Bioaccumulation of therapeutic drugs by human gut bacteria

Martina Klünemann, Sergej Andrejev, Sonja Blasche, Andre Mateus, Prasad Phapale, Saravanan Devendran, Johanna Vappiani, Bernd Simon, Timothy A. Scott, Eleni Kafkia, Dimitrios Konstantinidis, Katharina Zirngibl, Eleonora Mastrorilli, Manuel Banzhaf, Marie-Therese Mackmull, Felix Hövelmann, Leo Nesme, Ana Rita Brochado, Lisa Maier, Thomas Bock, Vinita Periwal, Manjeet Kumar, Yongkyu Kim, Melanie Tramontano, Carsten Schultz, Martin Beck, Janosch Hennig, Michael Zimmermann, Daniel C. Sévin, Filipe Cabreiro, Mikhail M. Savitski, Peer Bork (), Athanasios Typas () and Kiran R. Patil ()
Additional contact information
Martina Klünemann: European Molecular Biology Laboratory
Sergej Andrejev: European Molecular Biology Laboratory
Sonja Blasche: European Molecular Biology Laboratory
Andre Mateus: European Molecular Biology Laboratory
Prasad Phapale: European Molecular Biology Laboratory
Saravanan Devendran: European Molecular Biology Laboratory
Johanna Vappiani: Cellzome, GlaxoSmithKline R&D
Bernd Simon: European Molecular Biology Laboratory
Timothy A. Scott: University College London
Eleni Kafkia: Medical Research Council Toxicology Unit
Dimitrios Konstantinidis: European Molecular Biology Laboratory
Katharina Zirngibl: European Molecular Biology Laboratory
Eleonora Mastrorilli: European Molecular Biology Laboratory
Manuel Banzhaf: European Molecular Biology Laboratory
Marie-Therese Mackmull: European Molecular Biology Laboratory
Felix Hövelmann: European Molecular Biology Laboratory
Leo Nesme: European Molecular Biology Laboratory
Ana Rita Brochado: European Molecular Biology Laboratory
Lisa Maier: European Molecular Biology Laboratory
Thomas Bock: European Molecular Biology Laboratory
Vinita Periwal: European Molecular Biology Laboratory
Manjeet Kumar: European Molecular Biology Laboratory
Yongkyu Kim: European Molecular Biology Laboratory
Melanie Tramontano: European Molecular Biology Laboratory
Carsten Schultz: European Molecular Biology Laboratory
Martin Beck: European Molecular Biology Laboratory
Janosch Hennig: European Molecular Biology Laboratory
Michael Zimmermann: European Molecular Biology Laboratory
Daniel C. Sévin: Cellzome, GlaxoSmithKline R&D
Filipe Cabreiro: University College London
Mikhail M. Savitski: European Molecular Biology Laboratory
Peer Bork: European Molecular Biology Laboratory
Athanasios Typas: European Molecular Biology Laboratory
Kiran R. Patil: European Molecular Biology Laboratory

Nature, 2021, vol. 597, issue 7877, 533-538

Abstract: Abstract Bacteria in the gut can modulate the availability and efficacy of therapeutic drugs. However, the systematic mapping of the interactions between drugs and bacteria has only started recently1 and the main underlying mechanism proposed is the chemical transformation of drugs by microorganisms (biotransformation). Here we investigated the depletion of 15 structurally diverse drugs by 25 representative strains of gut bacteria. This revealed 70 bacteria–drug interactions, 29 of which had not to our knowledge been reported before. Over half of the new interactions can be ascribed to bioaccumulation; that is, bacteria storing the drug intracellularly without chemically modifying it, and in most cases without the growth of the bacteria being affected. As a case in point, we studied the molecular basis of bioaccumulation of the widely used antidepressant duloxetine by using click chemistry, thermal proteome profiling and metabolomics. We find that duloxetine binds to several metabolic enzymes and changes the metabolite secretion of the respective bacteria. When tested in a defined microbial community of accumulators and non-accumulators, duloxetine markedly altered the composition of the community through metabolic cross-feeding. We further validated our findings in an animal model, showing that bioaccumulating bacteria attenuate the behavioural response of Caenorhabditis elegans to duloxetine. Together, our results show that bioaccumulation by gut bacteria may be a common mechanism that alters drug availability and bacterial metabolism, with implications for microbiota composition, pharmacokinetics, side effects and drug responses, probably in an individual manner.

Date: 2021
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DOI: 10.1038/s41586-021-03891-8

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