Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide
Open accessAbstract
AIMS: Recent metabolomics and animal model studies show trimethylamine-N-oxide (TMAO), an intestinal microbiota-dependent metabolite formed from dietary trimethylamine-containing nutrients such as phosphatidylcholine (PC), choline, and carnitine, is linked to coronary artery disease pathogenesis. Our aim was to examine the prognostic value of systemic choline and betaine levels in stable cardiac patients. METHODS AND RESULTS: We examined the relationship between fasting plasma choline and betaine levels and risk of major adverse cardiac events (MACE = death, myocardial infraction, stroke) in relation to TMAO over 3 years of follow-up in 3903 sequential stable subjects undergoing elective diagnostic coronary angiography. In our study cohort, median (IQR) TMAO, choline, and betaine levels were 3.7 (2.4-6.2)μM, 9.8 (7.9-12.2)μM, and 41.1 (32.5-52.1)μM, respectively. Modest but statistically significant correlations were noted between TMAO and choline (r = 0.33, P < 0.001) and less between TMAO and betaine (r = 0.09, P < 0.001). Higher plasma choline and betaine levels were associated with a 1.9-fold and 1.4-fold increased risk of MACE, respectively (Quartiles 4 vs. 1; P < 0.01, each). Following adjustments for traditional cardiovascular risk factors and high-sensitivity C-reactive protein, elevated choline [1.34 (1.03-1.74), P < 0.05], and betaine levels [1.33 (1.03-1.73), P < 0.05] each predicted increased MACE risk. Neither choline nor betaine predicted MACE risk when TMAO was added to the adjustment model, and choline and betaine predicted future risk for MACE only when TMAO was elevated. CONCLUSION: Elevated plasma levels of choline and betaine are each associated with incident MACE risk independent of traditional risk factors. However, high choline and betaine levels are only associated with higher risk of future MACE with concomitant increase in TMAO.
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- Findingown data§ Abstract
TMAO and choline showed a modest but statistically significant correlation (r = 0.33, P < 0.001).
“Modest but statistically significant correlations were noted between TMAO and choline (r ¼ 0.33, P , 0.001) and less between TMAO and betaine (r ¼ 0.09, P , 0.001).”
- Also stated in: § Baseline characteristics and relation of plasma choline and betaine levels and cardiovascular risks · plain
“Modest but statistically significant correlations were noted between TMAO and choline (r ¼ 0.33, P , 0.001) and between TMAO and betaine (r ¼ 0.09, P , 0.001).”
Quote in the paperNot a substantial claim - Also stated in: § Baseline characteristics and relation of plasma choline and betaine levels and cardiovascular risks · plain
- Findingown data§ Interaction between choline, betaine, and trimethylamine-N-oxide in predicting future major adverse cardiac event risk
When all three metabolites were included in the model, only TMAO predicted MACE risk (HR 1.73, 95% CI 1.3-2.31, P < 0.01).
“Remarkably, only TMAO predicted MACE risk when all three metabolites were included in the model [HR: 1.73 (1.3 -2.31), P , 0.01].”
Quote in the paperSubstantial claim - Findingown data§ Interaction between choline, betaine, and trimethylamine-N-oxide in predicting future major adverse cardiac event risk
Betaine was a far poorer precursor for TMAO than choline, producing 100-fold less d9-TMAO.
“Of note, however, compared with comparable oral challenge of d9-choline, 14 betaine was a far poorer precursor for TMAO, as it produced 100-fold less d9-TMAO (Figure 3A and B).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] source
Not checked in the free run.
- Findingown data§ Abstract
Higher plasma betaine levels were associated with a 1.4-fold increased risk of MACE (quartile 4 vs. quartile 1, P < 0.01).
“Higher plasma choline and betaine levels were associated with a 1.9-fold and 1.4-fold increased risk of MACE, respectively (Quartiles 4 vs. 1; P , 0.01, each).”
- Also stated in: § Baseline characteristics and relation of plasma choline and betaine levels and cardiovascular risks · plain
“Higher plasma choline or betaine levels were each associated with increased risk for MACE (1.9-fold and 1.4-fold, respectively; Quartile 4 vs. 1, P , 0.01, each; Table 2).”
Quote in the paperSubstantial claim - Also stated in: § Baseline characteristics and relation of plasma choline and betaine levels and cardiovascular risks · plain
- Findingown data§ Abstract
Higher plasma choline levels were associated with a 1.9-fold increased risk of MACE (quartile 4 vs. quartile 1, P < 0.01).
“Higher plasma choline and betaine levels were associated with a 1.9-fold and 1.4-fold increased risk of MACE, respectively (Quartiles 4 vs. 1; P , 0.01, each).”
- Also stated in: § Baseline characteristics and relation of plasma choline and betaine levels and cardiovascular risks · plain
“Higher plasma choline or betaine levels were each associated with increased risk for MACE (1.9-fold and 1.4-fold, respectively; Quartile 4 vs. 1, P , 0.01, each; Table 2).”
Quote in the paperSubstantial claim - Also stated in: § Baseline characteristics and relation of plasma choline and betaine levels and cardiovascular risks · plain
- Findingown data§ Abstract
When TMAO was added to the adjustment model, neither choline nor betaine predicted MACE risk.
“Neither choline nor betaine predicted MACE risk when TMAO was added to the adjustment model, and choline and betaine predicted future risk for MACE only when TMAO was elevated.”
- Also stated in: § Interaction between choline, betaine, and trimethylamine-N-oxide in predicting future major adverse cardiac event risk · plain
“Further, while choline and betaine each predicted future risk for MACE within 3 years following adjustments for traditional cardiovascular risk factors, addition of TMAO to the model completely attenuated the association for choline and significantly attenuate the association of betaine for MACE risk (Figure 4A and B).”
Quote in the paperSubstantial claim - Also stated in: § Interaction between choline, betaine, and trimethylamine-N-oxide in predicting future major adverse cardiac event risk · plain
- Findingown data§ Abstract
After adjustment for traditional cardiovascular risk factors and hs-CRP, elevated betaine predicted increased MACE risk (HR 1.33, 95% CI 1.03-1.73, P < 0.05).
“Following adjustments for traditional cardiovascular risk factors and high-sensitivity C-reactive protein, elevated choline [1.34 (1.03-1.74),P , 0.05], and betaine levels [1.33 (1.03-1.73),P , 0.05] each predicted increased MACE risk.”
- Also stated in: § Baseline characteristics and relation of plasma choline and betaine levels and cardiovascular risks · plain
“Following adjustments for traditional risk factors and hs C-reactive protein, elevated choline [hazard ratio, 1.34 (95% CI, 1.03-1.74,P , 0.05)], and betaine levels [hazard ratio, 1.33 (95% CI: 1.03 -1.73, P , 0.05)] each predicted increased MACE risk (Table 2).”
Quote in the paperSubstantial claim - Also stated in: § Baseline characteristics and relation of plasma choline and betaine levels and cardiovascular risks · plain
- Findingown data§ Abstract
After adjustment for traditional cardiovascular risk factors and hs-CRP, elevated choline predicted increased MACE risk (HR 1.34, 95% CI 1.03-1.74, P < 0.05).
“Following adjustments for traditional cardiovascular risk factors and high-sensitivity C-reactive protein, elevated choline [1.34 (1.03-1.74),P , 0.05], and betaine levels [1.33 (1.03-1.73),P , 0.05] each predicted increased MACE risk.”
- Also stated in: § Baseline characteristics and relation of plasma choline and betaine levels and cardiovascular risks · plain
“Following adjustments for traditional risk factors and hs C-reactive protein, elevated choline [hazard ratio, 1.34 (95% CI, 1.03-1.74,P , 0.05)], and betaine levels [hazard ratio, 1.33 (95% CI: 1.03 -1.73, P , 0.05)] each predicted increased MACE risk (Table 2).”
Quote in the paperSubstantial claim - Also stated in: § Baseline characteristics and relation of plasma choline and betaine levels and cardiovascular risks · plain
- Findingown data§ Abstract
TMAO and betaine showed a modest but statistically significant correlation (r = 0.09, P < 0.001).
“Modest but statistically significant correlations were noted between TMAO and choline (r ¼ 0.33, P , 0.001) and less between TMAO and betaine (r ¼ 0.09, P , 0.001).”
- Also stated in: § Baseline characteristics and relation of plasma choline and betaine levels and cardiovascular risks · plain
“Modest but statistically significant correlations were noted between TMAO and choline (r ¼ 0.33, P , 0.001) and between TMAO and betaine (r ¼ 0.09, P , 0.001).”
Quote in the paperNot a substantial claim - Also stated in: § Baseline characteristics and relation of plasma choline and betaine levels and cardiovascular risks · plain
- Findingown data§ Interaction between choline, betaine, and trimethylamine-N-oxide in predicting future major adverse cardiac event risk
After gut flora suppression with antibiotics, no detectable d9-TMAO was observed in plasma following oral d9-betaine challenge.
“Notably, no detectable d9-TMAO was observed in plasma following oral d9-betaine challenge (Figure 3C), consistent with gut flora involvement in oral betaine metabolism into TMAO.”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
Gut microbiota play an obligate role in TMAO formation from ingested choline, phosphatidylcholine, and carnitine in both animal models and humans.
“Gut microbiota have been shown to play an obligate role in TMAO formation from ingested choline, PC, and carnitine in both animal models and humans.14,16”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ Introduction
The connection between dietary choline and betaine and heart disease in human subjects is unclear.
“The connection between dietary choline and betaine and heart disease in subjects is unclear.”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data§ Discussion
The human clinical observation results are consistent with the previously recognized mechanistic role of TMAO in accelerated atherosclerosis.
“The results of these human clinical observation studies are thus consistent with the previously recognized mechanistic role of TMAO in accelerated atherosclerosis”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
TMAO formation from oral betaine has an obligatory requirement for intact gut flora.
“Importantly, we show that the TMAO formed from oral betaine has an obligatory requirement for intact gut flora, similar to previous observations with dietary choline.”
Quote in the paperSubstantial claim - Premisecitation§ Discussion
Choline, betaine, and TMAO are all metabolites formed following ingestion of dietary phosphatidylcholine.
“Choline, betaine, and TMAO are all metabolites formed following ingestion of dietary PC. 14,17”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ Discussion
Studies of acute increases in dietary intake of choline-rich foods show that they do not always lead to substantial increases in urinary TMA or TMAO in healthy subjects.
“At the same time, studies looking at acute increase in dietary intake (meal) of choline-rich foods show that they do not always lead to substantial increases in urinary TMA or TMAO in healthy subjects, 23”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [23] source
Not checked in the free run.
- Interpretationown data§ Interaction between choline, betaine, and trimethylamine-N-oxide in predicting future major adverse cardiac event risk
Oral betaine can serve as a precursor for TMAO formation.
“These results directly demonstrate for the first time that oral betaine can serve as a precursor for TMAO formation.”
Quote in the paperSubstantial claim - Premisecitation§ Discussion
In prior human studies, antibiotic administration had limited effects on circulating choline and betaine levels despite abolishing TMAO levels after ingestion of stable-isotope-labelled d9-phosphatidylcholine.
“Interestingly, the administration of antibiotics in humans in our prior studies had limited effects on circulating choline and betaine levels, despite abolition of TMAO levels, upon ingestion of stable-isotope-labelled d9-PC.17”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] source
Not checked in the free run.
- May combine two claims. 8
- Classified as probably not a substantial claim. 3
May combine two claims.
Findingown data§ AbstractIn the study cohort, the median plasma levels were 3.7 mM for TMAO, 9.8 mM for choline, and 41.1 mM for betaine.
“In our study cohort, median (IQR) TMAO, choline, and betaine levels were 3.7 (2.4 -6.2) mM, 9.8 (7.9 -12.2) mM, and 41.1 (32.5-52.1)mM, respectively.”
- Also stated in: § Baseline characteristics and relation of plasma choline and betaine levels and cardiovascular risks · plain
“The median (inter-quartile ranges) for choline, betaine, and TMAO plasma levels was 9.8 (7.9 -12.2) mM, 41.1 (32.5-52.1)mM, and 3.7 (2.4 -6.2) mM, respectively.”
Quote in the paperNot a substantial claim- Also stated in: § Baseline characteristics and relation of plasma choline and betaine levels and cardiovascular risks · plain
May combine two claims.
Findingown data§ AbstractCholine and betaine predicted increased MACE risk only among subjects with elevated TMAO levels, not among those with low TMAO levels.
“Neither choline nor betaine predicted MACE risk when TMAO was added to the adjustment model, and choline and betaine predicted future risk for MACE only when TMAO was elevated.”
- Also stated in: § Interaction between choline, betaine, and trimethylamine-N-oxide in predicting future major adverse cardiac event risk · plain
“cox regression analysis adjusted for multiple traditional risk factors reveals that choline and betaine predict increased MACE risk, but only among those with concomitant elevated TMAO levels and not in those with low TMAO levels (Figures 5 and 6).”
Quote in the paperSubstantial claim- Also stated in: § Interaction between choline, betaine, and trimethylamine-N-oxide in predicting future major adverse cardiac event risk · plain
May combine two claims.
Premisecitation§ DiscussionSystemic levels of choline, betaine, and TMAO are each independently associated with the prevalence of cardiovascular disease.
“Moreover, systemic levels of choline, betaine, and TMAO each are independently associated with the prevalence of CVD. 14”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] source
Not checked in the free run.
May combine two claims.
Premisecitation§ DiscussionTMAO itself inhibits reverse cholesterol transport and alters cholesterol and sterol metabolism in multiple compartments, including suppression of bile acid pool size and altered composition.
“Prior mechanistic studies in mice reveal that TMAO itself inhibits reverse cholesterol transport, and also alters cholesterol and sterol metabolism in multiple different compartments, including suppression of bile acid pool size and altered composition.16”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown data§ Statistical analysisAnalyses adjusted for age, sex, systolic blood pressure, LDL cholesterol, HDL cholesterol, smoking, diabetes mellitus, and hs-CRP to predict incident 3-year MACE risks.
“Adjustments were made for individual traditional risk factors including age, sex, systolic blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, smoking, diabetes mellitus, and hs C-reactive protein to predict incident 3-year MACE risks.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductown data§ Study populationAll subjects were followed for 3 years from enrollment, with adjudication of MACE defined as all-cause mortality, non-fatal myocardial infarction, or non-fatal stroke.
“All subjects were followed over a period of 3 years from time of enrollment including adjudication of MACE(which includes the future development of all-cause mortality, non-fatal myocardial infarction, or non-fatal stroke).”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ DiscussionEnterohepatic circulation of bile likely helps maintain intestinal microbial colonies by providing a steady substrate source and blunts the impact of acute dietary choline changes on plasma TMAO levels.
“Furthermore, enterohepatic circulation of bile, which is exceedingly high in total choline content, likely contributes both to the maintenance of intestinal microbial colonies by providing a steady source of substrates for their metabolism, 24 and blunts the impact of acute changes in dietary choline on plasma TMAO levels.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [24] source
Not checked in the free run.
May combine two claims.
Premisecitation§ DiscussionThe authors' group has established the obligatory role of intestinal microbiota in TMAO production from dietary choline and other TMA nutrients in humans, and the association between elevated fasting TMAO and higher incident risks of long-term MACEs.
“We have also established the obligatory role of intestinal microbiota in the production of TMAO from dietary choline and other TMA nutrients in humans, 16,17 and the association between elevated fasting levels of TMAO and higher incident risks of long-term MACEs.17”
Quote in the paperSubstantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
Study design and conductown data§ Study populationThe study prospectively recruited 3903 sequential stable subjects undergoing elective, non-urgent coronary angiography without evidence of acute coronary syndrome.
“We prospectively recruited sequential stable subjects (n ¼ 3903) undergoing elective, non-urgent coronary angiography at the Cleveland Clinic without any evidence of acute coronary syndrome (cardiac troponin I ≤0.03 ng/mL).”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ IntroductionElevated TMAO levels predict increased prevalent cardiovascular disease risk and increased incident risk of major adverse cardiovascular events in large-scale human clinical studies.
“Moreover, elevated levels of TMAO have been shown to predict increased prevalent cardiovascular disease (CVD) risk, and increased incident risk of major adverse cardiovascular events (MACE ¼ myocardial infarction, stroke, and death) in large-scale human clinical studies.14,16,17”
Quote in the paperSubstantial claim0 of 3 sources checked
The authors state this as an assumption.
The relationship between TMAO and the clinical prognostic value of choline or betaine was unknown at the time of the study.
“the relationship between TMAO and the clinical prognostic value of choline or betaine is unknown.”
The authors state this as an assumption.
Whether orally ingested betaine produces TMAO was unknown at the time of the study.
“Surprisingly, although a TMA-containing species, whether orally ingested betaine produces TMAO or not is unknown.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
TMAO levels are associated with cardiovascular disease risks in a variety of cohorts.
“Numerous recent case–control and longitudinal studies have shown a striking association between trimethylamine N‐oxide (TMAO) levels and cardiovascular disease risks in a variety of cohorts.1, 2, 3, 4, 5, 6, 7, 8, 9, 10”
From Trimethylamine N‐Oxide Promotes Vascular Inflammation Through Signaling of Mitogen‐Activated Protein Kinase and Nuclear Factor‐κB (2016) · cites this paper as [4]
Trimethylamine-N-oxide (TMAO) is produced by gut microbes from dietary choline, phosphatidylcholine and L-carnitine.
“Specifically, gut microbiota-mediated metabolism of phosphatidylcholine, choline or L-carnitine each have been shown to ultimately produced trimethylamine-N-oxide (TMAO), and in multiple clinical studies, TMAO levels have been shown to be associated with cardiovascular risks8–10, 13.”
TMAO can also be produced from betaine, which is an oxidation product of choline.
“TMAO may also be generated from betaine, which is an oxidation product of choline [9].”
From Microbiota‐dependent metabolite trimethylamine‐N‐oxide is associated with disease severity and survival of patients with chronic heart failure (2015) · cites this paper as [9]
The prognostic value of choline and betaine depends on a simultaneous elevation of TMAO levels.
“whereas the prognostic values of choline and betaine depend on concomitant elevation of TMAO levels, suggesting links between alterations of the microbiota, dietary composition and atherosclerosis [9].”
From Microbiota‐dependent metabolite trimethylamine‐N‐oxide is associated with disease severity and survival of patients with chronic heart failure (2015) · cites this paper as [9]
Elevated circulating carnitine, choline, or betaine levels are each associated with future MI, stroke, or death independent of traditional risk factors, but their prognostic value is primarily restricted to those with elevated TMAO.
“Thus, while elevated circulating carnitine, choline, or betaine levels (all substrates of gut microbiota and dietary precursors of TMA/TMAO production) were each associated with future risk of MI, stroke, or death independent of traditional risk factors, their prognostic values were primarily restricted to those with concomitantly elevated TMAO levels (39,55).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [55]
In larger cohorts, the prognostic value for CVD was largely confined to TMAO formation, especially from choline and L-carnitine.
“subsequent analyses in larger cohorts revealed that the prognostic value was largely confined to the formation of TMAO, especially from choline and L-carnitine (39,55).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [55]
TMAO levels are strongly linked to cardiovascular disease risks.
“a metabolite shown to be both mechanistically linked to atherosclerosis and whose levels are strongly linked to cardiovascular disease (CVD) risks.”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [55]
In multiple human studies, elevated TMAO is independently associated with prevalent CVD and incident risks for MI, stroke, death, and revascularization.
“In multiple human studies, elevated TMAO has been independently associated with prevalent CVD and incident risks for MI, stroke, death, and revascularization.”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [55]
Labeled betaine or phosphatidylcholine given in vivo produced d9-TMA and d9-TMAO directly in plasma and urine.
“In vivo studies in which trimethyl-d9-labeled betaine or PC were ingested showed a direct generation of d9-TMA and d9-TMAO within plasma and urine (37,39,55).”
From The contributory role of gut microbiota in cardiovascular disease (2014) · cites this paper as [55]
Plasma TMAO levels in subjects are associated with prevalent and incident cardiovascular disease risks.
“plasma levels in subjects are associated with prevalent and incident cardiovascular disease risks (5, 7, 9, 10).”
From Transmission of Atherosclerosis Susceptibility with Gut Microbial Transplantation (2015) · cites this paper as [9]
Of the 22 studies, 2 only investigated combinations of TMAO and choline, betaine, or l-carnitine, so they were not included in the analysis for TMAO.
“Of the 22 studies, 2 only investigated combinations of TMAO and choline, betaine,9 or l‐carnitine4; thus we did not include the 2 studies4, 9 in the analysis for TMAO, although these studies were eligible for the analysis of TMAO precursors and risk of MACE.”
In another study, only TMAO predicted the risk of major adverse cardiovascular events when choline, betaine, and TMAO were simultaneously included in the multivariate-adjusted model.
“In another study, it was found that only TMAO predicted the risk of MACE when choline, betaine, and TMAO were simultaneously included in the multivariate‐adjusted model, and choline and betaine predicted risk of MACE only among participants with an above median value of TMAO (>3.7 μmol/L) concentrations.9”
In another study, choline and betaine predicted risk of major adverse cardiovascular events only among participants with an above median value of TMAO (>3.7 μmol/L).
“In another study, it was found that only TMAO predicted the risk of MACE when choline, betaine, and TMAO were simultaneously included in the multivariate‐adjusted model, and choline and betaine predicted risk of MACE only among participants with an above median value of TMAO (>3.7 μmol/L) concentrations.9”
TMA is also obtained from bacterial metabolism of dietary betaine.
“TMA also is obtained from bacterial metabolism of dietary betaine (120).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [120]
In stable cardiac patients, elevated plasma choline and betaine were associated with incident mortality, myocardial infarction, and stroke risk, independent of traditional risk factors.
“Elevated concentrations of plasma choline and betaine, assessed in stable cardiac patients, were associated with incident mortality, myocardial infarction, and stroke risk, independent of other traditional risk factors.”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [120]
Choline and betaine were predictive only when plasma TMAO also increased simultaneously.
“However, these metabolites were predictive only when a simultaneous increase in plasma TMAO concentrations was observed (120).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [120]
Multiple human and animal studies support mechanistic and clinical prognostic associations between TMAO formation and cardiometabolic disease risks.
“multiple human and animal studies supporting both mechanistic and clinical prognostic associations between TMAO formation and cardiometabolic disease risks have been reported8–16.”
From Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential (2018) · cites this paper as [10]
TMAO exacerbates atherosclerosis in a genetic knockout mouse model.
“TMAO exacerbates atherosclerosis in a genetic knockout mouse model, in part by promoting forward cholesterol transport and by inhibiting reverse cholesterol transport (8, 10, 19, 20).”
TMAO inhibits reverse cholesterol transport.
“TMAO exacerbates atherosclerosis in a genetic knockout mouse model, in part by promoting forward cholesterol transport and by inhibiting reverse cholesterol transport (8, 10, 19, 20).”
TMAO promotes forward cholesterol transport.
“TMAO exacerbates atherosclerosis in a genetic knockout mouse model, in part by promoting forward cholesterol transport and by inhibiting reverse cholesterol transport (8, 10, 19, 20).”
In humans, elevated plasma levels of TMAO are positively correlated with an increased risk for major adverse cardiovascular events and death.
“In humans, a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events and death is reported.”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [33]
In 3903 sequential stable subjects undergoing elective diagnostic coronary angiography, elevated plasma levels of choline and betaine were each associated with poor prognosis even after adjusting for traditional cardiovascular risk factors.
“In 3903 sequential stable subjects undergoing elective diagnostic coronary angiography, elevated plasma levels of choline and betaine were each associated with poor prognosis even after adjusting for traditional cardiovascular risk factors.”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [33]
High choline and betaine levels are associated with higher risk of future major cardiac events only with concomitant increased levels of TMAO.
“However, high choline and betaine levels are associated with higher risk of future major cardiac events only with concomitant increased levels of TMAO [33].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [33]
Substantial evidence indicates that elevated TMAO levels are associated with cardiovascular disease.
“Thus, substantial evidence indicates that elevated TMAO levels are associated with cardiovascular disease (CVD).”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [33]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Choline and betaine medians are reversed in Table 1
MinorTable 1 assigns 9.8 mM to betaine and 41.1 mM to choline, whereas the Results text assigns those values the other way around. The quartile ranges in Table 2 also align with the Results text.
“| Betaine (mM) | 9.8 (7.9-12.2) | | Choline (mM) | 41.1 (32.5-52.1) |”
“The median (inter-quartile ranges) for choline, betaine, and TMAO plasma levels was 9.8 (7.9 -12.2) mM, 41.1 (32.5-52.1)mM, and 3.7 (2.4 -6.2) mM, respectively.”
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Flagged first, then by citations
Research works printed but not linked: 2
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Cited by
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Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk
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“Nevertheless, recent studies suggest that these elevated levels are only associated with higher risk of MACE when high TMAO levels are concomitantly present [57].”
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Self-citationγ-Butyrobetaine Is a Proatherogenic Intermediate in Gut Microbial Metabolism of L-Carnitine to TMAO
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Transmission of Atherosclerosis Susceptibility with Gut Microbial Transplantation
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Self-citationTrimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease
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Self-citationMicrobial modulation of cardiovascular disease
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Self-citationSerum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden
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The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance
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Self-citationFood, immunity, and the microbiome
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Fecal microbiota transplantation broadening its application beyond intestinal disorders
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Diabetes is Associated with Higher Trimethylamine N-oxide Plasma Levels
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“We put a special focus on metabolites that are known to be associated with cardiovascular disease and CVR factors (including diabetes) such as amino-acids (including BCAA), phospholipids (PCs), phenylalanine, TMAO and indoxyl sulfate.”
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- Authors
- Wang, Z., Tang, W. H. W., Buffa, J. A., Fu, X., Britt, E. B., Koeth, R. A., Levison, B. S., Fan, Y., Wu, Y., & Hazen, S. L.
- Affiliations
- Cleveland Clinic (US)
- Cleveland State University (US)
- Corresponding author
- Hazen, S. L.
- Venue
- European Heart Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-02-03
- Volume
- 35
- Issue
- 14
- Pages
- 904-910
- ISSN
- 0195-668X (ISSN-L)
- 1522-9645
- PMC
- PMC3977137
- OpenAlex
- W2166052068
- Cited by
- 559
- References
- 22
- Citations by year
- 2026: 14 · 2025: 27 · 2024: 39 · 2023: 38 · 2022: 71 · 2021: 56 · 2020: 60 · 2019: 50 · 2018: 56 · 2017: 41 · 2016: 51 · 2015: 38 · 2014: 18
- FWCI
- 20.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Heart Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EngagedScholarship @ Cleveland State University (Cleveland State University) (submittedVersion)
- Funders
- Office of Dietary Supplements (R01 HL103866, P20 HL113452)
- American Heart Association (12SDG12050473)
- Cleveland Clinic
- National Institutes of Health (UL1TR000439)
- National Heart, Lung, and Blood Institute (R01HL103931, P20HL113452, P01HL076491, P01HL098055, R01HL103866)
- National Institute of General Medical Sciences (T32GM007250)
- National Center for Advancing Translational Sciences
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- trimethylamine N-oxide, choline, betaine, gut microbiota, major adverse cardiac events, coronary artery disease, phosphatidylcholine, L-carnitine, cardiovascular risk prediction, stable coronary artery disease, plasma metabolites
- MeSH terms
- Animals, Betaine, Cardiovascular Diseases, Choline, Female, Humans, Intestinal Mucosa, Male, Methylamines, Middle Aged, Prognosis, Prospective Studies, Risk Factors, Risk Assessment, Mice, Kaplan-Meier Estimate, Microbiota
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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