Trimethylamine N-Oxide: The Good, the Bad and the Unknown

Abstract

Trimethylamine N-oxide (TMAO) is a small colorless amine oxide generated from choline, betaine, and carnitine by gut microbial metabolism. It accumulates in the tissue of marine animals in high concentrations and protects against the protein-destabilizing effects of urea. Plasma level of TMAO is determined by a number of factors including diet, gut microbial flora and liver flavin monooxygenase activity. In humans, a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events and death is reported. The atherogenic effect of TMAO is attributed to alterations in cholesterol and bile acid metabolism, activation of inflammatory pathways and promotion foam cell formation. TMAO levels increase with decreasing levels of kidney function and is associated with mortality in patients with chronic kidney disease. A number of therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that utilize TMAO as substrate and the development of target-specific molecules with varying level of success. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies examining the cellular signaling in physiology and pathological states in order to establish the role of TMAO in health and disease in humans.

Keywords: cardiovascular disease; dysbiosis; microbiome; uremic toxin.

Figure 1

Schematic representation of the link between diet, gut microbiota, TMAO and the clinical manifestations of this uremic toxin. Both host and gut microbial metabolism of trimethylammonium-containing nutrients (e.g., choline, phosphatidylcholine, and l-carnitine) result in the formation of TMA. In liver, FMOs convert TMA into TMAO. Clinical effects of TMAO includes alteration of cholesterol and sterol metabolism, progression of CKD, atherosclerosis, heart attack, metabolic syndrome, type II DM, and alternations in bile acid metabolism and sterol transporters both within the liver and intestine. TMA, Trimethylamine; TMAO, Trimethylamine N-Oxide; FMOs, flavin-containing monooxygenases.