[Elucidating mechanism of Biejia-Ruangan Compound Tablets against alcoholic liver disease through gut-liver axis...

Based on the gut-liver axis, this study integrated multi-omics and network pharmacology strategies to explore the mechanism of Biejia-Ruangan Compound Tablets(BRC), a preferred Chinese patent medicine for anti-hepatic fibrosis, in alleviating alcoholic liver disease(ALD). The Lieber-DeCarli ethanol liquid diet was used to establish the ALD model, and the pharmacodynamic effects of BRC were evaluated. Non-targeted metabolomics and network pharmacology were employed to screen key metabolites and pathways, while multiple technical methods such as immunohistochemistry were used to verify key molecules in the gut-liver axis. The results showed that BRC significantly improved liver morphology and pathological damage in mice, reduced organ indices, and decreased serum levels of aspartate aminotransferase(AST) and alanine aminotransferase(ALT). BRC also alleviated hepatocellular steatosis, inflammatory infiltration, and fibrosis, and reduced the levels of reactive oxygen species(ROS) and partially restored superoxide dismutase(SOD) activity. Metabolomic analysis indicated that BRC could significantly reverse the disordered metabolic profiles of the intestine and liver, and increase the level of the differential metabolite prostaglandin E_2(PGE_2), which may be closely related to the adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK) signaling pathway. Compared with the model group, BRC effectively upregulated the expression of prostaglandin G/H synthase-2(COX-2) in the small intestine, inhibited the levels of inflammatory factors such as lipopolysaccharide(LPS), tumor necrosis factor-α(TNF-α), and interleukin-1β(IL-1β) in the liver, and promoted the expression of phosphorylated AMP-activated protein kinase catalytic subunit α2(p-AMPKα2), forkhead box protein O1(FOXO1), and peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α) in the liver, as well as the activity of cytoplasmic phosphoenolpyruvate carboxykinase 1(PCK1). In conclusion, BRC may alleviate ALD by alleviating hepatic inflammation, oxidative stress, and metabolic disorders through the gut-liver axis via the COX-2/AMPK/FOXO1/PGC-1α/PCK1 signaling pathway. This study provides a scientific basis and new insights for the clinical application of BRC and the prevention and treatment of ALD with TCM.