Targeting the gut-liver-heart axis: Role of bacterial TMA lyase and human FMO-3 in atherosclerosis and dietary interventions

Cardiovascular diseases (CVD) are the most common and leading cause of death worldwide. Atherosclerosis, a chronic inflammatory disease, is one of the onsets of CVD and is caused by the accumulation of plaque on the arterial walls. The gut microbiota interacts with the host via many pathways. One of the metabolism-dependent pathways involves trimethylamine (TMA) and its oxidized product, trimethylamine-N-oxide (TMAO). TMA and TMAO production are primarily driven by the microbial metabolism of choline and L-carnitine. Bacterial TMA lyase and hepatic flavin-containing monooxygenase-3 (FMO-3) have been reported to play a crucial role in the development of coronary plaques and progression of atherosclerosis. The roles of these enzymes have been well characterised to a great extent; however, strategies to inhibit their activity and improve human health remain largely unexplored. This review highlights the involvement of gut bacterial metabolites, TMA and TMAO, in the pro-atherosclerotic mechanisms and emphasises on carbohydrate-based prebiotics as potential interventions. It further evaluates in vivo evidence on natural and small molecules that attenuate TMA and TMAO generation. Future perspectives on integrating prebiotic glyco-therapeutic strategies with enzyme-targeted approaches of TMA lyase and FMO-3 inhibition will provide a foundation to develop microbiota-based interventions that lower TMA and/or TMAO while preserving essential host metabolic functions.