The association between trimethylamine N-oxide levels and ischemic stroke occurrence: a meta-analysis and Mendelian randomization study

Background Trimethylamine-N-oxide (TMAO), an intestinal microbiota-derived choline metabolite, has been found to be associated with ischemic stroke (IS) in more and more studies. However, the causal role of TMAO on IS occurrence remains perplexing.Methods We comprehensively screened the related clinical studies on PubMed, Web of Science, and Embase. Case-control and cohort studies that reported the TMAO levels of both IS patients and healthy controls were included, and the risk of bias was assessed according to the criteria by the Centre for Evidence-Based Medicine in Oxford, UK. A meta-analysis of the retrieved publications was performed with a random-effect model to analyze the connection between TMAO levels and IS events. Besides, a Mendelian randomization (MR) analysis was performed to study the causal effect of TMAO on IS, with pooled data of TMAO and IS obtained from genome-wide association studies (GWAS). The following methods were used: MR-Egger, weighted median, inverse-variance weighted, simple mode, and weighted mode. The study has been registered in INPLASY (Registration number: INPLASY2023100027).Results Eight cohort or case-control studies covering 2444 cases and 1707 controls were identified. The pooled data indicated that the IS patients tended to have higher TMAO levels compared with the controls (mean difference: 1.97 mu M; 95% confidence interval [CI]: 0.87, 3.07; P = 0.0005), while distinctive heterogeneity (I-2 = 96%, P < 0.00001) was observed. Sub-group analysis revealed that the heterogeneity of the studies might be derived from the studies themselves. However, no causal effect of TMAO on IS was observed (P > 0.05) in the Mendelian randomization analysis of this study.Conclusion We confirmed that IS patients tend to have higher TMAO levels than healthy individuals, while our findings of MR analysis did not support the causal role of TMAO in IS occurrence. Therefore, more studies are required for a better understanding of the relationship between TMAO levels and IS onset.