Abstract
Trimethylamine-N-oxide (TMAO) is generated in a microbial-mammalian co-metabolic pathway mainly from the digestion of meat-containing food and dietary quaternary amines such as phosphatidylcholine, choline, betaine, or L-carnitine. Fish intake provides a direct significant source of TMAO. Human observational studies previously reported a positive relationship between plasma TMAO concentrations and cardiometabolic diseases. Discrepancies and inconsistencies of recent investigations and previous studies questioned the role of TMAO in these diseases. Several animal studies reported neutral or even beneficial effects of TMAO or its precursors in cardiovascular disease model systems, supporting the clinically proven beneficial effects of its precursor, L-carnitine, or a sea-food rich diet (naturally containing TMAO) on cardiometabolic health. In this review, we summarize recent preclinical and epidemiological evidence on the effects of TMAO, in order to shed some light on the role of TMAO in cardiometabolic diseases, particularly as related to the microbiome.
Highlights
Cardiovascular diseases (CVD) are the leading cause of mortality and disability, especially in old age [1]
Coronary artery disease (CAD), myocardial infarction, stroke, heart failure (HF), atrial fibrillation (AF), and chronic kidney disease (CKD) are known to be closely associated with type 2 diabetes (T2D) [4,5], as well atherosclerosis [6], all of which are linked to inflammation [6,7]
Normal mice have the majority of circulating cholesterol being carried by HDL particles, so they never develop atherosclerotic lesions on a chow diet; this is changed in the apoE−/− mouse model, where the ApoE protein is inactivated, which leads to enrichment in very low-density cholesterol (VLDL-c) [210]
Summary
Cardiovascular diseases (CVD) are the leading cause of mortality and disability, especially in old age [1]. It was found to have antioxidant and cytoprotectant properties [87] and was shown to be associated with a lower risk of cardiometabolic morbidity and mortality [88] It is part of the biochemical network leading to TMA production, its contribution to plasma TMA/TMAO levels requires further investigation [37]. Similar to an acute supplementation of 2100 mg choline, 2970 mg L-carnitine, or 1670 mg TMAO by healthy volunteers, sea food consumption resulted in an increase in postprandial urinary excretion of TMA and TMAO after 24 h [41]. In a study with 40 healthy young men, consumption of meals producing TMAO provided directly from fish led to a significant increase in postprandial plasma TMA and TMAO levels, peaking at around 0.2 μM and 150 μM, respectively, 2 h post meals. L-carnitine (as well as betaine and erythritol) was found to be an osmoprotectant and anti-inflammatory for human corneal epithelial cells [103]
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