Human gut Actinobacteria boost drug absorption by secreting P-glycoprotein ATPase inhibitors
Than S. Kyaw,
Chen Zhang,
Moriah Sandy,
Kai Trepka,
Shenwei Zhang,
Luis A. Ramirez Hernandez,
Lorenzo Ramirez,
Janice J.N. Goh,
Kristie Yu,
Vincent Dimassa,
Elizabeth N. Bess,
Jacob G. Brockert,
Darren S. Dumlao,
Jordan E. Bisanz,
Peter J. Turnbaugh
Affiliations
Than S. Kyaw
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA
Chen Zhang
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA
Moriah Sandy
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA; Quantitative Metabolite Analysis Center, Benioff Center for Microbiome Medicine, University of California San Francisco, San Francisco, CA 94143, USA
Kai Trepka
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA
Shenwei Zhang
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA
Luis A. Ramirez Hernandez
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA
Lorenzo Ramirez
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA
Janice J.N. Goh
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA
Kristie Yu
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA
Vincent Dimassa
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA
Elizabeth N. Bess
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA
Jacob G. Brockert
Quantitative Metabolite Analysis Center, Benioff Center for Microbiome Medicine, University of California San Francisco, San Francisco, CA 94143, USA
Darren S. Dumlao
Quantitative Metabolite Analysis Center, Benioff Center for Microbiome Medicine, University of California San Francisco, San Francisco, CA 94143, USA
Jordan E. Bisanz
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA; Corresponding author
Peter J. Turnbaugh
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143, USA; Chan-Zuckerberg Biohub-San Francisco, San Francisco, CA 94158, USA; Corresponding author
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 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.
