Summary of Main Results
This systematic review synthesizes current evidence on gut microbiota composition and gut-derived metabolites in patients with HF. Overall, the findings demonstrate consistent alterations in both microbial diversity and functional metabolism, reflecting disrupted host-microbiota interactions in HF.

In terms of gut microbiota diversity, most studies reported reduced richness and diversity in HF patients compared with HCs, irrespective of the indices applied. This pattern was particularly evident in HFpEF and mixed HF phenotypes, whereas one study of HFrEF patients observed increased diversity, suggesting potential phenotype-specific differences. Despite this heterogeneity, the overall trend supports the notion that HF is associated with diminished microbial richness and diversity.

At the compositional level, HF patients exhibited significant shifts in microbial structure compared with HCs, as confirmed by beta diversity analyses. Across studies, reductions in Firmicutes and Bacteroidota, accompanied by increases in Proteobacteria, Actinobacteria, and Bacillota, were recurrently observed at the phylum level. Family level alterations included lower abundances of Lachnospiraceae and Oscillospiraceae and higher abundances of Enterobacteriaceae, Acidaminococcaceae, and Nocardiaceae. Genera enriched in HF included Enterobacter, Shigella, Klebsiella, Streptococcus, Lactobacillus, and Akkermansia, while key health-associated taxa such as Faecalibacterium, Roseburia, and Lachnospira were consistently depleted. At the species level, increases in pathogenic or opportunistic organisms such as Yersinia enterocolitica and Ruminococcus gnavus were reported, alongside reductions in beneficial species including Eubacterium rectale and Dorea longicatena. Collectively, these taxonomic changes reflect a dysbiotic profile characterized by loss of butyrate-producing bacteria and expansion of opportunistic taxa.

Gut microbiota derived metabolites and functional pathways also showed clear alterations in HF. TMAO was the most consistently reported metabolite, with most studies identifying elevated levels in HF patients. Increased TMAO was linked to enrichment of Escherichia and Klebsiella, and further associated with adverse ventricular remodeling, greater disease severity, and poor prognosis. In contrast, SCFAs, particularly butyrate and propionate, were frequently reduced in HF, paralleling the depletion of SCFA-producing taxa such as Lachnospiraceae, Ruminococcaceae, and Dialister. This loss corresponds to impaired gut barrier integrity, diminished anti-inflammatory signaling, and reduced cardioprotective effects.

Other notable findings included elevated lactic acid and long-chain fatty acids, together with reduced levels of amino acid-derived and anti-inflammatory metabolites such as glutamine, histidine, serotonin, and GABA. These metabolic shifts collectively indicate an imbalance toward pro-inflammatory and pro-atherogenic signalling. Functional pathway analyses further highlighted this dysregulation, with enrichment of carbohydrate degradation (e.g., trehalose, glycerol, pentose phosphate), fatty acid β-oxidation, amino acid catabolism, and steroid hormone synthesis pathways in HF patients. These changes were frequently driven by Proteobacteria and other opportunistic taxa, providing mechanistic links to intestinal inflammation, immune activation, and maladaptive host microbe interactions.

Alpha and Beta Diversity Changes in HF Patients Compared to HCs
Alpha diversity describes the microbial community within a single sample, capturing both the richness and evenness of microbial species. Richness reflects the total number of distinct taxa present, while evenness refers to how uniformly these taxa are distributed. A community is considered “richer” when it harbors a greater variety of microbial species rather than being dominated by only a few. Assessing alpha diversity is particularly important in HF research, as reduced diversity may indicate gut dysbiosis, loss of beneficial microbes, and disruption of metabolic and immune homeostasis.¹⁰ Beta diversity, on the other hand, measures the variation in microbial composition between samples or groups, providing insights into how community structure shifts across populations or environments.²⁴ Evaluating both alpha and beta diversity is therefore essential in HF, as alterations in these measures reflect changes in gut microbiota ecosystems that may influence inflammation, metabolic pathways, and overall disease progression. Specifically, reduced alpha diversity may signal an imbalance in microbial communities, while differences in beta diversity highlight how the gut microbiota profile of HF patients diverges from that of healthy individuals.^25,26

In this review, Yafarova et al.¹⁹ reported an increase in microbial richness and diversity in HFrEF patients, with significant differences observed in alpha-diversity indices (Pielou, Chao1 and PD-whole-tree) between HF patients and HCs (P < 0.001). This finding may be attributed to compensatory changes or overgrowth of opportunistic bacteria in response to the altered gut environment, including factors such as intestinal congestion or modified dietary and metabolic patterns in HF.²⁷ In contrast, some of the included studies, reported a significant reduction in microbial richness and diversity (P < 0.05).^15-18,20,22 This reduction is often linked to dysbiosis, where beneficial commensal bacteria such as Faecalibacterium and Roseburia spp. are lost and replaced by a less diverse, more pathogenic microbial community like Enterobacteriaceae or other opportunistic taxa, potentially due to reduced gut perfusion and chronic inflammation in HF patients.⁶ This dysbiosis may lead to reduced production of SCFAs and impaired gut barrier function, contributing to HF progression.²⁸ Supporting this trend, a recent meta-analysis by Huang et al.,²⁹ and a systematic review by Simadibrata et al.,³⁰ both reported reduced richness and diversity of microbial communities, accompanied by significant alterations in beta diversity. Interestingly, Zhang et al.²¹ found a significant decrease in microbial richness (p < 0.05) but no significant change in diversity (p > 0.05). This may suggest that while the number of distinct microbial taxa decreased, the distribution and evenness among the remaining taxa remained relatively stable, indicating a more balanced yet narrowed microbial population.

With respect to beta diversity, eight studies consistently reported significant differences in microbial composition between HF patients and HCs (p < 0.05). This indicates that, regardless of whether diversity increased or decreased, the overall microbial structure in HF patients diverges distinctly from that of healthy individuals, reflecting disease-associated shifts in metabolic and inflammatory pathways.¹¹ By contrast, Yang et al.²⁰ observed no statistically significant diversity differences within the HC group, highlighting that healthy gut microbiota tends to maintain stable diversity and structural balance.

Taken together, these findings suggest that HF is characterized by heterogeneous but consistently altered microbial diversity patterns, ranging from reductions in richness and evenness to compensatory expansions of opportunistic taxa. Meanwhile, healthy individuals maintain more stable and diverse microbial communities, underscoring the role of gut dysbiosis in shaping HF pathophysiology.

Gut Microbial Taxa Associated with HF Patients Compared to HCs
The human gut microbiome is increasingly regarded as a functional “organ” with key roles in metabolism, immunity, the nervous system, and endocrine regulation.³¹ It hosts the largest microbial community in the body, comprising trillions of microorganisms encoding more than three million microbial genes which far exceeds the ~23,000 genes of the human genome, underlining its major contribution to human health.^32,33

In healthy individuals, the microbiota is dominated by strict anaerobes, which outnumber facultative anaerobes and aerobes by up to 100-fold.³⁴ Although more than 50 bacterial phyla have been detected in the human gut, Firmicutes and Bacteroidota together represent ~90% of the total community, while Actinobacteria, Proteobacteria, and Verrucomicrobia are present in lower proportions.^35,36 The Firmicutes include SCFA-producing taxa such as Clostridium, Ruminococcus, Roseburia, and Faecalibacterium, whereas Bacteroidota are mainly represented by Bacteroides and Prevotella.^34,35 Actinobacteria are enriched for Bifidobacterium, while Proteobacteria and Verrucomicrobia are maintained at relatively low levels in health. The colon, harboring the highest microbial density, is particularly enriched with butyrate producers such as Anaerostipes and Butyrivibrio, which support mucosal health and host energy metabolism.³⁵ Despite variability at the species level, functional redundancy ensures stability of key microbial functions, including SCFA production, across individuals.³⁴ Collectively, these features define a resilient and balanced microbial ecosystem in health.

In contrast, HF is consistently associated with dysbiosis, characterized by reduced microbial diversity, depletion of commensals, and enrichment of opportunistic taxa.^10,37-39 At the phylum level, HF patients generally display decreased Firmicutes and Bacteroidota with corresponding enrichment of Proteobacteria and Actinobacteria. For example, Sun et al.¹⁷ reported that Firmicutes accounted for 72.4% of the gut microbiota in HCs but only 59.5% in CHF patients, while Proteobacteria were significantly higher in patients (21.3% vs. 6.9%). Similarly, Actinobacteria were more abundant in HF (2.7% vs. 0.9%), whereas Bacteroidota were modestly higher in controls (17.7% vs. 14.9%). These results indicate that healthy individuals preserve higher levels of commensal Firmicutes and lower levels of opportunistic Proteobacteria.

At the genus level, HCs consistently maintain greater abundance of SCFA-producing taxa. In Sun et al.¹⁷ Faecalibacterium represented 22.8% of the microbiota in controls but only 10.5% in CHF patients. Conversely, pathogenic genera such as Shigella, Klebsiella, and Enterococcus were markedly reduced in controls. Other studies reinforce this protective profile, Huang et al.¹⁵ observed higher Dialister and Anaerostipes in controls,¹⁵ Zhang et al.²¹ reported elevated Firmicutes, and Agathobacter, while Peng et al.¹⁶ described greater abundance of Faecalibacterium, Blautia, Prevotella, Clostridia, and Peptostreptococcaceae in controls.¹⁶ Collectively, these findings underscore the preservation of diverse SCFA producers as a hallmark of healthy gut ecology.

In HF populations, the opposite trend is observed, with consistent enrichment of pathobionts. Commonly reported taxa include Shigella, Klebsiella, Streptococcus, and Akkermansia.^{14,16-18,20-23} Additional enriched taxa, such as Prevotella, Bacteroides, Sutterella, and Megasphaera, suggest that HF-associated dysbiosis extends beyond the simple SCFA producer versus pathobiont imbalance.^15,16,22 Importantly, disease severity appears to shape microbial shifts such as Klebsiella and Lactobacillus increase in advanced HF (NYHA IV), while Bifidobacterium declines progressively with worsening disease, potentially serving as a severity marker.^15,21 At the species level, HF patients show depletion of Faecalibacterium prausnitzii, a major anti-inflammatory commensal, alongside enrichment of pro-inflammatory species such as Ruminococcus gnavus and Streptococcus spp.¹⁸ Mendelian randomization and genome-wide association studies further support causality which Bacteroides dorei emerged as the most consistently HF-associated species across large biobanks, while SCFA producers such as Butyrivibrio and Faecalibacterium prausnitzii were inversely associated with HF risk.⁴⁰

Taken together, these findings highlight a reproducible dysbiotic signature in HF, marked by loss of SCFA-producing commensals and enrichment of pathobionts. In contrast, HCs maintain a balanced, SCFA rich community with lower abundance of opportunistic taxa. These taxonomic differences underpin functional consequences, including reduced SCFA generation, increased TMAO production, and altered BA metabolism, thereby providing mechanistic links between the gut microbiome and HF progression.

Alterations in Gut-Derived Metabolites and Functional Pathways in HF Patients Compared to HCs
This systematic review highlights that patients with HF consistently display alterations in gut-derived metabolites and functional pathways compared with HCs. These interconnected changes are summarized in Figure 2, which provides an overview of microbial metabolites implicated in HF. To complement this, Figure 3 illustrates the contrasting microbial and metabolic profiles in HCs, characterized by preserved eubiosis, intact gut barrier function, and balanced metabolite production. Together, Figures 2 and 3 highlight the dysbiosis-eubiosis continuum that underpins gut-heart interactions in health and disease.

Among these, TMAO emerged as the most frequently reported metabolite, mentioned in five of the included studies, making it the central focus in the literature. TMAO is a small odourless molecule with molecular mass of 75.11 g/mol.⁴¹ TMAO is generated from dietary precursors such as choline, L-carnitine, betaine, and phosphatidylcholine which are metabolized into trimethylamine (TMA) by gut microbial enzymes such as choline-TMA lyase (cutC/D), carnitine monooxygenase (cntA/B), betaine reductase and TMAO reductase primarily produced by Firmicutes (Clostridium), Proteobacteria (Escherichia, Klebsiella) and Bacteroidota before undergo hepatic oxidation by flavin-containing monooxygenase (FMO) into TMAO.^42,43 Circulating TMAO has been linked to several mechanisms relevant to HF, including vascular inflammation, oxidative stress, myocardial fibrosis, and impaired cardiac contractility.⁴⁴

Most studies reported increased TMAO levels in HF patients.^14,16,21,23 For example, two of the included studies^21,23 associated higher TMAO with enrichment of Klebsiella and Escherichia (Proteobacteria), both known TMAO producers, and demonstrated links with more severe HF phenotypes and poor prognosis. Ahmad et al.¹⁴ further associated elevated TMAO with congestion, impaired intestinal barrier integrity, and systemic inflammation. One of the included studies, identified upregulated steroid hormone synthesis alongside increased TMAO, suggesting possible interactions with vascular tone and sodium-water balance.¹⁶ Consistent with these findings, recent meta-analysis by Li et al.,²⁶ and systematic review by Zhang et al.,⁴² have reported that HF is associated with elevated circulating TMAO, supporting the concept that gut dysbiosis may contribute to maladaptive cardiovascular remodeling. In contrast, Yafarova et al.¹⁹ reported lower TMAO levels in HFrEF patients, which correlated positively with carbohydrate intake and the abundance of Firmicutes (Lachnospiraceae). The authors suggested that widespread use of statins and aspirin in that population may have lowered circulating TMAO levels. Collectively, these findings indicate that while TMAO is consistently emphasized, its levels vary with diet, medication, and clinical subtype, but overall evidence supports its role as a biomarker of gut-heart axis dysregulation.

Beyond TMAO, multiple other metabolites and pathways were dysregulated across the included studies. SCFAs, mainly acetate, propionate, and butyrate, are important products of bacterial fermentation of resistant starches and dietary fibers. They are primarily generated by Firmicutes (Faecalibacterium, Roseburia, Ruminococcus), Bacteroidota (Bacteroides), and Actinobacteria (Bifidobacterium).^40,45 Two of the included studies, conducted in HFpEF and mixed HF populations, consistently reported lower SCFA levels in patients compared with controls, reflecting the loss of SCFA-producing bacteria.^17,22 One of the included studies however, observed no significant changes in SCFA or butyrate levels, possibly due to small sample sizes, medication use, or the confounding effects of COVID-19 in their study population.¹⁴ Consistently, metagenomic analyses have shown reduced abundance of butyrate-producing genes in HF patients.⁴⁶ In contrast, HCs as illustrated in Figure 3 exhibited preserved enrichment of SCFA producers, consistent with a protective metabolic profile.

Mechanistic studies help explain why these changes are clinically relevant. In the gut, SCFAs strengthen the intestinal barrier by enhancing tight junctions and stimulating mucus production, thereby preventing translocation of harmful microbial products such as LPS into circulation.³⁹ Butyrate also supports colonocyte energy metabolism through PPAR-γ signaling, while butyrate and propionate promote the expansion of regulatory T cells, maintaining immune balance.^47,48 Beyond the gut, SCFAs act on the cardiovascular system by activating G protein-coupled receptors (GPR41, GPR43, and GPR109A), influencing vascular tone and blood pressure, and regulating inflammatory and metabolic pathways through epigenetic mechanisms.^49,50

Animal studies provide further support for these protective roles. In murine models, supplementation with SCFAs or fiber-rich diets reduced hypertension, cardiac hypertrophy, and fibrosis,⁵¹ while SCFA administration after myocardial infarction promoted favorable immune remodeling in the heart and improved recovery.¹¹ Conversely, experimental models of SCFA depletion demonstrated gut dysbiosis, systemic inflammation, vascular dysfunction, and insulin resistance, all of which exacerbate HF progression.^38,52 Together, Figure 2 shows reduced SCFA signaling in HF, whereas Figure 3 illustrates preserved SCFA production and systemic benefits in HCs.

Several studies also highlighted disruptions in amino acid metabolism. Protective metabolites such as glutamine, histidine, GABA, and serotonin were consistently reduced^14,15 loss of these metabolites may reduce antioxidant capacity, impair vascular regulation, and worsen systemic inflammation. Conversely, harmful metabolites such as phenylacetylglutamine (PAGln) were elevated, with Zhang et al.²¹ showing that PAGln promotes sympathetic overactivation by acting on β-adrenergic receptors. Indoxyl sulfate (IS), another harmful metabolite, showed no significant change in,¹⁹ although previous studies linked IS with cardiovascular events.⁵³ A study by Yang et al.²⁰ expanded on these findings by identifying upregulation of amino acid catabolic pathways, including proline, lysine, phenylalanine, and arginine degradation, driven by Proteobacteria (Enterobacter, Shigella). These alterations were linked to intestinal inflammation, metabolic stress, and systemic immune activation. In contrast, HCs showed preserved amino acid metabolism, with enrichment of protective metabolites (glutamine, histidine, and serotonin), reflecting balanced microbial and host pathways.

Other pathways were also dysregulated, particularly those involving LPS and BA metabolism. Evidence shows that LPS, a structural component of Gram-negative bacterial membranes, is a central mediator of gut-heart interactions in HF. One of the included studies reported that HF patients had higher circulating levels of soluble CD14 (sCD14) and soluble CD163 (sCD163), both well-established markers of LPS exposure and monocyte/macrophage activation.¹⁴ Elevated sCD14 has previously been linked to adverse cardiomyopathy outcomes and increased mortality risk, while sCD163 reflects macrophage activation and has been shown to predict incident cardiovascular events.^54,55 Together with other evidence, these findings suggest that sCD14 and sCD163 are not only markers of microbial translocation but also promising biomarkers of HF progression.^56,57

Mechanistically, LPS engages toll-like receptor 4 (TLR4) on immune and endothelial cells, activating NF-κB signaling and driving release of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-8, while suppressing the anti-inflammatory cytokine IL-10.⁵⁸ LPS also interacts directly with CD14, amplifying these responses.⁵⁹ Wang et al.¹⁸ provides direct evidence for this pathway, reporting elevated IL-6, IL-8, and TNF-α alongside reduced IL-10 in HF patients, consistent with gut-derived LPS signalling and systemic inflammation.  Importantly, not all LPS molecules exert equal effects: Bacteroides-derived LPS is relatively weak, Escherichia coli LPS is highly pro-inflammatory, and Prevotella-derived LPS displays intermediate potency. Given that HF patients show microbial shifts toward Enterobacteriaceae and other Gram-negative taxa,²⁰ the resulting exposure to more immunostimulatory LPS chemotypes may help explain the strong inflammatory profile observed in HF (Figure 2). Conversely, HCs (Figure 3) exhibited intact epithelial barrier function, reduced LPS translocation, and immune homeostasis.

BA metabolism was also disrupted, reflecting the interplay between the gut microbiome, host lipid metabolism, and cardiac function. One of the included studies, reported increased long-chain fatty acids and reduced anti-inflammatory metabolites and neurotransmitters, consistent with impaired BA and cholesterol homeostasis.¹⁵ The depletion of Parasutterella (Proteobacteria), a genus crucial for BA metabolism, was linked to disrupted cholesterol pathways, while enrichment of Prevotella (Bacteroidota) and Enterocloster (Firmicutes) suggested compensatory activation of amino acid and extracellular matrix (ECM) related metabolism. Similarly, Peng et al.¹⁶ observed that expansion of Proteobacteria, Actinobacteria, and Nocardiaceae was associated with increased steroid hormone synthesis and elevated TMAO, reinforcing the convergence of BA, lipid, and TMAO related pathways in HF.

These observations align with earlier reports showing an altered BA pool in chronic HF, characterized by reduced circulating primary BAs and elevated secondary BAs.³⁹ Such changes are clinically important: secondary BAs modulate vascular tone, cardiac contractility, and immune responses through receptors such as FXR and TGR5, while higher secondary to primary BA ratios have been linked to systemic inflammation and worse outcomes in HF. Conversely, pharmacological modulation of BAs may offer therapeutic benefits. For example, ursodeoxycholate, a secondary BA, improved peripheral blood flow in HF patients, possibly through its endotoxin-neutralizing properties.⁶⁰

Conversely, in HCs, a diverse and balanced microbial community maintains a robust intestinal epithelial barrier, which effectively prevents the translocation of inflammatory agents like LPS into the systemic circulation⁶¹ as presented in Figure 3. This barrier integrity reduces endotoxemia and systemic inflammation, which is fundamental to a healthy cardiovascular system.²⁷ A healthy gut is characterized by low levels of opportunistic pathogens from the Proteobacteria and Bacteroidota phyla.¹⁶ This composition is associated with a decrease in the production of harmful metabolites. For instance, the low abundance of Klebsiella and Bacteroidota contributes to a reduction in the production of TMA and its liver-derived product, TMAO, which are known to be pro-atherogenic and pro-inflammatory. Additionally, the decreased abundance of Shigella is linked to a reduction in specific amino acids, further highlighting a shift away from a disease-promoting metabolic profile.¹⁷ Other than that, a healthy gut also rich in beneficial bacteria like Faecalibacterium, Roseburia, and Ruminococcus (from the Firmicutes phylum), produces SCFAs that not only nourish the colonocytes but also exert potent anti-inflammatory effects.⁶²

HCs also showed broader and more balanced metabolic capacity. One of the included studies, reported enrichment of metabolites such as citramalate, pyroglutamate, inosine, riboflavin, and succinate in HCs, reflecting preserved amino acid, vitamin, and energy metabolism.¹⁸ Functional predictions revealed enrichment of replication/repair and terpenoid/polyketide pathways in HCs. This aligns with evidence that healthy gut microbiota produces SCFAs, vitamins (K, B12, folic acid, biotin), endocannabinoids, and BA derivatives that support metabolic and immune balance.⁶³ Importantly, eubiosis in HCs prevents overgrowth of pathobionts through competitive exclusion, antimicrobial peptides, and SCFA production, maintaining resilience and reducing inflammation.

Collectively, these findings demonstrate that HF is not driven by a single metabolite but by a network of disrupted microbial functions. TMAO remains the most consistent biomarker, but reductions in SCFAs, accumulation of harmful metabolites such as PAGln, LPS-driven inflammation, and BA and amino acids dysregulation all contribute to impaired energy metabolism, immune imbalance, and vascular dysfunction (Figure 2). Comparisons with HCs emphasize the preservation of diverse metabolic pathways in eubiosis (Figure 3), contrasting with the restricted and pro-inflammatory metabolite profile in HF.

Key points summary
In summary, this systematic review highlights several consistent patterns linking gut microbiota dysbiosis with heart failure pathophysiology:

1. Reduced microbial diversity and loss of commensal SCFA-producing taxa (Faecalibacterium, Roseburia, Lachnospira) are common in HF, contributing to impaired gut barrier integrity and inflammation.
2. Enrichment of pathogenic and TMAO-producing bacteria (Klebsiella, Escherichia, Streptococcus) is associated with elevated TMAO levels, adverse cardiac remodeling, and disease progression.
3. Disruption of key metabolic pathways, including decreased SCFAs and increased pro-inflammatory metabolites (e.g., PAGIn, LPS), underpins immune activation and endothelial dysfunction in HF.
4. Altered bile acid and amino acid metabolism further reflects systemic metabolic dysregulation linking the gut and heart.
5. Comparisons with healthy controls consistently show preserved microbial richness, balanced metabolite production, and reduced inflammation, emphasizing the gut-heart axis as a critical therapeutic target.

Collectively, these findings demonstrate that HF-related gut dysbiosis is multifactorial, involving microbial, metabolic, and immunological alterations. Future studies should employ longitudinal and multi-omics approaches to clarify causal mechanisms and evaluate microbiota-targeted interventions for HF management.

Limitations
This review has several important limitations. First, only ten studies met the eligibility criteria, representing just four countries, with more than half (six studies) conducted in China. This limited geographical diversity reduces the generalizability of the findings and makes direct comparisons across studies challenging.

Second, heterogeneity in study methods, particularly in sample collection, storage, processing, and sequencing techniques, may have influenced the reported microbial profiles and metabolites, thereby limiting comparability.

Third, adjustment for potential confounders varied considerably. While some studies implemented comprehensive adjustments^14,17,20 several did not adjust for key variables such as age, sex, comorbidities, medications, or lifestyle factors.^16,18,19 Others only applied partial adjustments, such as controlling for BMI, smoking, or alcohol use but omitting diet and medication data.^15,21 In two studies, medication and lifestyle information were not reported at all.^19,22 Because gut microbiota is highly sensitive to intrinsic factors (e.g., age, comorbidities, HF severity) and extrinsic factors (e.g., diet, medication use, cultural practices), these uncontrolled variables may have significantly biased the associations observed.

Fourth, evidence for HF subtypes was limited. Only one study examined HFrEF exclusively,¹⁹ one focused on HFpEF,²² three included mixed subtypes^17,20,23 and none directly investigated HFmrEF. Consequently, pooling findings across HF subtypes may mask clinically relevant differences. Current evidence suggests that gut dysbiosis may follow distinct mechanistic pathways across HF phenotypes. In HFrEF, impaired cardiac output can lead to intestinal hypoperfusion and ischemia, increasing permeability and favoring pathogenic bacterial overgrowth, which amplifies systemic inflammation.⁶⁴ In contrast, HFpEF is primarily driven by endothelial dysfunction, with gut involvement typically arising in the context of right-sided congestion.⁶⁵ Dysbiosis is therefore expected to differ between HFrEF and HFpEF.⁶⁶ HFmrEF remains poorly characterized, with no human studies directly exploring its gut microbiome profile. This gap in the literature limits interpretation of subtype-specific changes and underscores the need for future studies to clarify whether gut microbiome alterations contribute differently to HFrEF, HFpEF, and HFmrEF.

Fifth, the predominance of cross-sectional designs (8 of 10 studies) prevents any inference regarding temporality or causality. It remains unclear whether dysbiosis contributes to HF onset and progression, or arises as a consequence of the disease and its treatment. Only two cohort studies were available, and even these had limited follow-up or single-center designs, restricting their ability to capture longitudinal changes. Prospective, multi-center cohort studies are required to establish causal links between gut microbiota and HF outcomes.

Finally, several limitations of the review process itself should be acknowledged. The literature search was confined to three major databases (PubMed, Scopus, Web of Science), and additional studies indexed elsewhere or in the grey literature may have been missed. Restricting the review to English-language publications introduces a risk of language bias, while limiting the timeframe to 2021-2025 may have excluded earlier relevant studies. By including only peer-reviewed original research articles, we also cannot exclude the possibility of publication bias. For quality assessment, we applied the Newcastle-Ottawa Scale, which is widely used but has restricted sensitivity in capturing unique sources of bias in microbiome research. Lastly, because of the small number and heterogeneity of studies, we synthesized the data narratively rather than performing a meta-analysis, limiting our ability to quantify pooled effect sizes and formally evaluate heterogeneity.

Research gaps
Several studies have reported gut microbiota dysbiosis in HF, including reduced microbial diversity and loss of SCFA producing taxa. However, most available studies focus on taxonomic alterations without integrating functional and metabolite pathways, leading to a fragmented understanding of the gut-heart axis.⁶⁶ Existing research is further limited by small sample sizes, heterogeneous methodologies⁴⁵ and inadequate adjustment for key confounders such as diet, medications, and comorbidities.^16,18,19 Most available studies are cross-sectional, with limited longitudinal research to show changes over time, and insufficient evidence describing phenotype-specific alterations, particularly in HFmrEF.⁵⁶ Moreover, lack of systematic review has synthesized recent evidence (2021-2025) to provide an updated and comprehensive perspective. This gap limits the development of targeted microbiota-based therapies and hinders the translation of gut microbiome research into clinical HF management.

Implications
The evidence linking gut microbiome dysbiosis with HF underscores opportunities for therapeutic innovation. Depletion of SCFA producing taxa and enrichment of TMAO-producing bacteria suggest that dietary modulation, prebiotic and probiotic supplementation, and postbiotic therapies may help restore microbial balance and attenuate systemic inflammation.⁶⁷ Importantly, these findings also indicate that therapeutic strategies should target restoration of specific commensal genera such as Faecalibacterium and Roseburia, while reducing overgrowth of Klebsiella and Escherichia that drive TMAO production. Beyond clinical practice, these findings emphasize the importance of integrating cardiology, microbiology, and nutrition expertise to develop microbiota targeted strategies, supported by longitudinal studies and standardized methodologies.

Building on these insights, incorporation of microbiome profiling into HF risk assessment and disease monitoring could enable early identification of dysbiosis-related phenotypes, guiding personalized nutritional or probiotic interventions. Clinically, endpoints such as circulating TMAO concentrations, fecal SCFA levels, systematic inflammatory markers (e.g., IL-6, TNF-α), and echocardiographic measures of ventricular function should be considered in interventional trials to ensure measurable translational outcomes. Integration of gut microbial biomarkers alongside conventional cardiac indicators (NT-proBNP, troponins) could improve diagnostic precision and risk stratification in clinical cardiology. Furthermore, translation of microbiota-targeted therapies into clinical use will require harmonized regulatory and safety frameworks, particularly for high-impact interventions such as fecal microbiota transplantation.

At a broader level, health policies promoting fiber-rich, minimally processed diets may contribute to both prevention and management of HF through favorable effects on microbial ecology, while also providing measurable targets for population-based monitoring of cardiometabolic outcomes. Incorporating microbiome considerations into public health nutrition strategies could thus represent a sustainable approach to mitigating HF burden globally.

Recommendations
Future research should prioritize well-designed, large-scale, and longitudinal studies that address the current limitations in sample size, geographical diversity, and methodological heterogeneity observed in existing evidence on gut microbiota dysbiosis in HF.⁶⁸ Multi-center investigations incorporating participants from diverse ethnic and dietary backgrounds are essential to enhance the generalizability of findings.⁶⁹ Standardized protocols for sample collection, processing, and sequencing should be adopted to minimize technical variability and allow for robust cross-study comparisons.⁷⁰

In addition, mechanistic studies employing gnotobiotic or humanized animal models are needed to establish causal relationships between SCFA depletion, TMAO elevation, and HF progression. Identification of microbial gene clusters involving TMA/TMAO synthesis could facilitate the development of targeted inhibitors or CRISPR- based modulation strategies. Integrative multi-omics approaches, including metagenomics, metabolomics, and transcriptomics, are recommended to elucidate causal links between microbial composition, functional pathways, and HF progression, particularly focusing on key metabolites such as TMAO and SCFAs.⁷¹

In addition to compositional profiling, clinical trials should incorporate primary endpoints including reduction in plasma TMAO levels, restoration of SCFA-producing taxa abundance (Faecalibacterium, Roseburia, Bifidobacterium), improvements in systemic inflammation (e.g., reduction in IL-6, CRP), and cardiac outcomes such as left ventricular ejection fraction, NT-proBNP, and hospitalization rates. Subtype-specific analyses, especially in HFmrEF, remain a critical gap and should be addressed to better define phenotype-dependent microbial signatures.⁷²

Interventional studies exploring dietary modification, prebiotics, probiotics, synbiotics, or fecal microbiota transplantation should be rigorously designed to determine their therapeutic potential in restoring SCFA producing taxa (e.g., Faecalibacterium, Roseburia) and mitigating harmful microbial metabolites linked to adverse cardiovascular outcomes.⁷³ Furthermore, future studies should account for key confounding factors, including medication use, comorbidities, and lifestyle, to ensure reliable associations between gut dysbiosis and HF.⁷⁴ A more holistic investigation of the gut-heart axis, integrating environmental, metabolic, and immune determinants, will provide a foundation for the development of precise microbiota-targeted interventions in HF management.