Jie Dong, Lei Chen, Nan Zheng, Ming Yang
Circulating TMAO is significantly associated with increased AF risk, with the magnitude of risk markedly augmented in the postoperative cardiac surgery setting,positioning TMAO as a context-dependent biomarker that requires interventional evidence before being considered a target for gut microbiota-directed interventions.
OBJECTIVE: To quantify the association between circulating trimethylamine N-oxide (TMAO) and atrial fibrillation (AF) risk and determine how this association is modified by clinical background.
METHODS: We performed a systematic review and meta-analysis by searching PubMed, Web of Science, EMBASE, Scopus, and ProQuest for studies published up to April 2026. Studies reporting quantitative associations between circulating TMAO levels and AF outcomes were included. Meta-analytic pooling of odds ratios (ORs) and hazard ratios (HRs) was conducted using R packages meta under random-effects models. Pre-specified subgroup analyses were performed by clinical setting and AF outcome type. Heterogeneity was quantified using I2 statistics and τ 2, with influence diagnostics and assessment of publication bias using Galbraith plots, Baujat plots, and Egger's test.
RESULT: Of the 15 included studies, 9 were included in the quantitative meta-analysis, comprising 8 odds-ratio and 2 hazard-ratio studies with one overlapping. The random-effects meta-analysis of the eight odds ratio studies demonstrated a significant positive association between TMAO and AF (pooled OR 1. 35, 95% CI 1. 15-1. 59, p = 0. 0003). Substantial heterogeneity was observed (I2 = 68.3%, p = 0Subgroup analysis revealed that only 1 of the 8 studies (12. 5%) reported postoperative AF after cardiac surgery, in which the association was significantly stronger (OR 2. 88, 95% CI 1. 35-6. 15) compared with spontaneous incident AF (pooled OR 1. 31, 95% CI 1. 12-1. 52; between-group p = 0. 045). A trim-and-fill sensitivity analysis adjusting for potential publication bias attenuated the pooled estimate (OR 1.18, 95% CI 0.95-1.47). Analysis of two studies reporting hazard ratios showed extreme heterogeneity (I2 = 92.5%) precluding a reliable pooled estimate.
CONCLUSION: Circulating TMAO is significantly associated with increased AF risk, with the magnitude of risk markedly augmented in the postoperative cardiac surgery setting,positioning TMAO as a context-dependent biomarker that requires interventional evidence before being considered a target for gut microbiota-directed interventions.