Trimethylamine N-oxide and major adverse cardiac and cerebrovascular events: results of umbrella review and meta-analysis.

BACKGROUND: Circulating trimethylamine N-oxide (TMAO) may be a causal factor or marker for major adverse cardiac and cerebrovascular events (MACE), but evidence in humans is limited to observational studies with inherent uncertainties. METHODS: We conducted an umbrella systematic review and meta-analysis of human studies. The search in MEDLINE, Web of Science, Cochrane Library and PROSPERO (last updated in February 2025) identified 120 publications that met our inclusion criteria. RESULTS: The pooled hazard ratio (HR) and 95% confidence intervals (95%CIs) from 34 cohort studies on TMAO and MACE = 1.20 (1.12-1.27), the prediction interval (PI) was 0.93-1.54, and I2 = 73.3%. After correction for publication bias (p < 0.001 Egger's test), the pooled HR (95%CIs) was 1.10 (1.03-1.17). The pooled odds ratio (95%CIs) from 18 case-control studies after accounting for publication bias was 1.05 (0.94-1.18). As a diagnostic test, the estimated pooled area under the curve (95%CIs) for TMAO was 72.8 (68.8-77.1)%, PI = 54.7%-97.1%, I2 = 93.8%, n = 24 studies. The mean (95%CIs) sensitivity and specificity of TMAO were 65.3 (56.1-74.5)% and 79.0 (65.4-92.6)%, respectively. The data did not suggest a threshold for elevated TMAO concentrations. CONCLUSIONS: Previously reported association estimates between TMAO and MACE in human studies are systematically overestimated. The results do not support TMAO being a causal factor or marker of MACE and related conditions. Harmonisation of TMAO measurements between labs and cohort studies in healthy people that address confounding factors remain critically needed.