Naringin Alleviates Atherosclerosis in ApoE–/– Mice by Regulating Cholesterol Metabolism Involved in Gut Microbiota Remodeling

Naringin, a major flavonoid in citrus, has potential for preventing atherosclerosis. The presence in the colon of a large amount of naringin after oral intake might affect the gut microbiota. We investigated the role of gut microbiota remodeling in the alleviation of atherosclerosis by naringin. Naringin significantly alleviated atherosclerosis and lowered the serum and liver cholesterol levels by 24.04 and 28.37% in ApoE^-/- mice fed with a high-fat diet. Nontarget metabolomics showed that naringin modulated the hepatic levels of cholesterol derivatives and bile acids. Naringin increased the excretion of bile acids and neutral sterols by 1.6- and 4.3-fold, respectively. The main potential pathway by which naringin alleviated atherosclerosis was the gut microbiota-liver-cholesterol axis. Naringin modulated the abundances of bile salt hydrolase- and 7α-dehydroxylase-producing bacteria, promoting bile acid synthesis from cholesterol by upregulating CYP7A1 via suppression of the FXR/FGF15 pathway. In addition, naringin facilitated reverse cholesterol transport by downregulating PCSK9/IDOL. The results provide insight into the atherosclerosis-alleviation mechanisms of citrus flavonoids and a scientific basis for the development of functional foods containing citrus flavonoids.