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.

Influence of Early Life, Diet, and the Environment on the Microbiome

“…58 Additionally, they also showed that low adherence to the Mediterranean diet led to decreases in urinary trimethylamine oxide levels, which is associated with higher cardiovascular risk. 58,59 Several studies have shown that consumption of foods encompassing the typical Mediterranean diet improved obesity, inflammation, and lipid profile and were associated with an increases in Lactobacillus , Bifidobacterium , and Prevotella , but with decreases in Clostridium levels. 53,60 …”

The roles of gut microbiota and circadian rhythm in the cardiovascular protective effects of polyphenols

“…Trimethylamine-N-oxide (TMAO), a compound that is generated by a two-step process by both the host and by gut microbiota, is implicated in the development of atherosclerosis. Dietary L-carnitine, choline, and lecithin are converted to trimethylamine by the TMA-generating lyase (CutC/D) of gut microbiota, especially Firmicutes and Proteobacteria, then host flavin-containing monoamine oxidases (FMO) are responsible for the conversion to TMAO (Rath, Heidrich, Pieper, & Vital, 2017;Velasquez, Ramezani, Manal, & Raj, 2016). Plasma TMAO concentration is positively correlated to the mortality risk in patients with stable coronary artery disease, carotid intima-media thickness in obese individuals or patients with thrombosis risk (Kiouptsi & Reinhardt, 2018;Randrianarisoa et al, 2016;Senthong et al, 2016;Wang et al, 2011;Zhu et al, 2016).…”

Proceedings of the 2017 ASPEN Research Workshop—Gastric Bypass: Role of the Gut

“…TMAO enhances the accumulation of cholesterol in macrophages, the deposition of foam cells in arterial walls, and the formation of atherosclerosis, all factors associated with an increased risk for cardiovascular disease and death. 203,204 Circulating choline can also be oxidized to betaine, a metabolite involved in methylation reactions and detoxification of homocysteine, in the liver and in the kidneys. In humans, elevated plasma concentrations of TMAO, choline, and betaine are associated with an increased risk for a major adverse cardiovascular event, even after adjusting for traditional risk factors.…”

“…TMA is oxidized to trimethylamine-N-oxide (TMAO) in the liver. TMAO enhances the accumulation of cholesterol in macrophages, the deposition of foam cells in arterial walls and the formation of atherosclerosis, all factors associated with an increased risk of cardiovascular disease and death 203,204 . Circulating choline can also be oxidized to betaine, a metabolite involved in methylation reactions and detoxification of homocysteine, in the liver and in the kidneys.…”