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 BockVinita 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, Kiran R. Patil

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)533-538
Number of pages6
JournalNature
Volume597
Issue number7877
DOIs
StatePublished - Sep 23 2021

ASJC Scopus subject areas

  • General

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