Dietary Modulation of Gut Microbiome in High Cholesterol Diet–Induced Atherosclerosis

Atherosclerosis is increasingly understood as a metabolically driven disease influenced by diet and lifestyle factors. Beyond traditional risk factors, the gut microbiota play a critical role in atherogenesis. Dietary patterns alter the gut microbiota to favor the synthesis of proatherogenic metabolites, like TMAO and branched‐chain amino acid (BCAA), which contribute to the progression of atherosclerosis. This study investigated the impact of different diets, cornstarch, casein, and soya oil, on gut microbial composition, serum TMAO and BCAA levels, and hepatic expression of flavin‐containing monooxygenase 3 (FMO3) in high cholesterol diet (HCD)–induced atherosclerosis in a rabbit model. Atherosclerotic animals exhibited elevated TMAO and BCAA levels along with increased hepatic FMO3 expression, corresponding to an overrepresentation of TMA‐producing taxa such as Clostridium , Ruminococcus , and methanogenic archaea . In contrast, the cornstarch‐fed group showed significant suppression of FMO3 expression and serum TMAO, along with enrichment of beneficial genera like Olsenella and Dorea, and depletion of TMA‐associated species. The casein and soya oil diets resulted in a partial microbial and metabolic recovery, with sustained presence of TMA‐generating bacteria and persistent FMO3 activity. These findings demonstrate that dietary modulation of high‐carbohydrate diet can effectively lower TMAO biosynthesis and may serve as a promising nutritional approach to reduce TMAO mediated cardiovascular diseases.