DM;Vilches-Moure JG;Smith M;Sonnenburg JL;Bhatt AS;Huang KC;Monack D
通讯作者：
Monack D
一类重要的微生物胆汁酸的生物合成途径。
影响因子：
14.8
作者：
Devlin AS;Fischbach MA
通讯作者：
Fischbach MA
影响因子：
16.6
作者：
Haberman, Yael;Karns, Rebekah;Denson, Lee A.
通讯作者：
Denson, Lee A.
影响因子：
5.3
作者：
Jin, SK;Scotto, KW
通讯作者：
Scotto, KW