CoChat
Sign Up
Cited by 504Gut microbiota and healthPolyamine Metabolism and ApplicationsMetabolism and Genetic Disorders

Trimethylamine N-oxide: the good, the bad and the unknown.

Open access
Velasquez, Manuel, Ramezani, Ali, Manal, Alotaibi, Raj, Dominic·2016·Toxins
DOI 10.3390/toxins8110326PMC PMC5127123
Open this paper in CoChat — free accountOpen PDF

Abstract

Trimethylamine N-oxide (TMAO) is a small colorless amine oxide generated from choline, betaine, and carnitine by gut microbial metabolism. It accumulates in the tissue of marine animals in high concentrations and protects against the protein-destabilizing effects of urea. Plasma level of TMAO is determined by a number of factors including diet, gut microbial flora and liver flavin monooxygenase activity. In humans, a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events and death is reported. The atherogenic effect of TMAO is attributed to alterations in cholesterol and bile acid metabolism, activation of inflammatory pathways and promotion foam cell formation. TMAO levels increase with decreasing levels of kidney function and is associated with mortality in patients with chronic kidney disease. A number of therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that utilize TMAO as substrate and the development of target-specific molecules with varying level of success. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies examining the cellular signaling in physiology and pathological states in order to establish the role of TMAO in health and disease in humans.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review summarizes the biology of trimethylamine N-oxide (TMAO), a gut-microbiota-derived metabolite of dietary choline, betaine, and carnitine, and its reported associations with cardiovascular disease and chronic kidney disease. It concludes that despite substantial evidence linking elevated TMAO to adverse outcomes, it remains unresolved whether TMAO is a mediator, a marker, or merely a bystander in disease.

Key findings

  • TMAO is generated from dietary choline/phosphatidylcholine and l-carnitine by gut microbiota (via TMA) and converted to TMAO by host hepatic flavin monooxygenases (FMO1/FMO3); plasma levels are determined by diet, gut flora, liver FMO activity, and kidney function.
  • In 349 apparently healthy subjects, median fasting plasma TMAO was 3.45 μM (IQR 2.25–5.79), not differing by sex but increasing with age; a genome-wide association study of 1973 humans concluded genes play only a marginal role.
  • Renal clearance of TMAO was 219 ± 78 mL/min versus urea 55 ± 14 and creatinine 119 ± 21 mL/min, indicating at least 50% of excretion occurs via tubular secretion; TMAO accumulates markedly in kidney disease (e.g., hemodialysis median 43 μM/L vs 1.41 ± 0.49 μM/L in normal/near-normal function; ESRD on dialysis ~40-fold higher than controls).
  • Evidence for a causal cardiovascular role is mixed: elevated TMAO was associated with poor prognosis in 3903 subjects undergoing coronary angiography and with a 2.8-fold increased mortality risk in 521 CKD patients, but other studies (e.g., 339 coronary angiography patients; a stroke/TIA case-control study) found no association or even inverse/decreased TMAO levels.

Methods

  • Narrative review (no systematic search or meta-analytic method described) synthesizing animal, in vitro, and human observational and interventional studies on TMAO biosynthesis, determinants, disease associations, mechanisms, and therapeutic strategies.
  • Cited human data include cohorts and trials of varying sizes (e.g., 1973 for heritability, 3903 angiography subjects, 521 CKD patients, 235 hemodialysis patients, 339 angiography patients, 271 participants, 80 controls/179 CKD patients, 227 cardiovascular surgery patients).
  • Therapeutic strategies reviewed include broad-spectrum antibiotics, archaeobiotics/methanogenic bacteria, dietary precursor reduction, resveratrol, meldonium, DMB, and FMO3 knockdown.

Limitations

  • Stated by the paper: the mechanism by which TMAO interacts with proteins and promotes atherogenesis "remains speculative"; it is "questioned whether TMAO is the mediator or a bystander in the disease process"; and it remains unclear whether elevated TMAO in CKD reflects increased generation or decreased elimination, or is a surrogate for other retention solutes.
  • Stated by the paper: contradictory findings exist across studies (e.g., no association between diet and TMAO in some cohorts; inverse correlation of TMAO with lesion size in one apoE−/− CETP mouse study), and the authors call for further studies on intracellular TMAO concentrations and cellular signaling.
  • Evident from the text: as a narrative review without a described systematic search strategy, study selection and synthesis are not reproducible, and many cited findings are associative rather than causal.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/toxins8110326

Cites

57 of 57 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 120 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Plasma level of TMAO is determined by factors including diet, gut microbial flora and liver flavin monooxygenase activity.

    “Plasma level of TMAO is determined by a number of factors including diet, gut microbial flora and liver flavin monooxygenase activity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Romano, 2015, Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide, MBio source

      Not checked in the free run.

  • Premisecitation

    TMAO is commonly found in a variety of marine microbiota, where it serves as an important substrate in the anaerobic metabolism of a number of bacteria.

    “TMAO is commonly found in a variety of marine microbiota, where it serves as an important substrate in the anaerobic metabolism of a number of bacteria [16].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Barrett, 1985, Bacterial reduction of trimethylamine oxide, Annu. Rev. Microbiol. source

      Not checked in the free run.

  • Premisecitation

    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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [33] Wang, 2014, Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide, Eur. Heart J. source

      Not checked in the free run.

    • cites [34] Tang, 2014, Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: Refining the gut hypothesis, J. Am. Coll. Cardiol. source

      Not checked in the free run.

  • Premisecitation

    In deep sea creatures, TMAO and, to a lesser extent, betaine, counteract the inhibitory effects of hydrostatic pressure on proteins.

    “Furthermore, in deep see creatures, TMAO, and, to a lesser extent, betaine, counteract the inhibitory effects of hydrostatic pressure on proteins [6].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Yancey, 2002, Unusual organic osmolytes in deep-sea animals: Adaptations to hydrostatic pressure and other perturbants, Comp. Biochem. Physiol. A Mol. Integr. Physiol. source

      Not checked in the free run.

  • Premisecitation

    In healthy humans given phosphatidylcholine challenge, plasma levels of TMAO were suppressed by oral administration of broad spectrum antibiotics.

    “Further evidence that the production of TMAO is dependent on metabolism by intestinal microbiota is provided by studies in healthy humans given phosphatidylcholine challenge, in which the plasma levels of TMAO were suppressed by oral administration of broad spectrum antibiotics [14].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Tang, 2013, Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk, N. Engl. J. Med. source

      Not checked in the free run.

  • May combine two claims. 27
  • Classified as probably not a substantial claim. 4

  • May combine two claims.

    Premisecitation

    L-carnitine is converted by gut microbiota into γ-butyrobetaine and then into TMA, which is subsequently converted into TMAO by host hepatic flavin monooxygenases 3 (FMO3).

    “According to this, l-carnitine is first converted into the intermediate metabolite γ-butyrobetaine and then into TMA, which is subsequently converted into TMAO by host hepatic flavin monooxygenases 3 (FMO3) [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] 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.

  • May combine two claims.

    Premisecitation

    In gnotobiotic mice, TMAO accumulates in the serum of animals colonized with TMA-producing bacteria, but not in animals colonized with bacteria that do not generate TMA from choline in vitro.

    “Studies in gnotobiotic mice have shown that TMAO accumulates in the serum of animals colonized with TMA-producing bacteria, but not in animals colonized with bacteria that do not generate TMA from choline in vitro [17].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Romano, 2015, Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide, MBio source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Urea destabilizes many macromolecular structures and inhibits cellular functions such as ligand binding, which is counteracted by TMAO.

    “For instance, urea destabilizes many macromolecular structures and inhibits cellular functions such as ligand binding, which is counteracted by TMAO [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Yancey, 2005, Organic osmolytes as compatible, metabolic and counteracting cytoprotectants in high osmolarity and other stresses, J. Exp. Biol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In humans, a mutation of FMO3 causes trimethylaminuria, characterized by a fishy body odor in urine, sweat, breath and other bodily excretions.

    “In humans, a mutation of the FMO3 causes trimethylaminuria, a condition wherein individuals excrete TMA, rather than TMAO. This condition known as fish odor syndrome is characterized by a fishy body odor in urine, sweat, breath and other bodily excretions [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Dolphin, 1997, Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome, Nat. Genet. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TMAO accumulates in the tissues of marine animals in high concentrations and protects against the protein-destabilizing effects of urea.

    “It accumulates in the tissue of marine animals in high concentrations and protects against the protein-destabilizing effects of urea.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Lidbury, 2014, Trimethylamine N-oxide metabolism by abundant marine heterotrophic bacteria, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

    • cites [2] Yancey, 2005, Organic osmolytes as compatible, metabolic and counteracting cytoprotectants in high osmolarity and other stresses, J. Exp. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TMAO is either transported to tissues for accumulation as an osmolyte or cleared by the kidney.

    “TMAO is then either transported to the tissues for accumulation as an osmolyte or, more commonly, cleared by the kidney [3,9,13,14].”
    Quote in the paperNot a substantial claim0 of 4 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 [9] Tang, 2015, Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease, Circ. Res. source

      Not checked in the free run.

    • cites [13] Ierardi, 2015, Intestinal microbial metabolism of phosphatidylcholine: A novel insight in the cardiovascular risk scenario, Hepatobiliary Surg. Nutr.

      Not checked in the free run.

    • cites [14] Tang, 2013, Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk, N. Engl. J. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TMAO levels increase with decreasing levels of kidney function and are associated with mortality in patients with chronic kidney disease.

    “TMAO levels increase with decreasing levels of kidney function and is associated with mortality in patients with chronic kidney disease.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Missailidis, C., Hallqvist, J., Qureshi, A.R., Barany, P., Heimburger, O., Lindholm, B., Stenvinkel, P., and Bergman, P. (2016). Serum trimethylamine-N-oxide is strongly related to renal function and predicts outcome in chronic kidney disease. PLoS ONE, 11. source

      Not checked in the free run.

    • cites [9] Tang, 2015, Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease, Circ. Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    TMAO is found in tissues of marine organisms including marine elasmobranch, where it protects against adverse effects of temperature, salinity, high urea and hydrostatic pressure.

    “It is frequently found in the tissues of a variety of marine organisms [1] including marine elasmobranch, in which TMAO is known to protect against the adverse effects of temperature, salinity, high urea and hydrostatic pressure.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Lidbury, 2014, Trimethylamine N-oxide metabolism by abundant marine heterotrophic bacteria, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TMAO is formed from trimethylamine (TMA), which is generated by gut microbiota from dietary choline and phosphatidylcholine (lecithin).

    “TMAO is formed from trimethylamine (TMA), which is generated by the action of gut microbiota from dietary choline and phosphatidylcholine (lecithin) [8,9].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Kaysen, 2015, Associations of trimethylamine N-oxide with nutritional and inflammatory biomarkers and cardiovascular outcomes in patients new to dialysis, J. Ren. Nutr. source

      Not checked in the free run.

    • cites [9] Tang, 2015, Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease, Circ. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There was a significant reduction (about 60%) in plasma TMA and TMAO during a single hemodialysis session, and post-dialysis levels were not significantly different from control subjects.

    “There was a significant reduction (about 60%) in plasma TMA and TMAO during a single hemodialysis session and the post-dialysis levels were not significantly different from that in control subjects.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Bain, 2006, Accumulation of trimethylamine and trimethylamine-N-oxide in end-stage renal disease patients undergoing haemodialysis, Nephrol. Dial. Transplant. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TMAO generated by gut microbiome exacerbates impaired glucose tolerance, inhibits hepatic insulin signaling, and promotes adipose tissue inflammation in mice maintained on a high-fat high-sugar diet.

    “Indeed, TMAO generated by gut microbiome exacerbates impaired glucose tolerance, inhibits hepatic insulin signaling, and promotes adipose tissue inflammation in mice that are maintained on a high-fat high-sugar diet [17].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Romano, 2015, Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide, MBio source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TMAO has a small volume of distribution-about one half that of urea-but a higher renal clearance compared to urea and creatinine.

    “Studies on pharmacokinetics [25] and renal clearance of TMAO [26] in healthy human subjects suggest that TMAO has a small volume of distribution—about one half that of urea—but a higher renal clearance compared to urea and creatinine.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Akesson, 1989, Pharmacokinetics of triethylamine and triethylamine-N-oxide in man, Toxicol. Appl. Pharmacol. source

      Not checked in the free run.

    • cites [26] Hai, X., Landeras, V., Dobre, M.A., DeOreo, P., Meyer, T.W., and Hostetter, T.H. (2015). Mechanism of prominent trimethylamine oxide (TMAO) accumulation in hemodialysis patients. PLoS ONE, 10. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with stable heart failure, TMAO levels were increased and elevated levels were associated with increased risk of death.

    “In another study, TMAO levels were increased in patients with stable heart failure and elevated levels were associated with increased risk of death [34].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Tang, 2014, Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: Refining the gut hypothesis, J. Am. Coll. Cardiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 349 apparently healthy subjects, fasting plasma TMAO median concentration was 3.45 μM (IQR 2.25-5.79), did not differ by sex, but increased with advancing age.

    “Wang et al. measured fasting plasma levels of TMAO in 349 apparently healthy subjects using stable isotope dilution liquid chromatography tandem mass spectrometry (LC/MS/MS) and reported a median concentration of 3.45 μM (Interquartile Range 2.25–5.79), which did not differ by sex, but the levels increased with advancing age [21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Wang, 2014, Measurement of trimethylamine-N-oxide by stable isotope dilution liquid chromatography tandem mass spectrometry, Anal. Biochem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Feeding male Wistar rats a phospholipid-protein complex from Antarctic krill increased plasma levels of TMAO, choline, and carnitine, but there was no correlation between plasma choline and TMAO in rats fed PPC.

    “Another contradictory finding was reported by Bjørnda et al. who demonstrated that feeding male Wistar rats a phospholipid-protein complex (PPC) from Antarctic krill increased the plasma levels of TMAO, choline, and carnitine. However, there was no correlation between plasma choline and TMAO in rats fed PPC [37].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Bjorndal, 2015, A phospholipid-protein complex from antarctic krill reduced plasma homocysteine levels and increased plasma trimethylamine-N-oxide (TMAO) and carnitine levels in male wistar rats, Mar. Drugs source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 339 patients undergoing coronary angiography, plasma levels of TMAO or betaine were not associated with a history of myocardial infarction, angiographically-assessed presence of coronary heart disease, or incident cardiovascular events during 8 years of follow-up.

    “The plasma levels of TMAO or betaine were not found to be associated with a history of myocardial infarction, the angiographically-assessed presence of coronary heart disease, or the incident cardiovascular events during 8 years of follow-up.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Mueller, 2015, Plasma levels of trimethylamine-N-oxide are confounded by impaired kidney function and poor metabolic control, Atherosclerosis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice supplemented with dietary TMAO showed a significant reduction in cholesterol absorption, as well as liver expression of bile acid synthetic enzymes Cyp7a1 and Cyp27a1.

    “Also, mice supplemented with dietary TMAO showed a significant reduction in cholesterol absorption, as well as liver expression of bile acid synthetic enzymes cytochrome P450, family 7, subfamily a, polypeptide 1 (Cyp7a1) and cytochrome P450, family 27, subfamily a, polypeptide 1 (Cyp27a1) [3].”
    Quote in the paperSubstantial claim0 of 1 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.

  • May combine two claims.

    Premisecitation

    In a case-control study of patients with large-artery atherosclerotic ischemic stroke and transient ischemic attack, asymptomatic atherosclerosis participants did not exhibit an obvious change in gut microbiota and blood TMAO levels; stroke and transient ischemic attack patients showed significant dysbiosis and their blood TMAO levels were decreased.

    “In a case-control study of patients with large-artery atherosclerotic ischemic stroke and transient ischemic attack, participants with asymptomatic atherosclerosis did not exhibit an obvious change in gut microbiota and blood TMAO levels; however, stroke and transient ischemic attack patients showed significant dysbiosis of the gut microbiota, and their blood TMAO levels were decreased [36].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Yin, 2015, Dysbiosis of gut microbiota with reduced trimethylamine-N-oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack, J. Am. Heart Assoc. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 235 hemodialysis patients, there was no significant association between serum TMAO concentrations and all-cause mortality, cardiovascular death, or hospitalizations.

    “On the other hand, Kaysen et al., did not find any significant association between serum TMAO concentrations and all-cause mortality, cardiovascular death, or hospitalizations in 235 hemodialysis patients [8].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Kaysen, 2015, Associations of trimethylamine N-oxide with nutritional and inflammatory biomarkers and cardiovascular outcomes in patients new to dialysis, J. Ren. Nutr. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TMAO concentration is an independent predictor for coronary atherosclerosis burden and predicted long-term mortality independent of traditional cardiac risk factors.

    “Stubbs et al. showed that TMAO concentration is an independent predictor for coronary atherosclerosis burden and predicted long-term mortality independent of traditional cardiac risk factors [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Stubbs, 2016, Serum trimethylamine-N-oxide is elevated in CKD and correlates with coronary atherosclerosis burden, J. Am. Soc. Nephrol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Atherosclerosis Risk in Communities study and the European Prospective Investigation into Cancer and Nutrition study did not report increased cardiovascular risk with increasing dietary intake of choline.

    “The Atherosclerosis Risk in Communities study [48] and the European Prospective Investigation into Cancer and Nutrition study [49] did not report increased cardiovascular risk with increasing dietary intake of choline.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [48] Bidulescu, 2007, Usual choline and betaine dietary intake and incident coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) study, BMC Cardiovasc. Disord. source

      Not checked in the free run.

    • cites [49] Dalmeijer, 2008, Prospective study on dietary intakes of folate, betaine, and choline and cardiovascular disease risk in women, Eur. J. Clin. Nutr. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    C57BL/6J mice fed with choline or TMAO exhibited tubulointerstitial fibrosis, collagen deposition and phosphorylation of Smad3.

    “Tang et al. showed that C57BL/6J mice fed with choline or TMAO exhibited tubulointerstitital fibrosis, collagen deposition and phosphorylation of Smad3; an important regulator of the profibrotic transforming growth factor-β/Smad3 signaling pathway [9].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Tang, 2015, Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease, Circ. Res. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    If the microbiome is the source of TMAO, antibiotic treatment should reduce circulating TMAO levels.

    “Assuming the microbiome is the source of TMAO, antibiotic treatment should reduce its circulating levels.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The microbiome is the source of TMAO.

  • May combine two claims.

    Premisecitation

    In HEMO study participants, higher TMAO concentrations were associated with a higher risk of sudden cardiac death, first cardiovascular event, and any-cause death, particularly in whites.

    “In HEMO study participants, higher TMAO concentrations were associated with a higher risk of sudden cardiac death, first cardiovascular event, and any-cause death, particularly in whites [46].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Shafi, T., Powe, N.R., Meyer, T.W., Hwang, S., Hai, X., Melamed, M.L., Banerjee, T., Coresh, J., and Hostetter, T.H. (2016). Trimethylamine N-oxide and cardiovascular events in hemodialysis patients. J. Am. Soc. Nephrol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    TMAO plays an important physiological role in lower animals, but in humans it is merely a remnant of the evolution of the osmolyte system.

    “Interestingly, TMAO plays an important physiological role in lower animals, but in humans it is merely a remnant of the evolution of the osmolyte system.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    DMB inhibited choline diet-enhanced endogenous macrophage foam cell formation and atherosclerotic lesion development in apoE−/− mice without alterations in circulating cholesterol levels.

    “DMB inhibited choline diet-enhanced endogenous macrophage foam cell formation and atherosclerotic lesion development in apoE−/− mice without alterations in circulating cholesterol levels [38].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Wang, 2015, Non-lethal Inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Meldonium did not influence bacterial growth and bacterial uptake of l-carnitine.

    “Meldonium, however, did not influence bacterial growth and bacterial uptake of l-carnitine [56].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Kuka, 2014, Suppression of intestinal microbiota-dependent production of pro-atherogenic trimethylamine N-oxide by shifting l-carnitine microbial degradation, Life Sci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DMB promoted reduction in microbial taxa associated with plasma TMA and TMAO levels and reduced the choline-diet-dependent enhancement in aortic root atherosclerotic lesion development.

    “Furthermore, DMB promoted reduction in microbial taxa that are associated with plasma TMA and TMAO levels and also reduced the choline-diet-dependent enhancement in aortic root atherosclerotic lesion development [38].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Wang, 2015, Non-lethal Inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DMB is a structural analog of choline and an inhibitor for TMA formation through inhibition of microbial TMA lyases.

    “3,3-dimethyl-1-butanol (DMB) is a structural analog of choline and an inhibitor for TMA formation through inhibition of microbial TMA lyases.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Wang, 2015, Non-lethal Inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis, Cell source

      Not checked in the free run.

29 of 29

  • The authors state this as an assumption.

    The microbiome is the source of TMAO.

    “Assuming the microbiome is the source of TMAO, antibiotic treatment should reduce its circulating levels.”

  • The paper relies on this without support.

    The gut microbiota plays a role in systemic inflammation, metabolic syndrome, vascular dysfunction and atherosclerosis.

    “Several lines of evidence indicate that the gut microbiota plays a role in systemic inflammation, metabolic syndrome, vascular dysfunction and atherosclerosis.”

  • The paper relies on this without support.

    Chronic antibiotic treatment is likely to lead to emergence of resistant bacteria.

    “However, antibiotics is not an ideal treatment since it could have other unwanted consequences, and also chronic treatment is likely to lead to emergence of resistant bacteria.”

  • The paper relies on this without support.

    FMO3 is the member of the FMO enzyme family with the highest activity level and is capable of oxidizing TMA to TMAO.

    “FMO3 is the member of the FMO enzyme family with the highest activity level and is capable of oxidizing TMA to TMAO.”

  • The paper relies on this without support.

    Individuals without functional FMO3 often exhibit a fishy odor, caused by trimethylaminuria.

    “It is important to recall that individuals without functional FMO3 often exhibit a fishy odor, which is caused by trimethylaminuria.”
5 of 5

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?

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Clarke, 1988, Purification and properties of trimethylamhe N-oxide reductase from ShewuneIIu sp. NCMB 400, J. Gen. Microbiol., 133, 319

Cited by

Sorted by citations

Related

Authors
Velasquez, M., Ramezani, A., Manal, A., & Raj, D.
Affiliations
George Washington University (US)
Corresponding author
Raj, Dominic
ORCID
Ramezani, Ali
Venue
Toxins
Publisher
MDPI AG
Published
2016-11-08
Volume
8
Issue
11
Pages
326
ISSN
2072-6651 (ISSN-L)
DOI
10.3390/toxins8110326
PMC
PMC5127123
OpenAlex
W2556034984
Semantic Scholar
5818fd932f9206395897eb321b710ef8fc9c9d4a
Cited by
504
References
57
Citations by year
2026: 28 · 2025: 57 · 2024: 62 · 2023: 61 · 2022: 67 · 2021: 49 · 2020: 72 · 2019: 46 · 2018: 49 · 2017: 12 · 2015: 1
FWCI
3.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Toxins (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
NIH (1R01DK073665-01A1, 1U01DK099924- 01, 1U01DK099914-01)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
trimethylamine N-oxide, gut microbiota, cardiovascular risk, chronic kidney disease, atherosclerosis, bile acid metabolism, cholesterol metabolism, inflammation, foam cell formation, flavin-containing monooxygenase, dietary choline, L-carnitine, betaine, broad-spectrum antibiotics, signal transduction
MeSH terms
Gastrointestinal Microbiome, Animals, Cardiovascular Diseases, Humans, Methylamines, Toxins, Biological, Renal Insufficiency, Chronic

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 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review