Trimethylamine N-Oxide in Relation to Cardiometabolic Health-Cause or Effect?

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.

Keywords: atherosclerosis; cardiometabolic health; cardiovascular disease; cause‒effect relationship; trimethylamine N-oxide (TMAO); type 2 diabetes.

Figure 1

Disease network around cardiovascular disease and metabolic syndrome. Trimethylamine N-oxide (TMAO) can originate either directly from fish consumption or indirectly from intake of dietary precursors (e.g., L-carnitine, choline, or betaine). Dysbiosis has a major influence on cardiometabolic diseases or disease factors. During cardiovascular disease/type 2 diabetes, TMAO levels were found to increase to 4–12 µM in patients, possibly resulting from a disturbed microbiome and/or a decreased intestinal barrier. In the kidney, TMAO is rapidly excreted via the urine. Increased TMAO levels, as observed in studies with patients, may signal a decreased renal function. Unfavorable contribution of TMAO may take place at extremely high concentrations in patients with severely impaired renal function, e.g., hemodialysis patients (dotted arrow). Moderately increased TMAO levels may be a compensatory mechanism in diseased populations. Arrows pointing in two directions: both affect each other.

Figure 2

Main biochemical conversions leading to trimethylamine (TMA) and TMAO. Modified from [37,38]. The compounds with an asterisk can originate from the diet. The conversions within the grey box (gut microbiome) are induced by the microbiota (mainly Firmicutes, Proteobacteria), and the resulting TMA is absorbed within the colon and converted to TMAO by liver FMOs (flavin monooxygenases). The possibly partial microbial degradation of TMA and TMAO (by methylotrophs and other occasional bacteria (Pseudomonas/Bacillus)) can result in the formation of formaldehyde within the colon; also, methylamines (including TMA/TMAO) could be substrates for the formation of nitrosamines [32,39]. If TMA is absorbed from the colon, 95% of it is converted to TMAO, which is then excreted in the urine [34]. Arrows pointing in two directions: reactions go in both directions.

Figure 3

Search method for finding literature on TMAO. A total of 1963 references (up to November 2019) on TMAO were further searched with the indicated search terms. Additional references were found by following up citations within the literature and during the review phase in April 2020.