Heart failure and cardiac transplantation continue to pose considerable challenges in clinical cardiology, especially due to tenacious immune dysfunction and inadequate regenerative capacity. Correspondingly, advances in microbiome research have drawn attention to the gut-heart axis; a complex interaction between intestinal microbes, systemic inflammation, and inadvertently, cardiovascular outcomes. This review evaluates the extent to which the gut microbiome influences regenerative treatments, particularly stem cell and exosome-based stratagems, in the context of heart failure and transplantation. A total of 22 studies were analyzed using systematic review methods based on PRISMA guidelines. Across studies, patterns of gut dysbiosis, explicitly, a loss of short-chain fatty acid (SCFA)-producing bacteria and increased levels of pro-inflammatory metabolites like Trimethylamine-N-oxide (TMAO) were consistently correlated with adverse clinical markers such as elevated CRP, lower ejection fraction, and higher rates of graft rejection. Evidence proposes that strategies directed at modulating the gut microbiome may enhance regenerative therapy functionality by reducing inflammation, improving cell integration, and limiting fibrosis. These findings underscore the need for integrated therapeutic frameworks combining regenerative and gut-targeted approaches.

Heart failure affects tens of millions globally and continues to remain a major contributor to cardiovascular mortality and morbidity. [1]. Even though pharmacologic and device-based interventions have enhanced survival ability, they often fall short in repairing damaged myocardium. For patients with advanced disease, transplantation is a key option; however, this option remains to be limited by donor shortages and post-operative complications [2]. Over the past two decades, regenerative strategies including mesenchymal stem cells (MSCs), exosomes, and engineered cardiac patches have been developed as possible alternatives to replace or repair dysfunctional heart tissue. [3-4] Despite encouraging results in preclinical studies, clinical outcomes have been inconsistent. Issues such as immune incompatibility, poor graft survival, and persistent inflammation have been persistent despite treatment.[5]

Contemporarily, an expanding amount of research has begun highlighting the influence of gut microbial communities on cardiovascular health. Dysbiosis, or microbial imbalance, has been increasingly documented as a factor in heart failure pathogenesis. [6]. Certain microbial profiles seem to influence both systemic inflammation and immune homeostasis which are critical factors in both heart failure and the success of regenerative or transplant therapies. [7]. This review investigates the current evidence on the role of the gut microbiome in influential outcomes of regenerative cardiac interventions.

Figure 1: Dysbiosis-induced gut permeability allows microbial metabolites and lipopolysaccharides (LPs) to enter the circulation, promoting systemic inflammation, immune activation, and adverse cardiac remodeling, which contribute to heart failure progression.

Alterations in Gut Microbiota and Clinical Impact in Heart Failure

Several analyses have documented microbial shifts in heart failure, typically marked by reduced diversity and loss of SCFA-producing genera like Faecalibacterium and Roseburia. These losses are often accompanied by an increase in pro-inflammatory taxa such as Enterobacteriaceae. [8]. These microbial discrepancies stimulus the production of metabolites with systemic effects. TMAO, a derivative of the microbial metabolism of dietary choline, is linked to vascular inflammation and fibrosis. In comparison, SCFAs support regulatory immune responses and preserve gut barrier integrity. [9] Moreover, a frequent finding in HF includes compromised intestinal integrity, facilitating translocation of bacterial products like lipopolysaccharides (LPS), further amplifying systemic inflammation and cardiac dysfunction. [10]

Regenerative Strategies in Cardiac Repair

Stem cell-based therapies have garnered interest due to their potential to reverse myocardial damage. MSCs, induced pluripotent stem-cells (iPSCs), and cardiac progenitor cells can differentiate, secrete paracrine factors, and stimulate endogenous repair pathways. [11]. Small vesicles secreted by these cells, called exosomes, carry bioactive lipids, proteins, and RNAs that encourage tissue repair without the challenges of cell engraftment. [12] Though, regenerative approaches remain hindered by low cell survival rates, immune barriers, and an often-hostile tissue environment. [13]

Microbiome’s Role in Immune Regulation of Regenerative Therapy

Gut microbes are key mediators of immune homeostasis. They influence antigen presentation by dendritic cells, regulate differentiation of T-cells, and modulate production of pro- and anti-inflammatory cytokines. [14] the forementioned pathways impact the immune response to regenerative therapies, particularly when foreign or engineered cells are involved. [15] Fluctuations in gut flora create immune response variability, possibly weakening cell therapy effectiveness or exacerbating tissue fibrosis. Identifying and modifying these interactions could improve therapy durability and precision.

Microbial Influence on Transplant Immunology and Recovery

The microbiome plays a dual role in cardiac transplant recipients by influencing immune reactivity and drug metabolism. Immunosuppressive drug metabolism can be augmented by certain bacterial taxa. One example of this is tacrolimus, which leads to variable drug levels and increased rejection risk.[16] Furthermore, dysbiosis in post-transplant patients correlates with a higher frequency of infections and gastrointestinal complications. ¹⁷ These effects highlight the importance of microbiome monitoring as part of transplant care.

Figure 2: Gut microbiota–derived SCFAs regulate immune function, reduce inflammation, and enhance regenerative therapy efficacy and cardiac repair in heart failure and cardiac transplantation.

This review was conducted using PRISMA methodology to synthesize available literature on the microbiome’s impact on regenerative therapies for HF and cardiac transplantation. Searches were carried out across PubMed, Embase, and Scopus using terms including “gut microbiota,” “heart failure,” “cardiac transplantation,” “stem cell therapy,” “SCFAs,” and “immune modulation.” Inclusion criteria were studies analyzing microbial composition in HF or transplant patients and reporting outcomes relevant to inflammation, cardiac performance, or therapy response. Both animal and human studies were eligible, provided original data were available. Review articles, commentaries, and studies lacking clinical relevance were excluded. From 3,211 records, 22 articles met inclusion criteria after full-text screening. Risk of bias was evaluated using SYRCLE and Newcastle-Ottawa tools for animal and observational studies, respectively.

Table 1: Summary of studies linking gut microbiome alterations to outcomes in heart failure and cardiac transplantation. [5, -8] [10, -14]

This table synthesizes evidence from human, animal, and review studies examining the gut–heart axis in the context of heart failure (HF) and cardiac transplantation. Across observational and experimental work, reduced abundance of short-chain fatty acid (SCFA)–producing taxa and increased Proteobacteria have been associated with impaired cardiac function, higher inflammatory markers, and worse clinical outcomes. In HF patients, elevated trimethylamine N-oxide (TMAO) levels have been linked to adverse cardiovascular events, while post-transplant populations exhibit dysbiosis that correlates with increased graft rejection risk, infection, and immune profile shifts. Animal studies further suggest that dysbiosis can 

impair regenerative therapy efficacy by reducing stem cell homing and promoting fibrosis and inflammation. Review articles propose mechanistic pathways by which SCFA signaling could modulate cell therapy success, though some remain theoretical. Collectively, these findings highlight the multifaceted role of the gut microbiome in influencing both disease progression and response to advanced therapies.

Abbreviations: HF, heart failure; SCFA, short-chain fatty acid; TMAO, trimethylamine N-oxide; LVEF, left ventricular ejection fraction; CRP, C-reactive protein; MSCs, mesenchymal stem cells.

Figure 3: Clinical outcomes by gut microbiome status. Compared with non-dysbiotic patients, those with dysbiosis demonstrated lower left ventricular ejection fraction (LVEF), higher C-reactive protein (CRP) levels, and higher post-transplant rejection rates. 11,12

The reviewed studies strengthen the hypothesis that gut microbial dysfunction diminishes immune regulation and regenerative efficacy. Dysbiosis correlated with pro-inflammatory profiles, elevated circulating toxins, and reduced myocardial recovery. These results set the stage for several promising clinical avenues. Integrating microbiome assessments into patient selection protocols may identify those at higher risk of poor response. Dietary interventions, probiotics, or even fecal transplants have the potential to fortify a healthy microbiome before starting regenerative therapy. Nonetheless, considerable challenges remain. Few longitudinal studies have measured microbiome changes during therapy. Techniques for microbiome analysis lack standardization, and the optimal composition for therapeutic response is not yet defined. Further research should attempt to establish clear causality, ascertain reproducible intervention protocols, and explore microbiome-based biomarkers to guide therapy.

Accumulating evidence proposes that the gut microbiome has a consequential impact on the outcome of regenerative therapies in heart failure and transplantation. Strategies that integrate microbial profiling and modulation may help overcome current therapeutic limitations. Bridging microbiome science with cardiology and immunotherapy holds promise for improving outcomes in these high-risk patient populations