The Polysaccharides from Balanophora harlandii Hook. Alleviated Alcoholic Steatohepatitis via Suppressing Bile Acid Synthesis Mediated by Intestinal FXR Activation.

Background: Disrupted bile acid homeostasis drives alcoholic steatohepatitis (ASH) progression, which has become a new therapeutic target for ASH. This study examined the impact and underlying mechanisms of polysaccharides from Balanophora harlandii Hook. (BHP) on bile acid synthesis and liver damage in ASH. Methods: A Binge-on-Chronic alcohol exposure model was established to assess the impact of BHP on alcohol-induced liver damage and bile acid (BA) metabolism. Fexaramine and glycine-β-MCA (Gly-MCA) were also utilized to explore a crucial role of intestinal FXR signaling activity in ASH mice. In vitro, intestinal epithelial cells were stimulated with alcohol to impair FXR activity. Results: BHP treatment mitigated weight loss, reduced hepatic lipid accumulation and inflammation in chronic alcohol-fed mice, demonstrating a significant hepatoprotective effect against ASH. Mechanistically, BHP treatment reduced intestinal conjugated BA levels and activated FXR-FGF15 signaling, which inhibited hepatic BA synthesis and mitigated the toxic effects of hepatic BA accumulation in ASH. However, the suppression of intestinal FXR activation notably diminished the ability of BHP to regulate BA synthesis and prevent liver damage in ASH mice. In vitro, BHP treatment also activated FXR signaling in intestinal epithelial cells, counteracting alcohol-induced FXR activity damage. Conclusions: BHP treatment effectively alleviated liver damage in mice with chronic alcohol exposure through reducing hepatic BA synthesis. The mechanisms behind the hepatoprotective effects of BHP suggested that correcting the shift in the intestinal BA profile and/or the intestinal FXR-FGF15 signaling are the potential therapies against alcoholic liver injury.