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
Open accessAbstract
AIMS: Carnitine and choline are major nutrient precursors for gut microbiota-dependent generation of the atherogenic metabolite, trimethylamine N-oxide (TMAO). We performed randomized-controlled dietary intervention studies to explore the impact of chronic dietary patterns on TMAO levels, metabolism and renal excretion. METHODS AND RESULTS: Volunteers (N = 113) were enrolled in a randomized 2-arm (high- or low-saturated fat) crossover design study. Within each arm, three 4-week isocaloric diets (with washout period between each) were evaluated (all meals prepared in metabolic kitchen with 25% calories from protein) to examine the effects of red meat, white meat, or non-meat protein on TMAO metabolism. Trimethylamine N-oxide and other trimethylamine (TMA) related metabolites were quantified at the end of each diet period. A random subset (N = 13) of subjects also participated in heavy isotope tracer studies. Chronic red meat, but not white meat or non-meat ingestion, increased plasma and urine TMAO (each >two-fold; P < 0.0001). Red meat ingestion also significantly reduced fractional renal excretion of TMAO (P < 0.05), but conversely, increased fractional renal excretion of carnitine, and two alternative gut microbiota-generated metabolites of carnitine, γ-butyrobetaine, and crotonobetaine (P < 0.05). Oral isotope challenge revealed red meat or white meat (vs. non-meat) increased TMA and TMAO production from carnitine (P < 0.05 each) but not choline. Dietary-saturated fat failed to impact TMAO or its metabolites. CONCLUSION: Chronic dietary red meat increases systemic TMAO levels through: (i) enhanced dietary precursors; (ii) increased microbial TMA/TMAO production from carnitine, but not choline; and (iii) reduced renal TMAO excretion. Discontinuation of dietary red meat reduces plasma TMAO within 4 weeks.
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- Findingown data
Red meat diet significantly increased fractional renal excretion of carnitine, c-butyrobetaine, and crotonobetaine compared with non-meat diet.
“In contrast, the fractional renal excretion of carnitine, c-butyrobetaine, and crotonobetaine increased significantly (P < 0.0001, P < 0.0001, and P = 0.0007, respectively) on the red meat diet in comparison to the non-meat diet (Figure 5D-F).”
Quote in the paperSubstantial claim - Findingown data
Red meat diet modestly but significantly reduced plasma betaine concentrations compared with non-meat or white meat diets.
“Interestingly, very modest but statistically significant reductions were noted in plasma betaine and urine choline concentrations following chronic consumption of the red meat diet compared with the non-meat or white meat diets (Figures 2A and 3).”
Quote in the paperNot a substantial claim - Findingown data
Red meat diet significantly increased c-butyrobetaine concentrations in plasma and urine.
“Two additional carnitine related metabolites generated by gut microbiota, c-butyrobetaine, and crotonobetaine, 16,19 both showed significant increases in both plasma (P < 0.0001 and P = 0.004, respectively) and urine (P < 0.0001 each) concentrations following 4 weeks of the red meat diet, though the relative magnitude of the increase was smaller than that for TMAO (Figures 2A and 3).”
Quote in the paperNot a substantial claim - Findingown data
Red meat diet significantly increased crotonobetaine concentrations in plasma and urine.
“Two additional carnitine related metabolites generated by gut microbiota, c-butyrobetaine, and crotonobetaine, 16,19 both showed significant increases in both plasma (P < 0.0001 and P = 0.004, respectively) and urine (P < 0.0001 each) concentrations following 4 weeks of the red meat diet, though the relative magnitude of the increase was smaller than that for TMAO (Figures 2A and 3).”
Quote in the paperNot a substantial claim - Findingown data
Plasma TMAO levels were most strongly correlated with choline and carnitine, particularly following 4 weeks of red meat and white meat diets.
“Notably, plasma levels of TMAO were most strongly correlated to choline and carnitine (and choline and carnitine with one another), particularly following 4 weeks of the red meat and white meat diets.”
Quote in the paperNot a substantial claim
- Findingown data
Increased dietary saturated fat had no effect on plasma TMAO concentrations.
“Thus, increased level of dietary-saturated fat had no effect on plasma concentrations of TMAO.”
Quote in the paperNot a substantial claim - Findingown data
SDMA is highly correlated with renal function (r>0.80; P<0.0001) in both men and women.
“Further, we too had performed unpublished untargeted metabolomics analyses and identified symmetric dimethylarginine (SDMA) as being highly correlated with renal function (r > 0.80; P < 0.0001) in both men and women alike (data not shown), and alternative published studies have similarly suggested SDMA serves as an excellent endogenous marker of renal function. 25”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Kielstein, 2006, Symmetric dimethylarginine (SDMA) as endogenous marker of renal function–a meta-analysis, Nephrol Dial Transplant source
Not checked in the free run.
- Findingown data
24h urine d3-TMA and d3-TMAO recovered after d3-carnitine ingestion were significantly higher after red meat or white meat diets compared to non-meat diet.
“For example, the 24 h urine d3-TMA and d3-TMAO recovered following ingestion of d3-carnitine was significantly (several-fold) higher in subjects following either the red meat or white meat diets compared to the non-meat diet (Figure 7A and B).”
Quote in the paperSubstantial claim - Findingown data
High vs low saturated fat diets for 4 weeks showed no significant differences in plasma levels of monitored metabolites.
“Plasma levels of each of the monitored metabolites following 4 weeks of low-vs.high-saturated fat diets failed to show any significant differences (Figure 4A).”
Quote in the paperSubstantial claim - Findingown data
24h urine d3-carnitine, d3-c-butyrobetaine, and d3-crotonobetaine were significantly increased following red meat diet.
“Similarly, the 24 h urine d3-carnitine, d3-c-butyrobetaine, and d3-crotonobetaine were all significantly increased in subjects following the red meat diet (Figure 7C-E).”
Quote in the paperSubstantial claim - Findingown data
24h urinary total d6-choline and d6-betaine showed no significant differences among diets, except a modest decrease after white meat vs red meat.
“Similarly, 24 h urinary total d6-choline and d6betaine recovered following each diet intervention showed no significant differences, except for a modest decrease following 4 weeks of white meat diet vs. red meat (Figure 6C and D).”
Quote in the paperSubstantial claim - Findingown data
24h urine choline-derived d6-TMA and d6-TMAO showed no significant differences within subjects following each diet.
“Remarkably, 24 h urine choline-derived d6-TMA and d6-TMAO showed no significant differences within subjects following the month long exposures to each of the distinct diets (Figure 6A and B).”
Quote in the paperSubstantial claim - Findingown data
Discontinuation of red meat diet and switch to white meat or non-meat diet led to marked reduction in fasting plasma TMAO.
“Moreover, when subjects discontinued the red meat diet and moved to either the white meat or non-meat diet, a marked reduction in fasting plasma TMAO level was observed (Figure 2B).”
- Also stated in: § Discussion · plain
“Interestingly, discontinuation of dietary red meat reduced plasma TMAO within 4 weeks.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
Fractional renal excretion of choline, betaine, carnitine, and c-butyrobetaine was significantly less than 100%.
“Lastly, in contrast to TMAO, the fractional renal excretion of choline, betaine, carnitine, and c-butyrobetaine were significantly less than 100%, indicating that after filtering through the kidneys, most of these metabolites are reabsorbed, but less so following chronic dietary red meat exposure (Figure 5B-E).”
Quote in the paperSubstantial claim - Findingown data
Baseline TMAO level after run-in diet tended to predict higher TMAO levels following other diet arms.
“It was interesting to note that following the initial 2 weeks defined run-in (baseline) diet, if a subject had a higher TMAO level at baseline, their TMAO level tended to be higher following other diet arms (compared with those with low TMAO at baseline, Figure 2C).”
Quote in the paperNot a substantial claim - Findingown data
Red meat diet significantly increased urine TMAO levels.
“A similar significant increase in urine levels of TMAO were noted following chronic ingestion of the red meat containing diet (P < 0.0001; Figure 3).”
Quote in the paperSubstantial claim - Findingown data
Chronic exposure to different diets substantially affected 24h production of d3-carnitine-derived metabolites.
“In contrast, chronic exposure to the different diets substantially affected 24 h production of the d3-carnitine-derived metabolites (Figure 7A-E).”
Quote in the paperSubstantial claim - Findingown data
Red meat diet modestly but significantly reduced urine choline concentrations compared with non-meat or white meat diets.
“Interestingly, very modest but statistically significant reductions were noted in plasma betaine and urine choline concentrations following chronic consumption of the red meat diet compared with the non-meat or white meat diets (Figures 2A and 3).”
Quote in the paperNot a substantial claim - Findingown data
Fractional renal excretion of TMAO and of the carnitine-family compounds (carnitine, gamma-butyrobetaine and crotonobetaine) was dynamically and differentially regulated by the preceding dietary exposure.
“the fractional renal excretion of TMAO and the carnitine family of nutrient precursors and metabolites (carnitine, c-butyrobetaine, and crotonobetaine) were all dynamically (and differentially) regulated by the preceding dietary exposure.”
Quote in the paperSubstantial claim - Findingown data
After one month on the red meat diet, fractional renal excretion of TMAO was significantly reduced.
“after 1 month of the red meat diet, fractional renal excretion of TMAO was significantly reduced”
Quote in the paperSubstantial claim - Findingown data
Carnitine, gamma-butyrobetaine and crotonobetaine all showed a marked 2- to 5-fold increase in fractional renal excretion after the red meat diet.
“carnitine and both of the other carnitine derived gut microbial metabolites, c-butyrobetaine and crotonobetaine, all showed marked (2-5 fold) elevation in fractional renal excretion following the red meat diet.”
Quote in the paperSubstantial claim - Findingown data
Switching from a red meat-rich diet to a white meat or non-meat protein source, while keeping calories and the proportion of protein in the diet the same, can substantially reduce TMAO levels within several weeks.
“switching from a diet rich in red meat to either a white meat or non-meat protein source (yet maintaining same calories, and proportion of protein in the diet) can substantially reduce TMAO levels within several weeks.”
Quote in the paperSubstantial claim - Premisecitation
Elevated plasma TMAO levels are observed in subjects at risk for incident CVD and adverse CVD events including heart attack, stroke, and death.
“Elevated plasma TMAO levels are observed in subjects at risk for incident cardiovascular disease (CVD) development and adverse CVD events including heart attack, stroke, and death.[1][2][3][4]”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [1] Wang, 2011, Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease, Nature source
Not checked in the free run.
- cites [2] Tang, 2013, Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk, N Engl J Med source
Not checked in the free run.
- cites [3] Koeth, 2013, Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis, Nat Med source
Not checked in the free run.
- Premisecitation
C-mannosyl tryptophan and pseudouridine were identified as excellent renal functional surrogates in a recent untargeted metabolomics study.
“In a recent untargeted metabolomics study examining nearly 500 analytes to identify those that most closely correlate with renal function, C-mannosyl tryptophan and pseudouridine were identified as excellent renal functional surrogates.24”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] Sekula, 2016, A metabolome-wide association study of kidney function and disease in the general population, J Am Soc Nephrol source
Not checked in the free run.
- Study design and conductown data
Diet order had no statistically significant effect on the observed effects of diet on monitored plasma and urine metabolites.
“When the impact of order of the diets was examined on plasma and urine levels, no statistically significant difference in the observed effects of diet on the monitored metabolites was observed.”
Quote in the paperNot a substantial claim - Premisecitation
TMAO is generated via a metaorganismal pathway beginning with gut microbiota-dependent formation of TMA from TMA-containing nutrient precursors.
“Trimethylamine N-oxide is generated via a metaorganismal pathway that begins with gut microbiota-dependent formation of trimethylamine (TMA) from TMA containing nutrient precursors (Figure 1A).[1][2][3]16”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [1] Wang, 2011, Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease, Nature source
Not checked in the free run.
- cites [2] Tang, 2013, Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk, N Engl J Med source
Not checked in the free run.
- cites [3] Koeth, 2013, Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis, Nat Med source
Not checked in the free run.
- Premisecitation
In small cross-sectional observational studies, plasma TMAO levels were modestly increased in omnivores relative to vegans/vegetarians.
“Interestingly, in small cross-sectional observational studies, plasma levels of TMAO were modestly increased in omnivores relative to vegans/vegetarians, and in recent clinical challenge studies, TMA and TMAO generation from oral carnitine was observed to be substantially reduced in vegans/vegetarians.3,19”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [3] Koeth, 2013, Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis, Nat Med source
Not checked in the free run.
- cites [19] Koeth, 2018, L-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans, J Clin Invest source
Not checked in the free run.
- Premisecitation
A diet enriched in meat, particularly red meat, has higher content of both choline and carnitine nutrient precursors for TMA and TMAO generation.
“Consequently, a diet enriched in meat, particularly red meat, has higher content of both choline and carnitine nutrient precursors for TMA and TMAO generation.1,3”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [1] Wang, 2011, Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease, Nature source
Not checked in the free run.
- cites [3] Koeth, 2013, Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis, Nat Med source
Not checked in the free run.
- Interpretationreasoning
Decreasing systemic TMAO levels is a rational potential therapeutic strategy for decreasing risks for development and progression of atherosclerotic heart disease.
“Thus, decreasing systemic levels of TMAO has become a rational potential therapeutic strategy for decreasing risks for the development and progression of atherosclerotic heart disease.8,[13][14][15]”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [8] Wang, 2015, Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis, Cell source
Not checked in the free run.
- cites [13] Roberts, 2018, Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential, Nat Med source
Not checked in the free run.
- cites [14] Brown, 2018, Microbial modulation of cardiovascular disease, Nat Rev Microbiol source
Not checked in the free run.
- Premisecitation
In recent clinical challenge studies, TMA and TMAO generation from oral carnitine was substantially reduced in vegans/vegetarians.
“Interestingly, in small cross-sectional observational studies, plasma levels of TMAO were modestly increased in omnivores relative to vegans/vegetarians, and in recent clinical challenge studies, TMA and TMAO generation from oral carnitine was observed to be substantially reduced in vegans/vegetarians.3,19”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [3] Koeth, 2013, Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis, Nat Med source
Not checked in the free run.
- cites [19] Koeth, 2018, L-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans, J Clin Invest source
Not checked in the free run.
- Interpretationreasoning
The metaorganismal TMAO pathway is a potential candidate to explain the association between red meat ingestion and heightened CVD risks.
“One potential candidate for this is the metaorganismal TMAO pathway.1,14,15”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [1] Wang, 2011, Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease, Nature source
Not checked in the free run.
- cites [14] Brown, 2018, Microbial modulation of cardiovascular disease, Nat Rev Microbiol source
Not checked in the free run.
- cites [15] Brown, 2017, Targeting of microbe-derived metabolites to improve human health: the next frontier for drug discovery, J Biol Chem source
Not checked in the free run.
- Interpretationreasoning
Factors alternative to traditional CVD risk factors may help explain the association between red meat ingestion and heightened CVD risks.
“Such findings arguably suggest that factors alternative to traditional CVD risk factors exist to help explain the association observed between red meat ingestion and heightened CVD risks.”
Quote in the paperSubstantial claim - Study design and conductown data
The findings on fractional renal excretion were robust because they were reproduced using several indices of renal function other than creatinine (C-mannosyl tryptophan, pseudouridine and SDMA).
“These findings appear to be robust, as they were observed using multiple different indices of renal function beyond creatinine (C-mannosyl tryptophan, pseudouridine, and SDMA).”
Quote in the paperSubstantial claim - Interpretationown data
The reduction in fractional renal excretion of TMAO would contribute to the rise in plasma TMAO levels observed on the red meat diet.
“which would contribute to the observed rise in plasma TMAO levels.”
Quote in the paperSubstantial claim - Premisecitation
In a meta-analysis of over 25,000 subjects with a mean follow-up of 4.3 years, the relative risk of all-cause mortality rose by 7.6% for each 10 micromol/L increment in TMAO.
“In one meta-analysis involving >25 000 subjects cumulatively with a mean follow-up duration amongst all studies examined of 4.3 ± 1.5 years, the relative risk for all-cause mortality was calculated to increase by 7.6% per each 10 lmol/L increment of TMAO.[10][11][12]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10][11][12]
Not checked in the free run.
- Premisecitation
Recent human observational and interventional studies show that TMAO levels can rise substantially (more than 10 micromol/L) with chronic supplementation.
“recent human observational and interventional studies show that TMAO levels can increase substantially (>10 lM) with chronic supplementation.4,5”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [4] Zhu, 2016, Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk, Cell source
Not checked in the free run.
- cites [5] Zhu, 2017, Gut microbe-generated trimethylamine N-oxide from dietary choline is prothrombotic in subjects, Circulation source
Not checked in the free run.
- May combine two claims. 27
- Classified as probably not a substantial claim. 10
May combine two claims.
Findingown dataFractional excretion of TMAO was higher and had a broader range (nearly zero to over 700%) than other metabolites, with almost half of subjects showing >100%, particularly after white meat and non-meat diets.
“First, compared to the other metabolites, the fractional excretion of TMAO was found to be both higher, and to demonstrate a remarkably broader range of values extending from nearly zero to over 700%, with a sizable proportion of subjects (almost half) showing >100%, particularly following the white meat and non-meat diet interventions.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataBaseline run-in diet had twice the carnitine level (56 mg) of the non-meat high-saturated fat diet (22 mg).
“Interestingly, examination of the carnitine content of the diets (Supplementary ma- terial online, Table S1) reveals the baseline diet had 2 Â the carnitine level (56 mg) of the non-meat (high-saturated fat) diet (22 mg).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataHigh vs low saturated fat diets produced no changes in plasma concentrations of choline, carnitine, c-butyrobetaine, and crotonobetaine, except a modest reduction in betaine with increased saturated fat.
“Similarly, no changes in plasma concentrations of other TMA containing compounds (choline, carnitine, cbutyrobetaine, and crotonobetaine; all P > 0.05, Figure 4B and D-F) were noted with high-vs.low-saturated fat except for a modest reduction in betaine levels with increased saturated fat (P < 0.05; Figure 4C).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataRed meat diet modestly but significantly increased serum creatinine (P=0.006) within normal range, and urine creatinine concentrations increased within normal range.
“We also noted that following the red meat diet, subjects showed a modest but significant (P = 0.006; Supplementary material online, Table S3) increase in serum creatinine (still within the normal range), while urine creatinine concentrations were increased (within normal range).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataNone of the surrogate indicators of renal function (C-mannosyl tryptophan, pseudouridine, SDMA) showed significant changes in plasma or urine levels based on diet, and all were highly correlated with creatinine.
“Notably, in contrast to creatinine, none of the surrogate indicators of renal function showed significant changes in plasma or urine levels based on diet, and all were highly correlated with creatinine (Supplementary material online, Tables S3 and S4).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPlasma TMAO levels were highly correlated with concurrently collected spot urine TMAO concentration (r=0.41), urine TMAO/creatinine (r=0.55), and 24h urine TMAO (r=0.74).
“In analyses examining the relationship between plasma and urine levels of TMAO, plasma TMAO levels were highly correlated with concurrently collected spot urine TMAO concentration (r = 0.41, P < 0.0001; N = 113) or urine TMAO/creatinine (r = 0.55, P < 0.0001; N = 113), and 24 h urine TMAO collections (r = 0.74, P < 0.001; N = 13).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataNo significant change in renal clearance of choline and only modest changes with betaine were observed among the three diets.
“In contrast, no significant change in renal clearance of choline and only modest changes with betaine were observed among the three diets (Figure 5C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataRed meat diet increased plasma TMAO levels approximately three-fold compared with white meat or non-meat diets, with some subjects showing over 10-fold increase.
“On average, plasma TMAO levels increased approximately three-fold (P < 0.0001) during the red meat diet, compared with the white meat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .or non-meat diets, with some subjects showing over a 10-fold increase (Figure 2A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe carnitine content of the red meat diet was 3.8-fold higher than that of the white meat diet and 7.9-fold higher than that of the non-meat diet.
“this in- crease was substantially less than the 3.8-fold and 7.9-fold higher car- nitine content present in the red meat diet compared with the white meat and non-meat diets, respectively (Supplementary material on- line, Table S1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe red meat diet supplied about 15% more total choline than the white meat diet and about 28% more than the non-meat diet.
“While the total choline content of the red meat diet provided approximately 15% and 28% more compared with the average daily total choline content of the white meat and non-meat diets, respectively (Supplementary material online, Table S1)”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn the present study, subjects had an average absolute change in median TMAO of 5.9 micromol/L during the red meat diet arm compared with the non-meat diet and 5.7 micromol/L compared with the white meat diet.
“subjects experienced on average an absolute change in median TMAO level of 5.9 lM and 5.7 lM during the red meat diet arm (compared with non-meat and white meat diets, respectively)”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationElevated circulating TMAO levels are associated with both CVD and mortality risks across multiple cohorts and continents, supporting clinical prognostic value.
“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]”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [10] Schiattarella, 2017, Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis, Eur Heart J source
Not checked in the free run.
- cites [11] Qi, 2018, Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies, J Cell Mol Med source
Not checked in the free run.
- cites [12] Heianza, 2017, 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 source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationTMAO is a gut microbiota-generated metabolite with mechanistic links to atherosclerotic heart disease.
“Trimethylamine N-oxide (TMAO) is a gut microbiota-generated metabolite with mechanistic links to the pathogenesis of atherosclerotic heart disease.[1][2][3][4][5]”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [1] Wang, 2011, Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease, Nature source
Not checked in the free run.
- cites [2] Tang, 2013, Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk, N Engl J Med source
Not checked in the free run.
- cites [3] Koeth, 2013, Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis, Nat Med source
Not checked in the free run.
May combine two claims.
PremisecitationCarnitine is enriched in red meat, and higher total choline content is found in beef and other meats, liver, and egg yolks.
“Carnitine is enriched in red meat, 3 and higher total choline content is found in beef and other meats, liver, and egg yolks.17”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [3] Koeth, 2013, Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis, Nat Med source
Not checked in the free run.
- cites [17] Conlon, 2014, The impact of diet and lifestyle on gut microbiota and human health, Nutrients source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPotential nutrient precursors for TMA production include c-butyrobetaine, crotonobetaine, and betaine.
“Beyond choline and carnitine, potential nutrient precursors for TMA production have been reported, including the carnitine related metabolites c-butyrobetaine and crotonobetaine, and the choline oxidation product betaine.1,16,19”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [1] Wang, 2011, Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease, Nature source
Not checked in the free run.
- cites [16] Koeth, 2014, γ-butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO, Cell Metab source
Not checked in the free run.
- cites [19] Koeth, 2018, L-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans, J Clin Invest source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBased upon epidemiological and nutrition studies, most dietary recommendations advise limiting red meat ingestion.
“Based upon the many epidemiological and nutrition studies suggesting a positive association between red meat ingestion and CVD risks, [27][28][29][30][31][32][33] most dietary recommendations advise limiting red meat ingestion.26”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [26] Piepoli, 2016, 2016 European guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR), Eur Heart J source
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- cites [27] Abete, 2014, Association between total, processed, red and white meat consumption and all-cause, CVD and IHD mortality: a meta-analysis of cohort studies, Br J Nutr source
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- cites [28] O'Connor, 2017, Total red meat intake of >/=0.5 servings/d does not negatively influence cardiovascular disease risk factors: a systemically searched meta-analysis of randomized controlled trials, Am J Clin Nutr source
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May combine two claims.
Interpretationown dataRed meat diet raises systemic TMAO levels by three mechanisms: enhanced nutrient density of dietary TMA precursors; increased microbial TMA/TMAO production from carnitine but not choline; and reduced renal TMAO excretion.
“Moreover, adherence to a red meat diet raises systemic TMAO levels by three different mechanisms: (i) enhanced nutrient density of dietary TMA precursors; (ii) increased microbial TMA/TMAO production from carnitine, but not choline; and (iii) reduced renal TMAO excretion.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSome TMA-containing compounds can participate in TMA/TMAO formation in a gut microbiota-dependent manner and can be generated by gut microbiota metabolism of L-carnitine.
“Some of these TMA containing compounds can participate in TMA/TMAO formation in a gut microbiota-dependent manner, and also be generated by gut microbiota metabolism of L-carnitine.1,3,16,19”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [1] Wang, 2011, Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease, Nature source
Not checked in the free run.
- cites [3] Koeth, 2013, Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis, Nat Med source
Not checked in the free run.
- cites [16] Koeth, 2014, γ-butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO, Cell Metab source
Not checked in the free run.
- cites [19] Koeth, 2018, L-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans, J Clin Invest source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown dataThe study used a randomized three-period crossover design.
“This dietary intervention study had a randomized three-period crossover design.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataMost of choline, betaine, carnitine, and c-butyrobetaine are reabsorbed after kidney filtration, but reabsorption is less following chronic red meat exposure.
“Lastly, in contrast to TMAO, the fractional renal excretion of choline, betaine, carnitine, and c-butyrobetaine were significantly less than 100%, indicating that after filtering through the kidneys, most of these metabolites are reabsorbed, but less so following chronic dietary red meat exposure (Figure 5B-E).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationStudies have shown dose-dependent TMA/TMAO formation with egg ingestion.
“Studies have also shown dose-dependent TMA/TMAO formation with egg ingestion.2,18”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [2] Tang, 2013, Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk, N Engl J Med source
Not checked in the free run.
- cites [18] Miller, 2014, Effect of egg ingestion on trimethylamine-N-oxide production in humans: a randomized, controlled, dose-response study, Am J Clin Nutr source
Not checked in the free run.
May combine two claims.
PremisecitationSome recent meta-analyses suggest association between red meat ingestion and adverse changes to traditional CVD risk factors is not as strong, despite relatively consistent association with hard endpoints like heart attack, stroke, mortality, and CVD development.
“However, some recent meta-analyses suggest the association between red meat ingestion and adverse changes to traditional CVD risk factors is not as strong, 28 despite the relatively consistent association with hard endpoints like heart attack, stroke, mortality, and CVD development.[29][30][31][32][33]”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [28] O'Connor, 2017, Total red meat intake of >/=0.5 servings/d does not negatively influence cardiovascular disease risk factors: a systemically searched meta-analysis of randomized controlled trials, Am J Clin Nutr source
Not checked in the free run.
- cites [29] Schwingshackl, 2017, Food groups and risk of all-cause mortality: a systematic review and meta-analysis of prospective studies, Am J Clin Nutr source
Not checked in the free run.
- cites [30] Haring, 2017, Red meat consumption and cardiovascular target organ damage (from the Strong Heart Study), J Hypertens source
Not checked in the free run.
May combine two claims.
Interpretationown dataBeyond the quantity of diet, the quality of diet composition with respect to protein source, but not saturated fat content, affects overall TMAO metabolism and excretion.
“beyond quantity, the quality of diet composition (with respect to protein source, but not saturated fat content) impacts overall TMAO metabolism and excretion.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAn observational study reported reduced urinary TMAO levels in subjects following a Mediterranean diet, and a trend toward lower urinary TMAO with greater reported adherence to the Mediterranean diet.
“Reduced urine TMAO levels were recently reported in an observational study among subjects following a Mediterranean diet in a post hoc cross-sectional analysis comparing omnivores vs. vegetarians or vegans 35 ; moreover, a trend towards reduced urinary TMAO levels was observed among subjects with increased reported compliance with the Mediterranean diet (based on the PREDIMED trial compliance tool”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] De Filippis, 2016, High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome, Gut source
Not checked in the free run.
May combine two claims.
Study design and conductown dataFractional excretion calculations used plasma and urine creatinine concentrations, which varied with diet, although three alternative metabolites used as surrogate markers of renal function gave qualitatively comparable results.
“Fractional excretion calculations utilized creatinine plasma and urine concentrations, which varied based on diet, though we also quantified three separate alternative metabolites identified to serve as surrogate markers of renal function, and observed qualitatively comparable results.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThe increases in plasma TMAO seen with the red meat diet would correspond to an approximately 4.5% higher relative risk of mortality than the non-meat diet and a 4.3% difference compared with the white meat diet.
“the increases in plasma TMAO observed with the red meat diet would correspond to an approximate 4.5% increase in relative risk of mortality compared with the non-meat diet, and a 4.3% difference in mortality compared with white meat diet.”
Quote in the paperSubstantial claim- The authors state this as an assumption: The changes in TMAO observed after one month of diet can be extrapolated to the mean follow-up of 4.3 years used in the meta-analysis.
May combine two claims.
Interpretationnone givenThese studies are the first to directly examine the relationship of dietary protein source to plasma TMAO levels using defined isocaloric randomized diets, and the time required to lower TMAO levels by changing diet.
“the present studies are the first to directly explore the relationship of dietary protein source to plasma TMAO levels with defined isocaloric randomized diets, and the time needed to reduce TMAO levels with dietary changes.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningA diet rich in red meat would be associated with heightened TMAO levels and potentially heightened risk of thrombotic events.
“The present studies thus suggest that a diet rich in red meat would be associated with heightened TMAO levels, and potential heightened thrombotic event risk.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationNumerous epidemiological studies show a dose-dependent heightened risk of thrombotic events, cardiovascular disease and mortality with red meat consumption.
“numerous epidemiological studies show a dose-dependent heightened risk of thrombotic events, CVD, and mortality risks with red meat consumption.[29][30][31][32][33]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29][30][31][32][33]
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationThe kidney is an important organ to maintain homoeostasis of plasma metabolites.
“The kidney is an important organ to maintain homoeostasis of plasma metabolites, 23 yet little is known about factors impacting renal excretion of TMAO or its related metabolites.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] Thurau, 1964, Autoregulation of renal blood flow and glomerular filtration rate, including data on tubular and peritubular capillary pressures and vessel wall tension, Circ Res
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenOnly two blood and urine visits were collected for each diet arm, which may not capture the total intra-individual variability of the subjects.
“Only two visits of blood and urine for each diet arm were collected, which may not reflect the total intra-individual variability in subjects.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThe Mediterranean diet in the PREDIMED trial, which reduced cardiovascular disease risk by 30%, was characterized by avoidance of red meat as a protein source.
“The Mediterranean diet in the PREDIMED trial, which showed a 30% reduction in CVD risk, was characterized by avoidance of red meat as a protein source.36,37”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [36] Estruch, 2013, Primary prevention of cardiovascular disease with a Mediterranean diet, N Engl J Med source
Not checked in the free run.
- cites [37] Estruch, 2018, Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts, N Engl J Med source
Not checked in the free run.
May combine two claims.
PremisecitationTMAO directly interacts with human and murine platelets, increasing their responsiveness and promoting a prothrombotic phenotype.
“TMAO has been shown to directly interact with platelets (human and murine), increasing their responsiveness, and promoting a prothrombotic phenotype.4,5”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [4] Zhu, 2016, Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk, Cell source
Not checked in the free run.
- cites [5] Zhu, 2017, Gut microbe-generated trimethylamine N-oxide from dietary choline is prothrombotic in subjects, Circulation source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThe time of blood collection after a meal was not controlled, which may cause fluctuation in plasma metabolite levels.
“Blood collection time after meal was not controlled, which may lead to fluctuation of plasma metabolite levels.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Few studies have systematically explored the influence of chronic dietary patterns on TMA and TMAO production, metabolism, and renal excretion.
“Few studies have systematically explored the influence of chronic dietary patterns on TMA and TMAO production, metabolism, and renal excretion.”
The paper relies on this without support.
The direct contribution of TMAO to CVD pathogenesis in humans is unclear.
“the direct contribution of TMAO to CVD pathogenesis in humans is unclear, and the impact of dietary interventions on TMAO have not been extensively investigated.”
The paper relies on this without support.
The impact of dietary interventions on TMAO has not been extensively investigated.
“the direct contribution of TMAO to CVD pathogenesis in humans is unclear, and the impact of dietary interventions on TMAO have not been extensively investigated.”
The paper relies on this without support.
Little is known about factors impacting renal excretion of TMAO or its related metabolites.
“yet little is known about factors impacting renal excretion of TMAO or its related metabolites.”
The authors state this as an assumption.
The changes in TMAO observed after one month of diet can be extrapolated to the mean follow-up of 4.3 years used in the meta-analysis.
“assuming changes observed following 1 month of diet can be extended to the mean length of follow-up (4.3 year) in the meta-analysis”
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?
There are safety concerns about augmenting dietary protein above 0.8 g/kg/d, especially from animal sources, because of concerns of accelerating coronary artery disease and heart failure incidence, as well as the potential for accelerating chronic kidney disease progression.
“There are, however, safety concerns about augmenting dietary protein above the 0.8 g·kg−1·d−1 range, especially from animal sources, because of concerns of accelerating coronary artery disease and HF incidence, as well as the potential for accelerating CKD progression.123–125”
From Malnutrition and Cachexia in Inpatients With Acute Cardiac Conditions: A Scientific Statement From the American Heart Association (2026) · cites this paper as [124]
The Discussion (page not supplied) describes an association between red-meat consumption and cardiovascular risk, supporting that part of the safety concern. It does not establish a risk threshold above 0.8 g/kg/day, address heart-failure incidence, or show that increased protein intake accelerates chronic kidney disease progression; its renal findings concern metabolite excretion in healthy participants. (LLM, conf=0.88)
Experimental — accuracy not yet measuredA randomized controlled trial found that chronic ingestion of red meat, but not white meat or non-meat, increased plasma and urine levels of trimethylamine N-oxide.
“A randomized controlled trial found that chronic ingestion of red meat, but not white meat or non-meat, increased plasma and urine levels of TMAO.142”
From Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer (2020) · cites this paper as [142]
In a recent human dietary intervention study, substantially higher levels of circulating trimethylamine N-oxide were observed when subjects consumed a red meat diet equivalent to 8 oz of steak daily for 1 month.
“In a recent human dietary intervention study examining protein source (red meat vs white meat vs non-meat), substantially higher levels of circulating TMAO were observed when subjects consumed a red meat diet (equivalent to 8oz of steak daily for 1 month)111.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [111]
Isotope tracer studies showed that a red meat rich diet induced functional remodeling of the gut microbial community to enhance carnitine-to-trimethylamine transformation, but not choline-to-trimethylamine generation.
“In addition to having enhanced nutrient density of TMA(O) precursors (including carnitine), isotope tracer studies showed the red meat rich diet induced functional remodeling of the gut microbial community to enhance carnitine→→TMA transformation, but not choline→TMA generation111.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [111]
Diets rich in phosphatidylcholine and carnitine are associated with heightened levels of TMAO, whereas vegetarian or vegan diets have reduced nutrient precursors.
“The TMAO pathway is an excellent example of this, given the nutrient precursors are more abundant in a Western diet, and diets rich in phosphatidylcholine and carnitine are associated with heightened levels of TMAO, whereas vegetarian or vegan diets have reduced nutrient precursors111, 118.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [111]
TMAO levels appear to be driven more by gut microbial community composition than by dietary intervention, and significant variation in TMAO production among individuals on a given diet is observed.
“Notably, however, TMAO levels appear to be driven more so by the gut microbial community composition than by the dietary intervention, and significant variation in TMAO production among individuals on a given diet is observed14, 111.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [111]
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.
Washout duration differs between methods and figure caption
MinorThe methods specify washout periods ranging from 2 to 7 weeks, while the Figure 1 caption describes 2-week washouts between each diet period.
“each separated by a 2-7 weeks washout period”
“with 2-week wash-out diets between each intervention dietary period”
Cites
2 retracted
RETRACTED: Primary Prevention of Cardiovascular Disease with a Mediterranean Diet
Estruch, R., Ros, E., Salas-Salvadó, J., Covas, M.-I., Corella, D., Arós, F., Gómez-Gracia, E., Ruiz-Gutiérrez, V., Fiol, M., Lapetra, J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1200303 · Cited by 4,257 · see citing works
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RetractedEuropean Guidelines on cardiovascular disease prevention in clinical practice (version 2012)
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“Studies have also shown dose-dependent TMA/TMAO formation with egg ingestion.(2,18) Beyond choline and carnitine, potential nutrient precursors for TMA production have been reported, including the carnitine related metabolites c-butyrobetaine and crotonobetaine, and the choline oxidation product betaine.”
BackgroundSelf-citationGut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk
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Self-citationThe TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance
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Self-citationSymmetric dimethylarginine (SDMA) as endogenous marker of renal function–a meta-analysis
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Gut microbiota and cardiovascular disease.
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“89”
Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer
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“disease, obesity, atherosclerosis, diabetes, heart failure, hypertension [37-39]”
BackgroundIntestinal Microbiota in Cardiovascular Health and Disease
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“(82) The gut microbiota converts nutrients such as choline or carnitine into trimethylamine, which is metabolized by liver flavin monooxygenases to trimethylamine N-oxide (TMAO),(83) while discontinuation of red meat consumption reduced TMAO levels within 4 weeks.(84) Numerous studies have demonstrated an association…”
BackgroundTrøseid, M., Andersen, G. Ø., Broch, K., & Hov, J. R. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2020.102649 · Cited by 406 · see citing works
“For now, dietary interventions, including adherence to a Mediterranean diet [104] or discontinuation of dietary red meat [33], are more accessible ways of reducing TMAO levels and possibly, cardiovascular risk.”
BackgroundYang, S., Li, X., Yang, F., Zhao, R., Pan, X., Liang, J., Tian, L., Li, X., Liu, L., Xing, Y., et al. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01360 · Cited by 347 · see citing works
Self-citationTMAO: how gut microbiota contributes to heart failure
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“, beef and pork), have a relatively high content of carnitine and choline, which are precursors to TMAO (15).”
BackgroundMethodMicrobiota Metabolites in Health and Disease
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Trimethylamine N-oxide (TMAO) in human health
Gątarek, P., & Kałużna-Czaplińska, J. (2020) · EXCLI journal · doi:10.17179/excli2020-3239 · Cited by 233 · see citing works
“…diabetes (Tai et al., 2015), kidney failure (Bain et al., 2006; Tang et al., 2015; Missailidis et al., 2016; Stubbs et al., 2016; Mafune et al., 2016), neurological disorders (Cryan and Dinan, 2012), and cancer (stomach, colon) (Erdman and Poutahidis, 2015; Dey and Ciorba, 2016; Wang et al., 2019).”
BackgroundKonopelski, P., & Mogilnicka, I. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031222 · Cited by 218 · see citing works
Sasso, J. M., Ammar, R. M., Tenchov, R., Lemmel, S. A., Kelber, O., Grieswelle, M., & Zhou, Q. A. (2023) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.3c00127 · Cited by 217 · see citing works
Vegetarian and vegan diets: benefits and drawbacks
Wang, T., Masedunskas, A., Willett, W. C., & Fontana, L. (2023) · European Heart Journal · doi:10.1093/eurheartj/ehad436 · Cited by 200 · see citing works
“62,63 Animal and human studies have shown that higher levels of circulating TMAO increase the risk of developing CVD, independent of traditional cardiometabolic risk factors, by inducing vascular inflammation and platelet activation.”
BackgroundWestern diets and chronic diseases
Adolph, T. E., & Tilg, H. (2024) · Nature Medicine · doi:10.1038/s41591-024-03165-6 · Cited by 203 · see citing works
Gupta, N., Buffa, J. A., Roberts, A. B., Sangwan, N., Skye, S. M., Li, L., Ho, K. J., Varga, J., DiDonato, J. A., Tang, W. H. W., et al. (2020) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.120.314139 · Cited by 184 · see citing works
Self-citationNonalcoholic Fatty Liver Disease Pandemic Fuels the Upsurge in Cardiovascular Diseases
Cai, J., Zhang, X., Ji, Y., Zhāng, P., She, Z., & Li, H. (2020) · Circulation Research · doi:10.1161/circresaha.119.316337 · Cited by 179 · see citing works
Bekhit, A. E. A., Giteru, S. G., Holman, B. W. B., & Hopkins, D. L. (2021) · Comprehensive Reviews in Food Science and Food Safety · doi:10.1111/1541-4337.12764 · Cited by 169 · see citing works
“Dietary fat was reported not to have an association with plasma TMA-N-O or its metabolites (Boutagy et al., 2015; Wang et al., 2019).”
BackgroundMethodInfluentialGut microbes impact stroke severity via the trimethylamine N-oxide pathway
Zhu, W., Romano, K. A., Li, L., Buffa, J. A., Sangwan, N., Prakash, P., Tittle, A. N., Li, X. S., Fu, X., Androjna, C., et al. (2021) · Cell Host & Microbe · doi:10.1016/j.chom.2021.05.002 · Cited by 165 · see citing works
Self-citationLong-Term Changes in Gut Microbial Metabolite Trimethylamine N-Oxide and Coronary Heart Disease Risk
Heianza, Y., Ma, W., DiDonato, J. A., Sun, Q., Rimm, E. B., Hu, F. B., Rexrode, K. M., Manson, J. E., & Qi, L. (2020) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.11.060 · Cited by 157 · see citing works
“A more recent study reported similar associations that intake of red meat increased TMAO levels, and discontinuation of red meat intake reduced plasma TMAO levels within 4 weeks (29).”
BackgroundBergeron, N., Chiu, S., Williams, P. T., M King, S., & Krauss, R. M. (2019) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqz035 · Cited by 160 · see citing works
Self-citationZhu, C., Sawrey-Kubicek, L., Beals, E., Rhodes, C. H., Houts, H. E., Sacchi, R., & Zivkovic, A. M. (2020) · Nutrition Research · doi:10.1016/j.nutres.2020.03.005 · Cited by 153 · see citing works
Trimethylamine N-Oxide in Relation to Cardiometabolic Health—Cause or Effect?
Papandreou, C., Moré, M. I., & Bellamine, A. (2020) · Nutrients · doi:10.3390/nu12051330 · Cited by 150 · see citing works
“Isotope tracing experiments revealed that TMAO was primarily generated from the L-carnitine; in addition, meat consumption led to a slight decrease in fractional renal TMAO excretion, possibly explaining in part the TMAO increase [95].”
BackgroundInfluentialWang, Q., Shen, Y., Wang, X., Fu, S., Zhang, X., Zhang, Y., & Wang, R. (2020) · Aging · doi:10.18632/aging.102645 · Cited by 129 · see citing works
“Yet, TMAO levels might be affected by modifications in gut microbiota composition, which possibly modulate TMA production [41].”
BackgroundLi, J., Li, Y., Ivey, K. L., Wang, D. D., Wilkinson, J. E., Franke, A., Lee, K. H., Chan, A., Huttenhower, C., Hu, F. B., et al. (2022) · Gut · doi:10.1136/gutjnl-2020-322473 · Cited by 137 · see citing works
Potential TMA-Producing Bacteria Are Ubiquitously Found in Mammalia
Rath, S., Rud, T., Pieper, D. H., & Vital, M. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.02966 · Cited by 130 · see citing works
Colon Carcinogenesis: The Interplay Between Diet and Gut Microbiota
Loke, Y. L., Chew, M. T., Ngeow, Y. F., Lim, W. W.-D., & Peh, S. C. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.603086 · Cited by 129 · see citing works
“Trimethylamine-N-Oxide Trimethylamine-N-oxide (TMAO) is a gut microbiotadependent metabolite of saltwater fish, eggs, dairy products, and especially, red meat (Velasquez et al., 2016; Chan et al., 2019; Wang et al., 2019).”
BackgroundOrgan, C. L., Li, Z., Sharp, T. E., Polhemus, D. J., Gupta, N., Goodchild, T. T., Tang, W. H. W., Hazen, S. L., & Lefer, D. J. (2020) · Journal of the American Heart Association · doi:10.1161/jaha.119.016223 · Cited by 127 · see citing works
Self-citationBiomarkers of meat and seafood intake: an extensive literature review
Cuparencu, C., Praticò, G., Hemeryck, L., Harsha, P. S. C. S., Noerman, S., Rombouts, C., Xi, M., Vanhaecke, L., Hanhineva, K., Brennan, L., et al. (2019) · Genes & Nutrition · doi:10.1186/s12263-019-0656-4 · Cited by 122 · see citing works
Rudzki, L., Stone, T. W., Maes, M. H. J., Misiak, B., Samochowiec, J., & Szulc, A. (2021) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110240 · Cited by 123 · see citing works
Vegetable-Based Diets for Chronic Kidney Disease? It Is Time to Reconsider
Cases, A., Cigarrán, S., Mas, S., & González‐Parra, E. (2019) · Nutrients · doi:10.3390/nu11061263 · Cited by 126 · see citing works
“A recent study of non-CKD populations revealed that TMAO production was mainly associated with the ingestion of red meat (rich in L-carnitine), while L-carnitine enhanced TMAO production in omnivores but not in vegetarians [67,68].”
BackgroundBuffa, J. A., Romano, K. A., Copeland, M. F., Cody, D. B., Zhu, W., Galvez, R., Fu, X., Ward, K., Ferrell, M., Dai, H. J., et al. (2021) · Nature Microbiology · doi:10.1038/s41564-021-01010-x · Cited by 114 · see citing works
Self-citationGao, Q., Wang, Y., Wang, X., Fu, S., Zhang, X., Wang, R., & Zhang, X. (2019) · Aging · doi:10.18632/aging.102352 · Cited by 118 · see citing works
“Whereas TMAO accumulation could be influenced by modifications in intestinal microbiota composition, which potentially modulates TMA generation [24].”
BackgroundRecent advances in modulation of cardiovascular diseases by the gut microbiota
Masenga, S. K., Hamooya, B., Hangoma, J., Hayumbu, V., Ertuglu, L. A., Ishimwe, J., Rahman, S., Saleem, M., Laffer, C. L., Elijovich, F., et al. (2022) · Journal of Human Hypertension · doi:10.1038/s41371-022-00698-6 · Cited by 121 · see citing works
“Since TMAO and p-cresylsulfate are eliminated through the kidney [71], the age-related decline in kidney function, which is seen in both men and women, may exacerbate the systemic accumulation of these metabolites further enhancing pathways that lead to cardiovascular disease [72].”
BackgroundSimó, C., & García‐Cañas, V. (2020) · Food & Function · doi:10.1039/d0fo01237h · Cited by 110 · see citing works
Winther, S. A., Oellgaard, J., Tofte, N., Tarnow, L., Wang, Z., Ahluwalia, T. S., Jorsal, A., Theilade, S., Parving, H., Hansen, T. W., et al. (2019) · Diabetes Care · doi:10.2337/dc19-0048 · Cited by 111 · see citing works
“, increased variation is observed where TMAO levels are low) (44).”
BackgroundSelf-citationThe complexities of the diet-microbiome relationship: advances and perspectives
Leeming, E. R., Louca, P., Gibson, R., Menni, C., Spector, T. D., & Roy, C. I. L. (2021) · Genome Medicine · doi:10.1186/s13073-020-00813-7 · Cited by 110 · see citing works
“For instance, trimethylamine N-oxide (TMAO), a product of trimethylamine (TMA) transformation by the liver, has been extensively associated with the negative health effects linked to red meat consumption [99].”
BackgroundThe bright and the dark sides of L-carnitine supplementation: a systematic review
Sawicka, A. K., Renzi, G., & Olek, R. A. (2020) · Journal of the International Society of Sports Nutrition · doi:10.1186/s12970-020-00377-2 · Cited by 113 · see citing works
Meat consumption and risk of ischemic heart disease: A systematic review and meta-analysis
Papier, K., Knüppel, A., Syam, N. R., Jebb, S. A., & Key, T. J. (2021) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2021.1949575 · Cited by 113 · see citing works
“Another mechanism that might be specific to red meat intake is trimethylamine-N-oxide (TMAO), which might contribute to an increased risk of IHD by promoting atherosclerosis (Wang et al. 2019; Heianza et al. 2020; Tang et al. 2013); red meat intake can lead increased circulating TMAO derived from intestinal microbiota…”
BackgroundModifiable Cardiovascular Risk, Hematopoiesis, and Innate Immunity
Schloss, M. J., Świrski, F. K., & Nahrendorf, M. (2020) · Circulation Research · doi:10.1161/circresaha.120.315936 · Cited by 107 · see citing works
Nutritional Metabolomics and the Classification of Dietary Biomarker Candidates: A Critical Review
Rafiq, T., Azab, S. M., Teo, K. K., Thabane, L., Anand, S. S., Morrison, K. M., de Souza, R. J., & Britz‐McKibbin, P. (2021) · Advances in Nutrition · doi:10.1093/advances/nmab054 · Cited by 105 · see citing works
Brunt, V. E., Casso, A. G., Gioscia‐Ryan, R. A., Sapinsley, Z. J., Ziemba, B. P., Clayton, Z. S., Bazzoni, A. E., VanDongen, N. S., Richey, J. J., Hutton, D. A., et al. (2021) · Hypertension · doi:10.1161/hypertensionaha.120.16895 · Cited by 110 · see citing works
Sankowski, B., Księżarczyk, K., Raćkowska, E., Szlufik, S., Koziorowski, D., & Giebułtowicz, J. (2020) · Clinica Chimica Acta · doi:10.1016/j.cca.2019.10.038 · Cited by 105 · see citing works
Xu, J., Moore, B. N., & Pluznick, J. L. (2022) · Hypertension · doi:10.1161/hypertensionaha.122.18558 · Cited by 110 · see citing works
Mamic, P., Chaikijurajai, T., & Tang, W. H. W. (2020) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2020.12.001 · Cited by 99 · see citing works
“Red meat is particularly high in TMAO precursors, but, reassuringly, dramatic reduction in circulating TMAO levels can be achieved after only few weeks of cessation of red meat intake [41].”
BackgroundSelf-citationPeña-Jorquera, H., Cid-Jofré, V., Landaeta-Díaz, L., Petermann-Rocha, F., Martorell, M., Zbinden-Foncea, H., Ferrari, G., Jorquera-Aguilera, C., & Cristi-Montero, C. (2023) · Nutrients · doi:10.3390/nu15143244 · Cited by 103 · see citing works
“Trimethylamine N-oxide (TMAO) is a compound that has gained interest due to its potential mechanistic links to atherosclerosis heart disease [81].”
BackgroundLow Fibre Intake is Associated with Gut Microbiota Alterations in Chronic Heart Failure
Mayerhofer, C. C. K., Kummen, M., Holm, K., Broch, K., Awoyemi, A., Vestad, B., Storm-Larsen, C., Seljeflot, I., Ueland, T., Bohov, P., et al. (2020) · ESC Heart Failure · doi:10.1002/ehf2.12596 · Cited by 95 · see citing works
“These results confirm the findings of a recent crossover study, which demonstrated an association between red meat and raised TMAO levels.(27) Our data suggest that TMAO is more related to dietary patterns than to microbiota alterations in HF, again emphasizing the importance of including dietary data in microbiota-re…”
ResultMetabolites Linking the Gut Microbiome with Risk for Type 2 Diabetes
Zhu, T., & Goodarzi, M. O. (2020) · Current Nutrition Reports · doi:10.1007/s13668-020-00307-3 · Cited by 100 · see citing works
Can Meat and Meat-Products Induce Oxidative Stress?
Macho‐González, A., Garcimartín, A., López‐Oliva, M. E., Bastida, S., Benedı́, J., Ros, G., Nieto, G., & Sánchez-Muniz, F. J. (2020) · Antioxidants · doi:10.3390/antiox9070638 · Cited by 106 · see citing works
Xiang, F., Zhang, Z., Xie, J., Xiong, S., Chen, Y., Liao, D., Xia, B., & Lin, L. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06341-5 · Cited by 100 · see citing works
“The long-term intake of red meat significantly increases the levels of the carnitine metabolites trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), leading to endothelial dysfunction and adverse cardiovascular events [241].”
Gut-Heart Axis: The Role of Gut Microbiota and Metabolites in Heart Failure
Snelson, M., Muralitharan, R. R., Liu, C., Markó, L., Forslund, S. K., Marques, F. Z., & Tang, W. H. W. (2025) · Circulation Research · doi:10.1161/circresaha.125.325516 · Cited by 106 · see citing works
“146,147 These included (1) reduction in nutrient precursor density in the diet (choline and carnitine); (2) increased microbial trimethylamine/TMAO production from carnitine (but interestingly, not choline, presumably via bloom of the low abundance microbes capable of completing the multistep…”
Self-citationLee, Y., Nemet, I., Wang, Z., 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. (2021) · Journal of the American Heart Association · doi:10.1161/jaha.120.020646 · Cited by 91 · see citing works
Self-citationDiet-gut microbiota interactions on cardiovascular disease
Zhang, X., & Gérard, P. (2022) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2022.03.028 · Cited by 94 · see citing works
“The dietary precursors phosphatidylcholine [86], choline [87], and L-carnitine [33], which are commonly present in cheese, red meat, seafood, egg yolks and other western style nutrients [88], are primarily metabolized by specific gut microbial enzymes to produce high levels of trimethylamine (TMA) [63,89–91].”
BackgroundBusnelli, M., Manzini, S., & Chiesa, G. (2019) · Nutrients · doi:10.3390/nu12010079 · Cited by 91 · see citing works
TMAO as a potential biomarker and therapeutic target for chronic kidney disease: A review
Ye, Z., Lulu, C., Xiangchang, Z., Fang, Q., Binjie, Z., Chunyang, L., Rao, T., & Dongsheng, O. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.929262 · Cited by 90 · see citing works
“In addition, long-term and excessive consumption of red meat (rich in carnitine and choline) can increase TMAO production and reduce renal excretion (Wang et al., 2019).”
BackgroundTang, 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 90 · see citing works
Self-citationZeng, Y., Guo, M., Xia, F., Teng, F., Tan, X., Li, X., Wang, M., Long, Y., & Xu, Y. (2021) · Advances in Nutrition · doi:10.1093/advances/nmab010 · Cited by 88 · see citing works
“Notably, the increase in plasma TMAO concentrations was, on average, 3-fold higher compared with either white meat or nonmeat sources (75).”
BackgroundSelf-citationGut Microbial Metabolites and Blood Pressure Regulation: Focus on SCFAs and TMAO
Poll, B. G., Cheema, M. U., & Pluznick, J. L. (2020) · Physiology · doi:10.1152/physiol.00004.2020 · Cited by 84 · see citing works
Dietary compounds in modulation of gut microbiota-derived metabolites
Feng, W., Liu, J., Cheng, H., Zhang, D., Tan, Y., & Peng, C. Y. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.939571 · Cited by 83 · see citing works
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 81 · see citing works
Self-citationWang, 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 80 · see citing works
Self-citationAndrikopoulos, P., Aron‐Wisnewsky, J., Chakaroun, R., Myridakis, A., Forslund, S. K., Nielsen, T., Adriouch, S., Holmes, B., Chilloux, J., Vieira‐Silva, S., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39824-4 · Cited by 86 · see citing works
“Within each western blot, the same amount of protein was loaded between samples and normalised accordingly.”
Relationship between elevated plasma trimethylamine N-oxide levels and increased stroke injury
Wu, C., Xue, F., Lian, Y., Zhang, J., Wu, D., Xie, N., Chang, W., Chen, F., Wang, L., Wei, W., et al. (2020) · Neurology · doi:10.1212/wnl.0000000000008862 · Cited by 71 · see citing works
“First, previous studies have shown that changes in dietary pattern can affect TMAO levels.(1,16) To avoid the impact of dietary management after admission on baseline TMAO levels, only patients who presented within 12 hours were included in the present study.”
ResultReichard, C. A., Naelitz, B. D., Wang, Z., Jia, X., Li, J., Stampfer, M. J., Klein, E. A., Hazen, S. L., & Sharifi, N. (2021) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-21-0766 · Cited by 64 · see citing works
“Targeted metabolites and isotope-labeled internal standards were monitored using electrospray ionization in positive-ion mode (except for p-cresol sulfate, which was monitored using negative-ion mode) withmultiple reactionmonitoring (MRM) as previously reported (27).”
MethodSelf-citationMicrobial Tryptophan Metabolism Tunes Host Immunity, Metabolism, and Extraintestinal Disorders
Liu, M., Nieuwdorp, M., de Vos, W. M., & Rampanelli, E. (2022) · Metabolites · doi:10.3390/metabo12090834 · Cited by 79 · see citing works
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 75 · see citing works
“Recent findings suggest that chronic ingestion of red meat may reduce excretion of TMAO(79).”
BackgroundInfluentialGriffin, L. E., Djurić, Z., Angiletta, C. J., Mitchell, C. M., Baugh, M. E., Davy, K. P., & Neilson, A. P. (2019) · Food & Function · doi:10.1039/c9fo00333a · Cited by 77 · see citing works
A Review of the Relationship between Gut Microbiome and Obesity
Zsálig, D., Berta, A., Tóth, V., Szabó, Z., Klara, S. M., Figler, M., Pusztafalvi, H., & Polyák, É. (2023) · Applied Sciences · doi:10.3390/app13010610 · Cited by 76 · see citing works
Microbiota in Gut‐Heart Axis: Metabolites and Mechanisms in Cardiovascular Disease
Kondapalli, N. B., Katari, V., Dalal, K. K., Paruchuri, S. M., & Thodeti, C. K. (2025) · Comprehensive physiology · doi:10.1002/cph4.70024 · Cited by 93 · see citing works
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 · see citing works
Self-citationUnraveling the Role of the Human Gut Microbiome in Health and Diseases
Khalil, M., Ciaula, A. D., Mahdi, L., Jaber, N., Palo, D. M. D., Graziani, A., Baffy, G., & Portincasa, P. (2024) · Microorganisms · doi:10.3390/microorganisms12112333 · Cited by 98 · see citing works
“Unabsorbed tryptophan can become the substrate for the microbiome to tryptamine, skatole, indole, and indole derivatives such as in-doxyl sulfate, indole-3-propionic acid, 3-methyl-indole, and [96].”
From taxonomy to metabolic output: what factors define gut microbiome health?
Wilmanski, T., Rappaport, N., Diener, C., Gibbons, S. M., & Price, N. D. (2021) · Gut Microbes · doi:10.1080/19490976.2021.1907270 · Cited by 73 · see citing works
“Microbial breakdown products of phosphatidylcholine and carnitine, particularly trimethylamine converted in the liver to TMAO, are commonly elevated in individuals on diets high in red meat.(121) TMAO has been shown to promote cardiovascular disease in animal models,(122) and is associated with increased risk of cardi…”
BackgroundGut microbiome and cardiovascular disease
Zhao, Y., & Wang, Z. (2020) · Current Opinion in Cardiology · doi:10.1097/hco.0000000000000720 · Cited by 68 · see citing works
Self-citationNeural Mechanisms in Cardiovascular Health and Disease
Ziegler, K. A., Engelhardt, S. H., Carnevale, D., McAlpine, C. S., Guzik, T. J., Dimmeler, S., & Świrski, F. K. (2025) · Circulation Research · doi:10.1161/circresaha.125.325580 · Cited by 85 · see citing works
“241,242 Finally, the aging process significantly alters the function and regulation of the ANS.”
Assessment of peripheral endothelial function predicts future risk of solid-tumor cancer
Toya, T., Sara, J. D. S., Corban, M., Taher, R., Godo, S., Herrmann, J., Lerman, L. O., & Lerman, A. (2019) · European Journal of Preventive Cardiology · doi:10.1177/2047487319884246 · Cited by 71 · see citing works
“For example, red meat raises the risk of CVD by increasing the plasma level of trimethylamine-N-oxide, as well as the risk of colorectal cancer.(33,34) Nevertheless, we could not adjust for the influence of diet and nutrition due to lack of data.”
BackgroundSoldán, M., Argalášová, Ľ., Hadvinová, L., Galileo, B., & Babjaková, J. (2024) · Nutrients · doi:10.3390/nu16183134 · Cited by 76 · see citing works
“However, Vanegas et al. found that the consumption of whole grains instead of refined grains leads to reduced numbers of pro-inflammatory Enterobacteriaceae [88,100,109,120].”
BackgroundDietary metabolic signatures and cardiometabolic risk
Shah, R. V., Steffen, L. M., Nayor, M. G., Reis, J. P., Jacobs, D. R., Allen, N. B., Lloyd‐Jones, D. M., Meyer, K. A., Cole, J. B., Piaggi, P., et al. (2022) · European Heart Journal · doi:10.1093/eurheartj/ehac446 · Cited by 67 · see citing works
Li, Z. H. (2024) · Gut · doi:10.1136/gutjnl-2024-331880 · Cited by 76 · see citing works
“13 14 17 This compound has been identified as an independent predictor and promoter of AS. 18 19 Studies have demonstrated that reducing TMAO production through interventions leads to a decrease in AS symptoms in both animals and humans.”
BackgroundCostabile, 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 67 · see citing works
Delgado, J., Ansorena, D., HECKE, T. V., Astiasarán, I., SMET, S. D., & Estévez, M. (2020) · Meat Science · doi:10.1016/j.meatsci.2020.108278 · Cited by 65 · see citing works
Modulation of Endothelial Function by TMAO, a Gut Microbiota-Derived Metabolite
Querio, G., Antoniotti, S., Geddo, F., Levi, R. C., & Gallo, M. P. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065806 · Cited by 70 · see citing works
“Indeed, it is now widely accepted that the microbial diversity of the gut is strictly influenced by the diet and vice versa, as the gut microbiota’s metabolism of different dietderived compounds can influence the host’s health [45].”
BackgroundXylitol is prothrombotic and associated with cardiovascular risk
Witkowski, M., Nemet, I., Li, X. S., Wilcox, J. D., Ferrell, M., Alamri, H. S., Gupta, N., Wang, Z., Tang, W. H. W., & Hazen, S. L. (2024) · European Heart Journal · doi:10.1093/eurheartj/ehae244 · Cited by 69 · see citing works
“42 Erythritol was quantified by stable isotope dilution LC-MS/MS as previously described.”
MethodSelf-citationMei, Z., Chen, G., Wang, Z., Usyk, M., Yu, B., Baeza, Y. V., Humphrey, G. C., Benítez, R. A. S., Li, J., Williams-Nguyen, J. S., et al. (2021) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqab001 · Cited by 60 · see citing works
“Consistently, a recent dietary intervention study also suggested that higher intake of dietary red meat could increase systemic TMAO concentrations through microbial TMA production from dietary carnitine, but not choline (45).”
BackgroundSelf-citationBalancing the Equation: A Natural History of Trimethylamine and Trimethylamine-N-oxide
Loo, R. L., Chan, Q. M., Nicholson, J. K., & Holmes, E. C. (2022) · Journal of Proteome Research · doi:10.1021/acs.jproteome.1c00851 · Cited by 60 · see citing works
The Nutritional Supplement L-Alpha Glycerylphosphorylcholine Promotes Atherosclerosis
Wang, Z., Hazen, J. E., Jia, X., Org, E., Zhao, Y., Osborn, L. J., Nimer, N. A., Buffa, J. A., Culley, M. K., Krajcik, D., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413477 · Cited by 52 · see citing works
“d6-choline [(N,N-dimethyl-d6)-choline, iodide salt] and [N,N,N-trimethyld9] glycerylphosphorylcholine (d9-GPC) were chemically synthesized and purified in our lab, as previously reported [21,71].”
MethodSelf-citationLi, S., Chen, S. X., Lu, X., Fang, A., Chen, Y., Huang, R.-Z., Lin, X., Huang, Z.-H., Ma, J.-F., Huang, B., et al. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03581-7 · Cited by 62 · see citing works
Circulating trimethylamine N-oxide levels following fish or seafood consumption
Wang, Z., Tang, W. H. W., O’Connell, T. F., Garcia, E., Jeyarajah, E. J., Li, X. S., Jia, X., Weeks, T. L., & Hazen, S. L. (2022) · European Journal of Nutrition · doi:10.1007/s00394-022-02803-4 · Cited by 63 · see citing works
“In recent dietary intervention studies, we observed that differences in chronic dietary protein source differentially impacted a subject’s fractional renal excretion of TMAO [14].”
BackgroundSelf-citationThe dietary source of trimethylamine N-oxide and clinical outcomes: an unexpected liaison
Evans, M., Dai, L., Avesani, C. M., Kublickiene, K. R., & Stenvinkel, P. (2023) · Clinical Kidney Journal · doi:10.1093/ckj/sfad095 · Cited by 65 · see citing works
“A study on protein source (red meat versus white meat versus non-meat) found that subjects consuming approximately 220 g of steak/day for 1 month had higher TMAO levels accompanied by a reduced fractional renal excretion rate of TMAO [33].”
BackgroundTacconi, E., Palma, G., Biase, D. D., Luciano, A., Barbieri, M., de Nigris, F., & Bruzzese, F. (2023) · Nutrients · doi:10.3390/nu15030563 · Cited by 62 · see citing works
Wu, W., Panyod, S., Liu, P., Chen, C., Kao, H., Chuang, H.-L., Chen, Y., Zou, H.-B., Kuo, H., Kuo, C.-H., et al. (2020) · Microbiome · doi:10.1186/s40168-020-00912-y · Cited by 58 · see citing works
Self-citationPosicionamento sobre o Consumo de Gorduras e Saúde Cardiovascular – 2021
Izar, M. C. D. O., Lottenberg, A. M., Giraldez, V. Z. R., Santos, R. D., Machado, R. M., Bertolami, A., Assad, M. H. V., Saraiva, J. F. K., Faludi, A. Á., Moreira, A. S. B., et al. (2021) · Arquivos Brasileiros de Cardiologia · doi:10.36660/abc.20201340 · Cited by 65 · see citing works
Trimethylamine-N-Oxide Pathway: A Potential Target for the Treatment of MAFLD
Li, X., Hong, J. W., Wang, Y., Pei, M., Wang, L., & Gong, Z. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.733507 · Cited by 58 · see citing works
Self-citationNutrition, gut microbiota, and alzheimer’s disease
Romanenko, M., Kholin, V., Koliada, A., & Vaiserman, A. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.712673 · Cited by 56 · see citing works
“Moreover, red meat intake decreased TMAO renal excretion (115).”
BackgroundGut Microbiota Modulation as a Novel Therapeutic Strategy in Cardiometabolic Diseases
Mutalub, Y. B., Abdulwahab, M., Mohammed, A., Yahkub, A. M., Al-Mhanna, S. B., Yusof, W., Tang, S. P., Rasool, A. H. G., & Mokhtar, S. S. (2022) · Foods · doi:10.3390/foods11172575 · Cited by 60 · see citing works
Nutrition and Rheumatoid Arthritis in the ‘Omics’ Era
Cassotta, M., Forbes-Hernández, T. Y., Cianciosi, D., Elexpuru-Zabaleta, M., Cano, S. S., Azpíroz, I. D., Bullón, B., Regolo, L., Álvarez-Suárez, J. M., Giampieri, F., et al. (2021) · Nutrients · doi:10.3390/nu13030763 · Cited by 57 · see citing works
Milani, C., Alessandri, G., Mancabelli, L., Mangifesta, M., Lugli, G. A., Viappiani, A., Longhi, G., Anzalone, R., Duranti, S., Turroni, F., et al. (2020) · Applied and Environmental Microbiology · doi:10.1128/aem.01864-20 · Cited by 54 · see citing works
“Notably, choline, a quaternary amine principally found in meats, is known as a precursor of trimethylamine (35, 36).”
BackgroundGut microbiome and its meta-omics perspectives: profound implications for cardiovascular diseases
Xu, J., & Yang, Y. (2021) · Gut Microbes · doi:10.1080/19490976.2021.1936379 · Cited by 56 · see citing works
“The conversion of TMAO in humans has been shown to arise via a multistep, metaorganismal, and microbe-dependent pathway commencing with the dietary precursors including choline,(94) phosphatidylcholine,(94,95) carnitine,(18) betaine,(94) γ-butyrobetaine (γ-BB),(96) and trimethyllysine (TML),(97) which are most abundan…”
Background
- Authors
- Wang, Z., Bergeron, N., Levison, B. S., Li, X. S., Chiu, S., Jia, X., Koeth, R. A., Li, L., Wu, Y., Tang, W. H. W., Krauss, R. M., & Hazen, S. L.
- Affiliations
- Cleveland Clinic (US)
- Touro University California (US)
- Department of Atherosclerosis Research, Children’s Hospital Oakland Research Institute, Martin Luther King Jr Way, Oakland, CA, USA
- Cleveland State University (US)
- Corresponding author
- Hazen, Stanley L
- ORCID
- Venue
- European Heart Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-12-10
- Volume
- 40
- Issue
- 7
- Pages
- 583-594
- ISSN
- 0195-668X (ISSN-L)
- 1522-9645
- PMC
- PMC6374688
- OpenAlex
- W2904124435
- Semantic Scholar
- e6c31002dc7272f769757169c410825c0b0308a3
- Cited by
- 496
- References
- 40
- Citations by year
- 2026: 62 · 2025: 70 · 2024: 62 · 2023: 59 · 2022: 72 · 2021: 73 · 2020: 68 · 2019: 28 · 2018: 1
- FWCI
- 15.11
- 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)
- Touro Scholar (Touro College) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (HL103866, R01 HL126827, R01 DK106000, RO1 HL106003, R01 HL130819)
- Leducq Foundation
- Clinical and Translational Science Unit
- 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 › Agricultural and Biological Sciences › Animal Science and Zoology › Meat and Animal Product Quality
- Keywords
- trimethylamine N-oxide, red meat, white meat, L-carnitine, choline, gut microbiota, renal excretion, saturated fat, dietary protein, isotope tracers
- MeSH terms
- Red Meat, Adult, Aged, Animals, Diet, Dietary Proteins, Feeding Behavior, Female, Humans, Male, Methylamines, Middle Aged, Poultry, Reference Values, Cross-Over Studies, Young Adult, Renal Elimination
About these checks
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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.
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