Abstract
Glucuronidation is an important detoxification pathway that operates in balance with gastrointestinal microbial β-glucuronidase (GUS) activity, which can regenerate bioactive metabolites from their glucuronidated forms. How this host-microbe interaction shapes the distribution and pool of glucuronidated metabolites (i.e., the glucuronidome) remains poorly understood. In this study, we employed pattern-filtering data science approaches in conjunction with untargeted LC-MS/MS metabolomics to map the glucuronidome in urine, serum, and colon/fecal samples from gnotobiotic and conventional mice, and in humans. We find that microbial colonization and GUS activity compress the colonic glucuronidome and expand urinary glucuronidome diversity, revealing a compartmental redistribution of glucuronidated metabolites. Reverse metabolomics of known glucuronidated chemicals and glucuronidation pattern filtering searches in public metabolomics datasets exposed the diversity of glucuronidated metabolites in human and mouse ecosystems. In summary, we present a glucuronidation fingerprint resource that provides broader access to and analysis of the glucuronidome. Together, this work establishes a scalable analytical framework and provides mechanistic insight into how microbial activity reshapes systemic glucuronidation, with implications for drug metabolism, diet-microbe interactions, and biomarker discovery.
Acknowledgements
The coauthors acknowledge the Huck Institutes of the Life Sciences Metabolomics Core Facility (RRID:SCR_023864) and the Host Microbial Analytic and Repository Core (H-MARC) of the Center for Molecular Studies in Digestive and Liver Diseases (NIH P30DK050306). A.D.P. discloses support from National Institutes of Health (NIH) grant S10OD021750, NIH/National Institute of Environmental Sciences grant R35 ES035027, and the US Department of Agriculture National Institute of Food and Federal Appropriations under project PEN047702 and accession number 7006412. G.H.P. was supported by the National Institutes of Health Grants ES028244 and by the USDA National Institute of Food and Federal Appropriations under Project PEN04607 and Accession number 7000371. J.E.B. was supported by the NIH/National Institute of General Medical Sciences R35 GM151045. A.D.P., G.D.W., and M.R.R. were supported by the Helmsley Charitable Trust. N.R.B. was supported by NIH/National Institutes of Diabetes and Digestive Disease grant F31 DK134090 and the One Health Microbiome Center seed grant. M.R.R. was supported by NIH grants GM152079 and DK139249. H.M.-R., M.W. and P.C.D. are supported by NIH 5U24DK133658-02. M.S.K. was supported by NIH/ National Institute of Allergy and Infectious Disease F31 AI183815 and National Institute of Diabetes and Digestive Disease T32 DK120509. E.S.F., C.T., K.B. and J.P.Z. are supported by the Center for Microbial Medicine at the Children’s Hospital of Philadelphia. The Infant Growth and Microbiome Study (B.S.Z., G.D.W.) was supported by an unrestricted donation from the American Beverage Foundation for a Healthy America to the Children’s Hospital of Philadelphia to support the Healthy Weight Program, the Research Institute of the Children’s Hospital of Philadelphia, The PennCHOP Microbiome Program, the NIH National Center for Research Resources Clinical and Translational Science Program (grant no. UL1TR001878), the National Institute of Digestive Diseases and Disorders of the Kidney (grant no. R01DK107565). J.P.Z. was supported by the National Institutes of Health grant R35GM138369.
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P.C.D. is an advisor and holds equity in Cybele, Sirenas, and BileOmix, and he is a scientific co-founder, advisor, holds equity and/or receives income from Ometa, Enveda, and Arome with prior approval by UC San Diego. P.C.D. consulted for DSM Animal Health in 2023. M.R.R. is a founder of Symberix, Inc., and has received funding from Merck and Lilly. M.W. is a co-founder of Ometa Labs LLC. G.D.W. is a member of advisory boards for Danone, BioCodex, and the Institute for the Advancement of Food and Nutrition Sciences. He has also received research funding from Nestle. J.P.Z. has previously consulted for Vedanta Biosciences, Inc., and AstraZeneca. The remaining authors declare no competing interests.
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Boyle, N.R., Sekela, J.J., Wang, M. et al. Glucuronidation metabolomic fingerprinting to map host-microbe metabolism. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73398-1
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DOI: https://doi.org/10.1038/s41467-026-73398-1
