Review
Trimethylamine-N-Oxide: Friend, Foe, or Simply Caught in the Cross-Fire?

https://doi.org/10.1016/j.tem.2016.10.005Get rights and content

Trends

Circulating TMAO is elevated in humans with cardiovascular disease, kidney disease, type 2 diabetes mellitus, and cancer.

Kidney function, the gut microbiome, and a FMO3 genotype and/or activity influence circulating TMAO and may confound the relation between TMAO and disease risk.

Restriction of animal source foods because of their TMAO-raising properties may be unjustified and could have unintended consequences.

Trimethylamine-N-oxide (TMAO), a gut-derived metabolite, has recently emerged as a candidate risk factor for cardiovascular disease and other adverse health outcomes. However, the relation between TMAO and chronic disease can be confounded by several factors, including kidney function, the gut microbiome, and flavin-containing monooxygenase 3 (FMO3) genotype. Thus, whether TMAO is a causative agent in human disease development and progression, or simply a marker of an underlying pathology, remains inconclusive. Importantly, dietary sources of TMAO have beneficial health effects and provide nutrients that have critical roles in many biological functions. Pre-emptive dietary strategies to restrict TMAO-generating nutrients as a means to improve human health warrant careful consideration and may not be justified at this time.

Section snippets

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.

References (80)

  • D. Tsikas

    Accurate quantification of dimethylamine (DMA) in human urine by gas chromatography-mass spectrometry as pentafluorobenzamide derivative: evaluation of the relationship between DMA and its precursor asymmetric dimethylarginine (ADMA) in health and disease

    J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.

    (2007)
  • H.L. Collins

    L-Carnitine intake and high trimethylamine N-oxide plasma levels correlate with low aortic lesions in ApoE(–/–) transgenic mice expressing CETP

    Atherosclerosis

    (2016)
  • M. Ufnal

    Trimethylamine-N-oxide: a carnitine-derived metabolite that prolongs the hypertensive effect of angiotensin II in rats

    Can. J. Cardiol.

    (2014)
  • W. Zhu

    Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk

    Cell

    (2016)
  • R.B. Kim

    Advanced chronic kidney disease populations have elevated trimethylamine N-oxide levels associated with increased cardiovascular events

    Kidney Int.

    (2016)
  • D.M. Mueller

    Plasma levels of trimethylamine-N-oxide are confounded by impaired kidney function and poor metabolic control

    Atherosclerosis

    (2015)
  • N. Serkova

    H-NMR-based metabolic signatures of mild and severe ischemia/reperfusion injury in rat kidney transplants

    Kidney Int.

    (2005)
  • X. Gao

    Dietary trimethylamine N-oxide exacerbates impaired glucose tolerance in mice fed a high fat diet

    J. Biosci. Bioeng.

    (2014)
  • R. Obeid

    Plasma trimethylamine N-oxide concentration is associated with choline, phospholipids, and methyl metabolism

    Am. J. Clin. Nutr.

    (2016)
  • J.C. Gregory

    Transmission of atherosclerosis susceptibility with gut microbial transplantation

    J. Biol. Chem.

    (2015)
  • D.H. Lang

    Isoform specificity of trimethylamine N-oxygenation by human flavin-containing monooxygenase (FMO) and P450 enzymes: selective catalysis by FMO3

    Biochem. Pharmacol.

    (1998)
  • D.M. Shih

    Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis

    J. Lipid Res.

    (2015)
  • D.M. Lambert

    In vivo variability of TMA oxidation is partially mediated by polymorphisms of the FMO3 gene

    Mol. Genet. Metab.

    (2001)
  • A. Turkanoglu Ozcelik

    Flavin containing monooxygenase 3 genetic polymorphisms Glu158Lys and Glu308Gly and their relation to ischemic stroke

    Gene

    (2013)
  • P. Detopoulou

    Dietary choline and betaine intakes in relation to concentrations of inflammatory markers in healthy adults: the ATTICA study

    Am. J. Clin. Nutr.

    (2008)
  • C. Poly

    The relation of dietary choline to cognitive performance and white-matter hyperintensity in the Framingham Offspring Cohort

    Am. J. Clin. Nutr.

    (2011)
  • H. Karlic et al.

    Supplementation of L-carnitine in athletes: does it make sense?

    Nutrition

    (2004)
  • J.J. DiNicolantonio

    L-Carnitine in the secondary prevention of cardiovascular disease: systematic review and meta-analysis

    Mayo Clin. Proc.

    (2013)
  • J.A. Humbert

    Trimethylaminuria: the fish-odour syndrome

    Lancet

    (1970)
  • R.J. Dutton et al.

    Taking a metagenomic view of human nutrition

    Curr. Opin. Clin. Nutr. Metab. Care

    (2012)
  • A.B. Shreiner

    The gut microbiome in health and in disease

    Curr. Opin. Gastroenterol.

    (2015)
  • W.H. Tang

    Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk

    N. Engl. J. Med.

    (2013)
  • Z. Wang

    Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease

    Nature

    (2011)
  • C.E. Cho

    Trimethylamine-N-oxide (TMAO) response to animal source foods varies among healthy young men and is influenced by their gut microbiota composition: a randomized controlled trial

    Mol. Nutr. Food Res.

    (2016)
  • M.E. Dumas

    Assessment of analytical reproducibility of 1H NMR spectroscopy based metabonomics for large-scale epidemiological research: the INTERMAP Study

    Anal. Chem.

    (2006)
  • S.H. Zeisel

    Formation of methylamines from ingested choline and lecithin

    J. Pharmacol. Exp. Ther.

    (1983)
  • N.E. Boutagy

    Probiotic supplementation and trimethylamine-N-oxide production following a high-fat diet

    Obesity (Silver Spring)

    (2015)
  • R.A. Koeth

    Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis

    Nat. Med.

    (2013)
  • K.A. Romano

    Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide

    MBio

    (2015)
  • S. Craciun et al.

    Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme

    Proc. Natl. Acad. Sci. U.S.A.

    (2012)
  • Cited by (143)

    View all citing articles on Scopus
    View full text