Innovative Carnitine-Fed Rats Model Reveals Resveratrol Butyrate Ester’s Multimechanistic Role in Reducing TMAO and Cardiovascular Risk
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BACKGROUND
Trimethylamine-N-oxide (TMAO), a metabolite produced from dietary carnitine through gut microbiota, is a recognized risk factor for cardiovascular disease (CVD). High-fat diets and carnitine supplementation exacerbate TMAO levels and related risks, making them valuable in developing experimental models for studying CVD. Resveratrol butyrate ester (RBE) and its monomer ED4 have shown potential in reducing TMAO levels and improving cardiovascular outcomes through metabolic and microbial modulation, but their precise mechanisms remain unclear.
METHODS AND RESULTS
A novel animal model was established using 36 male Sprague-Dawley rats fed a high-fat diet supplemented with carnitine to elevate serum TMAO levels, simulating dietary-induced CVD risks. Rats were divided into six groups: control diet (CN), high-fat diet (HFD), high-fat diet with carnitine (HFDC), HFDC with dimethylbutanol (HFDCB), CN with ED4 (CNM), and HFDC with ED4 (HFDCM). Physiological parameters, serum lipid profiles, SCFA levels, microbiota composition, and gene expression (OCTN2 and FMO3) were analyzed. ED4 supplementation reduced serum TMAO levels by upregulating OCTN2 expression, promoting urinary TMAO excretion, and restoring SCFA levels. ED4 also modulated gut microbiota, reducing TMA-producing bacteria (e.g., Bacteroides ), and improved cardiovascular markers, including reduced blood lipid levels and fat accumulation. While dimethylbutanol inhibited FMO3 expression to reduce TMAO, ED4 acted primarily through carnitine utilization and microbiota modulation. Both treatments enhanced urinary TMAO excretion and altered gut microbiota composition.
CONCLUSIONS
This study introduced an innovative animal model combining high-fat and carnitine-enriched diets to study TMAO-related cardiovascular risks. ED4 demonstrated multimechanistic effects in reducing TMAO levels and CVD risk factors by modulating gut microbiota, restoring SCFA levels, and enhancing carnitine metabolism. These findings highlight ED4’s therapeutic potential in cardiovascular protection and metabolic regulation. However, further research is needed to elucidate the molecular pathways underlying ED4’s effects on TMAO metabolism and its broader translational applications.
