Protective Effect of Palmitoleic Acid on Alcoholic Fatty Liver Injury in Mice: Insights from Gut Microbiota and Untargeted Metabolomics Analysis

Background: Alcoholic fatty liver disease (AFLD) represents an early, reversible stage within the spectrum of alcoholic liver disease. Palmitoleic acid (POA), classified as an ω-7 MUFA, has previously demonstrated hepatoprotective properties against non-alcoholic fatty liver disease, but the protective effect of it in AFLD and its impact on the intestinal flora and metabolites remain unclear. The research sought to elucidate the protective role of POA in AFLD in a murine model and corresponding mechanistic pathways. Methods: Thirty male Kunming mice were randomly distributed across five experimental cohorts: a healthy control group, an alcohol-exposed model group, and three POA-treated groups receiving daily different doses. With the exception of the control cohort, all animals underwent intragastric administration of 53% ethanol once daily. Multiple endpoints were evaluated, including hepatic function markers, lipid metabolic profiles, antioxidant capacity, liver histopathological features, colonic microbial composition, and intestinal metabolomic signatures. Results: Our findings revealed that POA supplementation markedly lowered hepatic and serum concentrations of ALT, AST, TBA, AKP, TBIL, TP, Alb, and MDA, while it concurrently returned HDL-C and TG levels, thereby effectively counteracting alcohol-triggered hepatic injury. Moreover, POA mitigated alcohol-associated gut microbial imbalance by decreasing Firmicutes/Bacteroidetes and remodeled the relative abundances of Turicibacter, Prevotellaceae UCG-001, Akkermansia and Bacteroides. Metabolomic profiling further demonstrated that POA normalized perturbed levels of Hispidol, Suberosin, Val-Trp-His, and N-acetylserine and influenced metabolic pathways related to digestion, lipid processing, and amino acid turnover. Correlation analyses validated robust interrelationships among key differential bacterial taxa, altered metabolites, and hepatic injury biomarkers in AFLD mice. Conclusions: In conclusion, POA exerts a protective effect against AFLD in mice, and this hepatoprotective effect is associated with the amelioration of gut dysbiosis and the restoration of intestinal metabolic profiles. These findings provide preliminary scientific evidence for the development of POA as a functional food ingredient for AFLD prevention and control.