Department of Environmental Medicine and Public HealthIcahn School of Medicine at Mount SinaiNew YorkNYUSA.
Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA.
Hepatol Commun. 2022 May;6(5):965-979. doi: 10.1002/hep4.1871. Epub 2021 Nov 26.
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.
进展在发展预测和治疗选择罕见的胆汁淤积性肝病，原发性硬化性胆管炎（PSC）和原发性胆汁性胆管炎（PBC），受到其发病机制的有限知识的阻碍。特别是，肝毒性和/或改变代谢的环境化学物质在这些疾病发病机制中的潜在作用仍然相对未被研究。此外，由于持续的胆汁淤积和随后的肝损伤或可能受到肝毒性化学物质的影响，代谢途径改变的程度尚不清楚。在这项研究中，我们应用了综合暴露组学-代谢组学方法来揭示 PSC 和 PBC 的潜在致病因素。我们使用非靶向高分辨率质谱法来描述血浆中外源化学物质和内源性代谢物的广泛范围，并测试它们与疾病的关联。暴露组全关联研究（EWAS）确定了与 PSC 和/或 PBC 相关的环境化学物质，包括农药、添加剂和持久性污染物，表明这些化合物在疾病发病机制中可能具有潜在作用。代谢组全关联研究（MWAS）发现与疾病相关的氨基酸、类二十烷酸、脂质、辅酶、核苷酸、线粒体和微生物代谢途径的改变，其中许多在 PSC 和 PBC 之间共享。值得注意的是，这项分析暗示了 5-脂氧合酶途径在这些疾病发病机制中的潜在作用。最后，EWAS × MWAS 网络分析揭示了环境剂与破坏代谢途径之间的联系，为 PSC 和 PBC 的潜在机制提供了深入了解。结论：本研究确立了联合暴露组学-代谢组学作为一种可推广的方法来识别潜在的致病环境剂并列举可能影响 PSC 和 PBC 的代谢改变，为诊断和治疗策略提供了基础。
