Fucoidan ameliorates alcoholic liver fibrosis through modulation of the gut-bile acid-liver metabolic axis

The protective effects of fucoidan on alcohol- and carbon tetrachloride-induced liver fibrosis and its potential mechanism were investigated in a mouse model, with a fucus on the gut-bile acid-liver metabolic axis. Fucoidan treatment significantly reduced collagen deposition and downregulated the expression of α-smooth muscle actin (α-SMA) and type III collagen (ColIII). Bile acid profiling demonstrated that fucoidan decreased total bile acids (TBA) levels in both serum and feces, with particularly marked reductions in deoxycholic acid (DCA) and muricholic acid (MCA). Conversely, fucoidan increased the level of taurodeoxycholic acid (TDCA). This treatment restored the metabolic imbalance of bile acids (BAs) caused by alcohol, thereby suppressing YAP-mediated hepatic stellate cells (HSCs) activation and associated inflammation. Mechanistically, fucoidan downregulated G protein-coupled bile acid receptor 1 (TGR5) and its downstream signaling, while also reducing farnesoid X receptor (FXR) expression and modulating the FXR/FGF15/CYP7A1 signaling to improve bile acid metabolism. Additionally, fucoidan alleviated alcohol-induced gut dysbiosis, as evidenced by increased abundance of Alloprevotella and decreased abundance of Lactobacillus . Importantly, when combined with cholestyramine, the protective effect of fucoidan on liver fibrosis significantly weakened. This confirmed that fucoidan exerted its inhibitory effect on the activation of HSCs by regulating the metabolic homeostasis of bile acids. Overall, fucoidan protects against alcoholic liver fibrosis by modulating the gut-bile acid-liver axis and inhibiting HSCs activation through the TGR5/SRC/YAP and FXR/FGF15/CYP7A1 signaling pathways.