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Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis
Abstract
AIMS: Gut microbiota-derived metabolite trimethylamine-N-oxide (TMAO) is emerging as a new potentially important cause of increased cardiovascular risk. The purpose of this meta-analysis was to systematically estimate and quantify the association between TMAO plasma levels, mortality, and major adverse cardio and cerebrovascular events (MACCE). METHODS AND RESULTS: MEDLINE, ISI Web of Science, and SCOPUS databases were searched for ad hoc studies published up to April 2017. Associations between TMAO plasma levels, all-cause mortality (primary outcome) and MACCE (secondary outcome) were systematically addressed. A total of 17 clinical studies were included in the analytic synthesis, enrolling 26 167 subjects. The mean follow-up in our study population was 4.3 ± 1.5 years. High TMAO plasma levels were associated with increased incidence of all-cause mortality [14 studies for 16 cohorts enrolling 15 662 subjects, hazard ratio (HR): 1.91; 95% confidence interval (CI): 1.40-2.61, P < 0.0001, I2 = 94%] and MACCE (5 studies for 6 cohorts enrolling 13 944 subjects, HR: 1.67, 95% CI: 1.33-2.11, P < 0.00001, I2 = 46%,). Dose-response meta-analysis revealed that the relative risk (RR) for all-cause mortality increased by 7.6% per each 10 μmol/L increment of TMAO [summary RR: 1.07, 95% CI (1.04-1.11), P < 0.0001; based on seven studies]. Association of TMAO and mortality persisted in all examined subgroups and across all subject populations. CONCLUSIONS: This is the first systematic review and meta-analysis demonstrating the positive dose-dependent association between TMAO plasma levels and increased cardiovascular risk and mortality.
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“High levels of TMAO have been associated with increased risk of cardiovascular disease and mortality.143–145”
From Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer (2020) · cites this paper as [145]
In the citing paper
“Notably, a clinical prognostic value of TMAO has been supported by multiple meta-analyses reaffirming that elevated circulating TMAO levels are associated with both CVD and mortality risks across multiple cohorts and continents.[10][11][12]”
From Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women (2019) · cites this paper as [10]
In the citing paper
“several recent meta-analyses confirm a strong clinical association between increased levels of TMAO and incident adverse cardiovascular event and mortality risks in multiple populations25–27.”
From Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential (2018) · cites this paper as [26]
In the citing paper
“While not all studies have observed the relationship between heightened TMAO levels and incident CVD risks, examination of extant clinical studies with TMAO in multiple meta-analyses have concluded that a strong relationship indeed exists between elevated circulating TMAO levels and both CVD risk and mortality in multiple cohorts on different continents105–107.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [105]
In the citing paper
“And in one recent meta-analysis comprising >25000 subjects, a 7.6% increase in all-cause mortality was noted for each 10μmol/L increment of TMAO105.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [105]
In the citing paper
“Although gene expression studies in humans have suggested gender differences in hepatic FMO3 expression, plasma levels of TMAO thus far reported have failed to show sex differences, and the prognostic value of TMAO appears to be similar in both men and women105.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [105]
In the citing paper
“These observations have since been replicated in multiple independent observational cohorts across a spectrum of CKD patients199–203.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [203]
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“This metabolite is a small, organic, gut microbiome-generated compound whose concentration increases after ingesting dietary L-carnitine and phosphatidylcholine rich foods such as red meat, eggs, and fish [27].”
BackgroundApplication of Metabolomics to Epidemiological Studies of Atherosclerosis and Cardiovascular Disease
Iida, M., Harada, S., & Takebayashi, T. (2019) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.rv17036 · Cited by 90
Mosterd, C. M., Kanbay, M., van den Born, B. H., van Raalte, D. H., & Rampanelli, E. (2021) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2021.101484 · Cited by 96
Leustean, A. M., Ciocoiu, M., Sava, A. C., Costea, C. F., Floria, M., Tărniceriu, C. C., & Tănase, D. M. (2018) · Journal of Diabetes Research · doi:10.1155/2018/5205126 · Cited by 94
“TMAO precursors such as choline, L-carnitine, γ-butyrobetaine, phosphatidylcholine, betaine, glycerophosphine, and crotonobetaine are metabolized by the intestinal microbiota to produce trimethylamine which is then further metabolized to TMAO by the monooxygenase 3 enzyme (FMO3) [18].”
BackgroundInfluentialYao, M., Liao, P., Zhao, X., & Wang, L. (2020) · BMC Cardiovascular Disorders · doi:10.1186/s12872-019-01310-5 · Cited by 90
“Although meta-analysis of TMAO and the risk of MACE has been performed previously [17, 26], our study was the first to investigate the prognostic value of TMAO in the CHD population.”
MethodResultCheng, X., Qiu, X., Liu, Y., Yuan, C., & Yang, X. (2019) · Thrombosis Research · doi:10.1016/j.thromres.2019.02.028 · Cited by 90
Tang, W. H. W., Li, X. S., Wu, Y., Wang, Z., Khaw, K., Wareham, N. J., Nieuwdorp, M., Boekholdt, S. M., & Hazen, S. L. (2021) · American Heart Journal · doi:10.1016/j.ahj.2021.01.020 · Cited by 92
Awoyemi, A., Mayerhofer, C. C. K., Felix, A. S., Hov, J. R., Moscavitch, S. D., Lappegård, K. T., Hovland, A., Halvorsen, S., Halvorsen, B. L., Gregersen, I., et al. (2021) · EBioMedicine · doi:10.1016/j.ebiom.2021.103511 · Cited by 88
“At a functional level, the microbiota-related metabolite trimethylamine N-oxide (TMAO) is associated with increased risk of adverse cardiovascular events and susceptibility for the development and severity of HF [6,7].”
BackgroundPontes, K. S. D. S., Guedes, M. R., Cunha, M. R. D., Mattos, S. D. S., Barreto Silva, M. I., Neves, M. F., Marques, B. C. A. A., & Klein, M. R. S. T. (2021) · Clinical Nutrition · doi:10.1016/j.clnu.2021.06.023 · Cited by 86
Serum levels of Trimethylamine-N-oxide in patients with ischemic stroke
Rexidamu, M., Li, H., Jin, H., & Huang, J. (2019) · Bioscience Reports · doi:10.1042/bsr20190515 · Cited by 84
Panyod, S., Wu, W., Chen, P.-C., Chong, K.-V., Yang, Y.-T., Chuang, H.-L., Chen, C., Chen, R.-A., Liu, P., Chung, C., et al. (2022) · npj Biofilms and Microbiomes · doi:10.1038/s41522-022-00266-3 · Cited by 86
Trimethylamine N-Oxide Promotes Cell Proliferation and Angiogenesis in Colorectal Cancer
Yang, S., Dai, H., Lu, Y., Li, R., Gao, C., & Pan, S. (2022) · Journal of Immunology Research · doi:10.1155/2022/7043856 · Cited by 86
Wang, M., Wang, Z., Lee, Y., Lai, H. T. M., Otto, M. C. D. O., Lemaître, R. N., Fretts, A. M., Sotoodehnia, N., Budoff, M. J., DiDonato, J. A., et al. (2022) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.121.316533 · Cited by 85
Trimethylamine-N-Oxide (TMAO) as a Rising-Star Metabolite: Implications for Human Health
Caradonna, E., Abate, F., Schiano, E., Paparella, F., Ferrara, F., Vanoli, E., Difruscolo, R., Goffredo, V. M., Amato, B., Setacci, C., et al. (2025) · Metabolites · doi:10.3390/metabo15040220 · Cited by 96
“To strengthen this evidence, a meta-analysis including 31,230 individuals and a systematic review analyzing 15,662 and 13,944 participants, with an average follow-up of 4.3 ± 1.5 years, found a dose-dependent positive correlation between plasma TMAO levels, cardiovascular events, and mortality [96].”
InfluentialWang, M., Li, X. S., Wang, Z., Otto, M. C. D. O., Lemaître, R. N., Fretts, A. M., Sotoodehnia, N., Budoff, M. J., Nemet, I., DiDonato, J. A., et al. (2023) · European Heart Journal · doi:10.1093/eurheartj/ehad089 · Cited by 84
Effects of Lifestyle Intervention on Plasma Trimethylamine N-Oxide in Obese Adults
Erickson, M. L., Malin, S. K., Wang, Z., Brown, J. M., Hazen, S. L., & Kirwan, J. P. (2019) · Nutrients · doi:10.3390/nu11010179 · Cited by 84
“6% increase in overall mortality risk [10].”
Koszewicz, M. A., Jaroch, J., Brzecka, A., Ejma, M., Budrewicz, S. P., Михалева, Л. М., Muresanu, C., Schield, P., Somasundaram, S. G., Kirkland, C. E., et al. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105277 · Cited by 82
Trimethylamine N -oxide: heart of the microbiota–CVD nexus?
Naghipour, S., Cox, A. J., Peart, J. N., Toit, E. F. D., & Headrick, J. P. (2020) · Nutrition Research Reviews · doi:10.1017/s0954422420000177 · Cited by 79
“about 8 % per 10 μM increment in plasma TMAO(72), and high-”
BackgroundDifferential effect of short-term popular diets on TMAO and other cardio-metabolic risk markers
Park, J. E., Miller, M. J., Rhyne, J., Wang, Z., & Hazen, S. L. (2019) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2019.02.003 · Cited by 76
Farhangi, M. A., Vajdi, M., & Asghari-Jafarabadi, M. (2020) · Nutrition Journal · doi:10.1186/s12937-020-00592-2 · Cited by 72
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Association of TrimethylamineN-Oxide and Related Metabolites in Plasma and Incident Type 2 Diabetes
Lemaître, R. N., Jensen, P. N., Wang, Z., Fretts, A. M., McKnight, B., Nemet, I., Biggs, M. L., Sotoodehnia, N., Otto, M. C. D. O., Psaty, B. M., et al. (2021) · JAMA Network Open · doi:10.1001/jamanetworkopen.2021.22844 · Cited by 71
Ilyas, A., Wijayasinghe, Y. S., Khan, I., Samaloty, N. M. E., Adnan, M., Dar, T. A., Poddar, N. K., Singh, L. R., Sharma, H., & Khan, S. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.964624 · Cited by 73
“6% per 10 μmol/L increments of plasma TMAO concentration (Schiattarella et al., 2017).”
BackgroundZhang, Q., Du, X., Li, H., Jiang, Y., Zhu, X., Zhang, Y., Niu, Y., Liu, C., Ji, J. S., Chillrud, S. N., et al. (2022) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2022.129031 · Cited by 69
Shih, D. M., Zhu, W., Schugar, R. C., Meng, Y., Jia, X., Miikeda, A., Wang, Z., Zieger, M., Lee, R., Graham, M., et al. (2019) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.119.312592 · Cited by 67
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Costabile, G., Vetrani, C., Bozzetto, L., Giacco, R., Bresciani, L., Rio, D. D., Vitale, M., Pepa, G. D., Brighenti, F., Riccardi, G., et al. (2021) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqab188 · Cited by 68
Hsu, C., Chang‐Chien, G., Lin, S., Hou, C., Lu, P., & Tain, Y. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9020336 · Cited by 66
“Therefore, whether plasma and urinary TMAO may aid in predicting CVD in early-stage pediatric CKD awaits further elucidation.”
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Circulating bile acids concentration is predictive of coronary artery disease in human
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Metadata
- Authors
- Schiattarella, G. G., Sannino, A., Toscano, E., Giugliano, G., Gargiulo, G., Franzone, A., Trimarco, B., Esposito, G., & Perrino, C.
- Affiliations
- University of Naples Federico II (IT)
- Baylor University Medical Center (US)
- University Hospital of Bern (CH)
- Corresponding author
- Perrino, Cinzia
- ORCID
- Venue
- European Heart Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-07-11
- Volume
- 38
- Issue
- 39
- Pages
- 2948-2956
- ISSN
- 0195-668X (ISSN-L)
- 1522-9645
- OpenAlex
- W2734440527
- Cited by
- 563
- References
- 51
- Citations by year
- 2026: 49 · 2025: 57 · 2024: 60 · 2023: 72 · 2022: 90 · 2021: 96 · 2020: 63 · 2019: 38 · 2018: 36 · 2017: 1
- FWCI
- 3.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Heart Journal (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- Ministero della Salute (GR-2009-1596220)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- trimethylamine N-oxide, gut microbiota, cardiovascular risk, all-cause mortality, major adverse cardiac and cerebrovascular events, dose-response relationship, plasma biomarkers, cardiovascular risk markers
- MeSH terms
- Gastrointestinal Microbiome, Aged, Cardiovascular Diseases, Cause of Death, Dose-Response Relationship, Drug, Female, Humans, Male, Methylamines, Middle Aged, Myocardial Infarction, Risk Factors, Biomarkers, Stroke
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