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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Inflammation
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1377236

Disrupted balance between pro-inflammatory lipid mediators and antiinflammatory specialized pro-resolving mediators is linked to hyperinflammation in patients with alcoholic hepatitis

Provisionally accepted
Wei Li Wei Li 1Ying Xia Ying Xia 2Jing Yang Jing Yang 3Arun Sanyal Arun Sanyal 4Vijay Shah Vijay Shah 5Naga P. Chalasani Naga P. Chalasani 6Qigui Yu Qigui Yu 1*
  • 1 Department of Microbiology and Immunology, School of Medicine, Indiana University Bloomington, Indianapolis, Indiana, United States
  • 2 Indiana Alzheimer Disease Center, School of Medicine, Indiana University Bloomington, Indianapolis, Indiana, United States
  • 3 School of Medicine, Indiana University Bloomington, Indianapolis, Indiana, United States
  • 4 Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, California, United States
  • 5 Gastroenterology Research Unit, Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Michigan, United States
  • 6 Division of Gastroenterology and Hepatology, Department of Medicine, School of Medicine, Indiana University Bloomington, Indianapolis, Indiana, United States

The final, formatted version of the article will be published soon.

    Alcoholic hepatitis (AH) is characterized by intense systemic and liver inflammation, posing significant risks of health complications and mortality. While inflammation is a crucial defense mechanism against injury and infection, its timely resolution is essential to prevent tissue damage and restore tissue homeostasis. The resolution of inflammation is primarily governed by specialized pro-resolving mediators (SPMs), lipid metabolites derived from ω-6 and ω-3 poly-unsaturated fatty acids (PUFAs). We investigated the balance between pro-inflammatory lipid mediators (PLMs) and SPMs in the ω-6 and ω-3 PUFA metabolic pathways and examined the impact of alcohol abstinence on profiles of PLMs and SPMs in AH patients. We used LC-MS/MS and ELISA to quantify levels of lipid mediators (LMs) and their precursors in the plasma samples from 58 AH patients, 29 heavy drinkers without overt liver diseases (HDCs), and 35 healthy controls (HCs). Subsequently, we assessed correlations of altered LMs with clinical parameters and inflammatory mediators. Furthermore, we conducted a longitudinal study to analyze the effects of alcohol abstinence on LMs over 6- and 12-month follow-ups. We found that AH patients exhibited significantly higher plasma levels of ω-6 PLMs (PGD2 and LTB4) and SPM RvE1 compared to HDCs or HCs. Conversely, the SPM LXA4 was significantly downregulated in AH patients. Some of these altered LMs were found to correlate with AH disease severity and various inflammatory cytokines. Particularly, the LTB4/LXA4 ratio was substantially elevated in AH patients relative to HDCs and HCs. This altered ratio displayed a positive correlation with the MELD score. Importantly, the majority of dysregulated LMs, particularly PLMs, were normalized following alcohol abstinence. Thus, imbalanced pro-resolving and inflammatory LMs are linked to hyperinflammation in AH patients.

    Keywords: Alcoholic hepatitis, specialized pro-resolving mediator, lipid mediator, longitudinal study, Alcohol Abstinence

    Received: 27 Jan 2024; Accepted: 31 Oct 2024.

    Copyright: © 2024 Li, Xia, Yang, Sanyal, Shah, Chalasani and Yu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Qigui Yu, Department of Microbiology and Immunology, School of Medicine, Indiana University Bloomington, Indianapolis, 46202, Indiana, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.