Gut Failure: A Review of the Pathophysiology and Therapeutic Potentials in the Gut-Heart Axis

Heart failure (HF) is a global healthcare burden affecting approximately 64.3 million people worldwide. Despite advances in prevention, diagnosis, and treatment, HF remains a leading cause of cardiovascular morbidity and mortality and is a major driver of hospitalization in those over 65 years of age, with an estimated 5-year mortality around 50%. HF is a clinical syndrome due to structural or functional cardiac disease, presenting with congestion and reduced cardiac output leading to inadequate tissue perfusion. Modern pharmacotherapy largely targets the neurohormonal axis (renin–angiotensin–aldosterone system and sympathetic nervous system), yet mortality remains high, particularly after hospitalization. This has prompted investigations into alternative pathophysiological mechanisms, including the role of chronic low-grade inflammation and possible disruption of intestinal barrier integrity. The gut-heart axis has emerged as a plausible link between intestinal dysfunction and HF through deleterious effects of HF on intestinal physiology/microbiota and, reciprocally, gut-derived inflammation and metabolites that exacerbate cardiac dysfunction. This review outlines current evidence on gut-related mechanisms in HF and potential therapeutic interventions targeting the gut-heart axis.

Microbiota and SCFAs: The gastrointestinal tract hosts diverse microbes dominated by Firmicutes and Bacteroides. Microbiota confer metabolic and immunomodulatory benefits, including SCFA production (acetate, propionate, butyrate). SCFAs fuel colonocytes, contribute to systemic energy, and modulate blood pressure, glucose, lipids, and immune responses. In HF, studies show dysbiosis with increased pathogenic taxa (e.g., Proteobacteria) and depletion of SCFA-producing bacteria (e.g., Ruminococcaceae, Lachnospiraceae, Faecalibacterium, Eubacterium rectale, Dorea longicatena) across HF phenotypes (HFrEF and HFpEF). Failing hearts shift fuel preference toward SCFAs, ketones, and lactate; acetate extraction is increased (~20%) in HFrEF, and butyrate oxidation can outpace ketone oxidation, suggesting that low circulating SCFAs may worsen energy deficits in HF. TMAO: Dietary choline, phosphatidylcholine, betaine, and L-carnitine are converted by gut microbial lyases to TMA, then hepatic FMO3 generates TMAO. TMAO is proatherogenic and prothrombotic, promoting vascular inflammation (NLRP3 activation), platelet hyperreactivity, endothelial dysfunction, and mitochondrial derangements. Western diets raise TMAO; vegetarian patterns are associated with lower levels. Elevated TMAO predicts worse outcomes in chronic and acute HF, correlates with NYHA class and congestion metrics, and is more strongly associated with risk in some ethnic groups (notably Caucasian cohorts). Evidence suggests prognostic value differs between HFrEF and HFpEF cohorts. Amino acid metabolites: Tryptophan metabolism via kynurenine and indole pathways yields metabolites linked to inflammation and HF risk. Higher kynurenine/tryptophan ratios predict incident HF and correlate with reduced functional capacity and mortality in established HF. Indoxyl sulfate, a uremic toxin of the indole pathway, associates with impaired systolic and diastolic function and predicts cardiovascular events and rehospitalization. Intestinal barrier dysfunction: Microbiota changes, reduced SCFAs, and HF-related hemodynamics (hypoperfusion, congestion) impair epithelial integrity, increasing paracellular permeability and reducing transcellular absorption. Small intestinal bacterial overgrowth is prevalent in HF and predicts adverse outcomes. Large intestinal bacterial overgrowth and mucosal biofilms are increased in CHF. Sugar-probe tests demonstrate reduced D-xylose absorption and increased lactulose/mannitol and sucralose excretion, consistent with tight junction (occludin/claudin) dysfunction. Secondary bile acids at high colonic concentrations can damage membranes and increase permeability; in CHF, secondary/primary bile acid ratios are elevated, though prognostic value is uncertain after adjustment. Trophic and hemodynamic changes: HF reduces splanchnic arterial flow (30–43% in major mesenteric vessels), increases bowel wall thickness (correlating with permeability), and causes mucosal hypoperfusion (elevated intragastric pCO2 during exercise). Morphologic small-intestinal changes include collagen deposition and increased IEC–capillary distance, impairing nutrient exchange—changes worse in advanced HF and cachexia. Systemic inflammation: Barrier disruption permits LPS translocation, activating TLR4 and NF-κB signaling with TNF-α, IL-6, and other cytokine release. TNF-α contributes to adverse remodeling, contractile depression, endothelial apoptosis, nitric oxide dysregulation, and cachexia; levels correlate with HF severity. Endotoxemia and cytokine activation are higher in decompensated CHF and reduce with decongestion, though immune cell hypersensitivity may sustain cytokine production. Lipoproteins may buffer LPS activity (endotoxin–lipoprotein hypothesis). Reduced SCFAs promote proinflammatory signaling (e.g., butyrate suppresses NF-κB; acetate reduces IL-6/IL-17a; butyrate increases IL-22 and Tregs). Dysbiosis can drive T-cell overactivation, contributing to remodeling and fibrosis; pressure overload remodels microbiota in a T-cell–dependent manner. Population studies link inflammatory bowel disease to increased ischemic heart disease and HF hospitalization. Therapeutic strategies: Cardiovascular risk factor control remains foundational. From the cardiac standpoint, guideline-directed HF therapy, hemodynamic assessment (e.g., point-of-care ultrasound), and congestion biomarkers (BNP/NT-proBNP complemented by Bio-ADM, soluble CD146, CA125 for extravascular congestion) are emphasized. From the gut standpoint: dietary interventions (Mediterranean and DASH diets) increase SCFA producers and lower TMAO and tryptophan-kynurenine metabolites, reduce HF incidence, and improve function/quality of life in some studies; Western diets raise TMAO. Microbial enzyme inhibition (TMA lyase inhibitors like iodomethylcholine) reduces TMAO and improves cardiac remodeling in mice. FMO3 inhibition lowers TMAO and thrombosis potential and improves remodeling in animal HF models, though side effects (hepatic inflammation, trimethylaminuria) are concerns. Microbiota modulation with probiotics and prebiotics shows mixed human results (e.g., Saccharomyces boulardii trials conflicting; rifaximin neutral on LVEF), while animal data are more favorable, including reduced TMAO and attenuated post-MI remodeling. Anti-inflammatory approaches: anti-TNF agents were neutral/negative in large HF trials; IL-1 receptor blockade (anakinra) improved exercise capacity in HFpEF and showed signals in AHF, with longer-duration trials ongoing. Other immunomodulators (ursodeoxycholic acid, ER-β agonists) have variable or experimental evidence.

This is a narrative review of the literature on gut–heart axis mechanisms in heart failure. The manuscript synthesizes findings from experimental animal studies, observational human cohorts, and interventional trials (dietary, microbial enzyme inhibition, probiotics/prebiotics, antibiotics, and anti-inflammatory therapies). No formal systematic review protocol or meta-analytic methods are described.

- HF is associated with chronic low-grade systemic inflammation potentially originating from the gut via dysbiosis, barrier disruption, and endotoxin translocation, creating a vicious cycle with HF-related congestion and hypoperfusion. - Microbiota in HF show reduced SCFA-producing taxa (e.g., Faecalibacterium, Ruminococcaceae, Lachnospiraceae) and increased pathogenic species (e.g., Proteobacteria). SCFAs provide up to ~10% of daily energy intake and have cardiometabolic and anti-inflammatory effects; failing hearts increase reliance on SCFAs (e.g., ~20% higher acetate extraction in HFrEF). - Elevated TMAO, generated from microbial metabolism of choline/carnitine and hepatic FMO3 oxidation, predicts mortality in CHF and adverse outcomes in AHF; levels correlate with NYHA class and congestion indices and are influenced by Western diets. - Amino acid–derived metabolites: higher kynurenine/tryptophan ratios predict incident HF and worse outcomes; indoxyl sulfate associates with systolic/diastolic dysfunction and increased CV events/rehospitalizations. - Intestinal barrier dysfunction in HF is evidenced by decreased D-xylose absorption and increased lactulose/mannitol and sucralose excretion, indicating tight junction impairment; small intestinal bacterial overgrowth is common and predicts outcomes across EF ranges; splanchnic flow is reduced by ~30–43% in HFrEF, and bowel wall thickness correlates with permeability. - Endotoxin (LPS) translocation activates TLR4/NF-κB signaling, increasing TNF-α and IL-6; decongestion lowers endotoxin, but cytokine levels may persist due to immune cell hypersensitivity; lipoproteins may buffer LPS. - Therapeutic potentials: Mediterranean and DASH diets associate with reduced HF incidence and improved function; TMA lyase and FMO3 inhibition reduce TMAO and improve remodeling in animals; probiotics/prebiotics show TMAO reduction and HF attenuation in animals but mixed human results; antibiotics may reduce intestinal LPS/cytokines but have not improved LVEF; IL-1 blockade shows promise for functional improvement, whereas anti-TNF has been neutral/negative in HF.

The compiled evidence supports a bidirectional gut–heart axis in which HF-induced hemodynamic derangements (congestion, hypoperfusion) impair intestinal barrier function and alter microbiota, promoting endotoxemia and systemic inflammation that worsen myocardial function and remodeling. Dysbiosis favors reduced SCFA production and increased harmful metabolites like TMAO and indoxyl sulfate, which contribute to vascular inflammation, thrombosis, and cardiac dysfunction. The findings reinforce the plausibility that targeting upstream gut luminal processes (dietary composition, microbial enzymes), barrier integrity, and early inflammatory signaling could mitigate HF progression. Translational implications include using diet to increase SCFA producers and reduce TMAO, enzymatic strategies (TMA lyase, FMO3) to blunt harmful metabolite generation, and selective immunomodulation (e.g., IL-1 blockade). However, human interventional data remain heterogeneous, with some neutral trials (anti-TNF, rifaximin, mixed probiotic results), underscoring the need for better patient selection, multi-target strategies, and robust biomarkers that reflect both intravascular and extravascular congestion and gut-derived inflammation.

HF and gut dysfunction are interlinked through complex, mutually reinforcing mechanisms involving dysbiosis, SCFA depletion, harmful metabolites (e.g., TMAO, indoxyl sulfate), intestinal barrier disruption, and systemic inflammation. While HF likely initiates many of these changes via congestion and hypoperfusion, gut-derived pathways may also precede and exacerbate cardiovascular disease. Future progress requires large, well-designed human studies that concurrently assess luminal composition, barrier integrity, and systemic inflammatory markers to clarify causal sequences and identify optimal targets. Ultimately, a multifaceted therapeutic approach—combining guideline-directed HF therapy with tailored gut-focused interventions (diet, microbial enzyme modulation, barrier support, and selective immunomodulation)—may improve HF outcomes.

- Narrative review without a formal systematic search or meta-analysis; potential selection bias of included evidence. - Heterogeneity of human studies (populations, HF phenotypes, endpoints) and limited sample sizes in several trials. - Conflicting or neutral results for some interventions (e.g., anti-TNF agents, rifaximin, Saccharomyces boulardii), limiting generalizability. - Dietary intake data are often lacking in cardiovascular studies, complicating interpretation of microbiota/metabolite associations. - Ethnic and dietary differences influence metabolite levels (e.g., TMAO), affecting external validity. - Adverse effect concerns for certain targets (e.g., FMO3 inhibition causing hepatic inflammation and trimethylaminuria) may limit clinical application.