Last Updated: March 16, 2022

    Trimethylamine N-oxide (TMAO) is a compound generated by gut microbial metabolism which is associated increased disease risk. However, it's questionable whether this association reflects causality.

    examine-databaseExamine Database


    Trimethylamine N-oxide (TMAO) is a compound generated by gut microbial metabolism that has been implicated in increased disease risk. Systematic reviews and meta-analyses[1][2] (whose results are shown in Figure 1) determined that TMAO is associated with a significantly higher risk of both all-cause mortality and cardiovascular events. One possible mechanism for TMAO's effects may be disruption of cholesterol transport by increasing forward transport and decreasing reverse cholesterol transport[3]. However, whether these associations are actually causal is open to question.[4][5]


    TMAO has been shown to be generated from substrates with a trimethylamine (TMA) moiety such as L-carnitine and choline[3]. L-carnitine is found in a variety of both plant and animal sources. However, levels of free L-carnitine are highest in meat products[6] and very low in fruits, vegetables, nuts, and grains. L-carnitine is also added into some popular energy drinks[7] with the expectation that it increases performance and helps to burn fat, although the evidence for those expectations is not clear. While vegetarians and vegans have considerably lower dietary intake of carnitine, studies show that their circulating levels in the blood are not drastically lower than people who consume meat and remain generally within the normal range[8]. This is because carnitine can be synthesized in the liver, kidney, and brain[9] if not enough is consumed in the diet.

    Several studies[10] have now demonstrated that dietary L-carnitine can be converted in the gut to TMA, at which point TMA can then be converted to TMAO in the liver by the enzyme flavin monooxygenase. However, researchers in 2013 discovered that a compound called γ-butyrobetaine (γ-BB) was formed[11] as an intermediate between L-carnitine and TMA formation in mice.

    Examine Database: TMAO

    Small Decrease
    Large Increase
    What works and what doesn't?

    Unlock the full potential of Examine

    Get started


    1. ^Schiattarella GG, Sannino A, Toscano E, Giugliano G, Gargiulo G, Franzone A, Trimarco B, Esposito G, Perrino CGut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysisEur Heart J.(2017 Oct 14)
    2. ^Qi J, You T, Li J, Pan T, Xiang L, Han Y, Zhu LCirculating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studiesJ Cell Mol Med.(2018 Jan)
    3. ^Tang WH, Hazen SLMicrobiome, trimethylamine N-oxide, and cardiometabolic diseaseTransl Res.(2017 Jan)
    4. ^Giuseppina Costabile, Claudia Vetrani, Lutgarda Bozzetto, Rosalba Giacco, Letizia Bresciani, Daniele Del Rio, Marilena Vitale, Giuseppe Della Pepa, Furio Brighenti, Gabriele Riccardi, Angela A Rivellese, Giovanni AnnuzziPlasma TMAO increase after healthy diets: results from 2 randomized controlled trials with dietary fish, polyphenols, and whole-grain cerealsAm J Clin Nutr.(2021 Jun 5)
    5. ^Jia J, Dou P, Gao M, Kong X, Li C, Liu Z, Huang TAssessment of Causal Direction Between Gut Microbiota-Dependent Metabolites and Cardiometabolic Health: A Bidirectional Mendelian Randomization AnalysisDiabetes.(2019 Sep)
    6. ^Demarquoy J, Georges B, Rigault C, Royer MC, Clairet A, Soty M, Lekounoungou S, LeBorgne F.Radioisotopic determination of l-carnitine content in foods commonly eaten in Western countries
    7. ^Wassef B, Kohansieh M, Makaryus ANEffects of energy drinks on the cardiovascular systemWorld J Cardiol.(2017 Nov 26)
    8. ^Lombard KA, Olson AL, Nelson SE, Rebouche CJCarnitine status of lactoovovegetarians and strict vegetarian adults and childrenAm J Clin Nutr.(1989 Aug)
    9. ^El-Hattab AW, Scaglia FDisorders of carnitine biosynthesis and transportMol Genet Metab.(2015 Nov)
    10. ^Ussher JR, Lopaschuk GD, Arduini AGut microbiota metabolism of L-carnitine and cardiovascular riskAtherosclerosis.(2013 Dec)
    11. ^Koeth RA, Levison BS, Culley MK, Buffa JA, Wang Z, Gregory JC, Org E, Wu Y, Li L, Smith JD, Tang WHW, DiDonato JA, Lusis AJ, Hazen SLγ-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAOCell Metab.(2014 Nov 4)

    Examine Database References

    1. L-Carnitine - Joanna J Samulak, Angelika K Sawicka, Emilia Samborowska, Robert A OlekPlasma Trimethylamine-N-oxide following Cessation of L-carnitine Supplementation in Healthy Aged WomenNutrients.(2019 Jun 13)
    2. PQQ - Harris CB, Chowanadisai W, Mishchuk DO, Satre MA, Slupsky CM, Rucker RBDietary pyrroloquinoline quinone (PQQ) alters indicators of inflammation and mitochondrial-related metabolism in human subjectsJ Nutr Biochem.(2013 Dec)