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

Atrial fibrillation (AF), a common and clinically significant cardiac rhythm disturbance, is associated with gut microbial dysbiosis. However, the precise role of the microbiota and associated metabolism in this condition remain unclear. Through integrated analysis of clinical cohorts and multiple animal models, we identified an intestinal symbiont, Ruminococcus gnavus (R. gnavus), which suppresses the occurrence of AF and atrial fibrosis by producing the leucine-derived branched-chain fatty acid isovaleric acid (IVA). R. gnavus colonization or exogenous IVA supplementation reduced AF susceptibility and improved fibrosis-driven atrial remodeling. Mechanistically, R. gnavus metabolizes dietary leucine into IVA through its unique enzyme 2-oxoisovalerate ferredoxin reductase γ-subunit (vorC). Microbiome-derived IVA activates G protein-coupled receptor 109A (GPR109A) on atrial cardiomyocytes, inhibiting interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) signaling activation and blocking gasdermin E (GSDME)-mediated pyroptosis through a STAT3-GSDME feedforward circuit. These results reveal that the microbial metabolism of dietary leucine and the production of IVA play pivotal roles in preventing AF onset and progression.