Abstract
Trimethylamine-N-oxide (TMAO), an intestinal microbiota-derived metabolite, is strongly linked to metabolic disorders, cardiovascular diseases, and liver injury. This study aimed to evaluate the therapeutic effects of 3-O-butanoylresveratrol (ED4), a resveratrol derivative, in a rat model with elevated systemic TMAO induced via osmotic pump infusion. ED4 supplementation significantly reduced serum triglycerides, cholesterol, low-density lipoprotein cholesterol, and the total cholesterol/high-density lipoprotein cholesterol ratio while improving liver function and reducing hepatic fat accumulation associated with high systemic TMAO levels. Additionally, ED4 restored short-chain fatty acid levels and modulated intestinal microbiota composition, increasing the abundance of beneficial species such as Romboutsia ilealis and Parabacteroides merdae. Serum metabolomics revealed ED4's role in enhancing energy and amino acid metabolism, contributing to improved metabolic health. These findings demonstrate that ED4 alleviates TMAO-associated risks by improving lipid metabolism, protecting liver function, and reshaping intestinal microbiota, highlighting its potential as a functional food component for managing cardiovascular disorders.