A drug-microbiome-drug interaction impacts co-prescribed medications for Parkinson's disease

  • Nat Microbiol. 2026 May;11(5):1387-1409. doi: 10.1038/s41564-026-02299-2.
Andrew A Verdegaal  1  2 ,  Joonseok Oh  3  4  5 ,  Bahar Javdan  6  7 ,  Ruojun Wang  6  8 ,  Qihao Wu  3  4  9 ,  Timothy R W Wang  1  2 ,  Jaime A González-Hernández  1  2 ,  Mohamed S Donia  6 ,  Jason M Crawford  3  4 ,  Andrew L Goodman  10  11
Affiliations
  • 1. Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT, USA.
  • 2. Microbial Sciences Institute, Yale University, West Haven, CT, USA.
  • 3. Department of Chemistry, Yale University, New Haven, CT, USA.
  • 4. Institute of Biomolecular Design and Discovery, Yale University, West Haven, CT, USA.
  • 5. Amgen, Cambridge, MA, USA.
  • 6. Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
  • 7. Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.
  • 8. Medpace, Dallas, TX, USA.
  • 9. Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
  • 10. Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT, USA. [email protected].
  • 11. Microbial Sciences Institute, Yale University, West Haven, CT, USA. [email protected].
PMID: 41942777 DOI: 10.1038/s41564-026-02299-2
Abstract

Simultaneous prescription of multiple drugs is widespread in medicine. Although the gut microbiome is implicated in drug responses, its role in mediating drug-drug interactions is unexplored. Catechol-O-methyltransferase inhibitors (COMT-I), a class of drugs used alongside levodopa (L-DOPA) to treat Parkinson's disease symptoms, can alter microbiome composition in patients. Here we characterize the Antibiotic properties of COMT-I drugs in vitro, ex vivo and in vivo and dissect how these interactions alter microbiome-mediated L-DOPA metabolism in vitro and ex vivo. Notably, in vitro iron availability determines COMT-I Antibiotic activity at multiple levels: extracellular iron can drive non-enzymatic inactivation of COMT-I, rescuing COMT-I-mediated Bacterial iron starvation responses. However, limitation of intracellular iron can protect sensitive bacteria from COMT-I Antibiotic activity. Co-administration of COMT-I and L-DOPA to human faecal microbial communities ex vivo results in COMT-I-dependent alterations to L-DOPA metabolism in an individual-specific manner. These studies highlight a role for the gut microbiome in mediating drug-drug interactions and identify microbial features that could predict individual responses to co-prescribed drugs.

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