Gut microbiome tied to atrial fibrillation risk

Clinical takeaway: Plasma trimethylamine N-oxide (TMAO), already available as a cardiovascular risk test, was independently associated with atrial fibrillation. This adds to the case for discussing dietary sources like red meat with at-risk patients.

A gut-microbial byproduct of red meat and other animal foods already used as a cardiovascular risk marker known as TMAO has been tied to MI, stroke, and kidney disease. A new Cleveland Clinic study extends that reach to atrial fibrillation, the most common arrhythmia. In more than 5,000 patients undergoing cardiac evaluation, higher plasma TMAO tracked with existing AF independent of standard risk factors. Mouse experiments then pointed to a mechanism: TMAO appears to disrupt the heart's autonomic signaling.

Current AF care manages the rhythm rather than its causes, which remain only partly mapped. That gap is what makes a modifiable, diet-linked signal worth attention. TMAO, generated by gut microbes from choline and carnitine and long tied to cardiovascular events, was measured in the GeneBank cohort to see whether it associated with AF.

In the full cohort, patients in the top one-third of plasma TMAO had roughly 1.7 times the odds of prevalent AF versus the bottom third, after adjustment for age, sex, diabetes, cardiovascular disease, blood pressure, smoking, BMI, and C-reactive protein. The association held after further adjustment for kidney function, and choline and betaine showed the same independent pattern.

TMAO appears to drive AF by disrupting the heart's autonomic control. It mimics acetylcholine, so it blocked the heart's M2 muscarinic receptor in engineered cells, and choline-fed mice showed faster heart rates, pointing to a shift toward sympathetic tone. In two mouse models, a TMAO- or choline-rich diet brought on AF sooner and made it easier to induce, an 11-fold jump in one strain, and a gut-restricted drug that blocks microbial TMAO reversed the effect.

The human analysis drew on a repository of stable patients undergoing elective cardiac evaluation, with plasma TMAO, choline, and betaine measured by mass spectrometry and AF history taken at enrollment. The causal and mechanistic work came from two mouse models of AF and from engineered cells expressing the M2 receptor.

Gut-targeted inhibitors have been tested in animal models of atherosclerosis, thrombosis, and heart failure, but this is the first to apply one to AF. Potential drug candidates for this target have not been tried in humans for any cardiac indication. Human trials would need to show that lowering TMAO can translate into fewer cardiac events.

"Most current treatments for atrial fibrillation focus on managing the condition, but our findings suggest there may be an opportunity to intervene much earlier through diet," said Robert Koeth, MD, PhD, senior author and electrophysiologist at Cleveland Clinic.

Source: Arjunan S, et al. J Clin Invest. 2026 Jul 24. Gut microbial trimethylamine N-oxide generation promotes risk of atrial fibrillation via muscarinic receptor-mediated autonomic dysfunction