Dose-response meta-analysis of plasma TMAO and stroke: validated linear risk threshold at 3.0 μmol/L

Stroke, especially the ischemic type, remains a leading global cause of death and disability, with modifiable risk factors offering prevention opportunities. Trimethylamine N-oxide (TMAO), a gut-derived metabolite, promotes vascular damage and is linked to stroke risk. Although prior studies have explored dose-response relationships, clinically actionable thresholds remain undefined, limiting translational applications. This study aims to advance the field by quantifying a continuous dose-response relationship and determining a specific risk threshold, which is currently lacking, to inform preventive strategies.

This PRISMA-compliant meta-analysis included 11 observational studies (n = 7,556) and encompassed two components: an overall meta-analysis of 10 studies to compare admission TMAO levels, and a dose-response meta-analysis that was specifically applied to the subset of 4 studies with sufficient data across multiple exposure categories. We pooled standardized mean differences (SMD) for admission TMAO levels and modeled dose-response curves using restricted cubic splines (knots at 2.37/3.45/5.95 μmol/L). Heterogeneity was quantified using the I ²-statistic, sensitivity was assessed using alternative statistical models and dose scaling approaches, and publication bias was evaluated with Egger's test and the trim-and-fill method.

Stroke patients showed significantly higher TMAO vs. controls (SMD = 0.55, 95% CI: 0.35, 0.74; P < 0.00001). Linear dose-response relationship: Each 1 μmol/L TMAO increase raised stroke risk by 8.9% (OR = 1.089, 95% CI: 1.023-1.158; P = 0.007). Risk threshold: TMAO > 3.0 μmol/L significantly increases the risk (OR > 1) and warrants preventive intervention. Cumulative risk escalated: 0 → 5 μmol/L: 53% risk increase (OR = 1.53); 0 → 20 μmol/L: 448% risk increase (OR = 5.48); robustness confirmed by sensitivity analysis (I ² = 35.9%; Cochran Q, P = 0.154).

TMAO exhibits a linear, dose-dependent association with stroke risk, with ≥ 3.0 μmol/L serving as a critical threshold for clinical intervention.