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

Ruminococcus gnavus abundance was reduced in patients with atrial fibrillation compared to controls.

• Finding was identified through integrated analysis of clinical cohorts and multiple animal models.
• R. gnavus suppresses the occurrence of AF and atrial fibrosis.
• The association was identified through gut microbiome profiling of clinical AF cohorts.

R. gnavus produces isovaleric acid (IVA), a leucine-derived branched-chain fatty acid, through a unique enzymatic pathway.

• R. gnavus metabolizes dietary leucine into IVA via its unique enzyme 2-oxoisovalerate ferredoxin reductase γ-subunit (vorC).
• IVA is classified as a branched-chain fatty acid.
• The vorC enzyme was identified as unique to R. gnavus in this metabolic pathway.

R. gnavus colonization reduced AF susceptibility and improved fibrosis-driven atrial remodeling in animal models.

• Studies used multiple animal models to assess AF susceptibility.
• R. gnavus colonization reduced both AF occurrence and atrial fibrosis.
• Effects were demonstrated in the context of fibrosis-driven atrial remodeling.

Exogenous IVA supplementation reduced AF susceptibility and improved atrial remodeling.

• Exogenous IVA supplementation recapitulated the protective effects of R. gnavus colonization.
• IVA supplementation reduced AF susceptibility in animal models.
• IVA improved fibrosis-driven atrial remodeling.

Microbiome-derived IVA activates G protein-coupled receptor 109A (GPR109A) on atrial cardiomyocytes.

• GPR109A was identified as the receptor mediating IVA's cardioprotective effects on atrial cardiomyocytes.
• GPR109A activation by IVA inhibited IL-6/STAT3 signaling.
• Receptor activation was identified as the upstream mechanistic step in IVA's protective pathway.

IVA inhibits IL-6/STAT3 signaling activation in atrial cardiomyocytes downstream of GPR109A.

• GPR109A activation by IVA led to inhibition of interleukin-6 (IL-6) and signal transducer and activator of transcription 3 (STAT3) signaling.
• STAT3 signaling suppression was identified as a key intermediate mechanistic step.
• This inhibition ultimately blocked GSDME-mediated pyroptosis.

IVA blocks gasdermin E (GSDME)-mediated pyroptosis through a STAT3-GSDME feedforward circuit.

• GSDME-dependent pyroptosis was identified as a mechanistic driver of AF.
• A STAT3-GSDME feedforward circuit was identified, whereby STAT3 promotes GSDME expression/activation.
• IVA disrupts this feedforward circuit by suppressing STAT3 activity.
• GSDME-mediated pyroptosis was blocked as the terminal effector mechanism.

Microbial metabolism of dietary leucine and production of IVA play pivotal roles in preventing AF onset and progression.

• The leucine-IVA-GPR109A-STAT3-GSDME axis represents a gut-heart signaling axis.
• Both AF onset and progression were implicated.
• The pathway links dietary intake (leucine) to gut microbial metabolism (R. gnavus/vorC) to cardiac outcomes.