PDF(Pubmed)
Abstract：
Drug efflux transporters are a major determinant of drug efficacy and toxicity. A canonical example is P-glycoprotein (P-gp), an efflux transporter that controls the intestinal absorption of diverse compounds. Despite a rich literature on the dietary and pharmaceutical compounds that impact P-gp activity, its sensitivity to gut microbial metabolites remains an open question. Surprisingly, we found that the cardiac drug-metabolizing gut Actinobacterium Eggerthella lenta increases drug absorption in mice. Experiments in cell culture revealed that E. lenta produces a soluble factor that post-translationally inhibits P-gp ATPase efflux activity. P-gp inhibition is conserved in the Eggerthellaceae family but absent in other Actinobacteria. Comparative genomics identified genes associated with P-gp inhibition. Finally, activity-guided biochemical fractionation coupled to metabolomics implicated a group of small polar metabolites with P-gp inhibitory activity. These results highlight the importance of considering the broader relevance of the gut microbiome for drug disposition beyond first-pass metabolism.
摘要：
药物外排转运蛋白是药物疗效和毒性的主要决定因素。典型的例子是P-糖蛋白（P-gp），控制不同化合物的肠道吸收的外排转运蛋白。尽管有关影响P-gp活性的饮食和药物化合物的文献很多，它对肠道微生物代谢产物的敏感性仍然是一个悬而未决的问题。令人惊讶的是,我们发现心脏药物代谢的肠道放线菌能增加小鼠的药物吸收。细胞培养实验表明，E.lenta产生一种可溶性因子，该因子在翻译后抑制P-gpATPase外排活性。P-gp抑制在伊格雷科中保守，但在其他放线菌中却不存在。比较基因组学鉴定了与P-gp抑制相关的基因。最后,活性引导的生化分级与代谢组学相结合，涉及一组具有P-gp抑制活性的小极性代谢物。这些结果突出了考虑肠道微生物组对药物处置的更广泛相关性的重要性，而不是首过代谢。
