{"doi":"10.1111/acer.70109","title":"Effects of soluble epoxide hydrolase inhibition on liver injury and gut microbiota in mice chronically fed ethanol","abstract":"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.","journal":"Alcohol Clinical and Experimental Research","year":2025,"id":532619,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9611,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":491642,"name":"Jeffrey Warner","orcid":"0000-0003-2022-7854","position":1,"is_corresponding":false},{"id":1414169,"name":"Yasmeen Abdelfadil","orcid":null,"position":2,"is_corresponding":false},{"id":491643,"name":"Josiah Hardesty","orcid":"0000-0003-1955-3046","position":3,"is_corresponding":false},{"id":1414170,"name":"Rui Treves","orcid":null,"position":4,"is_corresponding":false},{"id":295146,"name":"Chao Lei","orcid":"0000-0002-5220-086X","position":5,"is_corresponding":false},{"id":661296,"name":"Hannah E. Hanford","orcid":"0000-0003-4851-998X","position":6,"is_corresponding":false},{"id":295155,"name":"Craig J. McClain","orcid":"0000-0002-7219-8939","position":7,"is_corresponding":false},{"id":491645,"name":"Irina Kirpich","orcid":"0000-0002-9545-6451","position":8,"is_corresponding":false},{"id":491644,"name":"Dennis Warner","orcid":"0000-0002-5303-6870","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-19T02:51:23.237536Z","pmid":"40611388","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}