Human gut Actinobacteria boost drug absorption by secreting P-glycoprotein ATPase inhibitors

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 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 ActinobacteriumEggerthella lentaincreases drug absorption in mice through post-translational inhibition of P-gp ATPase efflux activity. P-gp inhibition is conserved in theEggerthellaceaefamily 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 byE. lentarelated 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.

Challenges and opportunities of strain diversity in gut microbiome research

“…Random Forest classifier/regression models are particularly adept at this task as they have straight forward metrics for each feature's importance/predictive value and they generally consider combinations of explanatory variables in their decision trees (Chen and Ishwaran, 2012). Indeed, we have used variants of this approach across multiple manuscripts (Koppel et al, 2018;Maini Rekdal et al, 2019Bess et al, 2020;Pröbstel et al, 2020;Alexander et al, 2022;Kyaw et al, 2022;Noecker et al, 2022;Paik et al, 2022). These comparative genomics approaches are attractive because phenotypes can be screened at a relatively low-throughput scale and they bypass the need for genetic tools.…”