Gut Microbiota Composition Affects Procyanidin A2-Attenuated Atherosclerosis in ApoE–/– Mice by Modulating the Bioavailability of Its Microbial Metabolites

Procyanidin A2 (PCA2) has been shown to improve lipid metabolism. However, it remains to know whether it can play a role in preventing atherosclerosis (AS) through gut microbiota. This study examined the effect of PCA2 on high fat diet (HFD)-induced AS in ApoE–/– mice with an intact and antibiotic-depleted microbiota. PCA2 administration for 12 weeks attenuated HFD-induced AS in ApoE–/– mice, evidenced by obviously alleviating the histological abnormalities of the aorta, lipid accumulation, oxidative stress, and inflammation, which were accompanied by downregulating the expression of vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 and upregulating peroxisome proliferator-activated receptor gamma, cholesterol 7 alpha-hydroxylase, and ATP-binding cassette transporter A1. Moreover, PCA2 treatment reshaped the gut microbiota imbalance caused by HFD, especially reducing the ratio of Firmicutes/Bacteroidetes and increasing the abundance of Verrucomicrobia. However, antibiotic intervention almost offset the alleviation of AS by PCA2 and prevented the biotransformation of PCA2 by gut microbiota, thus resulting in a 2327.21–6.27-fold decrease in its microbial metabolites of plasma. There was a marked correlation among the microbiota composition, the bioavailability of PCA2-derived microbial metabolites, and AS indicators. The findings indicate that the gut microbiota robustly influences the bioavailability of microbial metabolites that may partially drive the AS resilience property of PCA2.