%0 Journal Article
%T Human gut Actinobacteria boost drug absorption by secreting P-glycoprotein ATPase inhibitors.
%A Kyaw TS
%A Zhang C
%A Sandy M
%A Trepka K
%A Zhang S
%A Ramirez Hernandez LA
%A Ramirez L
%A Goh JJN
%A Yu K
%A Dimassa V
%A Bess EN
%A Brockert JG
%A Dumlao DS
%A Bisanz JE
%A Turnbaugh PJ
%J iScience
%V 27
%N 6
%D 2024 Jun 21
%M 38947502
%F 6.107
%R 10.1016/j.isci.2024.110122
%X 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.