Gut microbiota-dependent trimethylamine-N-oxide (TMAO) shows a U-shaped association with mortality but not with recurrent venous thromboembolism

INTRODUCTION Gut microbiota-dependent trimethylamine-N-oxide (TMAO) correlates with arterial thrombotic events including myocardial infarction and stroke, and mortality. However, the association of TMAO with recurrent venous thromboembolism (VTE) and mortality remains unknown. METHODS TMAO plasma levels were assessed by high performance liquid chromatography in 859 patients aged ≥65 years with acute VTE and categorized into low (6.57 μmol/L) based on the 25th and 75th percentile. Associations of TMAO with recurrent VTE, major or non-major bleeding, and mortality were investigated. RESULTS During a mean follow-up of 28 months, 106 patients developed recurrent VTE, 259 had major or non-major bleeding events, and 179 patients died. The risk of recurrent VTE did not differ significantly between patients with low, medium (adjusted subhazard ratio [SHR], 1.38; 95% confidence interval [CI], 0.81 to 2.36; p = 0.232) and high TMAO levels (SHR, 1.44; 95% CI, 0.80 to 2.58, p = 0.221). Compared with low TMAO levels, the adjusted hazard ratio [HR] for mortality was 0.68 (95% CI, 0.47 to 0.98, p = 0.039) in patients with medium TMAO levels and 1.02 (95% CI, 0.68 to 1.52, p = 0.922) in patients with high TMAO levels. Fractional polynomial Cox-regression confirmed a U-shaped association (adjusted p = 0.045), with the lowest mortality risk in patients with TMAO around 4 μmol/L. TMAO was not associated with major or non-major bleeding. CONCLUSION TMAO showed a U-shaped association with mortality in elderly patients with acute VTE and was not associated with recurrent VTE and major or non-major bleeding