A team led by Professors Yuan Zuyi, Wu Yue, and Li Ting from the First Affiliated Hospital of Xi'an Jiaotong University (XJTU) published a research paper titled Gut Microbiota-Derived Isovaleric Acid Alleviates Atrial Fibrillation by Suppressing GSDME-Dependent Pyroptosis in Cell Metabolism, a top-tier international journal in the field of metabolism.

The study reveals a novel mechanism by which gut commensal bacteria regulate atrial cell pyroptosis through the metabolite isovaleric acid (IVA), thereby influencing the progression of atrial fibrillation (AF). This discovery provides potential microbial targets and metabolic intervention strategies for AF treatment.

Starting with multi-omics data from clinical cohorts, the research team examined the characteristics of gut microbiota and serum metabolites in AF patients. The results showed a significant reduction in Ruminococcus gnavus (R. gnavus) in the intestines of AF patients, along with markedly lower levels of the serum metabolite isovaleric acid.

Further validation using germ-free mouse models and microbiota transplantation experiments confirmed that supplementing R. gnavus or genetically engineered bacteria can significantly increase serum IVA levels and reduce susceptibility to AF.

Mechanistic studies revealed that isovaleric acid binds to the GPR109A receptor on the surface of atrial cardiomyocytes, inhibiting the cAMP/PKA/CREB signaling axis. This reduces the phosphorylation and nuclear translocation of STAT3, ultimately downregulating the expression of GSDME (a key execution protein of pyroptosis) and blocking atrial cardiomyocyte death.

This study is the first to systematically elucidate the molecular mechanism by which gut-derived isovaleric acid inhibits atrial cardiomyocyte pyroptosis and delays AF progression via the GPR109A-STAT3-GSDME signaling axis. It provides new biomarkers and intervention targets for preventing and treating AF, opening new avenues for precision therapy strategies based on gut microorganisms.