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- W4306174620 abstract "SUMMARY 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 reports that P-gp expression depends on the microbiome, the mechanisms responsible and their physiological relevance remain unclear. Surprisingly, we found that the cardiac drug-metabolizing gut Actinobacterium Eggerthella lenta increases drug absorption in mice through post-translational inhibition of 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 identified a cluster of isoflavonoids produced by E. lenta related to plant-derived P-gp inhibitors. These results highlight the unexpected overlap between diet- and microbiome-derived compounds, and the importance of considering the broader relevance of the gut microbiome for drug disposition beyond first-pass metabolism. One Sentence Summary The gut bacterium Eggerthella lenta secretes inhibitors of P-glycoprotein ATPase activity, accelerating drug absorption." @default.
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- W4306174620 date "2022-10-14" @default.
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- W4306174620 title "Human gut Actinobacteria boost drug absorption by secreting P-glycoprotein ATPase inhibitors" @default.
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- W4306174620 doi "https://doi.org/10.1101/2022.10.13.512142" @default.
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