The gut-heart axis: fecal microbiome shifts following SGLT2 inhibitor initiation in heart failure - a pilot study
I Avivi, N Zmora, D Teshuva, O HavakukAbstract
Background
Heart failure (HF) is associated with gut dysbiosis, including reduced microbial diversity and depletion of beneficial bacteria that produce short-chain fatty acids (SCFAs), such as butyrate, which strengthen intestinal tight junctions.1,2 This dysbiosis may impair gut barrier function and promote systemic inflammation, potentially worsening HF.3 Modulation of the gut microbiome is therefore a plausible pathway for the beneficial effects of SGLT2 inhibitors in HF.
Purpose
To evaluate gut microbiome composition patterns following SGLT2 initiation in HF, and to assess correlations between microbiome alterations and clinical parameters.
Methods
Seven symptomatic HF patients were prospectively enrolled. Patients with recent antibiotic exposure or conditions known to affect microbiome composition were excluded. Stool samples were collected at baseline and at 3 months post–SGLT2i initiation and underwent 16S rRNA gene sequencing. Genus-level relative abundances were compared using paired t-tests. Beta-diversity (overall microbiome composition similarity between samples) was assessed by PCA and PERMANOVA. The primary clinical outcome was 6-minute walk test (6MWT) distance; correlations with bacterial abundances were evaluated using Spearman's correlation. NT-proBNP levels, echocardiography, and cardiopulmonary exercise testing were also performed at both timepoints.
Results
SGLT2i treatment significantly increased the abundance of two butyrate-producing genera: Lachnospiraceae group (p=0.010, increased in 7/7 patients) and Butyricicoccus (p=0.038, increased in 4/7, unchanged in 3/7) (Figure 1A). Overall microbiome composition remained stable (PERMANOVA p=0.99), indicating targeted enrichment rather than global disruption. 6MWT distance significantly improved from 295±65m to 363±57m (p=0.008). NYHA class improved in 5/7 patients (p=0.078). NT-proBNP and peak VO₂ responses were variable. Post-treatment abundances of Roseburia (ρ=0.86, p=0.014) and Lachnospiraceae NK4A136 group (ρ=0.79, p=0.036), both butyrate-producers, positively correlated with 6MWT distance (Figure 1B).
Conclusions
To our knowledge, this is the first study to demonstrate SGLT2i-associated microbiome changes in HF patients. SGLT2i treatment selectively enriched butyrate-producing gut bacteria and significantly improved functional capacity in HF patients. The parallel improvement in functional capacity and butyrate-producing bacteria suggests that gut microbiome modulation may represent an early mechanistic pathway contributing to SGLT2i benefit and should be further studied.Gut microbiome changes following SGLT2iFor image description, please refer to the figure legend and surrounding text.