Huang-Lian-Jie-Du-Decoction alleviates atherosclerotic plaque and lipid profile in HFD-induced ApoE-/- mice involve the gut microbiota-mediated TMA/FMO3/TMAO axis

Huang-Lian-Jie-Du-Decoction (HLJDD), a classic traditional Chinese medicine formula, is commonly used clinically to improve atherosclerosis (AS). Previous studies have primarily focused on the mechanisms of action of its blood-absorbed compounds, while less attention has been paid to its effects on gut microbiota. The trimethylamine (TMA)/flavin-containing monooxygenase 3 (FMO3)/trimethylamine N-oxide (TMAO) pathway, co-mediated by gut bacteria and the liver, plays a critical role in AS-related dyslipidemia. Using ApoE ^−/− mice fed a high-fat diet, this study evaluated HLJDD's effects on AS and gut microbiota. Results showed HLJDD reduced atherosclerotic plaques, macrophage infiltration, hepatic lipid accumulation, and serum lipids. It also altered gut microbiota diversity, increasing Verrucomicrobia and Akkermansia while decreasing Dubosiella and Clostridium , a key TMA-producing genus. Furthermore, HLJDD significantly lowered serum TMA and TMAO levels and downregulated hepatic FMO3 protein expression in AS mice. Our results indicate that HLJDD ameliorates atherosclerotic lesions and improves lipid dysregulation in HFD-induced ApoE ^−/− mice. The underlying mechanism may involve regulation of the TMA/FMO3/TMAO axis, which is associated with alterations in gut microbial communities, especially reduced abundance of Clostridium , as well as suppressed hepatic FMO3.