Study on Hypoglycemic and Lipid-lowering Effects of Flavanone Extracts from Quzhou Fructus Aurantii Based on “Gut Microbiota-Bile Acid Metabolism”

OBJECTIVE  To explore the hypoglycemic and lipid-lowering mechanisms of Quzhou Fructus Aurantii(QFA) flavanone extract and its primary monomer, neohesperidin, based on gut microbiota and bile acid metabolism.

METHODS C57BL/6 mice were randomly divided into 7 groups including control group, model group, metformin positive drug group(200 mg·kg⁻¹·d⁻¹), orlistat positive drug group(15.6 mg·kg⁻¹·d⁻¹), QFA group(300 mg·kg⁻¹·d⁻¹), low-dose neohesperidin group(50 mg·kg⁻¹·d⁻¹), and high-dose neohesperidin group(100 mg·kg⁻¹·d⁻¹). The control group was given regular chow and saline via gavage, while the model group received a high-fat diet(HFD) and saline via gavage. All other groups were given HFD and the corresponding drugs by gavage once daily for 13 weeks. Body weight was recorded weekly, and fasting blood glucose was measured in weeks 8 and 9, with OGTT and ITT tests performed in weeks 10 and 11, respectively. At the end of the experiment, liver and fat samples were collected and weighed. Histopathological changes in liver tissues were observed using HE and Oil Red O staining. Bile acid components in the serum, liver, and feces were measured by LC-MS/MS, and changes in gut microbiota were analyzed using 16S rRNA gene sequencing.

RESULTS  QFA flavanone extract and neohesperidin significantly reduced abdominal fat accumulation, decreased body weight, alleviated lipid droplet accumulation and adipocyte hypertrophy in the liver induced by an HFD, lowered fasting blood glucose, and improved glucose tolerance. Metabolomics analysis of bile acids showed that QFA flavanone extract significantly reduced serum taurochenodeoxycholic acid(P<0.05) and fecal α-muricholic acid and β-muricholic acid(P<0.05) levels. High-dose neohesperidin significantly reduced the level of hepatic tauro-β-muricholic acid(P<0.01) and increased the level of hepatic ursodeoxycholic acid(P<0.05). Additionally, both QFA extract and high-dose neohesperidin modulated HFD-induced gut microbiota dysbiosis, significantly increased the relative abundance of the probiotic Akkermansia_muciniphila(P<0.05) and decreased the relative abundance of the pathogenic bacterium Romboutsia_ilealis(P<0.01).

CONCLUSION  QFA extract rich in flavanones as well as neohesperidin exhibit promising hypoglycemic and lipid-lowering effects, potentially by regulating gut microbiota and bile acid metabolism to improve disorders of glucose and lipid metabolism.