Current Understanding of Gut Microbiota in Heart Failure

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Current Understanding of Gut Microbiota Alterations and Related Therapeutic Intervention Strategies in Heart Failure

Heart failure, the terminal stage of various cardiovascular diseases, represents a significant global health burden with high morbidity and mortality. Despite advancements in treatment, outcomes remain suboptimal, necessitating novel therapeutic approaches. Emerging evidence highlights the gut microbiota as a critical player in cardiovascular pathophysiology, particularly in heart failure. This review synthesizes current knowledge on gut microbiota alterations in heart failure and explores therapeutic strategies targeting this microbial ecosystem.

The Gut Microbiota: Composition and Physiological Roles

The human gut harbors over 10 14 microorganisms, collectively termed the gut microbiota, which comprises more than 2,000 bacterial species. Dominant phyla include Bacteroidetes and Firmicutes, with smaller contributions from Proteobacteria, Actinobacteria, and Verrucomicrobia. This microbial community performs essential functions, including nutrient metabolism, immune regulation, and maintenance of intestinal barrier integrity. Through fermentation of dietary fibers, gut bacteria produce short-chain fatty acids (SCFAs) like acetate, propionate, and butyrate, which serve as energy sources for colonocytes and modulate systemic inflammation. The gut microbiota also metabolizes host-derived compounds, such as bile acids (BAs), and dietary components like choline and L-carnitine into bioactive molecules that influence distant organs, including the heart.

Gut Microbiota Dysbiosis in Heart Failure

High-throughput sequencing technologies, including 16S rRNA and metagenomic analyses, have revealed distinct gut microbial signatures in heart failure patients compared to healthy individuals. Key findings include:

  1. Reduced Microbial Diversity: Patients with heart failure exhibit decreased richness of beneficial bacteria, particularly SCFA-producing taxa. For instance, Faecalibacterium prausnitzii (a major butyrate producer) and Eubacterium rectale are significantly depleted.
  2. Enrichment of Pathogenic Taxa: Increased abundances of Candida, Campylobacter, and Shigella species correlate with disease severity. Metagenomic studies also report elevated microbial genes involved in lipopolysaccharide (LPS) biosynthesis and trimethylamine (TMA) production.
  3. Age-Related Shifts: Older heart failure patients show more pronounced reductions in butyrate-producing bacteria compared to younger cohorts, suggesting age exacerbates dysbiosis.

These alterations disrupt gut barrier function, promote systemic inflammation, and contribute to metabolic derangements central to heart failure progression.

Mechanisms Linking Gut Dysbiosis to Heart Failure

Bacterial Translocation and “Leaky Gut”

Chronic heart failure reduces cardiac output, leading to intestinal hypoperfusion and mucosal edema. This “intestinal ischemia” disrupts the epithelial barrier, increasing permeability (“leaky gut”) and enabling bacterial translocation. Endotoxins like LPS enter systemic circulation, activating Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors. This triggers a pro-inflammatory cascade, elevating cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which exacerbate myocardial remodeling and dysfunction.

Metabolic Pathways

  1. Trimethylamine N-Oxide (TMAO) Pathway:
    Dietary choline and L-carnitine are metabolized by gut microbes (e.g., Clostridium species) into TMA, which is oxidized in the liver to TMAO. Elevated plasma TMAO levels correlate with adverse outcomes in heart failure, including increased 5-year mortality and worse New York Heart Association (NYHA) functional class. TMAO promotes fibrosis, diastolic dysfunction, and adverse ventricular remodeling.
  2. Short-Chain Fatty Acids (SCFAs):
    Depletion of SCFA-producing bacteria reduces anti-inflammatory signaling. Butyrate, for example, enhances gut barrier integrity via hypoxia-inducible factor (HIF) activation and suppresses inflammation by promoting regulatory T-cell differentiation. Low SCFA levels in heart failure may thus exacerbate intestinal and systemic inflammation.
  3. Bile Acid (BA) Metabolism:
    Gut bacteria deconjugate primary BAs into secondary BAs, which regulate host metabolism through farnesoid X receptor (FXR) signaling. Heart failure patients exhibit an increased secondary-to-primary BA ratio, linked to reduced survival. Dysregulated BA metabolism may impair lipid homeostasis and contribute to cardiac fibrosis.
  4. Uremic Toxins:
    In cardiorenal syndrome, gut microbiota-derived uremic toxins (e.g., indoxyl sulfate) stimulate cardiac fibroblast activation and collagen deposition via mitogen-activated protein kinase (MAPK) pathways, accelerating myocardial stiffening.

Therapeutic Interventions Targeting the Gut Microbiota

Dietary Modulation

High-fiber diets increase SCFA production, attenuating hypertension and myocardial fibrosis in animal models. The Dietary Approaches to Stop Hypertension (DASH) and Mediterranean diets are associated with improved outcomes in heart failure patients, likely via microbiota-mediated mechanisms. For example, acetate supplementation in hypertensive mice restored gut Bifidobacterium levels and reduced cardiac hypertrophy.

Probiotics and Prebiotics

Probiotics (live beneficial bacteria) and prebiotics (microbiota-fermentable fibers) show promise in preclinical and clinical studies:

  • Lactobacillus rhamnosus GR-1 improved left ventricular function and reduced hypertrophy in post-infarction rats.
  • Saccharomyces boulardii supplementation in heart failure patients increased left ventricular ejection fraction (LVEF) and reduced left atrial diameter.
  • Prebiotics like oligofructose enhance Bifidobacterium growth, which correlates with lower inflammation and improved metabolic parameters.

Antibiotics

Selective digestive decontamination (e.g., polymyxin B/tobramycin) reduces circulating endotoxins and inflammatory markers in heart failure patients. However, broad-spectrum antibiotics risk further dysbiosis and are not recommended for long-term use.

Fecal Microbiota Transplantation (FMT)

FMT from healthy donors restores microbial diversity and metabolic function. While effective for Clostridium difficile infection, its role in heart failure remains exploratory. Challenges include standardization of donor selection, dosing, and potential pathogen transmission.

Inhibitors of Microbial Metabolite Production

3,3-Dimethyl-1-butanol (DMB), a choline analog, inhibits microbial TMA lyases, reducing TMAO levels. In animal models, DMB attenuated atherosclerosis and may similarly benefit heart failure, though clinical trials are pending.

Conclusions and Future Directions

Gut microbiota dysbiosis is a hallmark of heart failure, characterized by loss of SCFA producers, enrichment of pathobionts, and altered metabolic pathways. Bacterial translocation and metabolites like TMAO and LPS drive inflammation and remodeling, while SCFA deficiency impairs barrier function and immune regulation. Therapeutic strategies—ranging from dietary interventions to microbiota transplantation—aim to restore symbiosis and improve outcomes.

Future research should prioritize large-scale, longitudinal studies to establish causality between specific microbial taxa and heart failure phenotypes. Elucidating the mechanisms of microbial metabolites and refining personalized therapies (e.g., genetically engineered probiotics) will be critical. Integrating multi-omics data (metagenomics, metabolomics) with clinical parameters may yield novel biomarkers and precision treatments for this complex syndrome.

https://doi.org/10.1097/CM9.0000000000000330

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