Ergosterol and β-sitosterol exert cholesterol-lowering effects by enhancing gut microbiota-mediated cholesterol sulfonation and total bile acid excretion in mice

Ergosterol and β-sitosterol are dietary sterols with cholesterol-lowering effects. They lower cholesterol by regulating cholesterol absorption and metabolism in the intestine and liver. Due to the low intestinal absorption rate of ergosterol and β-sitosterol, gut microbiota may play a key role in their anti-hypercholesterolemic effects. However, the precise mechanisms by which ergosterol and β-sitosterol modulate cholesterol absorption and metabolism <i>via</i> gut microbiota remain unclear. This study aims to investigate the relationship between the cholesterol-lowering effect of ergosterol and β-sitosterol and their regulation of gut microbiota. The results indicated that ergosterol and β-sitosterol promoted the excretion of cholesterol and bile acids and inhibited intestinal cholesterol absorption in hypercholesterolemic mice. They increased the intestinal proportion of Firmicutes and <i>Clostridium</i> to inhibit small intestinal FXR activity and activate hepatic FXR activity, consequently regulating the expression of bile acid transporters. Moreover, ergosterol and β-sitosterol elevated the cholesterol sulfate levels in the large intestine, which was linked to an increased proportion of <i>Bacteroidia</i> in the gut. Further experiments using the intestinal pseudo-sterility model revealed that the aforementioned effects of ergosterol and β-sitosterol depend on the presence of intestinal microbiota. The findings of this study provide novel insights into the cholesterol-lowering mechanism of ergosterol and β-sitosterol: they enhance cholesterol sulfonation and total bile acid excretion mediated by gut microbiota.