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

  • Cell Metab. 2026 Feb 3;38(2):370-387.e10. doi: 10.1016/j.cmet.2025.12.017.
Ning Ding  1 ,  Hao Wu  1 ,  Yiming Hua  1 ,  Rui Hua  1 ,  Bolin Li  2 ,  Yifei Xie  1 ,  Ying Xiong  1 ,  Ting Bai  1 ,  Xue Shi  3 ,  Ting Shen  4 ,  Peining Liu  1 ,  Junhui Liu  5 ,  Xiao Yang  5 ,  Yu Xu  1 ,  Zixuan Meng  1 ,  Beidi Lan  6 ,  Juan Zhou  1 ,  Bing Liu  3 ,  John Y-J Shyy  7 ,  Zuyi Yuan  8 ,  Yue Wu  9 ,  Ting Li  10
Affiliations
  • 1. Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Molecular Cardiology, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China.
  • 2. Department of Cardiology, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, Sichuan 610014, China.
  • 3. BioBank, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
  • 4. Department of Cardiology, Beijing Anzhen Hospital, Beijing, China.
  • 5. Department of Clinical Laboratory, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 6. Department of Cardiovascular Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
  • 7. Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
  • 8. Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Molecular Cardiology, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China. Electronic address: [email protected].
  • 9. Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Molecular Cardiology, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China. Electronic address: [email protected].
  • 10. Department of Cardiovascular Medicine, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Molecular Cardiology, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China. Electronic address: [email protected].
PMID: 41638192 DOI: 10.1016/j.cmet.2025.12.017
Abstract

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.

Keywords
GPR109A; GSDME; STAT3; atrial fibrillation; isovaleric acid; microbiota; pyroptosis.
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