OBJECTIVE To investigate the anti-hyperlipidemia effect of total flavonoids (TFA) from Folium Apocyni Veneti and to elucidate its regulatory role on gut microbiota composition and metabolic function.

METHODS An hyperlipidemia rat model was established by feeding the rats with a high-fat diet. Simvastatin (a positive control drug) and three doses of TFA were administered concurrently with model establishment. After the last administration, the rats were fasted and blood was collected from the abdominal aorta under anesthesia. Serum levels of triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), nitric oxide (NO), superoxide dismutase (SOD), and malondialdehyde (MDA) were measured in each group. Serum levels of angiotensin Ⅱ (Ang-Ⅱ) and vascular cell adhesion molecule-1 (VCAM-1) were measured by ELISA. Serum metabolite differences were analyzed using non-targeted metabolomics techniques, and changes in gut microbiota structure were detected by 16S rRNA sequencing. Correlation analysis was conducted between the pharmacological and pharmacodynamic indicators and the differentially expressed gut microbiota of TFA in lowering blood lipids and the differentially regulated metabolites by TFA to further explore the relationship between the metabolic pathways regulated by TFA and its pharmacodynamic effects and its role in regulating gut microbiota.

RESULTS TFA effectively reduced TG, TC, and LDL-C in the liver and serum, increased HDL-C, and significantly reduced serum LDL-C/HDL-C and the arteriosclerosis index (AI). Furthermore, TFA significantly increased serum NO and SOD levels and decreased Ang-II, VCAM-1, and MDA levels. Metabolomics analysis indicated that TFA improved serum metabolic disorders in model rats, mainly regulating pathways such as glycerophospholipid metabolism, pantothenic acid, and coenzyme A (CoA) biosynthesis. Gut microbiota analysis showed that TFA decreased the Firmicutes/Bacteroidetes (F/B) ratio and inhibited the abnormal proliferation of Proteobacteria and Actinobacteria.

CONCLUSION TFA can improve lipid metabolism disorders, enhance antioxidant capacity, inhibit free radical-induced lipid peroxidation, and has a certain protective effect on vascular endothelium in HLP rats. Its mechanism may be related to the regulation of metabolism and gut microbiota balance.