Gut microbiota-derived isovaleric acid alleviates atrial fibrillation by suppressing GSDME-dependent pyroptosis.

Summary

Across clinical cohorts and animal models, Ruminococcus gnavus–derived isovaleric acid reduced atrial fibrillation susceptibility and atrial fibrosis. IVA activates GPR109A on atrial cardiomyocytes, dampening IL-6/STAT3 signaling and blocking GSDME-dependent pyroptosis, thereby interrupting a STAT3–GSDME feedforward loop.

Key Findings

• R. gnavus colonization or exogenous isovaleric acid reduced AF susceptibility and atrial fibrosis in vivo.
• R. gnavus converts dietary leucine to isovaleric acid via the enzyme vorC (2-oxoisovalerate ferredoxin reductase γ-subunit).
• Isovaleric acid activates GPR109A on atrial cardiomyocytes, suppresses IL-6/STAT3 signaling, and blocks GSDME-dependent pyroptosis.

Clinical Implications

While not practice-changing yet, the data support clinical exploration of IVA supplementation, targeted probiotics (e.g., R. gnavus), or GPR109A agonism as novel anti-arrhythmic strategies and biomarkers linking diet–microbiome–AF risk.

Limitations

• Lack of interventional human trials; translational efficacy and safety of IVA or probiotics remain unproven.
• Dose–response, long-term effects, and generalizability across diverse AF phenotypes are not established.

Future Directions

Conduct early-phase trials of IVA supplementation or targeted probiotics; evaluate selective GPR109A agonists; longitudinally link dietary leucine–IVA axis to AF outcomes and patient subphenotypes.