Vinegar polyphenol extract alleviates alcohol-induced liver injury through suppressing the hepatic MAPK signaling pathway and restoring gut microbiota homeostasis and short-chain fatty acid generation in male mice.

Traditional brewed vinegar is rich in polyphenolic compounds that exhibit antioxidant, anti-inflammatory, and hepatoprotective activities. However, the protective mechanisms of vinegar polyphenol extract (VE) against alcohol-associated liver disease (ALD) involving gut homeostasis remain unclear. The phenolic composition of VE was characterized using UPLC-QTrap-MS/MS. Its hepatoprotective mechanisms in alcohol-treated mice were investigated through hepatic transcriptomic profiling and identification of key signaling pathways. Additionally, whether the hepatoprotective effects of VE were dependent on the gut microbiota were explored via antibiotic-mediated microbiota depletion and fecal microbiota transplantation. Twenty phenolic compounds were identified in VE, and 4-hydroxybenzoic acid was the predominant component accounting for 46.67%. VE administration at 750 mg kg-1 significantly reduced serum ALT and AST levels, attenuated hepatic oxidative stress and inflammation, and suppressed alcohol-induced phosphorylation of p38, JNK, and ERK1/2. Meanwhile, VE restored the integrity of the intestinal barrier and reduced the LPS burden. Moreover, VE remodeled the gut microbiota by upregulating Akkermansia and Bacteroides and reducing Escherichia, which was accompanied by restoration of SCFA generation, notably acetic acid and propionic acid. Microbiota depletion weakened the protective effects of VE, whereas fecal microbiota transplantation restored its hepatoprotective activity. These findings suggest that VE alleviates alcohol-associated liver disease by suppressing the hepatic MAPK signaling pathway and restoring intestinal homeostasis. VE is a promising food-derived functional ingredient for the prevention of ALD.