2. Academic Validation
  3. Activity of GPCR-targeted drugs influenced by human gut microbiota metabolism

Activity of GPCR-targeted drugs influenced by human gut microbiota metabolism

  • Nat Chem. 2025 Jun;17(6):808-821. doi: 10.1038/s41557-025-01789-w.
Qihao Wu # 1 2 3,  Deguang Song # 4,  Yanyu Zhao 1 2,  Andrew A Verdegaal 5 6,  Tayah Turocy 1 2,  Brianna Duncan-Lowey 4,  Andrew L Goodman 7 8,  Noah W Palm 9,  Jason M Crawford 10 11 12
Affiliations

Affiliations

  • 1 Department of Chemistry, Yale University, New Haven, CT, USA.
  • 2 Institute of Biomolecular Design and Discovery, Yale University, West Haven, CT, USA.
  • 3 Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
  • 4 Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
  • 5 Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA.
  • 6 Microbial Sciences Institute, Yale University, West Haven, CT, USA.
  • 7 Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA. andrew.goodman@yale.edu.
  • 8 Microbial Sciences Institute, Yale University, West Haven, CT, USA. andrew.goodman@yale.edu.
  • 9 Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. noah.palm@yale.edu.
  • 10 Department of Chemistry, Yale University, New Haven, CT, USA. jason.crawford@yale.edu.
  • 11 Institute of Biomolecular Design and Discovery, Yale University, West Haven, CT, USA. jason.crawford@yale.edu.
  • 12 Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA. jason.crawford@yale.edu.
  • # Contributed equally.
PMID: 40181149 DOI: 10.1038/s41557-025-01789-w
Abstract

Microbiota-mediated drug metabolism can affect pharmacological efficacy. Here we conducted a systematic comparative metabolomics investigation of drug metabolism modes by evaluating the impacts of human gut commensal bacteria on 127 G-protein-coupled receptor (GPCR)-targeted drugs. For the most extensively metabolized drugs in our screen, we elucidated both conventional and unconventional drug transformations and the corresponding activities of generated metabolites. Comparisons of drug metabolism by a gut microbial community versus individual species revealed both taxon intrinsic and collaborative processes that influenced the activity of the metabolized drugs against target GPCRs. We also observed iloperidone inactivation by generating unconventional metabolites. The human gut commensal bacteria mixture incorporated sulfur in the form of a thiophene motif, whereas Morganella morganii used a cascade reaction to incorporate amino-acid-derived tricyclic systems into the drug metabolites. Our results reveal a broad impact of human gut commensal bacteria on GPCR-targeted drug structures and activities through diverse microbiota-mediated biotransformations.

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