Disrupted balance between pro-inflammatory lipid mediators and anti-inflammatory specialized pro-resolving mediators...

Chronic excessive alcohol consumption leads to a spectrum of alcohol-associated liver diseases (ALD), including alcoholic hepatitis (AH). 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 an actively regulated process, 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 rectifying the dysregulated biosynthesis of PLMs and SPMs in AH patients.

LC-MS/MS and ELISA were used to quantify levels of bioactive 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 various markers of inflammatory cascade andmicrobial translocation. Furthermore, we conducted a longitudinal study to track changes in levels of LMs over 6- and 12-month follow-ups in AH patients who underwent alcohol abstinence.

AH patients exhibited significantly higher plasma levels of ω-6 PLMs (PGD ₂ and LTB ₄ ) and SPM RvE1 compared to HDCs and/or HCs. Conversely, key SPMs such as LXA4, RvD1, and several precursors in the ω-3 pathway were significantly downregulated in AH patients. Some of these altered LMs were found to correlate with AH disease severity, clinical parameters, and various inflammatory cytokines. In particular, 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, suggesting its potential utility as an indicator of disease severity in AH patients. Importantly, the majority of dysregulated LMs, particularly PLMs, were normalized following alcohol abstinence.

Our study reveals significant dysregulation in the levels of PLM metabolites and anti-inflammatory SPMs in both ω-6 and ω-3 PUFA pathways in AH patients. This disrupted biosynthesis, characterized by an overabundance of PLMs and a deficiency in SPMs, is linked to the heightened inflammation observed in AH patients. Importantly, our findings suggest an important role of alcohol abstinence in restoring the balance of these LMs and the potential therapeutic benefits of SPM supplements in alleviating the inflammatory cascade in AH patients.