Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target

Abstract

Trimethylamine N-oxide (TMAO) is a molecule generated from choline, betaine, and carnitine via gut microbial metabolism. The plasma level of TMAO is determined by several factors including diet, gut microbial flora, drug administration and liver flavin monooxygenase activity. In humans, recent clinical studies evidence a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events. A direct correlation between increased TMAO levels and neurological disorders has been also hypothesized. Several therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that use TMAO as substrate and the development of target-specific molecules. 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 to establish the role of TMAO in human health and disease. In this article, we reviewed dietary sources and metabolic pathways of TMAO, as well as screened the studies suggesting possible involvement of TMAO in the etiology of cardiovascular and neurological disorders, underlying the importance of TMAO mediating inflammatory processes. Finally, the potential utility of TMAO as therapeutic target is also analyzed.

Effect of Berberine on Atherosclerosis and Gut Microbiota Modulation and Their Correlation in High-Fat Diet-Fed ApoE−/− Mice

“…Trimethylamine N-oxide is an important pro-atherogenic metabolite produced by gut microbiota, and gut microbial enzymes were involved in the formation of its precursor trimethylamine (TMA) (Wang et al, 2011;Koeth et al, 2013). Previous studies confirmed that choline TMA lyase (K20038), betaine reductase (K21578, K21579) and L-carnitine CoAtransferase (K08298) are the main TMA-lyases involved in TMA production (Fennema et al, 2016;Zeisel and Warrier, 2017;Janeiro et al, 2018). Results at the KO level exhibited decreased abundance of betaine reductase (K21578, K21579) in both the high and low dose BBR groups compared to the model group, and was especially significantly in the low dose group (all p < 0.01, Figures 9A,B).…”

Detection of Early Disease Risk Factors Associated with Metabolic Syndrome: A New Era with the NMR Metabolomics Assessment

“…As an example, the gut microbiome product TMAO has been considered a shared risk factor between numerous diseases, such as IR, cancer, Alzheimer's disease (AD) and schizophrenia, among others [238,239]. Clinical studies have described that higher circulating levels of TMAO are correlated with a higher inflammatory response (↑ C-reactive protein, ↑ TNF-α, ↑ IL-6) [240]. Moreover, it is related to the synthesis of N-Nitroso compounds, which are involved in epigenetic alterations and DNA-damage that can lead to the induction of cancer [241].…”

Impact of Nutrition on Pulmonary Arterial Hypertension

“…Importantly, SCFAs, particularly butyric and acetic acid, which derive mainly from the bacterial fermentation of fiber, are considered to promote cardiovascular health. In contrast, trimethylamine-N-oxide (TMAO), a metabolite produced by the gut microbiota from choline, betaine, and carnitine, which are abundant in meat, eggs, and fish, is associated with excess risk of heart disease [134].…”