A multi-omic study links gut bacteria, microbial metabolites, and changes in heart function, pointing to biological relationships that could reshape how researchers investigate heart failure progression.
Study: Gut microbiome shifts in chronic systolic heart failure are associated with disease severity and clinical improvement. Image Credit: Lightspring / Shutterstock
A recent study published in the journal Nature Cardiovascular Research suggests that alterations in the gut microbiome in chronic systolic heart failure (HF) due to nonischemic cardiomyopathy (NICM) are associated with disease severity and clinical improvement.
The researchers found that Bifidobacterium, some strains of which produced indole-3-propionic acid (IPA) in laboratory experiments, may play a role in HF. In particular, greater Bifidobacterium abundance was associated with milder disease and improved functional status, while higher circulating IPA and predicted microbial butyrate production were associated with milder HF measures.
HF patients experience considerable morbidity and an increased risk of death. The condition is becoming more prevalent, and disease trajectories vary, while the mechanisms underlying disease progression remain poorly understood. The gut microbiome contributes to several biological pathways, but its role in chronic HF remains unclear. Most previous studies were cross-sectional, with small sample sizes and limited functional profiling.
About the study
In the present study, researchers combined microbiome and host multi-omic profiling to explore the association between the gut microbiome and outcomes in chronic systolic HF. Metagenomic sequencing of stool samples revealed gut microbiome composition, while differential abundance analysis identified microbial changes associated with HF. Metabolomics assessed microbiome-derived metabolites, and gene set enrichment analysis (GSEA) identified HF-associated functional groups.
The study population comprised 59 adults with chronic HF due to NICM, enrolled between July 2018 and March 2020, along with 50 healthy participants from the existing integrated Personal Omics Profiling (iPOP) study. Patients with primary ischemic cardiomyopathy, complex congenital heart disease, treated diabetes, advanced kidney or liver disease, autoimmune disorders, active malignancies, or recent abdominal surgery were excluded. Recent use of probiotics, antibiotics, radiation, or chemotherapy was also excluded. NICM patients had markedly reduced left ventricular ejection fraction (LVEF), mild-to-moderate LV dilatation, and impaired right ventricular (RV) function. The HF cohort was generally clinically well compensated.
Longitudinal analyses were performed in a subset of patients. Twenty-six HF patients returned for repeat multi-omic profiling and clinical assessment after an average of six months, while the researchers obtained longer-term clinical follow-up data for 51 patients after an average of 27 months. These analyses identified gut microbiome signatures and immune and metabolic features linked to disease severity and clinical improvement.
The researchers assessed clinical outcomes based on heart transplantation, placement of a left ventricular assist device (LVAD), hospice care, or death. They determined clinical improvement based on the Kansas City Cardiomyopathy Questionnaire (KCCQ-23), New York Heart Association (NYHA) functional classes, and LVEF. For the six-month analysis, improvement was defined as a decrease of at least one NYHA class, an LVEF increase of at least 5%, or a KCCQ overall summary score increase of at least five points. They integrated laboratory, cytokine, microbiota, and microbial pathway data using machine learning to distinguish HF patients from healthy individuals.
Results
In the guts of HF patients, alpha diversity and anti-inflammatory microbes, including Bifidobacterium and SCFA-producing microbes, were depleted. HF patients also had lower levels of the Lachnospiraceae family and Anaerobutyricum, Anaerostipes, Blautia, and Lachnospira genera than healthy controls. The genera Prevotella and Sutterella, which have been linked to pro-inflammatory host responses, were enriched among HF patients.
Functional analysis showed that pathways associated with SCFA, methane, and L-arginine production, as well as formaldehyde detoxification, were downregulated in HF patients. HF patients also showed enrichment of pathways involved in pro-inflammatory lipopolysaccharide (LPS) generation. Altered L-arginine and ornithine pathways were linked to different microbiome-immune interactions in HF. These pathways are involved in gut barrier function, inflammation, and the production of nitric oxide and polyamines, but the study did not establish that changes in the microbiome directly altered their systemic production.
GSEA showed depletion of formaldehyde detoxification and fermentative pathways and enrichment of those associated with lipid metabolism and purine and folate nucleotide synthesis. Metagenomics predicted lower gut microbial production of propionate and butyrate in HF patients. Circulating SCFA concentrations did not differ between the HF and healthy groups. Overall, the gut microbial functional profile in HF favored lipid oxidation over anaerobic carbohydrate fermentation.
Higher Bifidobacterium counts were linked to clinical improvement, with IPA identified as a candidate mechanistic link. A subset of the tested Bifidobacterium strains produced IPA in vitro, while circulating IPA levels and non-oxidative pentose phosphate pathway activity were associated with milder HF. Greater Bifidobacterium abundance was associated with less LV enlargement and RV dysfunction, whereas Butyricimonas enrichment and increased levels of L-kynurenine and conjugated bile acids, including glycocholic acid, were associated with severe HF and poor clinical outcomes. Guanosine and adenosine synthesis pathways also tracked with greater HF severity.
At follow-up, 12 HF patients experienced poor clinical outcomes, whereas 14 individuals showed clinical improvement. The association between Bifidobacterium and circulating IPA was sensitive to outliers, and IPA concentrations can reflect metabolism across multiple microbial taxa, dietary substrate availability, and host handling.
In the study dataset, the integrated model accurately differentiated chronic HF patients from healthy individuals (area under the receiver operating characteristic curve [AUC] = 0.95). Digoxin was associated with the Ruminococcaceae family, an association probably driven by the beneficial commensal Faecalibacterium prausnitzii. The genus- and species-level associations were no longer significant after correction for multiple comparisons. The authors proposed that digoxin could influence microbiome composition, but whether such changes contribute to its clinical effects remains uncertain.
Conclusions and Future Directions
The findings indicate that SCFA-producing and anti-inflammatory gut microbes may be depleted, with enrichment of pro-inflammatory microbes, in chronic HF. Dietary fiber intake may influence gut SCFA production and contribute to some of the microbiome differences observed in HF, but the study did not test whether increasing fiber improves clinical outcomes. Larger studies are needed to establish causal associations.
Bifidobacterium abundance and IPA may represent potential biomarkers of chronic HF, with higher levels associated with milder disease and clinical improvement. In future studies, researchers could explore the potential benefits of Bifidobacterium probiotic supplementation on HF outcomes across diverse populations, and the mediating role of microbial mechanisms such as IPA production and bile acid metabolism.
The authors cautioned that the single-center cohort was relatively small and predominantly White, with men comprising most of the HF group, and was restricted to patients with NICM-related systolic HF who were generally clinically well compensated. Differences in stool collection methods, extensive medication use, and exclusion of treated diabetes and other serious comorbidities may limit generalizability. The observational associations also cannot establish that microbiome changes cause HF progression or recovery.
Journal reference:
Mamic, P., Shi, H., Zhou, W. et al. (2026). Gut microbiome shifts in chronic systolic heart failure are associated with disease severity and clinical improvement. Nature Cardiovascular Research. DOI: 10.1038/s44161-026-00854-y, https://www.nature.com/articles/s44161-026-00854-y