The gut microbiota-derived metabolite trimethylamine-N-oxide (TMAO) is regarded as a major risk factor for cardiovascular events and diabetes. However, the association of TMAO with stroke has yet to be fully elucidated. The present meta-analysis was conducted to explore the association between TMAO and stroke. The present meta-analysis quantitatively summarized the results of studies that investigated the association between TMAO and stroke. The PubMed, Embase, Cochrane Library and Web of Science databases were systematically searched from January 1, 2001 to June 1, 2021. All studies that evaluated the association between TMAO and stroke were included in the present systematic review. The present meta-analysis included 30,808 participants and revealed that being in the higher TMAO category increased the odds of stroke by 68% (OR 1.83; 95% CI 1.02–3.29; P = 0.04), and that the mean TMAO concentration in stroke patients was 2.20 μmol/L higher than that of non-stroke controls (MD 2.20; 95% CI 1.23–3.16; P < 0.00001). In addition, TMAO plasma levels was associated with the risk of all-cause mortality, with a pooled HR of 1.89 (95% CI 1.15–3.08; P = 0.01). Both univariate analysis (UVA) and multivariate analysis (MVA) indicated that high TMAO levels significantly increased the risk of major adverse cardiovascular events (MACEs), with pooled RRs of 2.26 (95% CI 2.01–2.54; P < 0.00001) with UVA and 1.55 (95% CI 1.17–2.05; P = 0.002) with MVA respectively. In the current meta-analysis we revealed the positive association between circulating TMAO and stroke. Higher TMAO levels increased the risk of stroke and stroke patients experienced higher mean TMAO concentration. In addition, high TMAO plasma level was one of independent risk factors of MACEs and was associated with all-cause mortality.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Gruppen EG, Garcia E, Connelly MA, Jeyarajah EJ, Otvos JD, Bakker SJL, et al. TMAO is Associated with Mortality: Impact of Modestly Impaired Renal Function. Sci Rep. 2017;7:13781.
Mafune A, Iwamoto T, Tsutsumi Y, Nakashima A, Yamamoto I, Yokoyama K, et al. Associations among serum trimethylamine-N-oxide (TMAO) levels, kidney function and infarcted coronary artery number in patients undergoing cardiovascular surgery: a cross-sectional study. Clin Exp Nephrol. 2016;20:731–9.
Mente A, Chalcraft K, Ak H, Davis AD, Lonn E, Miller R, et al. The Relationship Between Trimethylamine-N-Oxide and Prevalent Cardiovascular Disease in a Multiethnic Population Living in Canada. Can J Cardiol. 2015;31:1189–94.
Hazen SL, Brown JM. Eggs as a dietary source for gut microbial production of trimethylamine-N-oxide. Am J Clin Nutr. 2014;100:741–3.
Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19:576–85.
Wu C, Li C, Zhao W, Xie N, Yan F, Lian Y, et al. Elevated trimethylamine N-oxide related to ischemic brain lesions after carotid artery stenting. Neurology. 2018;90:e1283–e1290.
Yin J, Liao SX, He Y, Wang S, Xia GH, Liu FT, et al. Dysbiosis of Gut Microbiota With Reduced Trimethylamine-N-Oxide Level in Patients With Large-Artery Atherosclerotic Stroke or Transient Ischemic Attack. J Am Heart Assoc. 2015;4:e002699.
Zheng L, Zheng J, Xie Y, Li Z, Gu X, Sun G, et al. Serum gut microbe-dependent trimethylamine N-oxide improves the prediction of future cardiovascular disease in a community-based general population. Atherosclerosis. 2019;280:126–31.
Nie J, Xie L, Zhao BX, Li Y, Qiu B, Zhu F, et al. Serum Trimethylamine N-Oxide Concentration Is Positively Associated With First Stroke in Hypertensive Patients. Stroke. 2018;49:2021–8.
Rexidamu M, Li H, Jin H, Huang J. Serum levels of Trimethylamine-N-oxide in patients with ischemic stroke. Biosci Rep. 2019;39:BSR20190515. https://doi.org/10.1042/BSR20190515.
Stubbs JR, Stedman MR, Liu S, Long J, Franchetti Y, West RE, et al. Trimethylamine N-Oxide and Cardiovascular Outcomes in Patients with ESKD Receiving Maintenance Hemodialysis. Clin J Am Soc Nephrol. 2019;14:261–7.
Guasch-Ferré M, Hu FB, Ruiz-Canela M, Bulló M, Toledo E, Wang DD, et al. Plasma Metabolites From Choline Pathway and Risk of Cardiovascular Disease in the PREDIMED (Prevention With Mediterranean Diet) Study. J Am Heart Assoc. 2017;6:e006524.
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25:603–5.
Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med. 1997;127:820–6.
DerSimonian R, Laird N. Meta-analysis in clinical trials revisited. Contemp Clin Trials. 2015;45:139–45. Pt A
Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719–48.
Haghikia A, Li XS, Liman TG, Bledau N, Schmidt D, Zimmermann F, et al. Gut Microbiota-Dependent Trimethylamine N-Oxide Predicts Risk of Cardiovascular Events in Patients With Stroke and Is Related to Proinflammatory Monocytes. Arterioscler Thromb Vasc Biol. 2018;38:2225–35.
Lever M, George PM, Slow S, Bellamy D, Young JM, Ho M, et al. Betaine and Trimethylamine-N-Oxide as Predictors of Cardiovascular Outcomes Show Different Patterns in Diabetes Mellitus: An Observational Study. PLoS One. 2014;9:e114969.
Li XS, Obeid S, Klingenberg R, Gencer B, Mach F, Räber L, et al. Gut microbiota-dependent trimethylamine N-oxide in acute coronary syndromes: a prognostic marker for incident cardiovascular events beyond traditional risk factors. Eur Heart J. 2017;38:814–24.
Liang Z, Dong Z, Guo M, Shen Z, Yin D, Hu S, et al. Trimethylamine N-oxide as a risk marker for ischemic stroke in patients with atrial fibrillation. J Biochem Mol Toxicol. 2019;33:e22246.
Mueller DM, Allenspach M, Othman A, Saely CH, Muendlein A, Vonbank A, et al. Plasma levels of trimethylamine-N-oxide are confounded by impaired kidney function and poor metabolic control. Atherosclerosis. 2015;243:638–44.
Senthong V, Wang Z, Li XS, Fan Y, Wu Y, Tang WH, et al. Intestinal Microbiota-Generated Metabolite Trimethylamine-N-Oxide and 5-Year Mortality Risk in Stable Coronary Artery Disease: The Contributory Role of Intestinal Microbiota in a COURAGE-Like Patient Cohort. J Am Heart Assoc. 2016;5:e002816.
Stubbs JR, House JA, Ocque AJ, Zhang S, Johnson C, Kimber C, et al. Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden. J Am Soc Nephrol. 2016;27:305–13.
Suzuki T, Heaney LM, Jones DJ, Ng LL. Trimethylamine N-oxide and Risk Stratification after Acute Myocardial Infarction. Clin Chem. 2017;63:420–8.
Tang WH, Wang Z, Fan Y, Levison B, Hazen JE, Donahue LM, et al. Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis. J Am Coll Cardiol. 2014;64:1908–14.
Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl J Med. 2013;368:1575–84.
Tang WH, Wang Z, Li XS, Fan Y, Li DS, Wu Y, et al. Increased Trimethylamine N-Oxide Portends High Mortality Risk Independent of Glycemic Control in Patients with Type 2 Diabetes Mellitus. Clin Chem. 2017;63:297–306.
Wang Z, Tang WH, Buffa JA, Fu X, Britt EB, Koeth RA, et al. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. Eur Heart J. 2014;35:904–10.
Winther SA, Øllgaard JC, Tofte N. Utility of Plasma Concentration of Trimethylamine N-Oxide in Predicting Cardiovascular and Renal Complications in Individuals With Type 1. Diabetes 2019;42:1512–20.
Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, Wang Z, et al. Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell. 2016;165:111–24.
Heianza Y, Ma W, Manson JE, Rexrode KM, Qi L Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta-Analysis of Prospective Studies. J Am Heart Assoc, 2017;6:e004947.
Schiattarella GG, Sannino A, Toscano E, Giugliano G, Gargiulo G, Franzone A, et al. Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis. Eur Heart J. 2017;38:2948–56.
Gao X, Tian Y, Randell E, Zhou H, Sun G. Unfavorable Associations Between Serum Trimethylamine N-Oxide and L-Carnitine Levels With Components of Metabolic Syndrome in the Newfoundland Population. Front Endocrinol. 2019;10:168.
Barrea L, Annunziata G, Muscogiuri G, et al. Trimethylamine-N-oxide (TMAO) as Novel Potential Biomarker of Early Predictors of Metabolic Syndrome. Nutrients. 2018;10:1971. https://doi.org/10.3390/nu10121971.
Dambrova M, Latkovskis G, Kuka J, Strele I, Konrade I, Grinberga S, et al. Diabetes is Associated with Higher Trimethylamine N-oxide Plasma Levels. Exp Clin Endocrinol Diabetes. 2016;124:251–6.
Mai V, McCrary QM, Sinha R, Glei M. Associations between dietary habits and body mass index with gut microbiota composition and fecal water genotoxicity: an observational study in African American and Caucasian American volunteers. Nutr J. 2009;8:49.
Daniel H, Gholami AM, Berry D. High-fat diet alters gut microbiota physiology in mice. ISME J. 2014;8:295–308.
Barrea L, Annunziata G, Muscogiuri G, Laudisio D, Di Somma C, Maisto M, et al. Trimethylamine N-oxide, Mediterranean diet, and nutrition in healthy, normal-weight adults: also a matter of sex? Nutrition. 2019;62:7–17.
Zhu Y, Jameson E, Crosatti M, Schäfer H, Rajakumar K, Bugg TD, et al. Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota. Proc Natl Acad Sci USA. 2014;111:4268–73.
Tuso P, Stoll SR, Li WW. A plant-based diet, atherogenesis, and coronary artery disease prevention. Perm J. 2015;19:62–7.
Zhao Y, Yang N, Gao J, Li H, Cai W, Zhang X, et al. The Effect of Different l-Carnitine Administration Routes on the Development of Atherosclerosis in ApoE Knockout Mice. Mol Nutr Food Res. 2018;62. https://doi.org/10.1002/mnfr.201700299.
Shah B, Newman JD, Woolf K, Ganguzza L, Guo Y, Allen N, et al. Anti-Inflammatory Effects of a Vegan Diet Versus the American Heart Association-Recommended Diet in Coronary Artery Disease Trial. J Am Heart Assoc. 2018;7:e011367.
Tripolt NJ, Leber B, Triebl A, Köfeler H, Stadlbauer V, Sourij H, et al. Effect of Lactobacillus casei Shirota supplementation on trimethylamine-N-oxide levels in patients with metabolic syndrome: An open-label, randomized study. Atherosclerosis. 2015;242:141–4.
Tang WH, Hazen SL. Probiotic therapy to attenuate weight gain and trimethylamine-N-Oxide generation: A cautionary tale. Obes (Silver Spring). 2015;23:2321–2.
Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005;5:13.
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Zhang, H., Yao, G. Significant correlation between the gut microbiota-derived metabolite trimethylamine-N-oxide and the risk of stroke: evidence based on 23 observational studies. Eur J Clin Nutr (2022). https://doi.org/10.1038/s41430-022-01104-7