Eucommia bark contains many bioactive compounds and has anti-hyperlipidemic effects. However, due to the slow growth rate of the plant, there is a limited supply of this resource. Studies have demonstrated that Eucommia leaves contain active ingredients similar to those of Eucommia bark and also have anti-hyperlipidemic effects. It is not currently clear whether Eucommia leaf can be used as a substitute for Eucommia bark. Furthermore, their mechanism of action for anti-hyperlipidemia by improving the structure of the gut microbiota is also unclear. We aimed to determine the composition of the active ingredients in EBE and ELE by HPLC, establish an HFD-induced hyperlipidemia model, and combine fecal microbiota transplantation (FMT) experiments to investigate the mechanism of EBE/ELE anti-hyperlipidemia by modifying the structure of intestinal microbiota, as well as to compare the effects of EBE and ELE. Our results showed that EBE and ELE contained similar active ingredients and significantly alleviated lipid metabolism disorders and blood glucose levels in the HFD-induced hyperlipidemia model. In this study, EBE and ELE significantly reduced the relative abundance of Desulfovibrionaceae and Erysipelotrichaceae and significantly increased the relative abundance of Ruminococcaceae. They also promoted the production of short-chain fatty acids (SCFAs) and activated the gene expression of the SCFA receptors G protein-coupled receptor 41 (GPR41) and GPR43. In addition, EBE and ELE can significantly increase the expression of the fasting-induced adipose factor (Fiaf) gene in the colon and inhibit the secretion of lipoprotein lipase (LPL) in the liver, thereby inhibiting triglyceride (TG) synthesis. They also significantly activate the expression of GPR41 and GPR43 genes in the epididymal fat tissue, leading to reduced lipid accumulation in adipocytes. These effects on the target genes were associated with changes in the abundance of Desulfovibrionaceae, Erysipelotrichaceae, and Ruminococcaceae bacteria in the intestinal microbiota. Thus, regulating the relative abundance of these microbes may serve as prospective targets for EBE/ELE to influence the Fiaf-LPL gut-liver axis and the SCFAs-GPR41/GPR43 gut-fat axis. In addition, there was no significant difference in the anti-hyperlipidemic effects of ELE and EBE, suggesting that Eucommia leaf may be a suitable alternative to Eucommia bark for managing hyperlipidemia by regulating the structure of the intestinal microbiota. These findings suggest that Eucommia leaves have great potential for development as a functional food with lipid-lowering properties.

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