Background: Gut microbial metabolites such as trimethylamine N-oxide (TMAO) and its precursors, namely betaine, L-carnitine, and choline, have been implicated as risk factors for cardiovascular events and mortality development. Therefore, we aim to perform a systematic review and meta-analysis to assess the validity of these associations.

Methods: MEDLINE and Scopus were queried from their inception to August 2023 to identify studies that quantified estimates of the associations of TMAO with the development of major adverse cardiovascular events (MACE) or death. A random-effects meta-analysis was conducted to pool unadjusted or multivariable-adjusted hazard ratios (HR) and their 95% confidence intervals. The primary endpoint was the risk of MACE and all-cause death.

Results: 30 prospective observational studies (n = 48 968) were included in the analysis. Elevated TMAO levels were associated with a significantly greater risk of MACE and all-cause death compared to low TMAO levels (

Hr: 1.41, 95% CI 1.2-1.54, P < .00001, I2 = 43%) and (

Hr: 1.55, 95% CI 1.37-1.75, P < .00001, I2 = 46%), respectively. Furthermore, high levels of either L-carnitine or choline were found to significantly increase the risk of MACE. However, no significant difference was seen in MACE in either high or low levels of betaine.

Conclusion: Elevated concentrations of TMAO were associated with increased risks of MACE and all-cause mortality. High levels of L-carnitine/choline were also significantly associated with an increased risk of MACE. However, no significant difference was found between high or low levels of betaine for the outcome of MACE.

Background: Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite produced from dietary nutrients. Many studies have discovered that circulating TMAO concentrations are linked to a wide range of health outcomes.

Objectives: This study aimed to summarize health outcomes related to circulating TMAO concentrations.

Methods: We searched the Embase, Medline, Web of Science, and Scopus databases from inception to 15 February, 2022 to identify and update meta-analyses examining the associations between TMAO and multiple health outcomes. For each health outcome, we estimated the summary effect size, 95% prediction CI, between-study heterogeneity, evidence of small-study effects, and evidence of excess-significance bias. These metrics were used to evaluate the evidence credibility of the identified associations.

Results: This umbrella review identified 24 meta-analyses that investigated the association between circulating TMAO concentrations and health outcomes including all-cause mortality, cardiovascular diseases (CVDs), diabetes mellitus (DM), cancer, and renal function. We updated these meta-analyses by including a total of 82 individual studies on 18 unique health outcomes. Among them, 14 associations were nominally significant. After evidence credibility assessment, we found 6 (33%) associations (i.e., all-cause mortality, CVD mortality, major adverse cardiovascular events, hypertension, DM, and glomerular filtration rate) to present highly suggestive evidence.

Conclusions: TMAO might be a novel biomarker related to human health conditions including all-cause mortality, hypertension, CVD, DM, cancer, and kidney function. Further studies are needed to investigate whether circulating TMAO concentrations could be an intervention target for chronic disease.This review was registered at www.crd.york.ac.uk/prospero/ as CRD42021284730.

Trimethylamine-N-oxide (TMAO) is a gut microbiome-derived metabolite of choline, L-carnitine and lecithin, abundant in animal source foods. In experimental models, higher blood TMAO levels enhance atherosclerotic cardiovascular disease (ASCVD). However in humans, most prior studies have evaluated high risk or secondary prevention populations, and no studies have investigated relationships in a diverse, multi-ethnic population. We evaluated 6,767 US adults free of ASCVD at baseline in the community-based Multi-Ethnic Study of Atherosclerosis (MESA), including 38% identifying as White; 28%, as Black; 22%, as Hispanic; and 12%, as Chinese adults. Plasma TMAO was measured serially at baseline and 5-years, and its time-varying association with incident ASCVD determined using Cox proportional hazards. Multivariate analyses adjusted for time-varying demographics, lifestyle factors, medical history, lipid measures, antibiotic use and dietary habits. During median 11.3 years follow-up, 852 ASCVD events occurred. After multivariate adjustment, TMAO associated with higher risk of ASCVD in a dose-dependent fashion, with hazard ratios across quintiles of 1.02, 1.17, 1.23, and 1.33 (95% CI 1.02, 1.74), respectively, compared to the lowest quintile (P-trend = 0.01). Risk appeared possibly larger among Hispanic and Chinese adults; and among individuals with lower baseline renal function; although these interactions did not achieve statistical significance. Plasma concentrations of TMAO associated with higher risk of incident ASCVD in this multi-ethnic US cohort, supporting a need to test dietary and pharmacologic interventions targeting the diet-microbiome axis for potential cardiovascular risk prevention in diverse populations.

Background Trimethylamine N-oxide (TMAO) is a gut microbiota-dependent metabolite of dietary choline, L-carnitine, and phosphatidylcholine-rich foods. On the basis of experimental studies and patients with prevalent disease, elevated plasma TMAO may increase risk of atherosclerotic cardiovascular disease (ASCVD). TMAO is also renally cleared and may interact with and causally contribute to renal dysfunction. Yet, how serial TMAO levels relate to incident and recurrent ASCVD in community-based populations and the potential mediating or modifying role of renal function are not established. Methods and Results We investigated associations of serial measures of plasma TMAO, assessed at baseline and 7 years, with incident and recurrent ASCVD in a community-based cohort of 4131 (incident) and 1449 (recurrent) older US adults. TMAO was measured using stable isotope dilution liquid chromatography-tandem mass spectrometry (laboratory coefficient of variation, <6%). Incident ASCVD (myocardial infarction, fatal coronary heart disease, stroke, sudden cardiac death, or other atherosclerotic death) was centrally adjudicated using medical records. Risk was assessed by multivariable Cox proportional hazards regression, including time-varying demographics, lifestyle factors, medical history, laboratory measures, and dietary habits. Potential mediating effects and interaction by estimated glomerular filtration rate (eGFR) were assessed. During prospective follow-up, 1766 incident and 897 recurrent ASCVD events occurred. After multivariable adjustment, higher levels of TMAO were associated with a higher risk of incident ASCVD, with extreme quintile hazard ratio (HR) compared with the lowest quintile=1.21 (95% CI, 1.02-1.42; -trend=0.029). This relationship appeared mediated or confounded by eGFR (eGFR-adjusted HR, 1.07; 95% CI, 0.90-1.27), as well as modified by eGFR (-interaction <0.001). High levels of TMAO were associated with higher incidence of ASCVD in the presence of impaired renal function (eGFR <60 mL/min per 1.73 m: HR, 1.56 [95% CI, 1.13-2.14]; -trend=0.007), but not normal or mildly reduced renal function (eGFR ≥60 mL/min per 1.73 m: HR, 1.03 [95% CI, 0.85-1.25]; -trend=0.668). Among individuals with prior ASCVD, TMAO associated with higher risk of recurrent ASCVD (HR, 1.25 [95% CI, 1.01-1.56]; -trend=0.009), without significant modification by eGFR. Conclusions In this large community-based cohort of older US adults, serial measures of TMAO were associated with higher risk of incident ASCVD, with apparent modification by presence of impaired renal function and with higher risk of recurrent ASCVD.

Aims: Little is known about associations of trimethylamine N-oxide (TMAO), a novel gut microbiota-generated metabolite of dietary phosphatidylcholine and carnitine, and its changes over time with all-cause and cause-specific mortality in the general population or in different race/ethnicity groups. The study aimed to investigate associations of serially measured plasma TMAO levels and changes in TMAO over time with all-cause and cause-specific mortality in a multi-ethnic community-based cohort.

Methods And Results: The study included 6,785 adults from the Multi-Ethnic Study of Atherosclerosis. TMAO was measured at baseline and year 5 using mass spectrometry. Primary outcomes were adjudicated all-cause mortality and cardiovascular disease (CVD) mortality. Secondary outcomes were deaths due to kidney failure, cancer, or dementia obtained from death certificates. Cox proportional hazards models with time-varying TMAO and covariates assessed the associations with adjustment for sociodemographics, lifestyles, diet, metabolic factors, and comorbidities. During a median follow-up of 16.9 years, 1704 participants died and 411 from CVD. Higher TMAO levels associated with higher risk of all-cause mortality [hazard ratio (HR): 1.12, 95% confidence interval (CI): 1.08-1.17], CVD mortality (

Hr: 1.09, 95%

Ci: 1.00-1.09), and death due to kidney failure (

Hr: 1.44, 95%

Ci: 1.25-1.66) per inter-quintile range, but not deaths due to cancer or dementia. Annualized changes in TMAO levels associated with higher risk of all-cause mortality (

Hr: 1.10, 95%

Ci: 1.05-1.14) and death due to kidney failure (

Hr: 1.54, 95%

Ci: 1.26-1.89) but not other deaths.

Conclusion: Plasma TMAO levels were positively associated with mortality, especially deaths due to cardiovascular and renal disease, in a multi-ethnic US cohort.

Background: A gut-microbial metabolite, trimethylamine N-oxide (TMAO), has been associated with coronary atherosclerotic burden. No previous prospective study has addressed associations of long-term changes in TMAO with coronary heart disease (CHD) incidence.

Objectives: The purpose of this study was to investigate whether 10-year changes in plasma TMAO levels were significantly associated with CHD incidence.

Methods: This prospective nested case-control study included 760 healthy women at baseline. Plasma TMAO levels were measured both at the first (1989 to 1990) and the second (2000 to 2002) blood collections; 10-year changes (Δ) in TMAO were calculated. Incident cases of CHD (n = 380) were identified after the second blood collection through 2016 and were matched to controls (n = 380).

Results: Regardless of the initial TMAO levels, 10-year increases in TMAO from the first to second blood collection were significantly associated with an increased risk of CHD (relative risk [RR] in the top tertile: 1.58 [95% confidence interval (CI): 1.05 to 2.38]; RR per 1-SD increment: 1.33 [95%

Ci: 1.06 to 1.67]). Participants with elevated TMAO levels (the top tertile) at both time points showed the highest RR of 1.79 (95%

Ci: 1.08 to 2.96) for CHD as compared with those with consistently low TMAO levels. Further, we found that the ΔTMAO-CHD relationship was strengthened by unhealthy dietary patterns (assessed by the Alternate Healthy Eating Index) and was attenuated by healthy dietary patterns (p interaction = 0.008).

Conclusions: Long-term increases in TMAO were associated with higher CHD risk, and repeated assessment of TMAO over 10 years improved the identification of people with a higher risk of CHD. Diet may modify the associations of ΔTMAO with CHD risk.

Trimethylamine-N-oxide (TMAO) is the main diet-induced metabolite produced by the gut microbiota, and it is mainly eliminated through renal excretion. TMAO has been correlated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) and related complications, such as cardiovascular mortality or major adverse cardiovascular events (MACE). Meta-analyses have postulated that high circulating TMAO levels are associated with an increased risk of cardiovascular events and all-cause mortality, but the link between TMAO and CVD remains not fully consistent. The results of prospective studies vary depending on the target population and the outcome studied, and the adjustment for renal function tends to decrease or reverse the significant association between TMAO and the outcome studied, strongly suggesting that the association is substantially mediated by renal function. Importantly, one Mendelian randomization study did not find a significant association between genetically predicted higher TMAO levels and cardiometabolic disease, but another found a positive causal relationship between TMAO levels and systolic blood pressure, which-at least in part-could explain the link with renal function. The mechanisms by which TMAO can increase this risk are not clearly elucidated, but current evidence indicates that TMAO induces cholesterol metabolism alterations, inflammation, endothelial dysfunction, and platelet activation. Overall, there is no fully conclusive evidence that TMAO is a causal factor of ASCVD, and, especially, whether TMAO induces or just is a marker of hypertension and renal dysfunction requires further study.

Aims: The microbiome-derived metabolite trimethylamine-N-oxide (TMAO) has attracted major interest and controversy both as a diagnostic biomarker and therapeutic target in atherothrombosis.

Methods And Results: Plasma TMAO increased in mice on 'unhealthy' high-choline diets and notably also on 'healthy' high-fibre diets. Interestingly, TMAO was found to be generated by direct oxidation in the gut in addition to oxidation by hepatic flavin-monooxygenases. Unexpectedly, two well-accepted mouse models of atherosclerosis, ApoE-/- and Ldlr-/- mice, which reflect the development of stable atherosclerosis, showed no association of TMAO with the extent of atherosclerosis. This finding was validated in the Framingham Heart Study showing no correlation between plasma TMAO and coronary artery calcium score or carotid intima-media thickness (IMT), as measures of atherosclerosis in human subjects. However, in the tandem-stenosis mouse model, which reflects plaque instability as typically seen in patients, TMAO levels correlated with several characteristics of plaque instability, such as markers of inflammation, platelet activation, and intraplaque haemorrhage.

Conclusions: Dietary-induced changes in the microbiome, of both 'healthy' and 'unhealthy' diets, can cause an increase in the plasma level of TMAO. The gut itself is a site of significant oxidative production of TMAO. Most importantly, our findings reconcile contradictory data on TMAO. There was no direct association of plasma TMAO and the extent of atherosclerosis, both in mice and humans. However, using a mouse model of plaque instability we demonstrated an association of TMAO plasma levels with atherosclerotic plaque instability. The latter confirms TMAO as being a marker of cardiovascular risk.

Context: Several studies suggest a relationship between trimethylamine N-oxide (TMAO) concentrations and increased cardiometabolic risk, but findings are controversial.

Objective: The aim of this systematic review and meta-analysis was to summarize evidence of the relationship between circulating TMAO levels and risk of hypertension and increased serum lipids in a dose-response and 2-class meta-analysis of discrete and continuous variables.

Data Sources: PubMed, Scopus, Cochrane, and ProQuest databases were searched.

Study Selection: Observational studies that reported disease status of participants (≥ 18 years), type of sample in which TMAO was measured (serum or plasma), and results based on at least 2 categories of TMAO concentrations, including relative risks, hazard ratios, or odds ratios with 95%CIs for cardiometabolic risk factors in association with circulating TMAO levels were selected. Papers were reviewed independently by both authors. The Newcastle-Ottawa Scale was used to assess the quality of included studies.

Data Extraction: The following data were extracted: first author's name, publication year, study design, study location, demographic information of participants, and concentrations of circulating TMAO.

Results: Eighteen studies were included in the meta-analysis. There was a dose-response relationship between circulating TMAO and increased odds of hypertension in cohort studies (P  for nonlinearity = 0.049), in plasma-derived TMAO samples (P  for nonlinearity = 0.043), in patients with cardiovascular disease (P  for nonlinearity = 0.048), and in apparently healthy individuals from community-based studies (P  for nonlinearity = 0.005). Moreover, the highest category of TMAO concentrations was associated with a 2.36 mmHg increase in systolic blood pressure when compared with the lowest category. The dose-response meta-analysis of continuous variables revealed that an increase in TMAO is associated with reduced high-density lipoprotein cholesterol in apparently healthy individuals and reduced high-density lipoprotein cholesterol and increased total cholesterol in patients with cardiovascular disease.

Conclusions: Circulating TMAO is positively associated with an increased risk of hypertension and other cardiometabolic disorders in adults.

Systematic Review Registration: PROSPERO identification number CRD42019138296.

Objective: To provide a theoretical basis for intestinal intervention in the treatment of coronary heart disease. Methods: Summarizing the mechanism of trimethylamine oxide (TMAO) inducing coronary heart disease and discussing the target of clinical intervention including TMAO generation, metabolism, and other links. The authors also clarified the potential clinical value of TMAO as a predictor of cardiovascular disease．. Results: The intestinal microbiota metabolite TMAO is closely related to the occurrence and development of coronary heart disease. TMAO can induce the development of coronary heart disease by promoting endothelial cell dysfunction, promoting foam cell formation, affecting cholesterol and bile acid metabolism, and promoting platelet activation and thrombosis. Diet, physical exercise, and other ways can reshape intestinal flora, inhibit TMAO generation, and help to prevent and cure coronary heart disease. In addition, TMAO has important clinical value in predicting risk stratification and evaluating the prognosis of coronary heart disease. Conclusion: TMAO can induce and assist in the development of coronary heart disease by promoting endothelial cell dysfunction, foam cell formation, and other mechanisms. At present, diet and physical exercise can reduce the production of TMAO to a certain extent, to prevent the occurrence and development of coronary heart disease. Furthermore, TMAO is a promising predictive marker for risk stratification and evaluating the prognosis of coronary heart disease.TMAO can not only directly induce coronary heart disease by promoting endothelial cell dysfunction, foam cell formation and other mechanisms, but also promote the occurrence and development of coronary heart disease by affecting the risk factors related to coronary heart disease (such as hypertension and diabetes). It has been confirmed that diet and physical exercise can reduce the production of TMAO to a certain extent and prevent the occurrence and development of coronary heart disease. In addition, TMAO is a valuable indicator for assessing risk stratification and prognosis of coronary heart disease.