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

Abstract

Ergosterol and β-sitosterol are dietary sterols with cholesterol-lowering effects. They lower cholesterol by regulating cholesterol absorption and metabolism in intestine and liver. As 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 via 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 Clostridium 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 contents, which was linked to an increased proportion of Bacteroidia 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 regulate gut microbiota-mediated bile acid metabolism and cholesterol sulfonation.