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Cited by 789Gut microbiota and healthNutritional Studies and DietOral microbiology and periodontitis research

Dietary metabolism, the gut microbiome, and heart failure

Open access
Tang, W. H. Wilson, Li, Daniel Y., Hazen, Stanley L.·2019·Nature Reviews Cardiology
DOI 10.1038/s41569-018-0108-7PMC PMC6377322
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Abstract

Advances in our understanding of how the gut microbiota contributes to human health and diseases have expanded our insight into how microbial composition and function affect the human host. Heart failure is associated with splanchnic circulation congestion, leading to bowel wall oedema and impaired intestinal barrier function. This situation is thought to heighten the overall inflammatory state via increased bacterial translocation and the presence of bacterial products in the systemic blood circulation. Several metabolites produced by gut microorganisms from dietary metabolism have been linked to pathologies such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus. These findings suggest that the gut microbiome functions like an endocrine organ by generating bioactive metabolites that can directly or indirectly affect host physiology. In this Review, we discuss several newly discovered gut microbial metabolic pathways, including the production of trimethylamine and trimethylamine N-oxide, short-chain fatty acids, and secondary bile acids, that seem to participate in the development and progression of cardiovascular diseases, including heart failure. We also discuss the gut microbiome as a novel therapeutic target for the treatment of cardiovascular disease, and potential strategies for targeting intestinal microbial processes.Metabolites produced by gut microorganisms from dietary metabolism have been linked to the pathogenesis of heart failure, suggesting that the gut microbiome functions like an endocrine organ. In this Review, Tang and colleagues discuss the gut microbial metabolic pathways involved in heart failure and propose the gut microbiome as a therapeutic target.Key pointsThe gut hypothesis of heart failure (HF) postulates that bowel wall oedema and impaired intestinal barrier function in HF can promote bacterial translocation and inflammation.Changes in the composition and diversity of the gut microbiota have been observed in patients with HF.Microbial metabolites, especially those derived from dietary nutrients, can generate paracrine and endocrine effects that can lead to an increased susceptibility to HF.Novel therapeutic strategies targeting gut microbial metabolic pathways and/or metabolites, as well as altering gut microbial composition, have the potential to modulate cardiovascular disease susceptibility and prevent progression to HF.

AI snapshot

Written from the paper’s full text.

TL;DR

This review proposes that the gut microbiome functions like an endocrine organ, producing dietary metabolites such as TMAO, short-chain fatty acids, and secondary bile acids that contribute to cardiovascular disease and heart failure. It summarizes mechanistic, animal, and clinical evidence and discusses microbiome-targeted therapeutic strategies, while noting that causal links in heart failure remain unproven.

Key findings

  • The TMA/TMAO pathway links dietary choline, phosphatidylcholine, and L-carnitine to microbial TMA production and hepatic FMO3-mediated TMAO generation. In 4,007 patients, the highest TMAO quartile was associated with a 2.5-fold increased risk of major adverse cardiovascular events; in CKD with eGFR <60 mL/min, high TMAO was associated with mortality HR 1.93 (95% CI 1.13–3.29). Animal studies showed choline or TMAO feeding worsened pressure-overload heart failure, while the TMA-lyase inhibitor DMB reduced atherosclerosis in ApoE−/− mice.
  • Short-chain fatty acids are produced in the colon, with an assumed approximate distribution of 60% acetate, 20% propionate, and 20% butyrate. SCFAs have been linked via Gpr41, Gpr43, and Olfr78 to blood pressure regulation; high-fiber or acetate feeding in a deoxycorticosterone acetate-salt hypertension mouse model decreased blood pressure, cardiac and renal fibrosis, and improved cardiovascular function.
  • Bile acid profiles are altered in heart failure: in a small cohort of 142 heart failure patients and 20 sex-matched controls, the primary-to-secondary bile acid ratio was decreased, driven mainly by lower primary bile acids, with a shifted secondary bile acid profile. FXR signaling studies show mixed effects, with both FXR activation and antagonism proposed to affect cardiac function.
  • Heart failure cohorts show gut dysbiosis, but findings are inconsistent. Kummen et al. used discovery and validation cohorts (n=44 and n=40) plus 266 population-based controls and found decreased microbial diversity, changes in fifteen core taxa, and depletion of Lachnospiraceae inversely associated with soluble CD25. Cui et al. analyzed metagenomes from 53 heart failure patients and found enrichment in LPS synthesis and TMAO-generation genes and decreased *Faecalibacterium prausnitzii*.

Methods

  • Narrative review; no new primary data are collected. The authors synthesize mechanistic pathways, animal models, observational cohorts, and clinical trials relating gut microbiota and dietary metabolites to heart failure and cardiovascular disease.
  • Evidence includes cited human studies such as the 4,007-patient TMAO cohort, the CKD mortality analysis, small heart failure microbiota cohorts, and trials including ACCLAIM (subgroup n=919), DASH (n=48; 24 per group), and a *Saccharomyces boulardii* pilot. Main analysis is qualitative synthesis, with tables summarizing clinical TMAO studies and heart failure microbiota studies.

Limitations

  • The paper states that the “gut hypothesis” in heart failure remains associative and has not demonstrated a causal link between gut microbial processes and heart failure pathogenesis. It also notes that microbiome studies in heart failure are a budding field with small cohorts, methodological discrepancies, and a need for reproducibility in adequately powered, clinically homogeneous studies.
  • The paper states that environmental and treatment-related factors—diet, medications, and disease physiology—confound links between specific taxa and disease. It also notes unresolved issues such as the unknown TMAO receptor and mixed mechanistic findings on TMAO and contractility.
  • Evident from the text: as a narrative review, it does not use a systematic search, risk-of-bias assessment, or quantitative meta-analysis; many cited therapeutic and mechanistic findings are preclinical, small, or preliminary.

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

Integrity signals

Registry

Crossref · 10.1038/s41569-018-0108-7

Cites

Statistics

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Claims the paper makes

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  • Premisecitation

    Intestinal wall thickening with edema can be observed in patients with heart failure.

    “Structurally, intestinal wall thickening with edema can be observed in patients with heart failure29.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Sandek, A. et al. Altered intestinal function in patients with chronic heart failure. J. Am. Coll. Cardiol. 50, 1561–1569 (2007). source

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  • Premisecitation

    Intramucosal acidosis can be observed in approximately half of patients with decompensated heart failure.

    “As a result, intramucosal acidosis can be observed in approximately half of patients with decompensated heart failure33.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Maynard, N. et al. Assessment of splanchnic oxygenation by gastric tonometry in patients with acute circulatory failure. JAMA 270, 1203–1210 (1993). source

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  • Premisecitation

    Collagen content in mucosal walls is increased in proportion to the severity of heart failure.

    “The collagen content in their mucosal walls is also increased, in proportion to the severity of heart failure35.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Arutyunov, G. P., Kostyukevich, O. I., Serov, R. A., Rylova, N. V. & Bylova, N. A. Collagen accumulation and dysfunctional mucosal barrier of the small intestine in patients with chronic heart failure. Int. J. Cardiol. 125, 240–245 (2008). source

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  • Premisecitation

    Increased paracellular transport can be observed in heart failure.

    “Therefore, increased paracellular transport can be observed in heart failure29.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Sandek, A. et al. Altered intestinal function in patients with chronic heart failure. J. Am. Coll. Cardiol. 50, 1561–1569 (2007). source

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  • Premisereasoning

    Heightened bacterial translocation occurs during heart failure as a consequence of structural and functional alterations of the gastrointestinal tract with splanchnic congestion and abnormalities of host immunological defense.

    “Evidence exists wherein heightened bacterial translocation occurs during heart failure as a consequence of one or more mechanisms including structural and functional alterations of the gastrointestinal tract that occur with splanchnic congestion, as well as with abnormalities of host immunological defense.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 29
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  • The quote only partly states this claim. 1

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    Premisecitation

    The current leaky gut hypothesis posits that bowel wall edema and impairment in barrier function during heart failure leads to translocation of gut microbiota components into the host circulation, endotoxemia, and a heightened systemic inflammatory state.

    “The current “leaky gut” hypothesis of heart failure3,4 posits that bowel wall edema and impairment in barrier function during heart failure leads to translocation of gut microbiota components into the host circulation, endotoxemia, and consequently, a heightened systemic inflammatory state29 (FIG. 1).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Anker, S. D. et al. Elevated soluble CD14 receptors and altered cytokines in chronic heart failure. Am. J. Cardiol. 79, 1426–1430 (1997). source

      Not checked in the free run.

    • cites [4] Krack, A., Sharma, R., Figulla, H. R. & Anker, S. D. The importance of the gastrointestinal system in the pathogenesis of heart failure. Eur. Heart J. 26, 2368–2374 (2005). source

      Not checked in the free run.

    • cites [29] Sandek, A. et al. Altered intestinal function in patients with chronic heart failure. J. Am. Coll. Cardiol. 50, 1561–1569 (2007). source

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    Premisecitation

    Endotoxin levels in patients with heart failure are reduced with diuretic or antibiotic therapy, but plasma cytokine levels have not always been observed to change.

    “Interestingly, while endotoxin levels in patients with heart failure have been shown to be reduced with diuretic or antibiotic therapy, plasma cytokine levels have not always been observed to change, suggesting a sustained effect as the disease process is triggered38,46.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [38] Niebauer, J. et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet 353, 1838–1842 (1999). source

      Not checked in the free run.

    • cites [46] Conraads, V. M. et al. Selective intestinal decontamination in advanced chronic heart failure: a pilot trial. Eur. J. Heart Fail. 6, 483–491 (2004). source

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    Premisecitation

    LPS levels are higher in blood samples recovered from the hepatic vein than from the systemic circulation, providing direct evidence that LPS can be translocated from the gut.

    “Moreover, targeted sampling studies have shown that LPS levels are higher in blood samples recovered from the hepatic vein as opposed to the systemic circulation (direct sampling from the ventricles), providing direct evidence that LPS can be translocated from the gut39.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39] Peschel, T. et al. Invasive assessment of bacterial endotoxin and inflammatory cytokines in patients with acute heart failure. Eur. J. Heart Fail. 5, 609–614 (2003). source

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    Premisecitation

    In heart failure subjects, heightened circulating levels of multiple cytokines (TNF, IL-1, and IL-6) are associated with more severe clinical symptoms and can predict poorer patient survival.

    “In heart failure subjects, heightened circulating levels of multiple cytokines (e.g., TNF, IL-1, and IL-6) are associated with more severe clinical symptoms and can predict poorer patient survival43–45.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [43] Deswal, A. et al. Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST). Circulation 103, 2055–2059 (2001). source

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    • cites [44] Rauchhaus, M. et al. Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation 102, 3060–3067 (2000). source

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    • cites [45] Ferrari, R. et al. Tumor necrosis factor soluble receptors in patients with various degrees of congestive heart failure. Circulation 92, 1479–1486 (1995). source

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    Interpretationnone given

    Research studies supporting the gut hypothesis are associative and have not demonstrated a causal link between gut microbial processes and heart failure pathogenesis.

    “However, research studies supporting the “gut hypothesis” thus far are associative in nature and have not demonstrated a causal link between gut microbial processes and heart failure pathogenesis.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Pluznick et al. demonstrated that microbiota produce SCFA to modulate blood pressure through SCFA interaction with host GPCRs Olfr78 and Gpr41, and antibiotic treatment can alter blood pressure in Olfr78 knockout mice.

    “Pluznick et al. demonstrated that microbiota could produce SCFA to modulate blood pressure through short-chain fatty acid interaction with the host G protein-coupled receptors (GPCRs) Olfr78 and Gpr41; antibiotic treatment can then alter blood pressure in Olfr78 knockout mice83.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Pluznick, J. L. et al. Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. Proc. Natl Acad. Sci. USA 110, 4410–4415 (2013). source

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    Premisecitation

    In cardiovascular disease, atherosclerosis and increased platelet activation were shown to be transmittable with microbial transplantation and linked to elevated TMAO production.

    “In the setting of cardiovascular disease, both atherosclerosis and increased platelet activation were shown to be transmittable with microbial transplantation and linked to elevated trimethylamine N-oxide (TMAO) production, a novel microbiota-obligate metabolite that we will review in detail in later sections81,82.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [81] Gregory, J. C. et al. Transmission of atherosclerosis susceptibility with gut microbial transplantation. J. Biol. Chem. 290, 5647–5660 (2015). source

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    • cites [82] Zhu, W. et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165, 111–124 (2016). source

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    Premisecitation

    Changes in the proportions of specific taxa of gut microbiota have been observed in various disease states including obesity, inflammatory bowel disease, type 1 and type 2 diabetes mellitus, biliary disease, and intestinal cancers.

    “Changes in the proportions of specific taxa of gut microbiota have been observed in various disease states, including obesity68,69, inflammatory bowel disease70, type 1 and type 2 diabetes mellitus71,72, biliary disease73, and intestinal cancers74,75 among many others.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [68] Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006). source

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    • cites [69] Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006). source

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    • cites [70] Morgan, X. C. et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol. 13, R79 (2012). source

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    • cites [71] Wen, L. et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455, 1109–1113 (2008). source

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    • cites [72] Qin, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012). source

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    Premisecitation

    Gut microbiota can play a role in the development of metabolic abnormalities such as insulin resistance and nonalcoholic fatty liver disease.

    “It has been demonstrated that the gut microbiota can play a role in the development of metabolic abnormalities such as insulin resistance and nonalcoholic fatty liver disease76,77.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [76] Le Roy, T. et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 62, 1787–1794 (2013). source

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    • cites [77] Dumas, M. E. et al. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proc. Natl Acad. Sci. USA 103, 12511–12516 (2006). source

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    Premisecitation

    More pathogenic microbes such as Candida, Campylobacter, Shigella, and Yersinia could be detected in the stools of heart failure patients and correlated with heart failure severity.

    “Newer studies showed that more pathogenic microbes such as Candida, Campylobacter, Shigella, and Yersinia could be detected in the stools of heart failure patients and correlated with heart failure severity88.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] Pasini, E. et al. Pathogenic gut flora in patients with chronic heart failure. JACC Heart Fail. 4, 220–227 (2016). source

      Not checked in the free run.

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    Premisecitation

    Luedde et al. showed in a small cohort of age and sex-matched patients that heart failure patients tended towards decreased intra-individual taxonomic diversity (alpha-diversity) whereas inter-individual diversity was able to distinguish between heart failure and control patients.

    “Using 16s rRNA sequencing, Luedde et al. showed in a small cohort of age and sex-matched patients that heart failure patients tended towards decreased intra-individual taxonomic diversity (alpha-diversity) whereas the inter-individual diversity was able to distinguish between heart failure and control patients90.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Luedde, M. et al. Heart failure is associated with depletion of core intestinal microbiota. ESC Heart Fail. 4, 282–290 (2017). source

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  • May combine two claims.

    Interpretationreasoning

    Increased intestinal permeability complements the effects of endotoxin in the circulation and promotes a vicious feedforward cycle of increased endotoxin translocation and inflammatory cytokine accumulation.

    “This increased permeability complements the effects of endotoxin in the circulation and promotes a vicious feedforward cycle of increased endotoxin translocation and inflammatory cytokine accumulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cui et al. analyzed metagenomic data of 53 heart failure patients and was able to distinguish patients with congestive heart failure from controls.

    “Extending Luedde et al’s findings, Cui et al. analyzed the metagenomic data of 53 heart failure patients and was also able to distinguish patients with congestive heart failure from controls91.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [91] Cui, X. et al. Metagenomic and metabolomic analyses unveil dysbiosis of gut microbiota in chronic heart failure patients. Sci. Rep. 8, 635 (2018).

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    Premisecitation

    Clinical studies testing the anti-TNF hypothesis revealed negative results and perhaps even increased cardiovascular events in the treatment group.

    “In brief, these studies revealed negative results and perhaps even increased cardiovascular events in the treatment group.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [54] Chung, E. S. et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 107, 3133–3140 (2003). source

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    • cites [55] Mann, D. L. et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 109, 1594–1602 (2004). source

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    Premisecitation

    Kummen et al. reaffirmed decreased microbial diversity in disease, identified changes in fifteen core taxa, and emphasized depletion of the Lachnospiraceae family inversely associated with increased soluble CD25.

    “They reaffirmed the decreased microbial diversity in disease, identified changes in fifteen core taxa, and emphasized a depletion of the Lachnospiraceae family (of which several members are butyrate producers) that was inversely associated with increased levels of soluble CD25, a marker for T-cell and macrophage activation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Kummen, M. et al. Gut microbiota signature in heart failure defined from profiling of 2 independent cohorts. J. Am. Coll. Cardiol. 71, 1184–1186 (2018). source

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    Premisecitation

    Animal studies have shown that the intestinal microbial environment can affect the efficiency of harvesting energy from the diet and affect obesity.

    “Animal studies have shown that the intestinal microbial environment can affect the efficiency of harvesting energy from the diet and affect obesity69.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006). source

      Not checked in the free run.

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    Premisecitation

    Transgenic overexpression of TNF in mice results in cardiac hypertrophy, ventricular dilation, and fibrosis.

    “Furthermore, transgenic overexpression of TNF in another mouse study resulted in cardiac hypertrophy, ventricular dilation, and fibrosis49.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Kubota, T. et al. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ. Res. 81, 627–635 (1997). source

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    Premisecitation

    Psychiatric disorders including autism and depression have been associated with alterations in gut microbiota.

    “Furthermore, psychiatric disorders, including autism and depression, have also been associated with alterations in gut microbiota in what is known as the “gut-brain hypothesis.”78–80”
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    • cites [78] Hsiao, E. Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451–1463 (2013). source

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    • cites [79] Foster, J. A. & McVey Neufeld, K. A. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 36, 305–312 (2013). source

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    • cites [80] Naseribafrouei, A. et al. Correlation between the human fecal microbiota and depression. Neurogastroenterol. Motil. 26, 1155–1162 (2014). source

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    Premisecitation

    Decreases in Faecalibacterium prausnitzii were observed in heart failure patients, previously characterized in elderly congestive heart failure patients.

    “Furthermore, they observed decreases in Faecalibacterium prausnitzii that have previously been characterized in elderly congestive heart failure patients92.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Kamo, T. et al. Dysbiosis and compositional alterations with aging in the gut microbiota of patients with heart failure. PLOS ONE 12, e0174099 (2017). source

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    Premisecitation

    Eubacterium Rectale was found to be increased by Sandek et al. using fluorescent in situ hybridization in gut mucosal biofilms but decreased by Kamo et al.

    “For example, Eubacterium Rectale, a gut symbiont and butyrate producer was found to be increased by Sandek et al. using fluorescent in situ hybridization in gut mucosal biofilms but decreased by Kamo et al29,92.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29] Sandek, A. et al. Altered intestinal function in patients with chronic heart failure. J. Am. Coll. Cardiol. 50, 1561–1569 (2007). source

      Not checked in the free run.

    • cites [92] Kamo, T. et al. Dysbiosis and compositional alterations with aging in the gut microbiota of patients with heart failure. PLOS ONE 12, e0174099 (2017). source

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    Premisecitation

    SCFAs play a role in colonic acid-base status.

    “Because of their abundance within the distal intestinal tract, SCFAs also play a role in colonic acid-base status119,120.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [119] Pouteau, E., Nguyen, P., Ballevre, O. & Krempf, M. Production rates and metabolism of short-chain fatty acids in the colon and whole body using stable isotopes. Proc. Nutr. Soc. 62, 87–93 (2003). source

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    • cites [120] Lefebvre, P., Cariou, B., Lien, F., Kuipers, F. & Staels, B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol. Rev. 89, 147–191 (2009). source

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    Premisecitation

    Nearly all of the bile acid pool in the large intestine comprises secondary bile acids with concentrations up to 1,000 μM.

    “Nearly all of the bile acid pool in the large intestine comprises secondary bile acids with concentrations up to 1,000µM.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Forman, B. M. et al. Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 81, 687–693 (1995). source

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    Premisenone given

    Bile acids and microbiota are inextricably linked: primary bile acids are biochemically modified by the microbiota, and the resulting bile acid pool composition can conversely affect the microbiota profile.

    “There is no doubt that bile acids and microbiota are inextricably linked as primary bile acids are biochemically modified by the microbiota while the resulting composition of the bile acid pool can conversely affect the microbiota profile.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Microbiota in the colon can further metabolize unrecycled bile acids to produce secondary bile acids such as deoxycholate, lithocholate, ursodeoxycholate, and numerous (at least 50) others.

    “However, microbiota in the colon can further metabolize any unrecycled bile acids to produce secondary bile acids such as deoxycholate (DCA), lithocholate (LCA), ursodeoxycholate (UDCA), and numerous (at least 50) others128,129.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [128] Gazawi, H. et al. The effects of bile acids on beta-adrenoceptors, fluidity, and the extent of lipid peroxidation in rat cardiac membranes. Biochem. Pharmacol. 59, 1623–1628 (2000). source

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    • cites [129] Wang, H., Chen, J., Hollister, K., Sowers, L. C. & Forman, B. M. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol. Cell 3, 543–553 (1999). source

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    Premisecitation

    Digoxin may be inactivated by the actinobacterium Eggerthella lenta.

    “For example, digoxin may be inactivated by the actinobacterium Eggerthella lenta107.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] Topping, D. L. & Clifton, P. M. Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiol. Rev. 81, 1031–1064 (2001). source

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    Premisecitation

    Primary bile acids are typically reabsorbed (>95%).

    “These primary bile acids are typically reabsorbed (>95%)127.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [127] Joubert, P. An in vivo investigation of the negative chronotropic effect of cholic acid in the rat. Clin. Exp. Pharmacol. Physiol. 5, 1–8 (1978). source

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  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Multiple discrepancies can be noted when comparing major bacterial groups identified in studies summarized in Table 2.

    “Multiple discrepancies can be noted when comparing major bacterial groups identified in studies summarized in Table 2.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Primary bile acids such as cholic and chenodeoxycholic acid are synthesized through oxidation of cholesterol in the liver.

    “The primary bile acids, such as cholic and chenodeoxycholic acid (CDCA), are synthesized through the oxidation of cholesterol in the liver126.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Binah, O., Rubinstein, I., Bomzon, A. & Better, O. S. Effects of bile acids on ventricular muscle contraction and electrophysiological properties: studies in rat papillary muscle and isolated ventricular myocytes. Naunyn Schmiedebergs Arch. Pharmacol. 335, 160–165 (1987). source

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    Premisecitation

    Gut microbiota within the distal intestinal tract foster fermentation processes that often produce short-chain fatty acids (SCFAs), a major nutrient source for the ceco-colonic epithelium.

    “Gut microbiota within the distal intestinal tract foster fermentation processes that often produce short-chain fatty acids (SCFAs), a major nutrient source for the ceco-colonic epithelium113.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Duncan, S. H., Louis, P., Thomson, J. M. & Flint, H. J. The role of pH in determining the species composition of the human colonic microbiota. Environ. Microbiol. 11, 2112–2122 (2009). source

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

    Premisecitation

    Secondary bile acids enter the enterohepatic circulation with any remaining excretion occurring through the feces.

    “These secondary bile acids also enter the enterohepatic circulation with any remaining excretion occurring through the feces130.”
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    • cites [130] Forman, B. M. et al. Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 81, 687–693 (1995). source

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  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Additional independent mechanisms by which SCFA modulate cardiac function likely exist and require further investigation.

    “Therefore, additional independent mechanisms by which SCFA modulate cardiac function likely exist and require further investigation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    High fiber and acetate feeding in a deoxycorticosterone acetate-salt hypertension mouse model resulted in decreased blood pressure, decreased cardiac and renal fibrosis, and improved cardiovascular function.

    “It was demonstrated that both high fiber and acetate feeding in a deoxycorticosterone acetate-salt hypertension mouse model resulted in decreased blood pressure, decreased cardiac and renal fibrosis, and improved cardiovascular function.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [124] Hamilton, J. P. et al. Human cecal bile acids: concentration and spectrum. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G256–G263 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Luedde et al. observed that Collinsella was decreased in the HF cohort while this genus has been found to be enriched in atherosclerosis.

    “Similarly, Luedde et al. observed that Collinsella was decreased in the HF cohort90 while this genus has been found to be enriched in atherosclerosis95.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [90] Luedde, M. et al. Heart failure is associated with depletion of core intestinal microbiota. ESC Heart Fail. 4, 282–290 (2017). source

      Not checked in the free run.

    • cites [95] Karlsson, F. H. et al. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nat. Commun. 3, 1245 (2012).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SCFA pharmacokinetics vary significantly between humans and smaller animals, which limits direct extrapolation of SCFA peripheral effects from animal models to human disease.

    “In addition, it is important to note that SCFA pharmacokinetics (such as production and tissue utilization) vary significantly between humans and smaller animals which limits the direct extrapolation of SCFA peripheral effects from animal models to human disease125.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Mayerhofer, C. C. K. et al. Increased secondary/primary bile acid ratio in chronic heart failure. J. Card. Fail. 23, 666–671 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both the composition and pool size of bile acids are altered in subjects with heart failure.

    “Studies suggest that both the composition and pool size of bile acids are altered in subjects with heart failure.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [131] Kawamata, Y. et al. A G protein-coupled receptor responsive to bile acids. J. Biol. Chem. 278, 9435–9440 (2003). source

      Not checked in the free run.

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

    Premisecitation

    The vast majority of SCFAs produced in the colon appears to be acetate, propionate, and butyrate, with an assumed approximate 60%, 20%, and 20% distribution, respectively.

    “Notably, the vast majority of SCFAs produced in the colon appears to be the simple aliphatic two, three and four carbon SCFAs acetate, propionate and butyrate, with an assumed approximate 60%, 20%, and 20% distribution, respectively69,113.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [69] Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006). source

      Not checked in the free run.

    • cites [113] Duncan, S. H., Louis, P., Thomson, J. M. & Flint, H. J. The role of pH in determining the species composition of the human colonic microbiota. Environ. Microbiol. 11, 2112–2122 (2009). source

      Not checked in the free run.

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

    Premisecitation

    Eubacterium Rectale has been associated with decreases in atherosclerosis.

    “It can be noted that this bacteria has also been associated w/ decreases in atherosclerosis95.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Karlsson, F. H. et al. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nat. Commun. 3, 1245 (2012).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There was a shift in the secondary bile acid profile, though the total secondary bile acid level remained similar.

    “Moreover, there was a shift in the secondary bile acid profile, though the total secondary bile acid level remained similar.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Kawamata, Y. et al. A G protein-coupled receptor responsive to bile acids. J. Biol. Chem. 278, 9435–9440 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Kummen et al. observed multiple genus belonging to the Lachnospiraceae family to be decreased in HF, but this family has consistently demonstrated positive associations with plasma TMAO levels.

    “Lastly, Kummen et al. observed multiple genus belonging to the Lachnospiraceae family to be decreased in HF93, but interestingly, this family has also consistently demonstrated positive associations with plasma TMAO levels82,96.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [93] Kummen, M. et al. Gut microbiota signature in heart failure defined from profiling of 2 independent cohorts. J. Am. Coll. Cardiol. 71, 1184–1186 (2018). source

      Not checked in the free run.

    • cites [82] Zhu, W. et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165, 111–124 (2016). source

      Not checked in the free run.

    • cites [96] Wang, Z. et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163, 1585–1595 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dietary precursors yield TMA through microbial enzyme complexes, enter portal circulation, and are metabolized by liver FMO (primarily FMO3) to produce TMAO.

    “These nutrients, found in high-fat foods, yield TMA through the action of multiple microbial enzyme complexes (described in a later section) and enters the portal circulation where further metabolism by host enzymes in the liver, called flavin-containing monooxygenases (FMO and primarily the FMO3 isoform), produce TMAO (FIG. 3).”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [82] Zhu, W. et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165, 111–124 (2016). source

      Not checked in the free run.

    • cites [96] Wang, Z. et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163, 1585–1595 (2015). source

      Not checked in the free run.

    • cites [156] Parab, S. N. & Rao, S. B. Distribution of trimethylamine oxie in some marine and freshwater fish. Curr. Sci. 53, 307–309 (1984).

      Not checked in the free run.

    • cites [157] Cladis, D. P., Kleiner, A. C., Freiser, H. H. & Santerre, C. R. Fatty acid profiles of commercially available finfish fillets in the United States. Lipids 49, 1005–1018 (2014). source

      Not checked in the free run.

    • cites [158] Weaver, K. L. et al. The content of favorable and unfavorable polyunsaturated fatty acids found in commonly eaten fish. J. Am. Diet. Assoc. 108, 1178–1185 (2008). source

      Not checked in the free run.

    • cites [159] Svensson, B. G., Akesson, B., Nilsson, A. & Paulsson, K. Urinary excretion of methylamines in men with varying intake of fish from the Baltic Sea. J. Toxicol. Environ. Health 41, 411–420 (1994). source

      Not checked in the free run.

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

    Premisecitation

    FXR mediates negative feedback control on bile acid synthesis through ileal increases of FGF15.

    “Furthermore, FXR mediates a negative feedback control on the synthesis of bile acids through ileal increases of FGF15141.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [141] Ali, A. H., Carey, E. J. & Lindor, K. D. Recent advances in the development of farnesoid X receptor agonists. Ann. Transl Med. 3, 5 (2015).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The TMA/TMAO pathway is mechanistically linked to atherosclerosis and heart failure susceptibility.

    “Subsequent animal model studies showed that this pathway was mechanistically linked to atherosclerosis156,158, and heart failure susceptibility160.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [156] Parab, S. N. & Rao, S. B. Distribution of trimethylamine oxie in some marine and freshwater fish. Curr. Sci. 53, 307–309 (1984).

      Not checked in the free run.

    • cites [158] Weaver, K. L. et al. The content of favorable and unfavorable polyunsaturated fatty acids found in commonly eaten fish. J. Am. Diet. Assoc. 108, 1178–1185 (2008). source

      Not checked in the free run.

    • cites [160] Yazdekhasti, N. et al. Fish protein increases circulating levels of trimethylamine-N-oxide and accelerates aortic lesion formation in apoE null mice. Mol. Nutr. Food Res. 60, 358–368 (2016). source

      Not checked in the free run.

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

    Premisecitation

    OCA is currently FDA approved for the treatment of primary biliary cholangitis.

    “OCA is currently FDA approved for the treatment of primary biliary cholangitis147–149.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [147] Cipriani, S., Mencarelli, A., Palladino, G. & Fiorucci, S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J. Lipid Res. 51, 771–784 (2010). source

      Not checked in the free run.

    • cites [148] von Haehling, S. et al. Ursodeoxycholic acid in patients with chronic heart failure: a double-blind, randomized, placebo-controlled, crossover trial. J. Am. Coll. Cardiol. 59, 585–592 (2012). source

      Not checked in the free run.

    • cites [149] Aouad, K. et al. Immunosuppressive effects of endotoxins and bile acids in vivo in the rat. Eur. J. Clin. Invest. 26, 45–48 (1996). source

      Not checked in the free run.

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

    Premisenone given

    FXR responds to CDCA as the most potent endogenous agonist among major bile acids, followed by DCA and LCA.

    “FXR responds to CDCA as the most potent endogenous agonist (amongst major bile acids) followed by DCA and LCA.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Antagonism of FXR has been suggested to improve cardiac function.

    “Antagonism of FXR has also been suggested to improve cardiac function.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Xu, Y. et al. Farnesoid X receptor activation increases reverse cholesterol transport by modulating bile acid composition and cholesterol absorption in mice. Hepatology 64, 1072–1085 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Male mice display 100-fold decreased liver Fmo3 mRNA compared to females, resulting in far lower natural levels of plasma TMAO.

    “male mice display 100-fold decreased liver Fmo3 mRNA compared to females, resulting in far lower natural levels of plasma TMAO171.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [171] Liberles, S. D. & Buck, L. B. A second class of chemosensory receptors in the olfactory epithelium. Nature 442, 645–650 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In that fish protein study, blood lipid levels remained similar between all diet groups, but TMAO was significantly elevated in the fish protein group.

    “It was observed that although blood lipid levels in the mice remained similar between all diet groups, TMAO was significantly elevated in the fish protein group.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] Zhu, W., Wang, Z., Tang, W. H. W. & Hazen, S. L. Gut microbe-generated trimethylamine N-oxide from dietary choline is prothrombotic in subjects. Circulation 135, 1671–1673 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The highest subgroup cutoff of 0.2ppm converts to 2.6μM, and these low levels of TMAO have never been implicated in disease.

    “In fact, the highest subgroup cutoff of 0.2ppm converts to 2.6µM. These low levels of TMAO have never been implicated in disease.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [171] Liberles, S. D. & Buck, L. B. A second class of chemosensory receptors in the olfactory epithelium. Nature 442, 645–650 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These findings were accompanied by increases in scavenger receptor CD36 and SRA1 protein, correlating with increased atherosclerosis burden.

    “These findings were accompanied by observations of increases in both the scavenger receptor CD36 and scavenger receptor A1 (SRA1) protein, correlating with the findings of increased atherosclerosis burden156,158.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [156] Parab, S. N. & Rao, S. B. Distribution of trimethylamine oxie in some marine and freshwater fish. Curr. Sci. 53, 307–309 (1984).

      Not checked in the free run.

    • cites [158] Weaver, K. L. et al. The content of favorable and unfavorable polyunsaturated fatty acids found in commonly eaten fish. J. Am. Diet. Assoc. 108, 1178–1185 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most fish do not contain TMAO, just as most fish do not contain significant amounts of omega-3 fatty acids.

    “In fact, most fish do not contain TMAO, just as most fish do not contain significant amounts of omega-3 fatty acids163,164.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [163] Pedrini, M. T., Levey, A. S., Lau, J., Chalmers, T. C. & Wang, P. H. The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: a meta-analysis. Ann. Intern. Med. 124, 627–632 (1996). source

      Not checked in the free run.

    • cites [164] Collins, H. L. et al. L-carnitine intake and high trimethylamine N-oxide plasma levels correlate with low aortic lesions in ApoE −/− transgenic mice expressing CETP. Atherosclerosis 244, 29–37 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The TMAO inflammatory response is believed to be mediated in part by endothelial cell NF-kB activation, with involvement of a GPCR.

    “This inflammatory response is believed to be mediated in part by endothelial cell NF-kB activation, with small-molecule inhibitor studies suggesting the involvement of a GPCR.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [173] Organ, C. L. et al. Removal of dietary trimethylamine N-oxide (TMAO) attenuates cardiac dysfunction in pressure overload induced heart failure [abstract]. Circulation 134 (Suppl. 1), 19293 (2016).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Antibiotic abrogation of gut microbiota results in improved phenotypes, and microbiota transplantation transmits TMA production potential and enhanced diet-dependent pro-atherogenic phenotype.

    “To prove causality, antibiotic abrogation of gut microbiota was shown to result in improved phenotypes, and microbiota transplantation studies with low versus high TMA generating community confirmed that one could successfully transmit TMA production potential and correspondingly, transmit enhanced diet dependent pro-atherogenic phenotype, thereby, satisfying a fundamental criteria of Koch’s postu”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] Gregory, J. C. et al. Transmission of atherosclerosis susceptibility with gut microbial transplantation. J. Biol. Chem. 290, 5647–5660 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    In subjects taking low-dose aspirin, elevation in TMAO levels by choline supplementation overcame the aspirin-induced reduction in platelet responsiveness, suggesting that aspirin resistance may in part be attributed to heightened generation of prothrombotic factors by the gut microbiota.

    “Thus, in subjects taking low-dose aspirin, elevation in TMAO levels by choline supplementation overcame the aspirin-induced reduction in platelet responsiveness, suggesting that socalled aspirin resistance may in part be attributed to heightened generation of prothrombotic factors by the gut microbiota.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [172] Ufnal, M. et al. Trimethylamine-N-oxide: a carnitine-derived metabolite that prolongs the hypertensive effect of angiotensin II in rats. Can. J. Cardiol. 30, 1700–1705 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In both omnivores and vegans, choline supplementation resulted in heightened TMAO levels and increased ADP-dependent aggregation responses.

    “In both omnivores and vegans alike, choline supplementation resulted in heightened TMAO levels and increased ADPdependent aggregation responses.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [172] Ufnal, M. et al. Trimethylamine-N-oxide: a carnitine-derived metabolite that prolongs the hypertensive effect of angiotensin II in rats. Can. J. Cardiol. 30, 1700–1705 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, choline supplementation or direct TMAO feeding resulted in higher systemic TMAO levels, enhanced myocardial fibrosis, and worsened hemodynamic and anatomic parameters after trans-aortic constriction (TAC).

    “In the heart failure setting, animal experiments from Organ et al. found that either choline supplementation (which raises circulating TMAO), or direct TMAO feeding in mice, resulted in higher systemic TMAO levels, enhanced myocardial fibrosis and worsened hemodynamic and anatomic parameters after trans-aortic constriction (TAC)160.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [160] Yazdekhasti, N. et al. Fish protein increases circulating levels of trimethylamine-N-oxide and accelerates aortic lesion formation in apoE null mice. Mol. Nutr. Food Res. 60, 358–368 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TMA is detected through the GPCR TAAR5 chemosensory receptor, to which TMA binds with high affinity, though TAAR5 does not recognize TMAO.

    “It is known that the TMAO precursor, TMA, is detected through the GPCR TAAR5 chemosensory receptor, to which TMA binds with high affinity, though TAAR5 is known not to recognize TMAO177.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [177] Troseid, M. et al. Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure. J. Intern. Med. 277, 717–726 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TMAO potentiates alternative signal transduction processes such as intracellular calcium signaling and platelet reactivity, or sustained increases in blood pressure after angiotensin infusion.

    “It is of interest that TMAO has been reported to potentiate alternative signal transduction processes such as intracellular calcium signaling and platelet reactivity, or sustained increases in blood pressure after angiotensin infusion82,178.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [82] Zhu, W. et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165, 111–124 (2016). source

      Not checked in the free run.

    • cites [178] Schuett, K. et al. Trimethylamine-N-oxide and heart failure with reduced versus preserved ejection fraction. J. Am. Coll. Cardiol. 70, 3202–3204 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In an independent Norwegian cohort, plasma TMAO levels were elevated in the heart failure cohort and predictive of transplant-free survival.

    “Similar findings have subsequently been reported in an independent Norwegian cohort where plasma TMAO levels were elevated in the heart failure cohort and predictive of transplant-free survival183.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [183] Hillege, H. L. et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation 113, 671–678 (2006). source

      Not checked in the free run.

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

    Premisecitation

    Black CKD populations tended to have better survival than white CKD counterparts within the same quintile of TMAO levels.

    “Shafi et al. reported that black CKD populations tended to have better survival than their white CKD counterparts within the same quintile of TMAO levels201.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [201] Heianza, Y., Ma, W., Manson, J. E., Rexrode, K. M. & 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. 6, e004947 (2017). source

      Not checked in the free run.

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

    Premisecitation

    A contributory and synergistic cardio-renal connection has long been recognized.

    “Beyond a myocardium centered focus on heart failure pathogenesis, a contributory and synergistic cardio-renal connection has long been recognized188.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [188] Cohen, J. J., Krupp, M. A., Chidsey, C. A. 3rd & Biltz, C. I. Effect of trimethylamine and its homologues on renal conservation of trimethylamine oxide by the spiny dogfish, Squalus acanthias. Am. J. Physiol. 196, 93–99 (1959). source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    Inhibition of TMA and TMAO production with 3,3-dimethyl-1-butanol resulted in significantly improved ventricular remodeling and hemodynamic parameters in mice on a western diet.

    “In this study, it was found that inhibition of TMA and TMAO production resulted in significantly improved ventricular remodeling and hemodynamic parameters of mice on a western diet180.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [180] Savi, M. et al. Trimethylamine-N-oxide (TMAO)-induced impairment of cardiomyocyte function and the protective role of urolithin B-glucuronide. Molecules 23, E549 (2018). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Increasing clinical use of pre- and probiotics may have unappreciated effects.

    “Similarly, increasing clinical use of pre- and probiotics may have unappreciated effects.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    There is a gap in the literature for additional dietary interventions as a definitive therapeutic route for heart failure.

    “Beyond the DASH diet, there is still a gap in the literature for additional dietary interventions as a definitive therapeutic route for heart failure.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The utility of sequencing the microbial genome for clinical practice is still unclear.

    “Although sequencing of the microbial genome is becoming more common in research practice, the utility of this methodology for clinical practice is still unclear.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Treatment of rats with a beverage containing L. plantarum 299v 24 hours before coronary ligation produced reduced infarct sizes and improved left ventricular function.

    “For example, treatment of rats with a beverage containing L. plantarum 299v 24 hours before coronary ligation reportedly produced reduced infarct sizes and improved left ventricular function86.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Lam, V. et al. Intestinal microbiota determine severity of myocardial infarction in rats. FASEB J. 26, 1727–1735 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    There is a complex association between gut microbiota and the cardiovascular system that can influence and even determine cardiovascular diseases.

    “Undoubtedly, there is a complex association between gut microbiota and the cardiovascular system that can influence and even determine cardiovascular diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    DMB is non-lethal to human commensals possessing CutC and suppresses TMA production in cultured human commensals and lowers TMAO in mice on a choline supplemented diet.

    “This inhibitor was found to be non-lethal to human commensals possessing CutC and fostered suppression of both TMA production in cultured human commensals and TMAO lowering in mice on a choline supplemented diet.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Wang, Z. et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163, 1585–1595 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DMB exposure reduces atherosclerosis progression in the apolipoprotein E−/− mouse model without significant adverse toxicity.

    “exposure to DMB was shown to also effectively reduce atherosclerosis progression in the apolipoprotein E−/− mouse model without significant adverse toxicity96.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Wang, Z. et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163, 1585–1595 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a small randomized controlled trial of 48 heart failure patients, the DASH diet group demonstrated better 6 minute walk performance and quality of life, and trended towards increased arterial elasticity after three months.

    “A small randomized, controlled clinical trial of 48 patients assigned to either a DASH diet (n=24) or general guidelines for HF management (n=24), those in the DASH group demonstrated better 6 minute walk performance, quality of life, and trended towards increased arterial elasticity after a three month intervention.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [218] Miro, O. et al. Adherence to mediterranean diet and all-cause mortality after an episode of acute heart failure: results of the MEDIT-AHF study. JACC Heart Fail. 6, 52–62 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the GR-1 study, 16s sequencing showed the treatment strain did not appear to colonize or alter gut community structure/composition.

    “However, it is notable that the 16s sequencing in the GR-1 study showed that the treatment strain did not appear to colonize or alter the gut community structure/composition.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [210] Levitan, E. B., Wolk, A. & Mittleman, M. A. Relation of consistency with the dietary approaches to stop hypertension diet and incidence of heart failure in men aged 45 to 79 years. Am. J. Cardiol. 104, 1416–1420 (2009). source

      Not checked in the free run.

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

    Premisecitation

    Meldonium is reported to reduce carnitine to TMA conversion.

    “meldonium, an analog of γ-butyrobetaine and carnitine, that is reported to be able to reduce carnitine to TMA conversion”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [231] Li, J. et al. An integrated catalog of reference genes in the human gut microbiome. Nat. Biotechnol. 32, 834–841 (2014). source

      Not checked in the free run.

    • cites [232] Martinez-del Campo, A. et al. Characterization and detection of a widely distributed gene cluster that predicts anaerobic choline utilization by human gut bacteria. MBio 6, e00042 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A randomized control pilot study with Saccharomyces boulardii showed benefits in heart failure patients, with improved left ventricular ejection fraction in the short term and decreases in serum creatinine and inflammatory markers.

    “Of interest, a randomized control pilot study with Saccharomyces boulardii was reported to show benefits in heart failure patients, with left ventricular ejection fraction being improved in the short term, along with decreases in serum creatinine and inflammatory markers211.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [211] Nguyen, H. T. et al. DASH eating pattern is associated with favorable left ventricular function in the multi-ethnic study of atherosclerosis. J. Am. Coll. Nutr. 31, 401–407 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Chronic inflammation, underlying comorbidities, antibiotics, diet, and probiotics can drastically alter the long-term composition of the gut microbiota and thereby impact health.

    “chronic inflammation, underlying comorbidities, antibiotics, diet, and probiotics can drastically alter the long-term composition of the gut microbiota and thereby impact our health.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Proper nutrition such as the Mediterranean diet can aid the prevention of cardiovascular events and the subsequent development of heart failure.

    “Proper nutrition such as the Mediterranean diet, can certainly aid the prevention of cardiovascular events and the subsequent development of heart failure.”
    Quote in the paperNot a substantial claim
74 of 74

  • The paper relies on this without support.

    The role of nutrition and diet in the causation, prevention, and management of heart failure remains poorly understood.

    “Also, the role of nutrition and diet in the causation, prevention, and management of heart failure remains poorly understood.”

  • The paper relies on this without support.

    There have only been a limited number of studies examining the role of gut microbiota in heart failure.

    “However, there have only been a limited number of studies examining the role of gut microbiota in heart failure.”

  • The paper relies on this without support.

    In disease states such as cholestasis, bile acids reach supraphysiologic levels.

    “As an example, in disease states such as cholestasis, bile acids will reach supraphysiologic levels.”

  • The paper relies on this without support.

    Findings from animal models of TMAO and heart failure are relevant to human heart failure.

    “These findings suggest that understanding why TMAO levels are elevated in the setting of heart failure may provide valuable insights into how gut microbiota may contribute to disease progression in heart failure.”

  • The paper relies on this without support.

    TMAO is strongly associated with heart failure.

    “With strong associations in heart failure, we look ahead and discuss strategies for targeted inhibition of TMAO production”

  • The paper relies on this without support.

    The gut microbiota can contribute to both normal health and disease susceptibility.

    “The realization that gut microbiota can contribute to both normal health and disease susceptibility provides a novel perspective”

  • The paper relies on this without support.

    Reduction of TMAO levels is beneficial for heart failure.

    “we look ahead and discuss strategies for targeted inhibition of TMAO production as a framework for other potential microbiota targets.”

  • The paper relies on this without support.

    DMB present in extra-virgin olive oil is bioavailable and active in humans at dietary levels.

    “DMB was also observed to be present in some cold-pressed extra-virgin olive oils96, a major component of the Mediterranean diet.”

  • The paper relies on this without support.

    Probiotics have an excellent safety record.

    “Though probiotics have an excellent safety record”
9 of 9

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?

  • 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.”

    From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [19]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • TNF administration study described as mice but cited study used rats

    Minor

    The text says TNF administration produced a dilated cardiomyopathy phenotype in mice, but the title of the cited study identifies rats as the experimental animals.

1 of 1

The citation lists haven’t been fetched yet

References 233 · Cited by 789

Research works printed but not linked: 2

  1. Parab, S. N. & Rao, S. B. Distribution of trimethylamine oxie in some marine and freshwater fish. Curr. Sci. 53, 307–309 (1984).
  2. Oakley, C. et al. The uremic metabolite, trimethylamine-N-oxide (TMAO), directly alters cardiac contractile function [abstract]. FASEB J. 31 (Suppl. 1), 688.3 (2017).

Authors
Tang, W. H. W., Li, D. Y., & Hazen, S. L.
Affiliations
  • Cleveland Clinic (US)
  • Cleveland Clinic Lerner College of Medicine (US)
Corresponding author
Tang, W. H. Wilson
ORCID
Venue
Nature Reviews Cardiology
Publisher
Springer Science and Business Media LLC
Published
2018-11-08
Volume
16
Issue
3
Pages
137-154
ISSN
  • 1759-5002 (ISSN-L)
  • 1759-5010
DOI
10.1038/s41569-018-0108-7
PMC
PMC6377322
OpenAlex
W2899852374
Semantic Scholar
2d188c8a4a0b7f0a587d01042154b977700f34d3
Cited by
789
References
233
Citations by year
2026: 87 · 2025: 122 · 2024: 129 · 2023: 144 · 2022: 104 · 2021: 101 · 2020: 67 · 2019: 32
FWCI
4.90
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Reviews Cardiology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL126827, P20HL113452, R01HL103866)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK106000)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
  • Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
Keywords
heart failure, gut microbiota, trimethylamine N-oxide, trimethylamine, short-chain fatty acids, secondary bile acids, bacterial translocation, intestinal barrier function, cardiovascular disease
MeSH terms
Gastrointestinal Microbiome, Animals, Anti-Bacterial Agents, Bacteria, Diet, Energy Metabolism, Heart Failure, Humans, Intestines, Nutritive Value, Probiotics, Host-Pathogen Interactions, Prebiotics, Dysbiosis

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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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