Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor-mediated autonomic dysfunction.

Summary

In a 5,090-participant cardiac catheterization cohort, higher plasma TMAO was independently associated with prevalent AF. Across multiple AF mouse models, dietary TMAO/choline accelerated AF onset via muscarinic receptor 2–mediated autonomic dysfunction, while a gut microbial CutC/D inhibitor (iodomethylcholine) reduced TMAO and delayed AF. Optical mapping revealed slowed conduction, shortened APD80, and reduced wavelength; atrial remodeling included left atrial dilation.

Key Findings

• Plasma TMAO independently associated with prevalent AF in 5,090 subjects (adjusted OR 1.7, 95% CI 1.3–2.1; P<0.01).
• Dietary TMAO/choline accelerated AF onset in CREM-IbΔC-X mice and increased inducible AF in C57BL/6J mice.
• Iodomethylcholine (CutC/D inhibitor) lowered TMAO (P<0.0001) and delayed choline-induced AF onset (P<0.01).
• Optical mapping: reduced conduction velocity, shortened APD80, and decreased wavelength with choline supplementation.
• Proposed mechanism: TMAO inhibits muscarinic receptor 2, causing autonomic dysfunction that promotes AF.
• Cecal metagenomics showed AF-associated microbial shifts with choline, attenuated by IMC.

Clinical Implications

TMAO quantification may aid AF risk stratification; dietary choline moderation and microbiome-directed therapies (e.g., CutC/D inhibitors) merit clinical testing as preventive strategies. Autonomic monitoring could serve as a pharmacodynamic readout.

Limitations

• Human component is cross-sectional for prevalent AF, limiting causal inference.
• Mechanistic findings are preclinical; human interventional data are lacking.
• Potential dietary and lifestyle confounding in human analyses.

Future Directions

Conduct randomized trials of microbiome-targeted strategies (CutC/D inhibition, dietary choline modulation) on AF incidence/recurrence; validate M2 receptor signaling changes in humans; integrate autonomic phenotyping to personalize therapy.