High-Resolution Exposomics and Metabolomics Reveals Specific Associations in Cholestatic Liver Diseases.
High-Resolution Exposomics and Metabolomics Reveals Specific Associations in Cholestatic Liver Diseases.
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DOI：
10.1002/hep4.1871
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发表时间：
2022-05
影响因子：
5.1
通讯作者：
Lazaridis, Konstantinos N.
中科院分区：
文献类型：
--
作者：
Walker, Douglas I.;Juran, Brian D.;Cheung, Angela C.;Schlicht, Erik M.;Liang, Yongliang;Niedzwiecki, Megan;LaRusso, Nicholas F.;Gores, Gregory J.;Jones, Dean P.;Miller, Gary W.;Lazaridis, Konstantinos N.
原发性硬化性胆管炎（PSC）和原发性胆道性胆管炎（PBC）这两种罕见的胆汁淤积性肝病的预后和治疗选择的进展，由于对其发病机制的了解有限而受到阻碍。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，代谢途径被改变的程度尚不清楚。在这项研究中，我们应用了一种综合的暴露组学-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表征血浆中广泛的外源性化学物质和内源性代谢物，并检测它们与疾病的关系。全暴露体关联研究（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，提示这些化合物在疾病发病机制中的潜在作用。全代谢组关联研究（MWAS）发现疾病相关的氨基酸、类二十烷酸、脂质、辅因子、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之间是共享的。值得注意的是，该分析暗示了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因子与中断代谢途径之间的联系，为PSC和PBC的潜在机制提供了见解。结论：本研究建立了暴露组学-代谢组学联合方法，作为一种通用的方法来识别潜在的致病环境因子，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基础。
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.
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影响因子：
16.6
作者：
Cordell HJ;Han Y;Mells GF;Li Y;Hirschfield GM;Greene CS;Xie G;Juran BD;Zhu D;Qian DC;Floyd JA;Morley KI;Prati D;Lleo A;Cusi D;Canadian-US PBC Consortium;Italian PBC Genetics Study Group;UK-PBC Consortium;Gershwin ME;Anderson CA;Lazaridis KN;Invernizzi P;Seldin MF;Sandford RN;Amos CI;Siminovitch KA
通讯作者：
Siminovitch KA
DOI：
10.1056/nejmra1506330
发表时间：
2016-09-22
期刊：
The New England journal of medicine
影响因子：
--
作者：
Lazaridis KN;LaRusso NF
通讯作者：
LaRusso NF
影响因子：
12.6
作者：
Lammert, Craig;Juran, Brian D.;Lazaridis, Konstantinos N.
通讯作者：
Lazaridis, Konstantinos N.
影响因子：
7.4
作者：
Broeckling, C. D.;Afsar, F. A.;Prenni, J. E.
通讯作者：
Prenni, J. E.
影响因子：
4.1
作者：
Gao, Bei;Chi, Liang;Lu, Kun
通讯作者：
Lu, Kun