Hepatoprotective potential of four fruit extracts rich in different structural flavonoids against alcohol-induced liver injury via gut microbiota-liver axis

Alcoholic liver injury (ALI) accounts for a major share of the global burden of non-viral liver disease. In the absence of specialized medications, research on using fruit flavonoids as a treatment is gaining momentum. This study investigated the hepatoprotective effects of four fruits rich in structurally diverse flavonoids: ougan (Citrus reticulata cv. Suavissima, OG), mulberry (Morus alba L., MB), apple (Malus × domestica Borkh., AP), and turnjujube (Hovenia dulcis Thunnb., TJ). A total of one flavanone glycoside, three polymethoxyflavones, two anthocyanins, one flavonol glycoside, and one dihydroflavonol were identified through UPLC analysis. In an acute ethanol-induced ALI mouse model, C57BL/6J mice were supplemented with 200 mg/kg·BW/day of different fruit extracts for three weeks. Our results showed that the four extracts exhibited promising benefits in improving lipid metabolism disorders, iron overload, and oxidative stress. RT-PCR and Western blot tests suggested that the potential mechanism may partially be attributed to the activation of the NRF2-mediated antioxidant response and the inhibition of ferroptosis pathways. Furthermore, fruit extracts administration demonstrated a specific regulatory role in intestinal microecology, with increases in beneficial bacteria such as Dubosiella, Lactobacillus, and Bifidobacterium. Spearman correlation analysis revealed strong links between intestinal flora, lipid metabolism, and iron homeostasis, implying that the fruit extracts mitigated ALI via the gut microbiota-liver axis. In vitro experiments reaffirmed the activity against ethanol-induced oxidative damage and highlighted the positive effects of flavonoid components. These findings endorse the prospective application of OG, MB, AP, and TJ as dietary supplements or novel treatments for ALI.