Warner_2025_Alcohol.Clin.Exp.Res.(Hoboken)__

BACKGROUND: Alcohol-associated liver disease (ALD) is a significant global health concern, with limited effective treatments currently available. Targeting a specific pathway of polyunsaturated fatty acid (PUFA) metabolism, in which beneficial FA-derived compounds, known as epoxy fatty acids (EpFAs), are rapidly converted into less active or inactive metabolites by the enzyme, soluble epoxide hydrolase (s-EH), has shown promise in treating various pathological conditions. In this study, the s-EH inhibitor, t-TUCB, was tested for its efficacy in attenuating liver damage induced by chronic ethanol (EtOH) consumption in an animal model that mimics early-stage ALD in humans. METHODS: C57BL6/J male mice were fed an EtOH-containing diet with or without t-TUCB for 8 weeks. Liver steatosis, inflammation, and injury were evaluated. Fecal 16S rRNA sequencing was performed to examine the impact of s-EH inhibition on the gut microbiota composition. RESULTS: EtOH-induced liver injury was attenuated in t-TUCB-treated mice, with a notable decrease in endoplasmic reticulum stress, hepatocyte cell death, and proinflammatory cytokine expression. There was no effect of t-TUCB on EtOH-induced hepatic steatosis. t-TUCB treatment shifted the liver lipid profile, increasing several EpFAs, such as 17,18-EpETE and 19,20-EpDPA. These EpFAs decreased apoptosis and LPS-induced expression of proinflammatory cytokines in vitro. t-TUCB treatment significantly increased Akkermansia muciniphila, a species known for its beneficial properties, in control but not in EtOH-fed mice. The EtOH-induced increase in bacteria taxa previously associated with liver injury, including the Peptostreptococcaceae family and the species, Alistipes massieliensis, was reduced in t-TUCB-treated mice. CONCLUSIONS: Our data demonstrate the beneficial effects of t-TUCB treatment on chronic EtOH-induced liver injury and gut microbiota imbalances, in turn, promoting liver health. These findings suggest that pharmacologic s-EH inhibition may serve as a promising strategy for reducing liver injury in ALD.