Salidroside attenuates NASH through regulating bile acid-FXR/TGR5 signaling pathway via targeting gut microbiota.

Nonalcoholic steatohepatitis (NASH) is a significant threat to human health. Our previous study revealed that salidroside attenuated NASH and regulated the gut microbiota. However, whether the therapeutic effect of salidroside depends on gut microbiota remains to be determined. Therefore, we conducted further experiments to elucidate the essential functions of gut microbiota-associated metabolic pathways in the anti-NASH effects of salidroside. Our results showed that salidroside effectively alleviated lipid accumulation and inflammatory injury in NASH mice. 16S rRNA sequencing revealed that salidroside increased the abundance of Bacteroides. Mice receiving fecal microbiota transplantation (FMT) from salidroside-treated also presented less hepatic steatosis and higher abundance of Bacteroides. Antibiotics eliminated the effects of salidroside on hepatic steatosis and the gut microbiota. Mechanistically, salidroside and FMT from salidroside-treated altered the bile acid (BA) profile by decreasing the levels of conjugated BAs and tauro-α/β-muricholic acid and activated downstream farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Furthermore, we found that inhibitors of bile salt hydrolase (BSH) and FXR/TGR5 abolished the effects of salidroside and reduced downstream carnitine palmitoyltransferase 1α and lipoprotein lipase expression. These data demonstrate that salidroside attenuated NASH via gut microbiota-BA-FXR/TGR5 signaling pathway and reveal the underlying mechanism of salidroside on NASH.