Emerging science reveals that an imbalanced gut may do more than upset your stomach; it could be fueling heart failure, offering hope for new therapies that start with the microbiome.
Review: The role of the gut microbiota and metabolites in heart failure and possible implications for treatment. Image Credit: Alexander_P / Shutterstock
In a recent review published in the journal Heart Failure Reviews, researchers synthesized evidence from nearly 50 peer-reviewed publications investigating links between heart failure (HF) and gut dysbiosis – the imbalance in gut microbial composition.
Their findings reveal that gut dysbiosis creates a compromised “leaky” gut barrier, allowing bacterial toxins and harmful metabolites, such as trimethylamine N-oxide (TMAO), to enter the bloodstream. This, in turn, drives systemic inflammation and directly damages the heart, highlighting the importance of gut microbial health in cardiovascular outcomes. This emerging “gut-heart axis” provides a new framework for understanding cardiovascular disease (CVD), opening the door for novel treatments, from targeted diets to microbial therapies.
Background
Heart failure (HF) is a serious cardiovascular condition where the heart is incapable of pumping sufficient blood to meet the body’s needs. It is a concerning public health crisis, with surveillance reports highlighting the disease’s increasing global prevalence. Furthermore, HF often co-occurs with other cardiovascular diseases (CVDs; e.g., hypertension and ischemic heart disease), underscoring the need for improved mechanistic understanding of HF’s risk factors.
Decades of research have established modifiable behaviors (e.g., diet, sleep, and smoking) and non-modifiable factors (e.g., age) as being closely linked to HF incidence and progression. However, other contributors, such as the gut microbiome, remain less well understood.
While conventional wisdom restricted the gut microbiome’s functional influence to digestive processes, a growing body of literature suggests that gut health is systemically intertwined with cardiovascular wellness. This review synthesizes current scientific understanding of this “gut-heart axis,” exploring how an imbalanced microbiome can contribute to the development and progression of HF.
About the review
The present review aims to comprehensively collate and elucidate recent scientific research investigating associations between gut imbalance and HF outcomes, thereby informing clinicians and policymakers of alternative HF mitigation and management strategies, and potentially unravelling novel avenues for CVD treatment.
Study data were obtained from major scientific repositories, including PubMed, ScienceDirect, and Springer, using a custom search strategy. Only publications from the last 12 years (2013–2025) were included in the review to ensure relevance and timeliness. All publications were subjected to a rigorous screening process (title, abstract, and full text), with only those linking gut microbial mechanisms or metabolites to HF outcomes included in the synthesis.
Risk factors associated with increased risk for HF (HF = heart failure) derived from McDonagh et al. (2021)
Review findings
This review reveals a bidirectional cascade of unfortunate events that begins in the gut and culminates in HF. Specifically, HF patients experience reduced blood flow to the gut, compromising the latter’s (intestinal wall) integrity and resulting in a condition termed “leaky gut”. In this state, microbes and harmful metabolites experience unrestricted access to systemic circulation, allowing them to enter and cause system-wide inflammation, which aggravates CVDs and nearly all chronic diseases.
A key bacterial offender identified in the research is the lipopolysaccharide (LPS) component of the outer cell membrane of gram-negative bacteria. Studies show that when LPS enters the bloodstream, it binds to Toll-like receptor 4 (TLR4) on the surface of cardiac muscle cells, triggering a pro-inflammatory response and activating the NF-κB pathway, damaging cytokines like tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6), which contribute to cardiac fibrosis, adverse remodeling, and heart function degradation.
Microbial metabolites that enter the bloodstream during the leaky gut condition have also been implicated in potentially life-threatening CVD outcomes. The most notorious is trimethylamine N-oxide (TMAO), produced when certain gut bacteria (Firmicutes and Proteobacteria) digest nutrients like choline and carnitine (abundant in red meat, eggs, and fish).
TMAO has previously been strongly associated with several adverse CVD outcomes, including atherosclerosis, inflammatory pathways activation, endothelial dysfunction, impaired cardiac contractility, platelet aggregation, and activation of the NLRP3 inflammasome, promoting cardiac fibrosis. A few animal studies suggest potential cardioprotective effects of low-dose TMAO in very specific contexts, though the overwhelming evidence points to its harmful role in HF.
Immune cells are key mediators in this process: Protective Treg cells (regulated by gut bacteria like Bacteroides fragilis) are suppressed in HF, while pro-inflammatory Th17 cells (stimulated by bacteria like segmented filamentous bacteria) drive cardiac inflammation.
Beneficial metabolites (particularly short-chain fatty acids [SCFAs] like butyrate) are produced by commensal bacteria and exert protective effects by binding receptors (GPR41/43/109A), inhibiting histone deacetylase (HDAC), and stimulating IL-22 production via HIF-1α to enhance gut barrier integrity. However, HF patients consistently demonstrate depletions in bacterial populations (e.g., Bifidobacteria and Bacteroides) that produce these metabolites. These factors aggravate HF, thereby triggering a positive feedback loop of progressively exacerbating gut dysbiosis and deteriorating cardiovascular health.
A critical unanswered question remains whether these gut alterations initiate HF progression or result from established cardiac dysfunction. Trials have shown mixed results for microbiota interventions. A Phase II trial found that adding antibiotics (rifaximin) or probiotics (S. boulardii) to standard care did not significantly improve cardiac function; however, a small pilot study with S. boulardii alone showed an improved ejection fraction.
Early-stage research on natural phytochemicals (e.g., allicin from garlic) also indicates potential for modulating TMAO production.
Conclusions
This review establishes a robust, bidirectional link between gut dysbiosis and HF, shifting our interest from a purely cardiac issue to a multi-system disorder. It highlights that a compromised gut is not just a symptom, but a potential driver of disease progression. This new knowledge opens up novel therapeutic avenues that focus on leveraging gut-based interventions to help improve heart outcomes.
Dietary interventions, such as the Mediterranean and DASH diets, may represent the first applications of this knowledge. These diets are rich in fiber and low in animal products, which helps reduce the substrates for TMAO production and supports SCFA-producing bacteria. More direct microbial interventions are also under investigation, including prebiotics, probiotics, and fecal microbiota transplantation (FMT); however, FMT remains experimental, with mixed TMAO results in animals.
While many of these approaches are still in early stages, they represent a promising and highly personalized future for heart failure management, where treating the gut may become a standard part of routine cardiovascular care.