Gut microbiome - A potential mediator of pathogenesis in heart failure and its comorbidities: State-of-the-art review

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Abstract

Gut microbiome (GMB) has been increasingly recognized as a contributor to development and progression of heart failure (HF), immune-mediated subtypes of cardiomyopathy (myocarditis and anthracycline-induced cardiotoxicity), response to certain cardiovascular drugs, and HF-related comorbidities, such as chronic kidney disease, cardiorenal syndrome, insulin resistance, malnutrition, and cardiac cachexia. Gut microbiome is also responsible for the “gut hypothesis” of HF, which explains the adverse effects of gut barrier dysfunction and translocation of GMB on the progression of HF. Furthermore, accumulating evidence has suggested that gut microbial metabolites, including short chain fatty acids, trimethylamine N-oxide (TMAO), amino acid metabolites, and bile acids, are mechanistically linked to pathogenesis of HF, and could, therefore, serve as potential therapeutic targets for HF. Even though there are a variety of proposed therapeutic approaches, such as dietary modifications, prebiotics, probiotics, TMAO synthesis inhibitors, and fecal microbial transplant, targeting GMB in HF is still in its infancy and, indeed, requires further preclinical and clinical evidence. In this review, we aim to highlight the role gut microbiome plays in HF pathophysiology and its potential as a novel therapeutic target in HF.

Introduction

Every year nearly 1 million adults in the United States are diagnosed with heart failure (HF), which is generally a result from cardiac injuries causing impairment of ventricular structure and function [1]. While we have made strides in treatment, this disease continues to have significant morbidity and mortality on par with many malignancies. Novel preventative and therapeutic HF targets are greatly needed, and gut microbiota (GMB), a community of symbiotic bacteria, fungi and viruses residing in our gastrointestinal (GI) tract, may be a source of such targets. Growing data suggests that GMB plays an important role in a myriad of important biological processes, many of which are implicated in pathogenesis and pathophysiology of cardiomyopathy (CM) and HF and its comorbidities. In this state-of-the-art review we summarize current knowledge on HF-associated GMB dysregulation and evidence supporting the role of the GMB in pathogenesis and progression of HF and its comorbidities. We close by reviewing prospects of targeting the GMB to prevent and treat HF.

Section snippets

Interplay Between the Gut and the Heart - the “Gut Hypothesis” of Heart Failure

Cardiac dysfunction induces acutely adaptive, but chronically maladaptive hemodynamic, neurohumoral and pro-inflammatory responses, which both affect the gut and are propagated by it [Fig. 1]. Gut ischemia develops in HF both due to elevated gut venous pressures and decreased blood flow in the splanchnic arteries [2]. The sequelae of chronic gut hypoperfusion and venous congestion include progressive interstitial edema and fibrosis of the gut wall, which correlate with HF severity, being most

Heart failure-associated gut dysbiosis - insights from association studies

Marked alterations in the structure and physiology of the GI tract in HF affect resident GMB communities. Methods used in the study of the GMB are reviewed extensively elsewhere [[13], [14], [15]], but in Table 1 we offer a brief primer on different approaches to study of GMB. A number of studies have examined GMB differences in HF compared to healthy individuals (Table 2 provides a summary of individual study findings) [2,3,5,[16], [17], [18], [19], [20], [21], [22]]. While heterogeneity in

Gut microbiome alterations in heart failure - more than just an association?

While these cross-sectional studies support an association between dysregulated GMB and HF pathophysiology, they do not in themselves offer a proof of the causal link between the two. Nonetheless, while the longitudinal clinical studies are still needed, in vitro, in vivo animal studies and small translational human studies have helped elucidate the active role GMB plays in the development of CM, HF, and HF-related co-morbidities.

Heart failure comorbidities and the role of the gut microbiota

Gut microbiome contributes not only to the development of cardiomyopathy and HF and to progression of HF but is also an active mediator in the pathogenesis of several conditions that develop as complications of HF, which increase the morbidity and mortality of patients with HF. Understanding how GMB is linked to HF-associated comorbidities may provide more insight into complex host-microbe relationships, which can serve as promising therapeutic targets.

Microbial-drug interactions and implications for heart failure therapeutics

While inter-individual variability in drug pharmacokinetics and pharmacodynamics caused by host genetic make-up (pharmacogenomics) has been well recognized, there is growing data to support resident GMB contributions to this phenomenon (pharmacomicrobiomics). Resident GMB and its metabolites can alter drug absorption and (in)activation. They can also compete for drug-metabolizing enzymes in the liver and alter their expression [129]. The drug-microbiome interactions are bidirectional - drugs

Targeting the Gut Microbiome to Prevent and Treat Heart Failure - Are We There Yet?

Different approaches to GMB modulation - ranging from broad and non-specific dietary interventions and fecal microbiota transplant (FMT) to ones involving specific and targeted microbial enzyme inhibition - have been proposed in many diseases. Given the role that the GMB plays in development and progression of cardiomyopathy and HF, development of its comorbidities, and modulation of the effects of HF therapy, the prospect of GMB as a preventative and therapeutic target in HF is being seriously

Conclusions

Accumulating evidence has suggested that GMB plays an important role in development and progression of HF, its comorbidities, and immune-mediated subtypes of cardiomyopathy, including myocarditis and anthracycline-induced cardiotoxicity. Microbial translocation, and altered structure and function of GMB have been consistently shown to contribute to HF, emphasizing the intense interaction between the gut and heart, known as the “gut hypothesis” of HF. Over the past decade, metabolomics has

Funding Support

Dr. Mamic is partially supported by a grant from the National Institutes of Health (F32HL143916). Dr. Tang is partially supported by grants from the National Institutes of Health (R01DK106000, R01HL126827).

Disclosure

Dr. Tang is a consultant for Sequana Medical A.G., Owkin Inc., and Relypsa Inc., and has received 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. All other authors have no relationships to disclose, both unrelated to the contents of this paper.

Fig. 1 shows that hemodynamic features of heart failure (HF), decreased cardiac output and elevated intracardiac

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