High-Resolution Exposomics and Metabolomics Reveals Specific Associations in Cholestatic Liver Diseases

• Type of Material: Article
• Authors: Douglas Walker, Emory University; Brian D Juran, Mayo Clinic; Angela C Cheung, The Ottawa Hospital; Erik M Schlicht, Mayo Clinic; Yongliang Liang, Emory University; Megan Niedzwiecki, Icahn School of Medicine at Mount Sinai; Nicholas F LaRusso, Mayo Clinic; Gregory J Gores, Mayo Clinic; Dean Jones, Emory University; Gary Miller, Emory University; Konstantinos N Lazaridis, Mayo Clinic
• Language: English
• Date: 2021-11-26
• Publisher: JOHN WILEY & SONS LTD
• Publication Version: Final Published Version
• Copyright Statement: © 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/hep4.1871
• Title of Journal or Parent Work: HEPATOLOGY COMMUNICATIONS
• Volume: 6
• Issue: 5
• Start Page: 965
• End Page: 979
• Grant/Funding Information: Supported by the National Institutes of Health (P30 ES023515, RC2 DK118619, and U2C ES030859), European Commission (874627), the Chris M. Carlos and Catharine N. Nicole Jockisch Carlos Foundation for Endowment Fund in Primary Sclerosing Cholangitis, and the Mayo Clinic.
• Keywords: CHEMICALS; Life Sciences & Biomedicine; COFFEE; Science & Technology; PRIMARY SCLEROSING CHOLANGITIS; Gastroenterology & Hepatology; ACID; NONYLPHENOL
• Research Categories: Environmental Sciences

Abstract

Progress in development of prognostic and therapeutic options for the rare cholestatic liver diseases, primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), is hampered by limited knowledge of their pathogeneses. In particular, the potential role of hepatotoxic and/or metabolism-altering environmental chemicals in the pathogenesis of these diseases remains relatively unstudied. Moreover, the extent to which metabolic pathways are altered due to ongoing cholestasis and subsequent liver damage or possibly influenced by hepatotoxic chemicals is poorly understood. In this study, we applied a comprehensive exposomics-metabolomics approach to uncover potential pathogenic contributors to PSC and PBC. We used untargeted high-resolution mass spectrometry to characterize a wide range of exogenous chemicals and endogenous metabolites in plasma and tested them for association with disease. Exposome-wide association studies (EWAS) identified environmental chemicals, including pesticides, additives and persistent pollutants, that were associated with PSC and/or PBC, suggesting potential roles for these compounds in disease pathogenesis. Metabolome-wide association studies (MWAS) found disease-associated alterations to amino acid, eicosanoid, lipid, co-factor, nucleotide, mitochondrial and microbial metabolic pathways, many of which were shared between PSC and PBC. Notably, this analysis implicates a potential role of the 5-lipoxygenase pathway in the pathogenesis of these diseases. Finally, EWAS × MWAS network analysis uncovered linkages between environmental agents and disrupted metabolic pathways that provide insight into potential mechanisms for PSC and PBC. Conclusion: This study establishes combined exposomics-metabolomics as a generalizable approach to identify potentially pathogenic environmental agents and enumerate metabolic alterations that may impact PSC and PBC, providing a foundation for diagnostic and therapeutic strategies.