Heart failure (HF) is a significant global health problem, affecting millions worldwide. Despite advancements in treatment, HF continues to cause high morbidity and mortality rates, particularly after hospitalization. Current pharmacotherapy primarily targets the neurohormonal axis, yet mortality remains high even with optimal medical therapy. The presence of low-grade inflammation in chronic HF and the hypothesis of intestinal barrier disruption have shifted attention to the gut-heart axis. This review aims to elucidate the connection between gut and heart dysfunction, exploring gut-related pathophysiological mechanisms in HF and suggesting potential therapeutic interventions targeting this complex axis to enhance HF management. The high mortality rates associated with HF, especially post-hospitalization, highlight the urgent need to understand the disease's complexities and identify novel therapeutic targets beyond the currently established neurohormonal axis therapies. The observation of low-grade inflammation and potential intestinal barrier disruption in chronic HF patients has led researchers to investigate the gut-heart axis, a bidirectional relationship where dysfunction in one organ affects the other. This review will explore this intricate relationship, examining the current evidence on gut-related pathophysiological mechanisms involved in HF, and proposing potential therapeutic strategies targeting the gut-heart axis to significantly improve future HF management.

The literature extensively supports the role of inflammation in heart failure progression. Early studies identified elevated levels of tumor necrosis factor-alpha (TNF-α) in patients with chronic HF. This, along with the hypothesis of intestinal barrier disruption, has spurred research into the gut's role in HF. Several studies have explored changes in gut microbiota composition, including the increase in pathogenic species and decrease in short-chain fatty acid (SCFA)-producing species in HF patients. These findings point towards a dysregulated gut microbiome contributing to the systemic inflammatory state observed in HF. Furthermore, research has investigated the effects of gut-derived metabolites, like trimethylamine-N-oxide (TMAO) and indoxyl sulfate (IS), on cardiovascular health and their association with HF outcomes. The contribution of intestinal barrier dysfunction and altered absorption/permeability has also been investigated, with studies highlighting the role of the apical junctional complex (AJC) and its impact on bacterial translocation. Several studies reviewed in this paper demonstrate a correlation between gut dysbiosis, inflammation, and adverse HF outcomes. This has been explored through studies using different techniques such as 16S rRNA gene sequencing and fecal cultures.

This review article utilizes a systematic approach to synthesize existing literature on the gut-heart axis in heart failure. The authors conducted a comprehensive review of relevant scientific publications, focusing on studies exploring the pathophysiological mechanisms linking gut dysfunction to heart failure. Databases such as PubMed and other relevant scientific literature databases were likely searched using keywords related to heart failure, gut microbiota, intestinal barrier, inflammation, and relevant metabolites. Inclusion and exclusion criteria were likely applied to select studies that met specific quality standards and relevance to the review's scope. The selected studies likely encompassed various methodologies, including observational studies, interventional trials, and animal models, investigating different aspects of the gut-heart axis. These methodologies included 16S rRNA gene sequencing for microbiome analysis, fecal cultures for identifying pathogenic bacteria, sugar probe tests for assessing intestinal permeability and absorption, and measurement of various biomarkers in blood samples. The data extracted from these studies was analyzed thematically, summarizing the findings related to altered microbiota composition, intestinal barrier dysfunction, systemic inflammation, and the impact of gut-derived metabolites on cardiovascular health. The authors then synthesized this information to create a cohesive understanding of the gut-heart axis's pathophysiological mechanisms in heart failure and to propose potential therapeutic interventions.

The review highlights several key pathophysiological derangements within the gut-heart axis in heart failure: 1. **Altered Microbiota Composition and SCFA Levels:** Patients with HF exhibit dysbiosis, characterized by a decrease in beneficial SCFA-producing bacteria (e.g., Ruminococcaceae, Lachnospiraceae, Faecalibacterium) and an increase in pathogenic species. This shift impacts SCFA production, which plays crucial roles in energy metabolism and immune modulation. 2. **Increased Trimethylamine-N-oxide (TMAO):** HF patients frequently show elevated TMAO levels. TMAO, derived from gut microbial metabolism of dietary components, promotes atherosclerosis, platelet hyperreactivity, and vascular inflammation, significantly contributing to adverse cardiovascular outcomes. 3. **Intestinal Barrier Dysfunction:** HF-associated hemodynamic changes (congestion and hypoperfusion) compromise intestinal barrier integrity, leading to increased permeability. This dysfunction is linked to reduced SCFA production, compromised enterocyte function, and AJC damage, resulting in bacterial translocation and systemic inflammation. 4. **Systemic Inflammation:** Bacterial translocation, triggered by increased intestinal permeability, leads to the release of lipopolysaccharide (LPS) and subsequent activation of the immune system. Elevated levels of proinflammatory cytokines (TNF-α, IL-6) contribute to myocardial dysfunction and HF progression. 5. **Dysregulation of Amino Acid Metabolism:** Alterations in tryptophan metabolism, leading to elevated kynurenine pathway metabolites and indoxyl sulfate, are observed in HF and associated with reduced functional capacity and worse prognosis. The review also notes that these interconnected factors create a vicious cycle, where initial cardiac dysfunction leads to gut derangements, which further exacerbate cardiac function.

The findings of this review strongly support the existence of a significant gut-heart axis in the pathophysiology of heart failure. The intricate interplay between cardiac dysfunction, altered gut microbiota, intestinal barrier damage, and systemic inflammation is clearly demonstrated. The identified pathophysiological mechanisms provide a foundation for developing novel therapeutic strategies. The observation that dietary modifications, microbiota manipulation, and targeting specific metabolic pathways (e.g., TMAO synthesis, inflammation) can influence the course of heart failure underscores the potential for clinical interventions. The review's findings highlight the need for a more holistic approach to managing HF, moving beyond single-target therapies to consider the complex interplay of factors influencing disease progression. The interconnected nature of the gut-heart axis necessitates a multifaceted therapeutic strategy targeting multiple points along the pathological cascade. Future research should focus on large-scale studies to validate the findings, clarify the causality between gut dysfunction and HF, and optimize therapeutic interventions.

This review comprehensively details the pathophysiological mechanisms linking gut dysfunction to heart failure. The gut-heart axis plays a critical role in HF development and progression, with altered microbiota, increased TMAO, intestinal barrier dysfunction, and systemic inflammation all contributing to adverse outcomes. Future research should focus on larger-scale clinical trials investigating the efficacy of multifaceted therapeutic interventions targeting multiple elements of the gut-heart axis, such as dietary modification, probiotics, prebiotics, lyase inhibition, FMO3 inhibition, and inflammation blockade. These interventions offer promising avenues for improving HF management and prognosis.

As a review article, this study is limited by the available literature. While the review incorporates a considerable body of research, the quality and quantity of studies on specific aspects of the gut-heart axis in HF vary. The absence of large-scale, prospective, human studies investigating specific interventions limits the ability to draw definitive conclusions about the efficacy of proposed therapies. The focus is predominantly on the established association and limited causal mechanisms, highlighting the need for future studies to establish firmer causal links. Further, the heterogeneous nature of heart failure itself may limit the generalizability of some findings. Finally, the review primarily focuses on the Westernized populations represented in the reviewed studies, which limits generalizability across different ethnic groups.