A recent study published in The Journal of Clinical Investigation suggests that trimethylamine N-oxide (TMAO), a compound produced when gut microbes convert nutrients such as choline into trimethylamine (TMA) and subsequently oxidized in the liver, is independently associated with prevalent atrial fibrillation (AF) in humans. The findings, released on Jul. 27, are based on a cohort of 5,090 individuals and complementary mouse experiments.
Researchers quantified TMAO, choline, and betaine levels in plasma samples from individuals undergoing elective cardiac catheterization at the Cleveland Clinic GeneBank. Those with recent myocardial infarction or elevated troponin I were excluded from the analysis. Using logistic regression models that accounted for age, sex, smoking habits, comorbidities, high-sensitivity C-reactive protein levels, and estimated glomerular filtration rate, the team found that higher plasma concentrations of TMAO were significantly associated with AF prevalence. The adjusted odds ratio comparing the highest to lowest concentration tertile for TMAO was 1.7.
In mouse models genetically engineered to express a variant of the human cyclic adenosine monophosphate response element modulator gene (CREM-IbΔC-X), animals fed diets supplemented with TMAO or choline developed AF earlier than those on standard chow diets. These mice also showed increased plasma TMAO levels after choline supplementation but did not display significant differences in body mass or notable liver pathologies compared to controls.
Further experiments demonstrated that inhibiting muscarinic receptor 2 signaling by TMAO may disrupt autonomic regulation of heart rhythm. Mice receiving TMAO supplementation had an eleven-fold increase in AF inducibility compared with controls during transesophageal pacing studies. Choline supplementation led to increased left atrial size at five and eight weeks; treatment with iodomethylcholine attenuated this enlargement at eight weeks.
The study also explored changes in gut microbiome composition related to dietary interventions and observed that reducing microbial conversion of choline to TMA decreased subsequent formation of circulating TMAO. However, researchers noted limitations: no human dietary intervention was tested; all mechanistic findings came from animal or cell studies; and recurrence following intervention withdrawal was not examined.
The authors concluded that their preclinical findings support further clinical investigation into strategies aimed at lowering circulating TMAO as potential approaches for preventing atrial fibrillation.
