Paeoniflorin improves atherosclerosis by regulating the gut microbiota and fecal metabolites

Atherosclerosis (AS) is a chronic inflammatory disease and a key factor in cardiovascular disease. Paeoniflorin (PF), a monomer component extracted from red and white paeony roots, has been used for the prevention and treatment of cardiovascular diseases, but the specific mechanism remains unclear. ApoE^-/- mice fed a high-fat diet were randomly divided into a model group, a PF treatment group, a positive control group, and a control group fed a non-high-fat diet. The mice in the PF group were treated with 100 mg/kg (PF-100), 50 mg/kg (PF-50), and 25 mg/kg (PF-25) of PF through gavage. The positive control group was administered 10 mg/kg atorvastatin calcium tablets through gavage. After 8 weeks of gavage, PF delayed the weight gain and reduced the elevated levels of serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol in ApoE^-/- mice, which had been induced by the high-fat diet. Concomitantly, PF alleviated aortic plaque formation and downregulated TLR4 and NF-κB expression. In terms of the underlying mechanism, PF altered linoleic acid metabolism, tryptophan metabolism, and steroid biosynthesis, as well as improved abnormalities in galactose metabolism, glycerophospholipid metabolism, and other metabolic pathways. Moreover, PF restored the dysbiosis of Firmicutes, Bacteroidota, and Actinobacteriota. Finally, it increased the abundance of <i>Lactobacillus</i>, <i>Bifidobacterium</i>, and other beneficial bacteria. Our results suggest that PF improves high-fat diet-induced AS and alleviates high-fat diet-induced intestinal barrier damage; moreover, its antiatherosclerotic effect may be related to improvements in intestinal metabolic disorders and altered abundance of microbiota.<b>IMPORTANCE</b>Atherosclerosis (AS) is a chronic progressive disease mainly characterized by vascular endothelial cell damage, inflammation, and lipid deposition. Inflammatory and immune-related mechanisms play a key role in the occurrence and development of AS. Our study showed that paeoniflorin can improve blood lipid levels, reduce arterial inflammation, restore intestinal permeability, regulate metabolites, increase the abundance of beneficial flora, and alleviate the occurrence of AS. Thus, our findings may contribute to the understanding of how traditional Chinese medicine exerts its holistic effects by modulating the microbiota-metabolite axis.