{Reference Type}: Journal Article
{Title}: Human gut Actinobacteria boost drug absorption by secreting P-glycoprotein ATPase inhibitors.
{Author}: Kyaw TS;Zhang C;Sandy M;Trepka K;Zhang S;Ramirez Hernandez LA;Ramirez L;Goh JJN;Yu K;Dimassa V;Bess EN;Brockert JG;Dumlao DS;Bisanz JE;Turnbaugh PJ;
{Journal}: iScience
{Volume}: 27
{Issue}: 6
{Year}: 2024 Jun 21
{Factor}: 6.107
{DOI}: 10.1016/j.isci.2024.110122
{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.