Modulation of the gut–liver axis via TMAO metabolism by Ramulus Mori alkaloids alleviates diabetic atherosclerosis

Diabetic atherosclerosis is a complex condition driven by intertwined metabolic disturbances including hyperglycemia, dyslipidemia, inflammation, and oxidative stress. The gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) has emerged as a key contributor that links metabolic disorders to vascular injury. In this study, we investigated whether Ramulus Mori (Sangzhi) Alkaloids (SZ-A), a natural extract enriched in alkaloids, functions as a “metabolic purifier” that alleviates diabetic atherosclerosis by reprogramming the gut–liver axis via TMAO metabolism. We induced a diabetic atherosclerosis model in ApoE −/− mice using streptozotocin and a high-fat, high-cholesterol diet. SZ-A administration markedly reduced atherosclerotic lesions and exerted multi-organ protective effects in model mice. Specifically, SZ-A enhanced intestinal barrier immunity by promoting Paneth cell-derived α-defensin secretion, reshaped gut microbiota composition by suppressing trimethylamine (TMA)-producing bacteria and TMA-lyase genes, and downregulated hepatic flavin-containing monooxygenase 3 expression, collectively leading to reduced systemic TMAO levels. Furthermore, SZ-A improved hepatic lipid metabolism and bile acid synthesis, attenuated systemic inflammation and oxidative stress, and inhibited oxidized low-density lipoprotein uptake by endothelial cells and macrophages. These integrated actions highlight the role of SZ-A as a multitarget regulator of the gut–liver axis, supporting its potential as a natural therapeutic agent for diabetic atherosclerosis.