Abstract
Purpose of Review
Over the past decade, the gut microbiome has been shown to play an important role in the pathogenesis of heart failure (HF) and serves as a mediator that links host genomes and environmental exposure (especially dietary intake) to the development and progression of HF. Given that alterations in gut microbial composition and metabolism are commonly seen in patients with HF, the use of gut microbial metabolites as diagnostic and prognostic biomarkers, as well as novel therapeutic targets for HF, is promising.
Recent findings
Alterations in gut microbial composition and function have bidirectional relationships with HF. Gut microbial metabolites, including short-chain fatty acids, bile acids, trimethylamine N-oxide (TMAO), and amino acid metabolites, have been shown to play a significant role in HF. For example, TMAO has been consistently demonstrated as an independent predictor of worse prognosis in patients with HF, and a potential therapeutic target for cardiac remodeling and HF. However, clinical studies on dietary interventions targeting gut microbial metabolites have demonstrated inconsistent findings, which could be from variations in the study population, gut microbial communities, and study designs.
Summary
Measurement of gut microbial metabolites can improve risk stratification and potentially identify HF patients who are more likely to respond to personalized pharmacologic or dietary interventions targeting specific pathways associated with the gut microbiome.
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Introduction
Heart failure (HF) has been one of the leading causes of morbidity and mortality, which accounts for 6.2 million patients, and over 1 million hospitalizations per year in the USA [1]. Although recent advances in treatment modalities have been shown to significantly reduce the risk of death and HF hospitalization, the mortality and rehospitalization rates remain unacceptably high regardless of left ventricular ejection fraction (EF) [2]. Therefore, novel insight into pathogenesis and pathophysiology of HF can lead to the development of more precise risk stratification and personalized comprehensive therapeutic approaches.
Over the past decade, the gut microbiome has been implicated to play an important role in the development and progression of HF and its comorbidities [3, 4]. Gut microbes filter and metabolize dietary nutrients and produce a variety of metabolites that can act as signaling molecules. Therefore, the gut microbiome can be considered a major endocrine organ directly influenced by dietary intake, which may have a greater influence on cardiometabolic profile compared to dietary macronutrients [5•]. In addition, dietary molecules can also affect gut microbial function and metabolism by modulating their gene expression [6]. Since each person’s dietary habit and gut microbial composition and function are different, targeting the gut microbiome may be an important key to personalized lifestyle or dietary modification, therapeutic interventions, and development of precision HF medicine.
Accumulating evidence suggests that changes in composition and metabolism of gut microbial communities contribute to a worse prognosis of both acute and chronic HF. Despite recent advances in microbial gene sequencing, the validity and reproducibility of the techniques used for identifying gut microbes are still evolving [7]. Instead, researchers have recently focused on the metabolomic approach for studying the gut microbial function and the complex relationship between host and microbes in HF. In this review, we discuss the interaction between HF and intestinal structure and function, gut microbial dysbiosis in HF, and gut microbiome-mediated metabolism and metabolites that have been shown to be associated with HF.
Gut Hypothesis in Heart Failure
The concept of how the gastrointestinal system is mechanistically linked to the pathogenesis of HF (often referred to as the “gut hypothesis of HF”) has been described since the early 2000s [8]. Hemodynamic features of HF can directly affect intestinal mucosa structure and function in different ways. Elevated intracardiac filling pressure and systemic venous congestion can cause bowel wall edema, whereas decreased cardiac output, adaptive redistribution of systemic perfusion, and venous hypertension may result in intestinal hypoperfusion and ischemia [3, 8]. It is believed that both bowel wall congestion and splanchnic ischemia may contribute to the disruption of intestinal mucosal barrier, increased intestinal permeability, and subsequent translocation of the gut microbiome and its components. Specifically, bacterial endotoxin and metabolites may enter into the systemic circulation, thereby activating immune response and inflammation [8,9,10], which is a major contributor to the development and progression of HF [11, 12]. Furthermore, endotoxin and inflammatory cytokines can also promote intestinal permeability [13,14,15,16], resulting in a vicious cycle of gut microbial endotoxin translocation, systemic inflammation, and worsening HF.
Besides inflammation, bowel wall ischemia, edema, and translocation of bacterial endotoxin can also worsen HF through different mechanisms. For instance, intestinal hypoxia and acidosis upregulate sodium-hydrogen exchanger 3 (NHE3) expression on intestinal epithelial cells, resulting in increased sodium and water absorption, and subsequent HF decompensation [17]. In addition, lipopolysaccharide (LPS), a virulence factor and endotoxin of Gram-negative bacilli, is able to bind to toll-like receptor 4 (TLR-4) on cardiomyocytes, resulting in decreased ventricular contractility [18,19,20]. Interestingly, LPS was found to be elevated in patients with decompensated HF and could be attenuated by diuretic drugs [21] and antibiotic therapy [22]. In chronic HF patients, LPS and inflammatory biomarkers track with the severity of HF [23]. However, advanced HF therapy (left ventricular assist device and heart transplantation) can reduce inflammation but not endotoxemia [23]. Interestingly, Jennings et al. [24] also demonstrated that gut microbial composition, endotoxemia, and inflammation were associated with the required dose of tacrolimus in heart transplant patients. Therefore, it is conceivable that the gut microbiome plays an important role in every stage of HF, from cardiac injury to end-stage HF and even after transplantation.
Meanwhile, the intense interaction between cardiovascular and gastrointestinal systems in HF exists and involves gut microbiome, immune response, and fluid balance [3]. In the future, indirect assessment of bowel wall integrity by measuring gut microbial endotoxin may lead to better risk prediction of HF decompensation, and novel therapeutic approaches targeting intestinal barrier function.
Patterns of Gut Dysbiosis in Heart Failure
Recently, a variety of patterns of changes in human gut microbial composition have been shown to be associated with HF [3]. For instance, the incidence of Clostridium difficile infection, which can occur following the disruption of commensal gut bacteria by antibiotics, was higher in patients with HF [25]. These observations support the hypothesis that HF might be associated with the overall depletion of the gut microbiome [23, 26, 27, 28••], as well as an increase in the abundance of some pathogenic Gram-negative bacteria [29]. In addition, some genera of the gut microbiome have also been shown to be enriched in HF, such as Ruminococcus gnavus [30•], Bacteroidetes, Prevotella, Hungatella, and Succiclasticum [28]. Even though research has focused on the association between altered gut microbial composition and HF, there have been a lot of discrepancies in the findings, which could be a result of diverse gut microbial communities, as well as significant variations in the structure and function of gut microbes [31]. Therefore, given the large amount of data and variable findings, we may have to rely on artificial intelligence and machine learning to better integrate the data in order for clinicians to gain more insight into the interpretation and utility of gut microbial genome and taxonomic profiling in HF patients [32].
Gut Microbiome-Derived Metabolites as Biomarkers in Heart Failure
Throughout life, the gut microbiome serves as an intestinal filter of a variety of dietary nutrients and produces metabolites, which are then reabsorbed into the bloodstream, and act as signaling molecules either with or without biochemical modification by host enzymes. Indeed, some of the metabolites have been shown to play a significant role in the host’s susceptibility to HF and are associated with adverse outcomes over time. Also, it is believed that interpersonal variation in the composition and function of the gut microbiome, as a result of different genomes and environmental exposure, may contribute to different severity and prognosis among HF patients, independently of traditional risk factors [3, 33]. Interestingly, disrupted circadian rhythm was also shown to negatively impact the function of the gut microbiome, leading to impaired ischemic cardiac healing and subsequent HF [34]. Nevertheless, identifying the composition and abundance of gut microbes requires complicated and sophisticated stool sample processing, including 16S rRNA gene sequencing and whole metagenomic shotgun sequencing. However, stool samples are often more challenging to collect, and analytical techniques are clinically less available and reproducible, in contrast to quantifying their circulating metabolites using metabolomic approaches [35, 36]. Hence, the use of gut microbial metabolites is relatively more pragmatic. However, while some previous clinical studies have demonstrated potential effects of different dietary interventions on gut microbial metabolites, their findings have been inconsistent (Table 1) [37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74], which could be explained by the diverse study population, different study designs, and variations in gut microbial composition and function.
Short-Chain Fatty Acids
Short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate, are produced by gut microbes from the fermentation of indigestible nutrients, such as dietary fiber, complex carbohydrates, resistant starch, and prebiotics, which serve as a major energy source and protectors of intestinal mucosa [75]. As a result, the altered metabolism of SCFAs is associated with disruption of the intestinal barrier and dysbiosis of the gut microbiome [76, 77]. Furthermore, SCFAs can also be absorbed into the enterohepatic and systemic circulation. Animal studies have demonstrated that SCFAs can bind to specific G protein-coupled receptors, thereby regulating blood pressure and renin-angiotensin-aldosterone system (RAAS) [78]. Interestingly, acetate can also be protective against mineralocorticoid-induced cardiac hypertrophy and fibrosis by the downregulation of cardiac and renal early growth response (Egr1), a transcription factor that regulates inflammation, ventricular hypertrophy, and cardiorenal fibrosis [79••]. Despite accumulating evidence suggests that HF patients have a significantly lower abundance of SCFA-producing gut microbes as assessed by 16S ribosomal RNA sequencing in fecal samples [30, 80, 81•], the use of plasma SCFA levels remains to be elucidated with only preliminary data from Sarah et al. [82] showing that HF patients had decreased plasma propionate and butyrate levels compared to healthy individuals. However, there are discrepancies on the role of a high-fiber diet and SCFA supplementation as potential therapeutic interventions in HF. Marques et al. [79••] showed that mice fed with a high-fiber diet and acetate had improved gut microbial profile, as well as attenuated blood pressure, inflammation, cardiac hypertrophy, and cardiorenal fibrosis. Similarly, a study on 84 patients with systolic HF revealed that low fiber intake was associated with gut microbiome dysbiosis, which led to a significantly higher risk of mortality and heart transplantation [28]. In contrast, in a mouse model of genetic dilated cardiomyopathy, fiber and acetate supplementation were not able to protect cardiomyocytes from apoptosis or adverse remodeling [83]. Therefore, the benefits of a high-fiber diet and SCFAs in patients with HF, especially those with lower SCFA levels or SCFA-producing microbes, are still under active investigations.
Bile Acids
Primary bile acids are emulsifiers produced by the liver from cholesterol, which facilitate the digestion and absorption of dietary fats and fat-soluble vitamins in the small intestine before being reabsorbed via enterohepatic circulation. Unabsorbed primary bile acids will then enter the colon in which the gut microbiome converts primary into secondary bile acids using bile salt hydrolases [84]. Interestingly, evidence has shown that bile acids are able to cause both favorable and unfavorable effects on cardiac structure and function. For instance, early studies showed that primary bile acids caused negative inotropic and chronotropic effects on cardiac muscle in rats [85, 86]. In addition, bile acids can also promote cardiac apoptosis and fibrosis following ischemic injury by binding to the farnesoid X receptor [87, 88]. In contrast, it is also believed that bile acids suppress nuclear factor-κB [89], a transcription factor that regulates inflammation and mediates cardiac hypertrophy and remodeling [90]. Moreover, activation of another type of bile acid receptors, Takeda G protein-coupled receptor 5 (TGR5), improves myocardial survival and response to stress [91].
Similarly, clinical studies also showed conflicting results on the type of bile acids associated with favorable outcomes in HF patients. For example, Mayerhofer et al. [92] demonstrated that HF patients had significantly higher ratios of secondary to primary bile acids, which were also associated with adverse clinical outcomes. On the other hand, HF patients supplemented with ursodeoxycholic acid, a secondary bile acid, had improved peripheral blood flow and lower inflammation [93]. Hence, it is possible that imbalance of bile acids, either an increase or decrease, is associated with the development and progression of HF, and the optimal values of both primary and secondary bile acids need to be determined, in order to utilize bile acids as prognostic biomarkers and therapeutic targets in HF.
Trimethylamine N-Oxide
Among previously discovered gut microbiome-mediated metabolites, trimethylamine N-oxide (TMAO) has been the most widely investigated gut microbiome-related biomarker in the cardiovascular field. TMAO is produced by gut microbes from choline, phosphatidylcholine, and l-carnitine, which can be found in eggs, red meat, dairy products, and some deep-sea fish [36, 94, 95]. It is now recognized that the enterohepatic circulation recycles choline and other nutrients thru biliary secretion, rendering a constant supply to the colonic microbes (and not just thru oral ingestion). Initially, choline and phosphatidylcholine are converted directly into trimethylamine (TMA) by gut microbial enzymes, TMA lyases, whereas l-carnitine (primarily from red meat sources) needs to be converted into γ-butyrobetaine, which is then metabolized by TMA lyase to form TMA [96]. Subsequently, TMA in the intestinal lumen is absorbed into the circulation and converted into TMAO by host enzymes, predominantly hepatic flavin monooxygenase 3 (FMO3) [97]. Not only has TMAO been mechanistically linked to atherosclerosis [96,97,98] but it has also been shown to play an important role in the pathogenesis of HF, including increased maladaptive ventricular remodeling [99], cardiac mitochondrial dysfunction [100], and impaired calcium regulation [101]. Interestingly, Li et al. [102] demonstrated that TMAO causes cardiac fibrosis and hypertrophy through transforming growth factor-β1 (TGF-β1)/Smad3 signaling activation, which are the same pathways observed in TMAO-mediated renal fibrosis [103]. Nevertheless, the exact mechanisms or cellular receptors by which TMAO promotes HF still remain to be elucidated.
Recent research has shed light on the role of TMAO as a diagnostic and prognostic biomarker in both acute and chronic HF. In chronic HF with reduced EF (HFrEF) patients, TMAO levels are significantly elevated and associated with HF severity and poor prognosis [104,105,106,107,108], albeit not tracking with titration of guideline-directed medical therapy [109••]. Interestingly, in heart transplant patients, an increase in γ-butyrobetaine is associated with acute graft rejection and atherosclerotic burden [110]. Similarly, elevated baseline TMAO has been shown to be an independent predictor of mortality and rehospitalization in patients with acute decompensated HF [111, 112]. However, studies on TMAO levels in patients with HF with preserved EF (HFpEF) have shown conflicting findings. Schuett et al. [113•] showed that TMAO was not associated with mortality in 395 patients with HFpEF, whereas TMAO was shown to be a good predictor for both short-term and long-term mortality and hospitalization in 118 patients with HFpEF [114]. Therefore, these findings support the complexity of the pathophysiology and phenotypes of HFpEF, and further investigations on the role of TMAO in HFpEF are needed.
In addition to being a novel biomarker in HF, TMAO has also been shown to be a potential therapeutic target in HF. Organ et al. [115••] showed that iodomethylcholine, a nonlethal microbial TMA lyase inhibitor that directly targets TMA production, improved cardiac function and prevented cardiac remodeling in a mouse HF model receiving a high choline diet. Similarly, Wang et al. [116••] demonstrated that 3,3-dimethyl-1-butamol (DMB), another nonlethal TMA lyase inhibitor, could attenuate pressure overload-induced cardiac hypertrophy and fibrosis by modulating TGF-β1/Smad3 signaling pathways. Given that the Mediterranean diet contains natural DMB found in extra-virgin olive oil [117], this finding may explain how the Mediterranean diet reduces the risk of incident HF as shown in some studies [118,119,120], whereas contradicting results were also shown [121, 122]. Similarly, there are also discrepancies in the effects of probiotics on TMAO levels. Even though Matsumoto et al. [123] demonstrated that Bifidobacterium animalis subsp. lactis LKM512 supplementation reduced TMA production in healthy subjects, other studies failed to show a significant impact of probiotics on TMAO levels [46,47,48].
These conflicting findings have led to the hypothesis that a reduction in the risk of developing HF following a Mediterranean (or non-red meat) diet may only be seen in patients who have significantly elevated baseline TMAO levels, which needs to be confirmed by post hoc analyses on previous studies, or clinical trials enrolling patients with elevated TMAO. Hence, since there are significant inter-individual variations in TMAO production and metabolism, TMAO measurement may identify patients who are more likely to benefit from therapeutic and dietary interventions targeting TMAO and subsequently lead to personalized treatment strategies and dietary recommendation, which serves as a fundamental of future precision HF medicine.
Amino Acid Metabolites
In addition to previously mentioned dietary nutrients, some specific amino acids, including tryptophan, tyrosine, and phenylalanine, can also be fermented and metabolized to uremic toxins by gut microbes, especially in patients with impaired kidney function [124]. Often considered as “uremic toxins,” the gut microbiome metabolizes tryptophan into indole, which is then converted into either indole-3-propionate (IPA) or indoxyl sulfate (IS). IPA has been shown to counteract the gut hypothesis of HF by protecting the intestinal mucosal barrier, reducing inflammation and gut dysbiosis [125, 126]. This hypothesis is supported by a clinical study demonstrating that patients with dilated cardiomyopathy had significantly less IPA levels [127]. In contrast, IS promotes maladaptive cardiac remodeling and fibrosis by activating inflammation and renin receptors [128,129,130,131]. Shimazu et al. [132] revealed that elevated IS was associated with diastolic dysfunction and adverse outcomes. Similarly, tyrosine and phenylalanine are converted into p-cresyl sulfate (PCS), which can activate RAAS, and cause cardiomyocyte apoptosis [131, 133]. Moreover, it also disrupts gap junctions and calcium regulation of cardiomyocytes [134]. Interestingly, compared to IS, PCS was shown to be a better independent predictor of mortality and hospitalization in HF patients [135]. Hence, the role of these uremic toxins in the development and progression of HF may become more important in patients with the cardiorenal syndrome, which could potentially lead to specific dietary restrictions or therapeutic interventions in this group of patients. For instance, Asanuma et al. [136] showed that a reduction in IS levels by a uremic toxin absorbent (AST-120) attenuated myocardial fibrosis and apoptosis in a dog model of right ventricular pacing-induced HF. These findings may imply that gut microbial metabolites such as IS can serve as potential mechanism biomarkers.
Conclusion and Future Direction
Altered hemodynamic status in HF affects the composition and function of the gut microbial community, whereas certain strains of gut microbes exert functional consequences (potentially via their metabolites) that can directly or indirectly contribute to the development and progression of HF. Gut microbial metabolites, including SCFAs, bile acids, TMAO, and amino acid metabolites, represent the complex host-microbe relationship. Genomic sequencing of the gut microbiome to date has been unable to confer clear diagnostic or prognostic information, and there is much hype on probiotic therapies that replace or diversify microbial species in the setting of dysbiosis. However, there is much hope that measuring microbial metabolites that are stable in biospecimens (e.g., TMAO, IS) may have the potential to facilitate better risk stratification in patients with HF and may identify subgroups of patients who are more likely to benefit from specific pharmacologic or dietary interventions. Since inter-individual variations in gut microbiome caused by different genomes and environmental exposure exist, gut microbial metabolites may help identify novel endophenotypes of HF by uncovering their underlying pathophysiologic underpinnings. For example, a subset of patients with the accumulation of “uremic toxins” despite relatively preserved renal function as measured by serum creatinine may signify an evolving chronic cardiorenal syndrome. Further studies will require the availability and standardizing of assay techniques, combined with the novel (and more specific) therapeutic strategies to target abnormalities identified by these mechanism biomarkers in order to change the clinical course of disease progression.
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al. Heart Disease and Stroke Statistics-2020 Update: a report from the American Heart Association. Circulation. 2020;141(9):e139–596.
Ziaeian B, Fonarow GC. Epidemiology and aetiology of heart failure. Nat Rev Cardiol. 2016;13(6):368–78.
Tang WHW, Li DY, Hazen SL. Dietary metabolism, the gut microbiome, and heart failure. Nat Rev Cardiol. 2019;16(3):137–54.
Sata Y, Marques FZ, Kaye DM. The emerging role of gut dysbiosis in cardio-metabolic risk factors for heart failure. Curr Hypertens Rep. 2020;22(5):38.
Berry SE, Valdes AM, Drew DA, Asnicar F, Mazidi M, et al. Human postprandial responses to food and potential for precision nutrition. Nat Med. 2020;26(6):964–73 Compared to meal macronutrients, gut microbiome had a greater influence on postpandrial lipid profile.
Ni Y, Li J, Panagiotou G. A Molecular-level landscape of diet-gut microbiome interactions: toward dietary interventions targeting bacterial genes. mBio. 2015;6(6):e01263–15.
Cao Y, Fanning S, Proos S, Jordan K, Srikumar S. A review on the applications of next generation sequencing technologies as applied to food-related microbiome studies. Front Microbiol. 2017;8:1829.
Krack A, Sharma R, Figulla HR, Anker SD. The importance of the gastrointestinal system in the pathogenesis of heart failure. Eur Heart J. 2005;26(22):2368–74.
Krack A, Richartz BM, Gastmann A, Greim K, Lotze U, Anker SD, et al. Studies on intragastric PCO2 at rest and during exercise as a marker of intestinal perfusion in patients with chronic heart failure. Eur J Heart Fail. 2004;6(4):403–7.
Sandek A, Bauditz J, Swidsinski A, Buhner S, Weber-Eibel J, von Haehling S, et al. Altered intestinal function in patients with chronic heart failure. J Am Coll Cardiol. 2007;50(16):1561–9.
Adamo L, Rocha-Resende C, Prabhu SD, Mann DL. Reappraising the role of inflammation in heart failure. Nat Rev Cardiol. 2020;17(5):269–85.
Murphy SP, Kakkar R, McCarthy CP, Januzzi JL. Inflammation in heart failure. J Am Coll Cardiol. 2020;75(11):1324–40.
Al-Sadi RM, Ma TY. IL-1β causes an increase in intestinal epithelial tight junction permeability. J Immunol. 2007;178(7):4641–9.
Hietbrink F, Besselink MG, Renooij W, de Smet MB, Draisma A, et al. Systemic inflammation increases intestinal permeability during experimental human endotoxemia. Shock (Augusta, Ga). 2009;32(4):374–8.
Al-Sadi R, Ye D, Boivin M, Guo S, Hashimi M, et al. Interleukin-6 modulation of intestinal epithelial tight junction permeability is mediated by JNK pathway activation of claudin-2 gene. PLOS ONE. 2014;9(3):e85345.
Ma TY, Boivin MA, Ye D, Pedram A, Said HM. Mechanism of TNF-α modulation of Caco-2 intestinal epithelial tight junction barrier: role of myosin light-chain kinase protein expression. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2005;288(3):G422–G30.
Polsinelli VB, Sinha A, Shah SJ. Visceral congestion in heart failure: right ventricular dysfunction, splanchnic hemodynamics, and the intestinal microenvironment. Current Heart Failure Reports. 2017;14(6):519–28.
Avlas O, Fallach R, Shainberg A, Porat E, Hochhauser E. Toll-like receptor 4 stimulation initiates an inflammatory response that decreases cardiomyocyte contractility. Antioxid Redox Signal. 2011;15(7):1895–909.
Tavener SA, Long EM, Robbins SM, McRae KM, Remmen HV, Kubes P. Immune Cell Toll-Like Receptor 4 Is Required for Cardiac Myocyte Impairment During Endotoxemia. Circ Res. 2004;95(7):700–7.
Fallach R, Shainberg A, Avlas O, Fainblut M, Chepurko Y, Porat E, et al. Cardiomyocyte toll-like receptor 4 is involved in heart dysfunction following septic shock or myocardial ischemia. J Mol Cell Cardiol. 2010;48(6):1236–44.
Niebauer J, Volk HD, Kemp M, Dominguez M, Schumann RR, et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet (London, England). 1999;353(9167):1838–42.
Conraads VM, Jorens PG, De Clerck LS, Van Saene HK, Ieven MM, et al. Selective intestinal decontamination in advanced chronic heart failure: a pilot trial. Eur J Heart Fail. 2004;6(4):483–91.
Yuzefpolskaya M, Bohn B, Nasiri M, Zuver AM, Onat DD, Royzman EA, et al. Gut microbiota, endotoxemia, inflammation, and oxidative stress in patients with heart failure, left ventricular assist device, and transplant. J Heart Lung Transplant. 2020;39(9):880–90.
Jennings DL, Bohn B, Zuver A, Onat D, Gaine M, Royzman E, et al. Gut microbial diversity, inflammation, and oxidative stress are associated with tacrolimus dosing requirements early after heart transplantation. PLOS ONE. 2020;15(5):e0233646.
Mamic P, Heidenreich PA, Hedlin H, Tennakoon L, Staudenmayer KL. Hospitalized Patients with Heart Failure and Common Bacterial Infections: A Nationwide Analysis of Concomitant Clostridium Difficile Infection Rates and In-Hospital Mortality. J Card Fail. 2016;22(11):891–900.
Luedde M, Winkler T, Heinsen F-A, Rühlemann MC, Spehlmann ME, Bajrovic A, et al. Heart failure is associated with depletion of core intestinal microbiota. ESC Heart Failure. 2017;4(3):282–90.
Kummen M, Mayerhofer CCK, Vestad B, Broch K, Awoyemi A, Storm-Larsen C, et al. Gut microbiota signature in heart failure defined from profiling of 2 independent cohorts. J Am Coll Cardiol. 2018;71(10):1184–6.
Mayerhofer CCK, Kummen M, Holm K, Broch K, Awoyemi A, et al. Low fibre intake is associated with gut microbiota alterations in chronic heart failure. ESC Heart Failure. 2020;7(2):456–66 Low fiber diet was associated with decreased gut microbial richness and Firmicutes phylum, as well as increased mortality and heart transplant.
Pasini E, Aquilani R, Testa C, Baiardi P, Angioletti S, Boschi F, et al. Pathogenic gut flora in patients with chronic heart failure. JACC: Heart Failure. 2016;4(3):220–7.
Cui X, Ye L, Li J, Jin L, Wang W, et al. Metagenomic and metabolomic analyses unveil dysbiosis of gut microbiota in chronic heart failure patients. Scientific Reports. 2018;8(1):635 Patients with HF had significantly different gut microbial profile, and decreased butyrate but increased TMAO production.
Zeevi D, Korem T, Godneva A, Bar N, Kurilshikov A, Lotan-Pompan M, et al. Structural variation in the gut microbiome associates with host health. Nature. 2019;568(7750):43–8.
Aryal S, Alimadadi A, Manandhar I, Joe B, Cheng X. Machine Learning Strategy for Gut Microbiome-Based Diagnostic Screening of Cardiovascular Disease. Hypertension. 2020;76(5):1555–62.
Zhernakova A, Kurilshikov A, Bonder MJ, Tigchelaar EF, Schirmer M, Vatanen T, et al. Population-based metagenomics analysis reveals markers for gut microbiome composition and diversity. Science. 2016;352(6285):565–9.
Mistry P, Reitz CJ, Khatua TN, Rasouli M, Oliphant K, Young ME, et al. Circadian influence on the microbiome improves heart failure outcomes. J Mol Cell Cardiol. 2020;149:54–72.
Morgan XC, Huttenhower C. Meta’omic analytic techniques for studying the intestinal microbiome. Gastroenterology. 2014;146(6):1437-48.e1.
Tang WHW, Bäckhed F, Landmesser U, Hazen SL. Intestinal microbiota in cardiovascular health and disease: JACC state-of-the-art review. J Am Coll Cardiol. 2019;73(16):2089–105.
Tonucci LB. Olbrich dos Santos KM, Licursi de Oliveira L, Rocha Ribeiro SM, Duarte Martino HS. Clinical application of probiotics in type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled study. Clin Nutr. 2017;36(1):85–92.
Ouwehand AC, Tiihonen K, Saarinen M, Putaala H, Rautonen N. Influence of a combination of Lactobacillus acidophilus NCFM and lactitol on healthy elderly: intestinal and immune parameters. Br J Nutr. 2009;101(3):367–75.
Klein A, Friedrich U, Vogelsang H, Jahreis G. Lactobacillus acidophilus 74-2 and Bifidobacterium animalis subsp lactis DGCC 420 modulate unspecific cellular immune response in healthy adults. Eur J Clin Nutr. 2008;62(5):584–93.
Ferrario C, Taverniti V, Milani C, Fiore W, Laureati M, de Noni I, et al. Modulation of fecal Clostridiales bacteria and butyrate by probiotic intervention with Lactobacillus paracasei DG varies among healthy adults. J Nutr. 2014;144(11):1787–96.
Lee Y, Ba Z, Roberts RF, Rogers CJ, Fleming JA, et al. Effects of Bifidobacterium animalis subsp. lactis BB-12(®) on the lipid/lipoprotein profile and short chain fatty acids in healthy young adults: a randomized controlled trial. Nutr J. 2017;16(1):39.
Culpepper T, Rowe CC, Rusch CT, Burns AM, Federico AP, Girard SA, et al. Three probiotic strains exert different effects on plasma bile acid profiles in healthy obese adults: randomised, double-blind placebo-controlled crossover study. Benefic Microbes. 2019;10(5):497–509.
Hibberd AA, Yde CC, Ziegler ML, Honoré AH, Saarinen MT, Lahtinen S, et al. Probiotic or synbiotic alters the gut microbiota and metabolism in a randomised controlled trial of weight management in overweight adults. Benefic Microbes. 2019;10(2):121–35.
Mobini R, Tremaroli V, Ståhlman M, Karlsson F, Levin M, Ljungberg M, et al. Metabolic effects of Lactobacillus reuteri DSM 17938 in people with type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2017;19(4):579–89.
Stadlbauer V, Leber B, Lemesch S, Trajanoski S, Bashir M, Horvath A, et al. Lactobacillus casei Shirota supplementation does not restore gut microbiota composition and gut barrier in metabolic syndrome: a randomized pilot study. PLoS One. 2015;10(10):e0141399.
Boutagy NE, Neilson AP, Osterberg KL, Smithson AT, Englund TR, Davy BM, et al. Probiotic supplementation and trimethylamine-N-oxide production following a high-fat diet. Obesity. 2015;23(12):2357–63.
Borges NA, Stenvinkel P, Bergman P, Qureshi AR, Lindholm B, Moraes C, et al. Effects of Probiotic Supplementation on Trimethylamine-N-Oxide Plasma Levels in Hemodialysis Patients: a Pilot Study. Probiotics and Antimicrobial Proteins. 2019;11(2):648–54.
Chen S, Jiang P-P, Yu D, Liao G-C, Wu S-L, et al. Effects of probiotic supplementation on serum trimethylamine-N-oxide level and gut microbiota composition in young males: a double-blinded randomized controlled trial. Eur J Nutr. 2020.
Lopes R, Theodoro JMV, da Silva BP, Queiroz VAV, de Castro Moreira ME, et al. Synbiotic meal decreases uremic toxins in hemodialysis individuals: a placebo-controlled trial. Food Res Int. 2019;116:241–8.
Guida B, Germanò R, Trio R, Russo D, Memoli B, Grumetto L, et al. Effect of short-term synbiotic treatment on plasma p-cresol levels in patients with chronic renal failure: a randomized clinical trial. Nutr Metab Cardiovasc Dis. 2014;24(9):1043–9.
Borges NA, Carmo FL, Stockler-Pinto MB, de Brito JS, Dolenga CJ, Ferreira DC, et al. Probiotic supplementation in chronic kidney disease: a double-blind, randomized, placebo-controlled trial. J Ren Nutr. 2018;28(1):28–36.
Rossi M, Johnson DW, Morrison M, Pascoe EM, Coombes JS, Forbes JM, et al. Synbiotics easing renal failure by improving gut microbiology (SYNERGY): a randomized trial. Clin J Am Soc Nephrol. 2016;11(2):223–31.
Pimentel G, Burton KJ, von Ah U, Bütikofer U, Pralong FP, Vionnet N, et al. Metabolic footprinting of fermented milk consumption in serum of healthy men. J Nutr. 2018;148(6):851–60.
Jones ML, Martoni CJ, Tamber S, Parent M, Prakash S. Evaluation of safety and tolerance of microencapsulated Lactobacillus reuteri NCIMB 30242 in a yogurt formulation: a randomized, placebo-controlled, double-blind study. Food Chem Toxicol. 2012;50(6):2216–23.
Burton KJ, Krüger R, Scherz V, Münger LH, Picone G, et al. Trimethylamine-N-oxide postprandial response in plasma and urine is lower after fermented compared to non-fermented dairy consumption in healthy adults. Nutrients. 2020;12(1).
Quercia S, Turroni S, Fiori J, Soverini M, Rampelli S, et al. Gut microbiome response to short-term dietary interventions in reactive hypoglycemia subjects. Diabetes Metab Res Rev. 2017;33(8).
Mitsou EK, Kakali A, Antonopoulou S, Mountzouris KC, Yannakoulia M, Panagiotakos DB, et al. Adherence to the Mediterranean diet is associated with the gut microbiota pattern and gastrointestinal characteristics in an adult population. Br J Nutr. 2017;117(12):1645–55.
De Filippis F, Pellegrini N, Vannini L, Jeffery IB, La Storia A, et al. High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. Gut. 2016;65(11):1812–21.
Pagliai G, Russo E, Niccolai E, Dinu M, Di Pilato V, et al. Influence of a 3-month low-calorie Mediterranean diet compared to the vegetarian diet on human gut microbiota and SCFA: the CARDIVEG Study. Eur J Nutr. 2020;59(5):2011–24.
Pignanelli M, Just C, Bogiatzi C, Dinculescu V, Gloor GB, et al. Mediterranean diet score: associations with metabolic products of the intestinal microbiome, carotid plaque burden, and renal function. Nutrients. 2018;10(6).
Guasch-Ferré M, Hu FB, Ruiz-Canela M, Bulló M, Toledo E, et al. Plasma metabolites from choline pathway and risk of cardiovascular disease in the PREDIMED (Prevention With Mediterranean Diet) study. J Am Heart Assoc. 2017;6(11).
Griffin LE, Djuric Z, Angiletta CJ, Mitchell CM, Baugh ME, Davy KP, et al. A Mediterranean diet does not alter plasma trimethylamine N-oxide concentrations in healthy adults at risk for colon cancer. Food Funct. 2019;10(4):2138–47.
Trefflich I, Marschall HU, Giuseppe RD, Ståhlman M, Michalsen A, et al. Associations between dietary patterns and bile acids-results from a cross-sectional study in Vegans and Omnivores. Nutrients. 2019;12(1).
van Faassen A, Hazen MJ, van den Brandt PA, van den Bogaard AE, Hermus RJ, Janknegt RA. Bile acids and pH values in total feces and in fecal water from habitually omnivorous and vegetarian subjects. Am J Clin Nutr. 1993;58(6):917–22.
Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19(5):576–85.
Wang Z, Bergeron N, Levison BS, Li XS, Chiu S, et al. 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. 2018;40(7):583–94.
Kandouz S, Mohamed AS, Zheng Y, Sandeman S, Davenport A. Reduced protein bound uraemic toxins in vegetarian kidney failure patients treated by haemodiafiltration. Hemodial Int. 2016;20(4):610–7.
Patel KP, Luo FJ, Plummer NS, Hostetter TH, Meyer TW. The production of p-cresol sulfate and indoxyl sulfate in vegetarians versus omnivores. Clin J Am Soc Nephrol. 2012;7(6):982–8.
González Hernández MA, Canfora EE, Pasmans K, Astrup A, Saris WHM, Blaak EE. The relationship between circulating acetate and human insulin resistance before and after weight loss in the DiOGenes study. Nutrients. 2020;12(2).
Alemán JO, Bokulich NA, Swann JR, Walker JM, De Rosa JC, et al. Fecal microbiota and bile acid interactions with systemic and adipose tissue metabolism in diet-induced weight loss of obese postmenopausal women. J Transl Med. 2018;16(1):244.
Straniero S, Rosqvist F, Edholm D, Ahlström H, Kullberg J, Sundbom M, et al. Acute caloric restriction counteracts hepatic bile acid and cholesterol deficiency in morbid obesity. J Intern Med. 2017;281(5):507–17.
van Nierop FS, Kulik W, Endert E, Schaap FG, Olde Damink SW, Romijn JA, et al. Effects of acute dietary weight loss on postprandial plasma bile acid responses in obese insulin resistant subjects. Clin Nutr. 2017;36(6):1615–20.
Erickson ML, Malin SK, Wang Z, Brown JM, Hazen SL, Kirwan JP. Effects of lifestyle intervention on plasma trimethylamine N-oxide in obese adults. Nutrients. 2019;11(1).
Washburn RL, Cox JE, Muhlestein JB, May HT, Carlquist JF, et al. Pilot study of novel intermittent fasting effects on metabolomic and trimethylamine N-oxide changes during 24-hour water-only fasting in the FEELGOOD trial. Nutrients. 2019;11(2).
Topping DL, Clifton PM. Short-Chain Fatty Acids and Human Colonic Function: Roles of Resistant Starch and Nonstarch Polysaccharides. Physiol Rev. 2001;81(3):1031–64.
Peng L, Li Z-R, Green RS, Holzman IR, Lin J. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J Nutr. 2009;139(9):1619–25.
de la Cuesta-Zuluaga J, Mueller NT, Álvarez-Quintero R, Velásquez-Mejía EP, Sierra JA, Corrales-Agudelo V, et al. Higher Fecal Short-Chain Fatty Acid Levels Are Associated with Gut Microbiome Dysbiosis, Obesity, Hypertension and Cardiometabolic Disease Risk Factors. Nutrients. 2018;11(1):51.
Pluznick JL, Protzko RJ, Gevorgyan H, Peterlin Z, Sipos A, Han J, et al. Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. Proc Natl Acad Sci U S A. 2013;110(11):4410–5.
Marques FZ, Nelson E, Chu P-Y, Horlock D, Fiedler A, et al. High-fiber diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in hypertensive mice. Circulation. 2017;135(10):964–77 High fiber intake and acetate supplementation reduced cardiac hypertrophy and fibrosis.
Kamo T, Akazawa H, Suda W, Saga-Kamo A, Shimizu Y, et al. Dysbiosis and compositional alterations with aging in the gut microbiota of patients with heart failure. PloS one. 2017;12(3):e0174099-e.
Kummen M, Mayerhofer CCK, Vestad B, Broch K, Awoyemi A, et al. Gut microbiota signature in heart failure defined from profiling of 2 independent cohorts. Journal of the American College of Cardiology. 2018;71(10):1184–6 HF patients had significantly decreased microbial richness and relative abundance of SCFA-producing gut microbes.
Sarah K, Nicolaas D, John T, Gabriella TH, Engelen M. Reduced short-chain fatty acid (SCFA) plasma concentrations are associated with decreased psychological well-being in clinically stable congestive heart failure patients. Current Developments in Nutrition. 2020;4(Supplement_2):42.
Jama HA, Fiedler A, Tsyganov K, Nelson E, Horlock D, Nakai ME, et al. Manipulation of the gut microbiota by the use of prebiotic fibre does not override a genetic predisposition to heart failure. Sci Rep. 2020;10(1):17919.
Foley MH, O’Flaherty S, Barrangou R, Theriot CM. Bile salt hydrolases: gatekeepers of bile acid metabolism and host-microbiome crosstalk in the gastrointestinal tract. PLoS Pathog. 2019;15(3):e1007581-e.
Binah O, Rubinstein I, Bomzon A, Better OS. Effects of bile acids on ventricular muscle contraction and electrophysiological properties: studies in rat papillary muscle and isolated ventricular myocytes. Naunyn Schmiedeberg's Arch Pharmacol. 1987;335(2):160–5.
Joubert P. An in vivo investigation of the negative chronotropic effect of cholic acid in the rat. Clin Exp Pharmacol Physiol. 1978;5(1):1–8.
Pu J, Yuan A, Shan P, Gao E, Wang X, Wang Y, et al. Cardiomyocyte-expressed farnesoid-X-receptor is a novel apoptosis mediator and contributes to myocardial ischaemia/reperfusion injury. Eur Heart J. 2013;34(24):1834–45.
Gao J, Liu X, Wang B, Xu H, Xia Q, Lu T, et al. Farnesoid X receptor deletion improves cardiac function, structure and remodeling following myocardial infarction in mice. Mol Med Rep. 2017;16(1):673–9.
Li YTY, Swales KE, Thomas GJ, Warner TD, Bishop-Bailey D. Farnesoid X receptor ligands inhibit vascular smooth muscle cell inflammation and migration. Arterioscler Thromb Vasc Biol. 2007;27(12):2606–11.
Gordon JW, Shaw JA, Kirshenbaum LA. Multiple facets of NF-κB in the heart. Circ Res. 2011;108(9):1122–32.
Eblimit Z, Thevananther S, Karpen SJ, Taegtmeyer H, Moore DD, et al. TGR5 activation induces cytoprotective changes in the heart and improves myocardial adaptability to physiologic, inotropic, and pressure-induced stress in mice. Cardiovasc Ther. 2018;36(5):e12462-e.
Mayerhofer CCK, Ueland T, Broch K, Vincent RP, Cross GF, Dahl CP, et al. Increased Secondary/Primary Bile Acid Ratio in Chronic Heart Failure. J Card Fail. 2017;23(9):666–71.
von Haehling S, Schefold JC, Jankowska EA, Springer J, Vazir A, Kalra PR, et al. Ursodeoxycholic acid in patients with chronic heart failure: a double-blind, randomized, placebo-controlled, crossover trial. J Am Coll Cardiol. 2012;59(6):585–92.
Cho CE, Taesuwan S, Malysheva OV, Bender E, Tulchinsky NF, Yan J, et al. Trimethylamine-N-oxide (TMAO) response to animal source foods varies among healthy young men and is influenced by their gut microbiota composition: a randomized controlled trial. Mol Nutr Food Res. 2017;61(1):1600324.
Papandreou C, Moré M, Bellamine A. Trimethylamine N-oxide in relation to cardiometabolic health-cause or effect? Nutrients. 2020;12(5).
Koeth Robert A, Levison Bruce S, Culley Miranda K, Buffa Jennifer A, Wang Z, et al. γ-Butyrobetaine Is a Proatherogenic Intermediate in Gut Microbial Metabolism of L -Carnitine to TMAO. Cell Metab. 2014;20(5):799–812.
Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, DuGar B, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472(7341):57–63.
Tang WHW, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368(17):1575–84.
Organ CL, Otsuka H, Bhushan S, Wang Z, Bradley J, et al. Choline diet and its gut microbe-derived metabolite, trimethylamine N-oxide, exacerbate pressure overload-induced heart failure. Circ Heart Fail. 2016;9(1):e002314-e.
Makrecka-Kuka M, Volska K, Antone U, Vilskersts R, Grinberga S, Bandere D, et al. Trimethylamine N-oxide impairs pyruvate and fatty acid oxidation in cardiac mitochondria. Toxicol Lett. 2017;267:32–8.
Savi M, Bocchi L, Bresciani L, Falco A, Quaini F, Mena P, et al. Trimethylamine-N-oxide (TMAO)-induced impairment of cardiomyocyte function and the protective role of urolithin B-glucuronide. Molecules. 2018;23(3):549.
Li Z, Wu Z, Yan J, Liu H, Liu Q, Deng Y, et al. Gut microbe-derived metabolite trimethylamine N-oxide induces cardiac hypertrophy and fibrosis. Lab Investig. 2019;99(3):346–57.
Gupta N, Buffa JA, Roberts AB, Sangwan N, Skye SM, Li L, et al. Targeted Inhibition of Gut Microbial Trimethylamine N-Oxide Production Reduces Renal Tubulointerstitial Fibrosis and Functional Impairment in a Murine Model of Chronic Kidney Disease. Arterioscler Thromb Vasc Biol. 2020;40(5):1239–55.
Tang WHW, Wang Z, Shrestha K, Borowski AG, Wu Y, Troughton RW, et al. Intestinal Microbiota-Dependent Phosphatidylcholine Metabolites, Diastolic Dysfunction, and Adverse Clinical Outcomes in Chronic Systolic Heart Failure. J Card Fail. 2015;21(2):91–6.
Trøseid M, Ueland T, Hov JR, Svardal A, Gregersen I, Dahl CP, et al. Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure. J Intern Med. 2015;277(6):717–26.
Tang WHW, Wang Z, Fan Y, Levison B, Hazen JE, Donahue LM, et al. Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis. J Am Coll Cardiol. 2014;64(18):1908–14.
Huang Y, Zheng S, Zhu H, Lu J, Li W, Hu Y. Gut microbe-generated metabolite trimethylamine-N-oxide and risk of major adverse cardiovascular events in patients with heart failure. Journal of the American College of Cardiology. 2020;75(11 Supplement 1):834.
Li W, Huang A, Zhu H, Liu X, Huang X, Huang Y, et al. Gut microbiota-derived trimethylamine N-oxide is associated with poor prognosis in patients with heart failure. Med J Aust. 2020;213(8):374–9.
Suzuki T, Yazaki Y, Voors AA, Jones DJL, Chan DCS, et al. Association with outcomes and response to treatment of trimethylamine N-oxide in heart failure: results from BIOSTAT-CHF. European Journal of Heart Failure. 2019;21(7):877–86 Elevated TMAO was associated with motality and/or hospitalization regardless of guideline-directed medical therapy in chronic HF patients.
Trøseid M, Mayerhofer CCK, Broch K, Arora S, Svardal A, Hov JR, et al. The carnitine-butyrobetaine-TMAO pathway after cardiac transplant: Impact on cardiac allograft vasculopathy and acute rejection. J Heart Lung Transplant. 2019;38(10):1097–103.
Suzuki T, Heaney LM, Bhandari SS, Jones DJL, Ng LL. Trimethylamine N-oxide and prognosis in acute heart failure. Heart. 2016;102(11):841–8.
Yazaki Y, Aizawa K, Israr MZ, Negishi K, Salzano A, Saitoh Y, et al. Ethnic differences in association of outcomes with trimethylamine N-oxide in acute heart failure patients. ESC Heart Failure. 2020;7(5):2373–8.
Schuett K, Kleber ME, Scharnagl H, Lorkowski S, März W, et al. Trimethylamine-N-oxide and heart failure with reduced versus preserved ejection fraction. Journal of the American College of Cardiology. 2017;70(25):3202–4 Prognostic utility of TMAO was greater in HFrEF compared to HFpEF.
Salzano A, Israr MZ, Yazaki Y, Heaney LM, Kanagala P, et al. Combined use of trimethylamine N-oxide with BNP for risk stratification in heart failure with preserved ejection fraction: findings from the DIAMONDHFpEF study. European Journal of Preventive Cardiology. 0(0):2047487319870355.
Organ CL, Li Z, Sharp TE, Polhemus DJ, Gupta N, et al. Nonlethal Inhibition of gut microbial trimethylamine N-oxide production improves cardiac function and remodeling in a murine model of heart failure. Journal of the American Heart Association. 2020;9(10):e016223 Withdrawal of TMAO from the diet and a TMA lyase inhibitor, iodomethylcholine, improved cardiac function and remodeling.
Wang G, Kong B, Shuai W, Fu H, Jiang X, Huang H. 3,3-Dimethyl-1-butanol attenuates cardiac remodeling in pressure-overload-induced heart failure mice. The Journal of Nutritional Biochemistry. 2020;78:108341. Inhibition of TMAO production by DMB was associated with improved pressure-induced cardiac remodeling
Wang Z, Roberts AB, Buffa JA, Levison BS, Zhu W, Org E, et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell. 2015;163(7):1585–95.
Tektonidis TG, Åkesson A, Gigante B, Wolk A, Larsson SC. A Mediterranean diet and risk of myocardial infarction, heart failure and stroke: a population-based cohort study. Atherosclerosis. 2015;243(1):93–8.
Tektonidis TG, Åkesson A, Gigante B, Wolk A, Larsson SC. Adherence to a Mediterranean diet is associated with reduced risk of heart failure in men. Eur J Heart Fail. 2016;18(3):253–9.
Chrysohoou C, Panagiotakos DB, Aggelopoulos P, Kastorini C-M, Kehagia I, Pitsavos C, et al. The Mediterranean diet contributes to the preservation of left ventricular systolic function and to the long-term favorable prognosis of patients who have had an acute coronary event. Am J Clin Nutr. 2010;92(1):47–54.
Papadaki A, Martínez-González MÁ, Alonso-Gómez A, Rekondo J, Salas-Salvadó J, Corella D, et al. Mediterranean diet and risk of heart failure: results from the PREDIMED randomized controlled trial. Eur J Heart Fail. 2017;19(9):1179–85.
Wirth J, di Giuseppe R, Boeing H, Weikert C. A Mediterranean-style diet, its components and the risk of heart failure: a prospective population-based study in a non-Mediterranean country. Eur J Clin Nutr. 2016;70(9):1015–21.
Matsumoto M, Kitada Y, Shimomura Y, Naito Y. Bifidobacterium animalis subsp. lactis LKM512 reduces levels of intestinal trimethylamine produced by intestinal microbiota in healthy volunteers: a double-blind, placebo-controlled study. Journal of Functional Foods. 2017;36:94–101.
Ramezani A, Raj DS. The gut microbiome, kidney disease, and targeted interventions. J Am Soc Nephrol. 2014;25(4):657–70.
Venkatesh M, Mukherjee S, Wang H, Li H, Sun K, Benechet AP, et al. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and toll-like receptor 4. Immunity. 2014;41(2):296–310.
Zhao Z-H, Xin F-Z, Xue Y, Hu Z, Han Y, Ma F, et al. Indole-3-propionic acid inhibits gut dysbiosis and endotoxin leakage to attenuate steatohepatitis in rats. Exp Mol Med. 2019;51(9):1–14.
Alexander D, Lombardi R, Rodriguez G, Mitchell MM, Marian AJ. Metabolomic distinction and insights into the pathogenesis of human primary dilated cardiomyopathy. Eur J Clin Investig. 2011;41(5):527–38.
Lekawanvijit S, Adrahtas A, Kelly DJ, Kompa AR, Wang BH, Krum H. Does indoxyl sulfate, a uraemic toxin, have direct effects on cardiac fibroblasts and myocytes? Eur Heart J. 2010;31(14):1771–9.
Hung S-C, Kuo K-L, Wu C-C, Tarng D-C. Indoxyl sulfate: a novel cardiovascular risk factor in chronic kidney disease. J Am Heart Assoc. 2017;6(2):e005022.
Yisireyili M, Saito S, Abudureyimu S, Adelibieke Y, Ng H-Y, Nishijima F, et al. Indoxyl Sulfate-Induced Activation of (Pro)renin Receptor Promotes Cell Proliferation and Tissue Factor Expression in Vascular Smooth Muscle Cells. PLOS ONE. 2014;9(10):e109268.
Sun C-Y, Chang S-C, Wu M-S. Uremic Toxins Induce Kidney Fibrosis by Activating Intrarenal Renin–Angiotensin–Aldosterone System Associated Epithelial-to-Mesenchymal Transition. PLOS ONE. 2012;7(3):e34026.
Shimazu S, Hirashiki A, Okumura T, Yamada T, Okamoto R, Shinoda N, et al. Association between indoxyl sulfate and cardiac dysfunction and prognosis in patients with dilated cardiomyopathy. Circ J. 2013;77(2):390–6.
Han H, Zhu J, Zhu Z, Ni J, Du R, et al. p-Cresyl sulfate aggravates cardiac dysfunction associated with chronic kidney disease by enhancing apoptosis of cardiomyocytes. Journal of the American Heart Association. 2015;4(6):e001852-e.
Peng Y-S, Ding H-C, Lin Y-T, Syu J-P, Chen Y, Wang S-M. Uremic toxin p-cresol induces disassembly of gap junctions of cardiomyocytes. Toxicology. 2012;302(1):11–7.
Wang C-H, Cheng M-L, Liu M-H, Shiao M-S, Hsu K-H, Huang YY, et al. Increased p-cresyl sulfate level is independently associated with poor outcomes in patients with heart failure. Heart Vessel. 2016;31(7):1100–8.
Asanuma H, Chung H, Ito S, Min K-D, Ihara M, Takahama H, et al. AST-120, an adsorbent of uremic toxins, improves the pathophysiology of heart failure in conscious dogs. Cardiovasc Drugs Ther. 2019;33(3):277–86.
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Dr. Tang is supported by grants from the National Institutes of Health (R01HL126827).
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Dr. Chaikijurajai has no relationships to disclose. Dr. Tang is a consultant for Sequana Medical A.G., Owkin Inc, and Relypsa Inc, and has received an honorarium from Springer Nature for authorship/editorship and American Board of Internal Medicine for exam writing committee participation, all unrelated to the contents of this paper.
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Chaikijurajai, T., Tang, W.H.W. Gut Microbiome and Precision Nutrition in Heart Failure: Hype or Hope?. Curr Heart Fail Rep 18, 23–32 (2021). https://doi.org/10.1007/s11897-021-00503-4
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DOI: https://doi.org/10.1007/s11897-021-00503-4