Trends in Endocrinology & Metabolism
ReviewTrimethylamine-N-Oxide: Friend, Foe, or Simply Caught in the Cross-Fire?
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Trimethylamine-N-Oxide: A Metabolite Linked to the Gut Microbiome
The relation between diet and health involves complex interactions among nutrients, genes, and many physiological systems, including the gut microbiome. Although long recognized for its role in the processing, biosynthesis, and utilization of nutrients [1], it is now clear that the gut microbiome has additional roles and might be modulating susceptibility to chronic diseases, such as cardiovascular disease, obesity, and cancer 1, 2. One purported mechanism involves the microbial production of
Dietary Sources of TMAO
TMAO, an amine oxide with the chemical formula (CH3)3NO, is found naturally in our diets in the preformed state (e.g., TMAO in fish), or can be generated within the human intestine from choline and carnitine, nutrients that are abundant in eggs and beef (Figure 1). Of these dietary sources, preformed TMAO in fish has the greatest impact on circulating TMAO concentrations. For example, consumption of fish yielded ∼50 times higher postprandial circulating TMAO concentrations compared with the
TMAO Metabolism
Choline and carnitine, dietary precursors of TMAO, must first undergo bacterial conversion in the mammalian gut to TMA, a fish-smelling odorant that is characteristic of degrading seafood. The obligate role of the gut microbiome in TMAO generation from dietary precursors within the intestine has been demonstrated through manipulation of the gut. Studies in humans revealed that circulating TMAO concentrations in response to choline and carnitine are suppressed after antibiotic treatment but
Functions of TMAO
TMAO has a range of biological effects across numerous species and tissue types. As an organic osmolyte, TMAO is used by water-stressed organisms and tissues to maintain cell volume. Mammalian kidneys accumulate TMAO to counteract the destabilizing effects of urea (and inorganic ions) on macromolecular structures (e.g., proteins and nucleic acids), and to offset the inhibitory effects of urea on functions such as ligand binding [19]. TMAO is also suggested to offset the destabilizing effects of
Cardiovascular Disease
A link between TMAO and cardiovascular disease risk first emerged in 2011. Using an untargeted metabolomics approach, investigators found a dose-dependent association between plasma concentrations of TMAO (as well as of choline and betaine) and cardiovascular disease risk among cardiac patients [4]. In a follow-up study with a different cohort of cardiac patients, this group showed that the highest quartile of fasting plasma concentrations of TMAO was predictive of death, myocardial infarction,
Important Modulators of TMAO in Relation to Disease Risk
At present, it is unclear whether TMAO contributes to disease pathogenesis or is simply a marker of an underlying pathogenic factor. In addition, fasting plasma concentrations of TMAO exhibit a relatively high degree of intraindividual variation, such that measurements taken from the same individual 1 year apart are weakly correlated [49]. This modest correlation of TMAO levels over time may confound the relation between TMAO and disease endpoints in longitudinal studies [49]. Furthermore,
Beneficial Effects of Diets Enriched in TMAO Precursors
While fish consumption (high in TMAO) has long been associated with reduced risk for cardiovascular disease [66], diets enriched in choline or carnitine are also associated with beneficial effects on human health [67]. Furthermore, animal source foods containing TMAO precursors are important sources of other nutrients, such as omega-3 fatty acids, iron and vitamin B12 [67].
As the precursor of phosphatidylcholine and acetylcholine, choline has a critical role in membrane biosynthesis and
Concluding Remarks and Future Perspectives
TMAO is a novel predictive risk factor of adverse cardiovascular outcomes mostly in patients with medical conditions or in animal models of disease. Circulating TMAO is also emerging as a risk factor for a growing number of additional chronic diseases, including kidney disease, T2DM, and cancer. Whether TMAO is a causative agent in disease development and progression, or simply a marker of an underlying pathology, remains inconclusive in humans. Important confounding factors that warrant
Acknowledgments
We would like to thank Tia M. Rains, Kevin C. Klatt, and Siraphat Taesuwan, as well as journal reviewers, for critically reviewing the manuscript. The authors received funding from the Egg Nutrition Center and the Division of Nutritional Sciences at Cornell University. C.E.C. was supported by the Canadian Institutes of Health Research (CIHR) postdoctoral fellowship.
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