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Cited by 1,051Gut microbiota and healthOral microbiology and periodontitis researchNutritional Studies and Diet

Gut microbiota and cardiovascular disease.

Open access
Witkowski, Marco, Weeks, Taylor L., Hazen, Stanley L.·2020·Circulation Research
DOI 10.1161/circresaha.120.316242PMC PMC7416843
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Abstract

Fecal microbial community changes are associated with numerous disease states, including cardiovascular disease (CVD). However, such data are merely associative. A causal contribution for gut microbiota in CVD has been further supported by a multitude of more direct experimental evidence. Indeed, gut microbiota transplantation studies, specific gut microbiota–dependent pathways, and downstream metabolites have all been shown to influence host metabolism and CVD, sometimes through specific identified host receptors. Multiple metaorganismal pathways (involving both microbe and host) both impact CVD in animal models and show striking clinical associations in human studies. For example, trimethylamine N-oxide and, more recently, phenylacetylglutamine are gut microbiota–dependent metabolites whose blood levels are associated with incident CVD risks in large-scale clinical studies. Importantly, a causal link to CVD for these and other specific gut microbial metabolites/pathways has been shown through numerous mechanistic animal model studies. Phenylacetylglutamine, for example, was recently shown to promote adverse cardiovascular phenotypes in the host via interaction with multiple ARs (adrenergic receptors)—a class of key receptors that regulate cardiovascular homeostasis. In this review, we summarize recent advances of microbiome research in CVD and related cardiometabolic phenotypes that have helped to move the field forward from associative to causative results. We focus on microbiota and metaorganismal compounds/pathways, with specific attention paid to short-chain fatty acids, secondary bile acids, trimethylamine N-oxide, and phenylacetylglutamine. We also discuss novel therapeutic strategies for directly targeting the gut microbiome to improve cardiovascular outcomes.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes evidence moving gut microbiota–cardiovascular disease research from associations to causal mechanisms, focusing on short-chain fatty acids, secondary bile acids, TMAO, and phenylacetylglutamine (PAG). It highlights metaorganismal pathways and therapeutic strategies such as non-lethal microbial enzyme inhibitors, while noting many findings remain preclinical.

Key findings

  • TMAO is a gut microbiota-dependent metabolite of choline, phosphatidylcholine, and carnitine; its clinical associations with CVD outcomes withstand adjustment for traditional risk factors, and one meta-analysis of >25,000 subjects found a 7.6% increase in all-cause mortality per 10 μmol/L increment of TMAO, with a plasma TMAO cutoff of approximately >6 μM predicting heightened adverse cardiac event risk.
  • PAG, a phenylalanine-derived gut microbial metabolite, was associated with incident major adverse cardiac events and validated in an independent cohort of 4000 stable cardiovascular subjects; functional studies show PAG interacts with α- and β-adrenergic receptors, and adverse phenotypes were attenuated with the β-blocker carvedilol.
  • SCFAs (acetate, propionate, butyrate) influence host blood pressure via receptors including Olfr78 and Gpr41; free SCFA levels are virtually undetectable in germ-free animals, and fecal transfer from hypertensive donors into germ-free mice transmitted heightened blood pressure, though transfer from normotensive Dahl salt-resistant rats into hypertensive Dahl salt-sensitive rats exacerbated hypertension.
  • Therapeutic targeting includes the non-lethal choline TMA lyase inhibitor DMB, which reduced atherosclerosis in mice; fluoromethylcholine (FMC) was over 10,000-fold more potent than DMB against cutC; and screening >1000 commonly prescribed non-antibiotic drugs found nearly a quarter inhibited growth of at least one human gut commensal.

Methods

  • Narrative review of recent microbiome research in CVD and related cardiometabolic phenotypes; no primary experimental data are reported.
  • Synthesizes animal model, human observational, dietary intervention, microbial transplantation, genetic, and pharmacological studies.
  • Focuses on microbiota and metaorganismal compounds/pathways, specifically short-chain fatty acids, secondary bile acids, TMAO, and PAG, plus therapeutic strategies targeting the gut microbiome.

Limitations

  • The paper states that much microbiome-CVD data are merely associative; sequencing techniques often do not reach species or strain level resolution, analyses often exclude less abundant microbes, and gene presence does not establish expression or activity, requiring experimental validation.
  • The paper states that probiotic and prebiotic results are highly variable, studies tend to be relatively small, animal model findings have not yet translated to clinical efficacy, and human clinical studies with choline TMA lyase inhibitors have not yet been reported.
  • Evident from the text: as a narrative review, it is not a systematic review or meta-analysis and includes speculative sections (e.g., evolutionary benefits of TMAO, renal TMAO transport) and unpublished data (Hazen, unpublished data).

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

Integrity signals

Registry

Crossref · 10.1161/circresaha.120.316242

Cites

172 of 172 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 168 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In mice, TMAO levels in kidney tissue largely exceed paired plasma levels collected at the same time from the same animals.

    “When measuring concentrations in various mouse tissues, we observed that TMAO levels in kidney tissue largely exceeded those observed in corresponding paired plasma samples collected at the same time from the same animals (Hazen, unpublished data).”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Microbial compositional changes have been reported in patients with cardiovascular disease risk factors including hypertension, dyslipidemia, insulin resistance, and other metabolic phenotypes.

    “microbial compositional changes have been reported in patients with numerous CVD risk factors including hypertension, dyslipidemia, insulin resistance, and other metabolic phenotypes10, 11.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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      Not checked in the free run.

  • Premisecitation

    Dietary addition of a single type of fiber can cause dramatic changes in the expression of genes required for bacterial metabolism of fiber glycans.

    “This is demonstrated in recent work showing that dietary addition of a single type of fiber can cause dramatic changes in the expression of genes required for bacterial metabolism of fiber glycans16.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • Premisecitation

    Administration of canakinumab, an antibody against interleukin-1β, reduces cardiovascular event risk independent of lipid level lowering.

    “Administration of canakinumab, an antibody against Interleukin(IL)-1β, showed that inhibition of the IL-1β pathway reduces cardiovascular event risk independent of lipid level lowering34.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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      Not checked in the free run.

  • Premisecitation

    Distinct changes in the microbial community structure and function are associated with multiple disease states, including cardiovascular disease.

    “In particular, distinct changes in the microbial community structure and function are associated with multiple disease states, including cardiovascular disease (CVD)1.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • May combine two claims. 55
  • Classified as probably not a substantial claim. 15

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    Premisecitation

    Patients with heart failure have alterations in intestinal integrity, and elevated levels of pro-inflammatory cytokines in the blood correlate with symptom severity and poorer outcomes.

    “Multiple studies show patients with heart failure have alterations in intestinal integrity, and that elevated levels of pro-inflammatory cytokines in the blood correlate with symptom severity and poorer outcomes20, 21.”
    Quote in the paperSubstantial claim0 of 2 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Human atherosclerotic plaques contain bacterial DNA.

    “human atherosclerotic plaques were noted to contain bacterial DNA, though whether or not the DNA was derived from live bacteria within the artery wall was not determined6.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Koren O, Spor A, Felin J, Fak F, Stombaugh J, Tremaroli V, Behre CJ, Knight R, Fagerberg B, Ley RE, Backhed F. Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proc Natl Acad Sci U S A. 2011; 108 Suppl 1: 4592– 4598 20937873 PMC3063583 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A gain-of-function C. sporogenes mutant present at only about 0.1% in the large intestine elevated circulating TMA and TMAO levels and enhanced thrombus formation and reduced time to cessation of blood flow following arterial injury in vivo.

    “While only present at a very low abundance (only ~ 0.1%) within the large intestine gut microbial community, the gain-of-function C. sporogenes mutant elevated circulating TMA and TMAO levels within the host, and both enhanced rate of thrombus formation and reduced time to cessation of blood flow following arterial injury in vivo14.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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      Not checked in the free run.

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    Premisecitation

    The Akkermansia intervention did not change body weight but improved insulin sensitivity and dyslipidemia in the treated group.

    “Although the intervention did not change body weight, the authors observed improvement in insulin sensitivity and dyslipidemia in the Akkermansia-treated group.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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      Not checked in the free run.

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    Premisecitation

    Intestinal hypoperfusion in heart failure alters mucosal function, as evidenced by increased paracellular permeability and augmented intestinal bacterial biofilm formation.

    “Intestinal hypoperfusion in heart failure alters mucosal function, as evidenced by increased paracellular permeability and augmented intestinal bacterial biofilm formation23.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Sandek A, Bauditz J, Swidsinski A, Buhner S, Weber-Eibel J, von Haehling S, Schroedl W, Karhausen T, Doehner W, Rauchhaus M, Poole-Wilson P, Volk HD, Lochs H, Anker SD. Altered intestinal function in patients with chronic heart failure. J Am Coll Cardiol. 2007; 50: 1561– 1569 17936155 source

      Not checked in the free run.

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

    Premisecitation

    Disruptions to the microbiome early in life can promote heightened adiposity.

    “Subsequently, it was discovered that disruptions to the microbiome early in life can promote heightened adiposity5.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Cho I, Yamanishi S, Cox L, Methe BA, Zavadil J, Li K, Gao Z, Mahana D, Raju K, Teitler I, Li H, Alekseyenko AV, Blaser MJ. Antibiotics in early life alter the murine colonic microbiome and adiposity. Nature. 2012; 488: 621– 626 22914093 PMC3553221 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Impaired gut barrier function leads to translocation of bacterial products into host circulation, which can result in a pro-inflammatory state.

    “Following the leaky gut concept, impaired gut barrier function leads to translocation of bacterial products into host circulation, which can result in a pro-inflammatory state.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Microbial transplantation can transmit heightened adiposity in the host.

    “Early work in the gut microbiome field demonstrated that alterations in fecal microbial community composition are associated with the development of obesity and insulin resistance, and that microbial transplantation could transmit heightened adiposity in the host2–4.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004; 101: 15718– 15723 15505215 PMC524219 source

      Not checked in the free run.

    • cites [3] Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A. 2005; 102: 11070– 11075 16033867 PMC1176910 source

      Not checked in the free run.

    • cites [4] Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006; 444: 1027– 1031 17183312 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Trimethylamine N-oxide and phenylacetyl glutamine are gut microbiota-dependent metabolites whose blood levels are associated with incident cardiovascular disease risks in large-scale clinical studies.

    “For example, trimethylamine N-oxide (TMAO) and more recently, phenylacetyl glutamine (PAG), are gut microbiota-dependent metabolites whose blood levels are associated with incident CVD risks in large scale clinical studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In heart failure, venous fluid overload, adaptive sympathetic activation resulting in redistribution of the systemic circulation, and low cardiac output contribute to bowel wall edema and reduced mucosal perfusion.

    “In the presence of heart failure, venous fluid overload, adaptive sympathetic activation resulting in redistribution of the systemic circulation, and low cardiac output contribute to bowel wall edema and reduced mucosal perfusion22.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Fudim M, Hernandez AF, Felker GM. Role of volume redistribution in the congestion of heart failure. J Am Heart Assoc. 2017; 6 PMC5586477 28862947 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When the gut barrier is impaired, lipopolysaccharide originating from Gram-negative bacteria can enter the host circulation, where it is mainly recognized by toll-like receptors on the surface of immune cells.

    “When the gut barrier is impaired, lipopolysaccharide (LPS) originating from Gram-negative bacteria can enter the host circulation, where it is mainly recognized by toll-like receptor (TLR)s on the surface of immune cells24.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In heart failure patients, bowel wall edema and impaired barrier function are often observed.

    “And in heart failure patients, we often observe bowel wall edema and impaired barrier function18, 19.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Polsinelli VB, Sinha A, Shah SJ. Visceral congestion in heart failure: Right ventricular dysfunction, splanchnic hemodynamics, and the intestinal microenvironment. Curr Heart Fail Rep. 2017; 14: 519– 528 29075956 PMC5681876 source

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      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In preclinical models, gavage of western diet-fed Apoe−/− mice with live Akkermansia muciniphila decreased intestinal permeability and lowered fecal and circulating lipopolysaccharide levels, which was associated with reduced aortic atherosclerosis independent of lipid metabolism.

    “Indeed, in preclinical models, gavage of western diet–fed Apoe−/− mice with live Akkermansia muciniphila decreased intestinal permeability and lowered fecal and circulating LPS levels, which was associated with reduced aortic atherosclerosis independent of lipid metabolism28.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    Many investigators have reported an association between cardiovascular disease phenotypes and changes in the relative abundance of specific microbial taxa, or gut bacterial richness or diversity.

    “Many investigators have reported an association between CVD phenotypes and changes in the relative abundance of specific microbial taxa, or gut bacterial richness or diversity.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Alterations in fecal microbial community composition are associated with the development of obesity and insulin resistance.

    “Early work in the gut microbiome field demonstrated that alterations in fecal microbial community composition are associated with the development of obesity and insulin resistance, and that microbial transplantation could transmit heightened adiposity in the host2–4.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004; 101: 15718– 15723 15505215 PMC524219 source

      Not checked in the free run.

    • cites [3] Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A. 2005; 102: 11070– 11075 16033867 PMC1176910 source

      Not checked in the free run.

    • cites [4] Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006; 444: 1027– 1031 17183312 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Changes in microbiota composition, diversity, and richness are associative, making it difficult to determine whether microbial changes drive disease states or are driven by them.

    “Changes in microbiota composition, diversity, and richness are associative, making it difficult to determine whether microbial changes are driving disease states or rather being driven by them.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Trimethylamine produced by gut microbes is transported to the liver via the portal vein and readily metabolized by host hepatic flavin monooxygenases, mainly FMO3, into trimethylamine N-oxide.

    “The TMA produced is then transported to liver via the portal vein and readily metabolized by host hepatic flavin monooxygenases (FMOs) (mainly FMO376) into TMAO9.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [76] Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen SL, Lusis AJ. Trimethylamine-n-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 2013; 17: 49– 60 23312283 PMC3771112 source

      Not checked in the free run.

    • cites [9] Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011; 472: 57– 63 21475195 PMC3086762 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Trimethylamine N-oxide was shown to predict cardiovascular disease risks in multiple clinical cohorts and to facilitate accelerated atherosclerosis in animal models.

    “Several analytes linked to phosphatidylcholine metabolism, including TMAO, were identified, and TMAO was shown to both predict CVD risks in multiple clinical cohorts, and facilitate accelerated atherosclerosis (as did nutrient precursors with an intact host gut microbiome) in animal models9.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Trimethylamine N-oxide has been shown to promote platelet reactivity and thrombosis potential, vascular inflammation and inflammasome activation, and heightened heart failure and chronic kidney disease related phenotypes in animal models.

    “It has also been shown to promote platelet reactivity and thrombosis potential14, 83–85, vascular inflammation and inflammasome activation86–88, heightened heart failure89–91 and CKD92–95 related phenotypes in animal models (Figure 2).”
    Quote in the paperSubstantial claim0 of 10 sources checked
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  • May combine two claims.

    Premisecitation

    When radiolabeled trimethylamine or trimethylamine N-oxide were orally administered to human volunteers, 95% of the dose label was excreted via the kidneys with the majority being trimethylamine N-oxide.

    “When radiolabeled TMA or TMAO were orally administered to human volunteers, 95% of the dose label was excreted via the kidneys with the majority being TMAO77.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Circulating levels of trimethylamine N-oxide associate with cardiovascular disease and predict outcomes in multiple cardiovascular disease phenotypes, including peripheral artery disease, coronary artery disease, acute coronary syndrome, and heart failure.

    “Circulating levels of TMAO have been shown to associate with CVD and predict outcomes in the presence of multiple CVD phenotypes, including peripheral artery disease (PAD)96, coronary artery disease (CAD)97, acute coronary syndrome (ACS)97–99, and heart failure100–104.”
    Quote in the paperSubstantial claim0 of 4 sources checked
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    • cites [98] Tan Y, Sheng Z, Zhou P, Liu C, Zhao H, Song L, Li J, Zhou J, Chen Y, Wang L, Qian H, Sun Z, Qiao S, Xu B, Gao R, Yan H. Plasma trimethylamine N-oxide as a novel biomarker for plaque rupture in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv. 2019; 12: e007281 30599768 source

      Not checked in the free run.

    • cites [99] Li XS, Obeid S, Klingenberg R, Gencer B, Mach F, Raber L, Windecker S, Rodondi N, Nanchen D, Muller O, Miranda MX, Matter CM, Wu Y, Li L, Wang Z, Alamri HS, Gogonea V, Chung YM, Tang WH, Hazen SL, Luscher TF. Gut microbiota-dependent trimethylamine N-oxide in acute coronary syndromes: A prognostic marker for incident cardiovascular events beyond traditional risk factors. Eur Heart J. 2017; 38: 814– 824 28077467 PMC5837488 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The gut microbial community can impact blood pressure regulation in the host, and short-chain fatty acids represent at least one of the microbial mediators that contribute to vasomotor tone and blood pressure.

    “Thus, numerous lines of evidence show that the gut microbial community can impact blood pressure regulation in the host, and that SCFAs represent at least one of the microbial mediators that contribute to vasomotor tone and blood pressure.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Gut microbiota modify primary bile acids via bile salt hydrolysis and bile acid 7α dehydroxylation, yielding secondary bile acids, many of which have hormone-like functions.

    “Gut microbiota modify primary BAs via bile salt hydrolysis and bile acid 7α dehydroxylation, yielding secondary BAs, many of which have hormone-like functions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Structurally specific bile acids play roles in modulation of host lipid metabolism, glucose/insulin metabolism, and inflammation.

    “More recent studies have shown structurally specific and distinct BAs also play additional roles, including but not limited to modulation of host lipid metabolism, glucose/insulin metabolism, and inflammation (Figure 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Gut microbial community composition is critical because there is an initial obligatory role of gut microbes in trimethylamine/trimethylamine N-oxide generation.

    “First, the gut microbial community composition is critical since there is an initial obligatory role of gut microbes in TMA(O) generation7, 9.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013; 19: 576– 585 23563705 PMC3650111 source

      Not checked in the free run.

    • cites [9] Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011; 472: 57– 63 21475195 PMC3086762 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Meta-analyses have concluded that a strong relationship exists between elevated circulating trimethylamine N-oxide levels and both cardiovascular disease risk and mortality in multiple cohorts on different continents.

    “While not all studies have observed the relationship between heightened TMAO levels and incident CVD risks, examination of extant clinical studies with TMAO in multiple meta-analyses have concluded that a strong relationship indeed exists between elevated circulating TMAO levels and both CVD risk and mortality in multiple cohorts on different continents105–107.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [105] Schiattarella GG, Sannino A, Toscano E, Giugliano G, Gargiulo G, Franzone A, Trimarco B, Esposito G, Perrino C. Gut microbe-generated metabolite trimethylamine-n-oxide as cardiovascular risk biomarker: A systematic review and dose-response meta-analysis. Eur Heart J. 2017; 38: 2948– 2956 29020409 source

      Not checked in the free run.

    • cites [106] Qi J, You T, Li J, Pan T, Xiang L, Han Y, Zhu L. 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. 2018; 22: 185– 194 28782886 PMC5742728 source

      Not checked in the free run.

    • cites [107] Heianza Y, Ma W, Manson JE, Rexrode KM, Qi L. 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. 2017; 6: e004947 28663251 PMC5586261 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Absence of hepatic PERK blunts TMAO-induced increases in Fox01 expression and improves glycemic indices.

    “Genetic manipulation demonstrated that the absence of hepatic PERK blunted the TMAO-induced increases in Fox01 expression and improved glycemic indices.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Chen S, Henderson A, Petriello MC, Romano KA, Gearing M, Miao J, Schell M, Sandoval-Espinola WJ, Tao J, Sha B, Graham M, Crooke R, Kleinridders A, Balskus EP, Rey FE, Morris AJ, Biddinger SB. Trimethylamine n-oxide binds and activates perk to promote metabolic dysfunction. Cell Metab. 2019; 30: 1141– 1151.e1145 31543404 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In animal models, gut microbiota suppression with oral poorly absorbed antibiotics is associated with decreased TMAO levels, improved endothelial function, reduced arterial stiffness, and lower oxidative stress.

    “In other animal model studies, gut microbiota suppression with oral poorly absorbed antibiotics was associated with decreased TMAO levels, improved endothelial function, reduced arterial stiffness, and lower oxidative stress129.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Brunt VE, Gioscia-Ryan RA, Richey JJ, Zigler MC, Cuevas LM, Gonzalez A, Vazquez-Baeza Y, Battson ML, Smithson AT, Gilley AD, Ackermann G, Neilson AP, Weir T, Davy KP, Knight R, Seals DR. Suppression of the gut microbiome ameliorates age-related arterial dysfunction and oxidative stress in mice. J Physiol. 2019; 597: 2361– 2378 30714619 PMC6487935 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In some aquatic animals, including a subset of deep sea fish, TMAO acts as an osmolyte and protects against pressure-induced protein destabilization.

    “In some aquatic animals, including a subset of deep sea fish, TMAO is reported to act as an osmolyte, and to protect against pressure-induced protein destabilization135, 136.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [135] Kelly RH, Yancey PH. High contents of trimethylamine oxide correlating with depth in deep-sea teleost fishes, skates, and decapod crustaceans. Biol Bull. 1999; 196: 18– 25 25575382 source

      Not checked in the free run.

    • cites [136] Yancey PH, Rhea MD, Kemp KM, Bailey DM. Trimethylamine oxide, betaine and other osmolytes in deep-sea animals: Depth trends and effects on enzymes under hydrostatic pressure. Cell Mol Biol (Noisy-le-grand). 2004; 50: 371– 376 15529747

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TMAO behaves as a chaotropic agent, with the ability to alter protein conformation and potentially serve as an allosteric modulator to proteins.

    “Due to its small size and combination of hydrophilic and hydrophobic properties, TMAO behaves as a chaotropic agent, with the ability to alter protein conformation and potentially serve as an allosteric modulator to proteins134.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] Schneck E, Horinek D, Netz RR. Insight into the molecular mechanisms of protein stabilizing osmolytes from global force-field variations. J Phys Chem B. 2013; 117: 8310– 8321 23822090 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A receptor for TMAO has been reported and shown to participate in TMAO-dependent effects on glucose and insulin metabolism.

    “Recently, a receptor for TMAO has been reported and shown to participate in TMAO-dependent effects on glucose and insulin metabolism133.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Chen S, Henderson A, Petriello MC, Romano KA, Gearing M, Miao J, Schell M, Sandoval-Espinola WJ, Tao J, Sha B, Graham M, Crooke R, Kleinridders A, Balskus EP, Rey FE, Morris AJ, Biddinger SB. Trimethylamine n-oxide binds and activates perk to promote metabolic dysfunction. Cell Metab. 2019; 30: 1141– 1151.e1145 31543404 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In atherosclerosis-prone ApoE−/− mice, dietary supplementation with choline led to augmented atherosclerotic lesion burden, higher aortic expression of scavenger receptors CD36 and scavenger receptor A, increased cholesterol-laden macrophage foam cell formation, and impaired in vivo reverse cholesterol transport.

    “In atherosclerosis-prone ApoE−/− mice, dietary supplementation with choline led to augmented atherosclerotic lesion burden, higher aortic expression of scavenger receptors (CD36 and scavenger receptor A), increased cholesterol laden macrophage foam cell formation9, and impaired in vivo reverse cholesterol transport7.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011; 472: 57– 63 21475195 PMC3086762 source

      Not checked in the free run.

    • cites [7] Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013; 19: 576– 585 23563705 PMC3650111 source

      Not checked in the free run.

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

    Premisecitation

    The receptor for TMA is the olfactory receptor TAAR5.

    “The receptor for TMA was identified long ago as a highly sensitive olfactory receptor called trace amine-associated receptor 5 (TAAR5)132.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Wallrabenstein I, Kuklan J, Weber L, Zborala S, Werner M, Altmüller J, Becker C, Schmidt A, Hatt H, Hummel T, Gisselmann G. Human trace amine-associated receptor taar5 can be activated by trimethylamine. PloS One. 2013; 8: e54950– e54950 23393561 PMC3564852 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The presence of the microbial cutC/D genes in human microbiota is associated with the ability to generate trimethylamine from choline, and with subsequent trimethylamine N-oxide accumulation.

    “The presence of the microbial cutC/D genes in human microbiota are associated with the ability to generate TMA from choline120, and with subsequent TMAO accumulation121.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [120] Romano KA, Vivas EI, Amador-Noguez D, Rey FE. Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-n-oxide. mBio. 2015; 6: e02481 25784704 PMC4453578 source

      Not checked in the free run.

    • cites [121] Romano KA, Martinez-Del Campo A, Kasahara K, Chittim CL, Vivas EI, Amador-Noguez D, Balskus EP, Rey FE. Metabolic, epigenetic, and transgenerational effects of gut bacterial choline consumption. Cell Host Microbe. 2017; 22: 279– 290.e277 28844887 PMC5599363 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TMAO stabilizes proteins to elevated hydrostatic pressure and impacts protein conformational changes and intracellular molecular crowding.

    “TMAO has been shown to stabilize proteins to elevated hydrostatic pressure, and is thought to both impact protein conformational changes, like those that occur with allosteric regulation, and modulate intracellular molecular crowding effects136, 138, 139.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [136] Yancey PH, Rhea MD, Kemp KM, Bailey DM. Trimethylamine oxide, betaine and other osmolytes in deep-sea animals: Depth trends and effects on enzymes under hydrostatic pressure. Cell Mol Biol (Noisy-le-grand). 2004; 50: 371– 376 15529747

      Not checked in the free run.

    • cites [138] Yancey PH, Siebenaller JF. Trimethylamine oxide stabilizes teleost and mammalian lactate dehydrogenases against inactivation by hydrostatic pressure and trypsinolysis. J Exp Biol. 1999; 202: 3597– 3603 10574736 source

      Not checked in the free run.

    • cites [139] Miller AL, Elam WA, Johnson BH, Khan SH, Kumar R, Thompson EB. Restored mutant receptor:Corticoid binding in chaperone complexes by trimethylamine n-oxide. PLoS One. 2017; 12: e0174183 28301576 PMC5354453 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TAAR5 shows high specificity for TMA and does not recognize TMAO.

    “TAAR5 shows high specificity for TMA, and does not recognize TMAO.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Wallrabenstein I, Kuklan J, Weber L, Zborala S, Werner M, Altmüller J, Becker C, Schmidt A, Hatt H, Hummel T, Gisselmann G. Human trace amine-associated receptor taar5 can be activated by trimethylamine. PloS One. 2013; 8: e54950– e54950 23393561 PMC3564852 source

      Not checked in the free run.

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

    Premisecitation

    Some bony fish use large amounts of TMAO for osmoregulation, and TMAO plasma levels increase with habitat depth, reaching up to 400 mmol/kg in snailfish caught at 7000 m in the South Pacific Ocean.

    “Indeed, some bony fish can use large amounts of TMAO for osmoregulation, and TMAO plasma levels within the fish increase with depth of the habitat, reaching levels up to 400mmol/kg in snailfish that were caught at 7000m depth in the South Pacific Ocean137.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Yancey PH, Gerringer ME, Drazen JC, Rowden AA, Jamieson A. Marine fish may be biochemically constrained from inhabiting the deepest ocean depths. Proc Natl Acad Sci USA. 2014; 111: 4461– 4465 24591588 PMC3970477 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FMO3 knock down impairs trimethylamine transformation into trimethylamine N-oxide, reducing plasma trimethylamine N-oxide levels and restoring cholesterol balance.

    “Consistent and complementary to these findings, FMO3 knock down has been shown to impair TMA transformation into TMAO, thus reducing plasma TMAO levels and concomitantly, restoring cholesterol balance114.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Warrier M, Shih DM, Burrows AC, Ferguson D, Gromovsky AD, Brown AL, Marshall S, McDaniel A, Schugar RC, Wang Z, Sacks J, Rong X, Vallim TA, Chou J, Ivanova PT, Myers DS, Brown HA, Lee RG, Crooke RM, Graham MJ, Liu X, Parini P, Tontonoz P, Lusis AJ, Hazen SL, Temel RE, Brown JM. The tmao-generating enzyme flavin monooxygenase 3 is a central regulator of cholesterol balance. Cell Rep. 2015; 10: 326– 338 25600868 PMC4501903 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [111] Wang Z, Bergeron N, Levison BS, Li XS, Chiu S, Jia X, Koeth RA, Li L, Wu Y, Tang WHW, Krauss RM, Hazen SL. 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. Eur Heart J. 2019; 40: 583– 594 30535398 PMC6374688 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In subjects with elevated trimethylamine N-oxide, the anti-platelet effects of aspirin may be attenuated, suggesting possible involvement of trimethylamine N-oxide in on-treatment platelet reactivity and aspirin resistance.

    “This suggests that in subjects with elevated TMAO, the anti-platelet effects of aspirin may be attenuated, highlighting the possible involvement of TMAO in on-treatment platelet reactivity and so-called “aspirin resistance”.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Healthy volunteers orally supplemented with choline exhibited higher levels of trimethylamine N-oxide and concomitant enhanced platelet responsiveness and aggregation.

    “In a subsequent human feeding study, healthy volunteers (both omnivore and vegan/vegetarian) that were orally supplemented with choline exhibited higher levels of TMAO and concomitant enhanced platelet responsiveness and aggregation77, 118.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [77] Al-Waiz M, Mitchell SC, Idle JR, Smith RL. The metabolism of 14c-labelled trimethylamine and its n-oxide in man. Xenobiotica. 1987; 17: 551– 558 3604260 source

      Not checked in the free run.

    • cites [118] Zhu W, Wang Z, Tang WHW, Hazen SL. Gut microbe-generated trimethylamine n-oxide from dietary choline is prothrombotic in subjects. Circulation. 2017; 135: 1671– 1673 28438808 PMC5460631 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vascular tissue factor promotes thrombosis and vascular inflammation, particularly in patients with type 2 diabetes who have higher levels of circulating trimethylamine N-oxide.

    “Vascular TF promotes thrombosis and vascular inflammation123, particularl y in patients with type 2 diabetes who have higher levels of circulating TMAO124–126.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [123] Witkowski M, Landmesser U, Rauch U. Tissue factor as a link between inflammation and coagulation. Trends Cardiovasc Med. 2016; 26: 297– 303 26877187 source

      Not checked in the free run.

    • cites [124] Witkowski M, Witkowski M, Saffarzadeh M, Friebel J, Tabaraie T, Ta Bao L, Chakraborty A, Dorner A, Stratmann B, Tschoepe D, Winter SJ, Krueger A, Ruf W, Landmesser U, Rauch U. Vascular miR-181b controls tissue factor-dependent thrombogenicity and inflammation in type 2 diabetes. Cardiovasc Diabetol. 2020; 19: 20 32066445 PMC7027062 source

      Not checked in the free run.

    • cites [125] Witkowski M, Weithauser A, Tabaraie T, Steffens D, Kränkel N, Witkowski M, Stratmann B, Tschoepe D, Landmesser U, Rauch-Kroehnert U. Micro-RNA-126 reduces the blood thrombogenicity in diabetes mellitus via targeting of tissue factor. Arterioscler Thromb Vasc Biol. 2016; 36: 1263– 1271 27127202 PMC4894779 source

      Not checked in the free run.

    • cites [126] Dambrova M, Latkovskis G, Kuka J, Strele I, Konrade I, Grinberga S, Hartmane D, Pugovics O, Erglis A, Liepinsh E. Diabetes is associated with higher trimethylamine N-oxide plasma levels. Exp Clin Endocrinol Diabetes. 2016; 124: 251– 256 27123785 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dietary supplementation of TMAO in C57BL/6J wildtype animals induces hepatic PERK expression, accompanied by increased Fox01 and impaired glycemic control.

    “Dietary supplementation of TMAO in C57BL/6J wildtype animals induced hepatic PERK expression, accompanied by increased Fox01, a key transcription factor in insulin singling and impaired glycemic control.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Chen S, Henderson A, Petriello MC, Romano KA, Gearing M, Miao J, Schell M, Sandoval-Espinola WJ, Tao J, Sha B, Graham M, Crooke R, Kleinridders A, Balskus EP, Rey FE, Morris AJ, Biddinger SB. Trimethylamine n-oxide binds and activates perk to promote metabolic dysfunction. Cell Metab. 2019; 30: 1141– 1151.e1145 31543404 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some anti-diabetic effects of metformin therapy appear to be mediated by alterations in gut microbiota composition, as microbial transplantation transmits anti-diabetic effects to germ-free mice from metformin-treated donors.

    “Recent studies by Bäckhed and colleagues show that some of the anti-diabetic effects of metformin therapy appear to be mediated by alterations in gut microbiota composition, since microbial transplantation studies reveal transmission of anti-diabetic effects in recipient germ free mice following fecal transfer from metformin treated donors160.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [160] Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Mannerås-Holm L, Ståhlman M, Olsson LM, Serino M, Planas-Fèlix M, Xifra G, Mercader JM, Torrents D, Burcelin R, Ricart W, Perkins R, Fernàndez-Real JM, Bäckhed F. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. 2017; 23: 850– 858 28530702 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Skye SM, Zhu W, Romano KA, Guo CJ, Wang Z, Jia X, Kirsop J, Haag B, Lang JM, DiDonato JA, Tang WHW, Lusis AJ, Rey FE, Fischbach MA, Hazen SL. Microbial transplantation with human gut commensals containing cutc is sufficient to transmit enhanced platelet reactivity and thrombosis potential. Circ Res. 2018; 123: 1164– 1176 30359185 PMC6223262 source

      Not checked in the free run.

    • cites [111] Wang Z, Bergeron N, Levison BS, Li XS, Chiu S, Jia X, Koeth RA, Li L, Wu Y, Tang WHW, Krauss RM, Hazen SL. 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. Eur Heart J. 2019; 40: 583– 594 30535398 PMC6374688 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The association of PAGln with incident risk for major adverse cardiac events was validated in an independent non-overlapping cohort of 4000 stable cardiovascular subjects and shown to be independent of traditional CVD risk factors in both diabetics and non-diabetics.

    “The association of PAGln with incident risk for major adverse cardiac events like heart attack, stroke and death was further validated in an independent and non-overlapping cohort comprised of 4000 stable cardiovascular subjects, and shown to be independent of traditional CVD risk factors in both diabetics and non-diabetics alike146.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [146] Nemet I, Saha PP, Gupta N, Zhu W, Romano KA, Skye SM, Cajka T, Mohan ML, Li L, Wu Y, Funabashi M, Ramer-Tait AE, Naga Prasad SV, Fiehn O, Rey FE, Tang WHW, Fischbach MA, DiDonato JA, Hazen SL. A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell. 2020; 180: 862– 877.e822 32142679 PMC7402401 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When fed to animals, DMB inhibits choline diet-dependent TMAO generation, reduces macrophage foam cell formation, and inhibits aortic atherosclerotic plaque development.

    “When fed to animals, DMB inhibited choline diet-dependent TMAO generation, reduced macrophage foam cell formation, and inhibited aortic atherosclerotic plaque development78.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Wang Z, Roberts AB, Buffa JA, Levison BS, Zhu W, Org E, Gu X, Huang Y, FZamanian-Daryoush M, Culley MK, DiDonato AJ, Fu X, Hazen JE, Krajcik D, DiDonato JA, Lusis AJ, Hazen SL. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell. 2015; 163: 1585– 1595 26687352 PMC4871610 source

      Not checked in the free run.

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

    Premisecitation

    These fish elevate plasma osmolarity by seasonal accumulation of TMAO and other organic solutes, depressing the freezing point of body fluids and allowing survival at sub-freezing temperatures.

    “These fish have the ability to elevate plasma osmolarity by seasonal accumulation of TMAO and other organic solutes, which depresses the freezing point of body fluids and allows them to survive at sub-freezing temperatures.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] Treberg JR, Wilson CE, Richards RC, Ewart KV, Driedzic WR. The freeze-avoidance response of smelt osmerus mordax: Initiation and subsequent suppression of glycerol, trimethylamine oxide and urea accumulation. J Exp Biol. 2002; 205: 1419– 1427 11976353 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In gonadectomized male mice, testosterone reduces hepatic FMO3 expression; in ovariectomized female mice, estrogen increases hepatic FMO3 expression.

    “Likewise, gonadectomized male mice treated with testosterone show reduced hepatic FMO3 expression, while ovariectomized female mice treated with estrogen exhibit increases in hepatic FMO3 expression76.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen SL, Lusis AJ. Trimethylamine-n-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 2013; 17: 49– 60 23312283 PMC3771112 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DMB serves as a non-lethal microbial enzyme inhibitor of choline→TMA transformation and reduces TMAO production in vivo without affecting microbial fitness.

    “Through a series of studies, DMB was shown to serve as a non-lethal microbial enzyme inhibitor of choline→TMA transformation, and to reduce TMAO production in vivo without affecting microbial fitness78.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Wang Z, Roberts AB, Buffa JA, Levison BS, Zhu W, Org E, Gu X, Huang Y, FZamanian-Daryoush M, Culley MK, DiDonato AJ, Fu X, Hazen JE, Krajcik D, DiDonato JA, Lusis AJ, Hazen SL. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell. 2015; 163: 1585– 1595 26687352 PMC4871610 source

      Not checked in the free run.

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

    Premisecitation

    In kidneys, an osmotic gradient from the cortico-medullary boundary to the inner medullary tip is maintained to allow water reabsorption and urine concentration (countercurrent multiplication).

    “In the kidneys, an osmotic gradient arising from the cortico-medullary boundary to the inner medullary tip is normally maintained as a mechanism that allows reabsorption of water and concentration of the urine, a process also called countercurrent multiplication143.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [143] Sands JM, Layton HE. The physiology of urinary concentration: An update. Semin Nephrol. 2009; 29: 178– 195 19523568 PMC2709207 source

      Not checked in the free run.

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

    Premisecitation

    High concentrations of TMAO may impair function, as reported for actomyosin motor activity.

    “By contrast, high concentrations of TMAO may at times also impair function, as was reported for the activity of the actomyosin motor142.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [142] Kumemoto R, Yusa K, Shibayama T, Hatori K. Trimethylamine N-oxide suppresses the activity of the actomyosin motor. Biochim Biophys Acta. 2012; 1820: 1597– 1604 22705940 source

      Not checked in the free run.

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

    Premisecitation

    TMAO is involved in the adaptive freeze avoidance response to extreme cold, acting as antifreeze, in Newfoundland smelt.

    “Other studies have reported that TMAO is involved in the adaptive freeze avoidance response to extreme cold – in other words, it acts as antifreeze – such as within Newfoundland smelt140.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] Treberg JR, Wilson CE, Richards RC, Ewart KV, Driedzic WR. The freeze-avoidance response of smelt osmerus mordax: Initiation and subsequent suppression of glycerol, trimethylamine oxide and urea accumulation. J Exp Biol. 2002; 205: 1419– 1427 11976353 source

      Not checked in the free run.

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

    Interpretationreasoning

    High levels of TMAO in the kidneys may function analogously to urea, playing a role in osmoregulation and renal function.

    “It seems plausible that high levels of TMAO in the kidneys may function analogously to urea, playing a role in osmoregulation and renal function.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Commonly prescribed medications may impact human gut microbial communities, thereby impacting host phenotypes through indirect effects mediated by changes in the gut microbiome.

    “These results suggest that commonly prescribed medications may impact human gut microbial communities, thereby impacting host phenotypes though indirect effects mediated by changes in the gut microbiome.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [111] Wang Z, Bergeron N, Levison BS, Li XS, Chiu S, Jia X, Koeth RA, Li L, Wu Y, Tang WHW, Krauss RM, Hazen SL. 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. Eur Heart J. 2019; 40: 583– 594 30535398 PMC6374688 source

      Not checked in the free run.

    • cites [118] Zhu W, Wang Z, Tang WHW, Hazen SL. Gut microbe-generated trimethylamine n-oxide from dietary choline is prothrombotic in subjects. Circulation. 2017; 135: 1671– 1673 28438808 PMC5460631 source

      Not checked in the free run.

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

    Premisecitation

    Adrenergic receptors are crucially involved in heart disease and platelet function.

    “Adrenergic receptors are crucially involved in heart disease147 and platelet function148.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [147] Wang J, Gareri C, Rockman HA. G-protein-coupled receptors in heart disease. Circ Res. 2018; 123: 716– 735 30355236 PMC6205195 source

      Not checked in the free run.

    • cites [148] Offermanns S Activation of platelet function through g protein-coupled receptors. Circ Res. 2006; 99: 1293– 1304 17158345 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    cutC inhibition by FMC and IMC results in microbial cytosolic choline elevation, which appears to be sensed as an abundant fuel source by the microbe.

    “In addition, cutC inhibition by FMC and iodomethylcholine (IMC) was shown to result in microbial cytosolic choline elevation, which appears to be sensed as an abundant fuel source by the microbe.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Roberts AB, Gu X, Buffa JA, Hurd AG, Wang Z, Zhu W, Gupta N, Skye SM, Cody DB, Levison BS, Barrington WT, Russell MW, Reed JM, Duzan A, Lang JM, Fu X, Li L, Myers AJ, Rachakonda S, DiDonato JA, Brown JM, Gogonea V, Lusis AJ, Garcia-Garcia JC, Hazen SL. Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat Med. 2018; 24: 1407– 1417 30082863 PMC6129214 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FMC and related halomethylcholines are poorly absorbed into the host, limiting systemic exposure and chances of side effects.

    “Interestingly, owing to their highly polar nature, FMC and related halomethylcholines were shown to be poorly absorbed into the host, limiting systemic exposure and thus chances of side effects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Roberts AB, Gu X, Buffa JA, Hurd AG, Wang Z, Zhu W, Gupta N, Skye SM, Cody DB, Levison BS, Barrington WT, Russell MW, Reed JM, Duzan A, Lang JM, Fu X, Li L, Myers AJ, Rachakonda S, DiDonato JA, Brown JM, Gogonea V, Lusis AJ, Garcia-Garcia JC, Hazen SL. Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat Med. 2018; 24: 1407– 1417 30082863 PMC6129214 source

      Not checked in the free run.

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

    Interpretationreasoning

    High levels of TMAO in the terminal stages of pregnancy may in theory better equip women to avoid severe blood loss during delivery.

    “These results suggest that high levels of TMAO in the terminal stages of pregnancy may in theory better equip women to avoid severe blood loss during delivery.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Human liver samples from female subjects show higher FMO1/3 expression and increased capacity for TMAO generation than those from males.

    “Studies by Bennett et al. found that human liver samples from female subjects showed higher FMO1/3 expression, and therefore an increased capacity for TMAO generation, than those from males.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen SL, Lusis AJ. Trimethylamine-n-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 2013; 17: 49– 60 23312283 PMC3771112 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human gene expression studies suggest gender differences in hepatic FMO3 expression, but reported plasma TMAO levels show no sex differences, and the prognostic value of TMAO appears similar in men and women.

    “Although gene expression studies in humans have suggested gender differences in hepatic FMO3 expression, plasma levels of TMAO thus far reported have failed to show sex differences, and the prognostic value of TMAO appears to be similar in both men and women105.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] Schiattarella GG, Sannino A, Toscano E, Giugliano G, Gargiulo G, Franzone A, Trimarco B, Esposito G, Perrino C. Gut microbe-generated metabolite trimethylamine-n-oxide as cardiovascular risk biomarker: A systematic review and dose-response meta-analysis. Eur Heart J. 2017; 38: 2948– 2956 29020409 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FMC is over 10,000-fold more potent an inhibitor of cutC than DMB and markedly blocks microbial choline catabolism.

    “The choline TMA lyase suicide substrate inhibitor fluoromethylcholine (FMC) was shown to be over 10,000 fold more potent an inhibitor of cutC than DMB, and markedly blocks microbial choline catabolism85.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Roberts AB, Gu X, Buffa JA, Hurd AG, Wang Z, Zhu W, Gupta N, Skye SM, Cody DB, Levison BS, Barrington WT, Russell MW, Reed JM, Duzan A, Lang JM, Fu X, Li L, Myers AJ, Rachakonda S, DiDonato JA, Brown JM, Gogonea V, Lusis AJ, Garcia-Garcia JC, Hazen SL. Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat Med. 2018; 24: 1407– 1417 30082863 PMC6129214 source

      Not checked in the free run.

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

    Premisecitation

    Microbial community alterations occur during pregnancy.

    “In addition, beyond FMO3 expression, microbial community alterations are known to occur during pregnancy145.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] Gohir W, Whelan FJ, Surette MG, Moore C, Schertzer JD, Sloboda DM. Pregnancy-related changes in the maternal gut microbiota are dependent upon the mother’s periconceptional diet. Gut Microbes. 2015; 6: 310– 320 26322500 PMC4826136 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Absence of microbiota alters cardiovascular homeostasis, including blood pressure regulation, myocardial repair following post-infarction cardiac repair, and thrombosis growth.

    “This is indirectly supported by the fact that absence of microbiota alters cardiovascular homeostasis, such as blood pressure regulation150, myocardial repair following post-infarction cardiac repair66, or thrombosis growth127 – functions that all involve ADRs.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [150] Honour J The possible involvement of intestinal bacteria in steroidal hypertension. Endocrinology. 1982; 110: 285– 287 7053989 source

      Not checked in the free run.

    • cites [66] Tang TWH, Chen HC, Chen CY, Yen CYT, Lin CJ, Prajnamitra RP, Chen LL, Ruan SC, Lin JH, Lin PJ, Lu HH, Kuo CW, Chang CM, Hall AD, Vivas EI, Shui JW, Chen P, Hacker TA, Rey FE, Kamp TJ, Hsieh PCH. Loss of gut microbiota alters immune system composition and cripples postinfarction cardiac repair. Circulation. 2019; 139: 647– 659 30586712 source

      Not checked in the free run.

    • cites [127] Jäckel S, Kiouptsi K, Lillich M, Hendrikx T, Khandagale A, Kollar B, Hörmann N, Reiss C, Subramaniam S, Wilms E, Ebner K, Brühl MV, Rausch P, Baines JF, Haberichter S, Lämmle B, Binder CJ, Jurk K, Ruggeri ZM, Massberg S, Walter U, Ruf W, Reinhardt C. Gut microbiota regulate hepatic von willebrand factor synthesis and arterial thrombus formation via toll-like receptor-2. Blood. 2017; 130: 542– 553 28572286 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    PAG impacts host physiology and fosters CVD-related phenotypes, likely explaining its association with incident CVD risk.

    “Additional functional studies revealed that the association of PAG with incident CVD risks likely occurs because the metabolite impacts host physiology, and fosters CVD related phenotypes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [146] Nemet I, Saha PP, Gupta N, Zhu W, Romano KA, Skye SM, Cajka T, Mohan ML, Li L, Wu Y, Funabashi M, Ramer-Tait AE, Naga Prasad SV, Fiehn O, Rey FE, Tang WHW, Fischbach MA, DiDonato JA, Hazen SL. A cardiovascular disease-linked gut microbial metabolite acts via adrenergic receptors. Cell. 2020; 180: 862– 877.e822 32142679 PMC7402401 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rodents show significant sexual dimorphism in FMO3 expression and TMAO levels, with females showing higher levels and greater atherosclerosis capacity.

    “Rodents show a significant sexual dimorphism with respect to FMO3 expression, and TMAO levels, with females showing higher levels (and greater atherosclerosis capacity9, 76).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011; 472: 57– 63 21475195 PMC3086762 source

      Not checked in the free run.

    • cites [76] Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen SL, Lusis AJ. Trimethylamine-n-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 2013; 17: 49– 60 23312283 PMC3771112 source

      Not checked in the free run.

67 of 67

  • The paper relies on this without support.

    Findings from animal models about gut microbiota-dependent metabolites and cardiovascular disease phenotypes are relevant to human cardiovascular disease.

    “Importantly, a causal link to CVD for these and other specific gut microbial metabolites/pathways have been shown through numerous mechanistic animal model studies.”

  • The paper relies on this without support.

    Vascular inflammation is critically involved in the pathogenesis of atherosclerosis and thrombotic complications.

    “Vascular inflammation is critically involved in the pathogenesis of atherosclerosis and thrombotic complications.”

  • The paper relies on this without support.

    The pathogenesis of type 2 diabetes goes beyond glycemic control, and traditional risk factors, including level of glucose control, poorly stratify CVD risk among diabetics.

    “The pathogenesis of type 2 diabetes goes beyond glycemic control, and traditional risk factors, including level of glucose control, poorly stratify CVD risk among diabetics.”

  • The paper relies on this without support.

    Currently, there is no clear evidence that antibiotics have efficacy in the treatment of CVD in humans.

    “Currently, there is no clear evidence that antibiotics have efficacy in the treatment of CVD in humans.”
4 of 4

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Authors
Witkowski, M., Weeks, T. L., & Hazen, S. L.
Affiliations
Cleveland Clinic (US)
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2020-07-31
Volume
127
Issue
4
Pages
553-570
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.120.316242
PMC
PMC7416843
OpenAlex
W3045783780
Semantic Scholar
6154383f1a97fbdec3ea3b1045d2c52540b8643a
Cited by
1,051
References
172
Citations by year
2026: 185 · 2025: 225 · 2024: 221 · 2023: 196 · 2022: 153 · 2021: 69 · 2020: 2
FWCI
10.17
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Heart, Lung, and Blood Institute (P01HL147823, R01HL103866)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
Keywords
gut microbiota, cardiovascular disease, trimethylamine N-oxide, phenylacetylglutamine, short-chain fatty acids, secondary bile acids, gut microbiota metabolites, adrenergic receptors, gut microbiota transplantation, cardiometabolic disease, microbiome-targeted therapy, host-microbe interactions
MeSH terms
Gastrointestinal Microbiome, Fecal Microbiota Transplantation, Host Microbial Interactions, Animals, Bile Acids and Salts, Cardiovascular Diseases, Carnitine, Choline, Disease Models, Animal, Fatty Acids, Volatile, Feces, Glutamine, Humans, Methylamines, Mice, Inbred C57BL, Thrombosis, Vasculitis, Signal Transduction, Atherosclerosis, Mice

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.

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