Based on the gut–heart axis: Polygonum capitatum improves atherosclerosis by modulating gut microbiota and TMAO, supporting MCPIP1/p53-associated endothelial protection

Polygonum capitatum (PC), known as "Tou Hua Liao" (Chinese name), is an essential source of Hmong medicinal plants, which has been used for treating various human diseases. This study examined whether PC has lipid-lowering and anti-atherosclerotic effects and explored the underlying mechanisms. We focused on PC's influence on gut microbiota-derived metabolites. First, we analyzed animal-derived serum containing PC components and the botanical compounds of PC by UPLC-MS/MS to identify potential bioactive constituents. Second, we treated high-fat diet-fed hamsters with PC to determine whether the treatment improved plasma lipids and attenuated atherosclerosis progression. We then assessed PC's effects on the gut microbiota by 16S rDNA sequencing and performed fecal microbiota transplantation in hamster models. Finally, we used human umbilical vein endothelial cells (HUVECs) to probe molecular mechanisms by which PC might inhibit oxidative stress and apoptosis. In a diet-induced atherosclerotic hamster model, PC treatment reduced atherosclerosis by decreasing lipid accumulation, oxidative stress, and apoptosis, and it restored gut microbiota balance while markedly lowering the abundance of TMAO-producing bacteria. PC also exerted antioxidant and anti-apoptotic effects and inhibited endothelial apoptosis via an MCPIP1-dependent mechanism. Together, these results indicate that PC suppresses atherosclerosis through two likely pathways: reduction of gut microbiota-derived TMAO production and inhibition of oxidative stress-driven endothelial apoptosis. Network pharmacology analysis of PC-specific blood-absorbed components supports these findings.