Gut microbiota-associated metabolite trimethylamine N-Oxide and the risk of stroke: a systematic review and dose-response meta-analysis

Aims: Several epidemiological studies have examined the association between trimethylamine N-Oxide (TMAO) and stroke risk; however, the results are still inconclusive. The purpose of this meta-analysis was to evaluate the relationship between TMAO concentrations and stroke risk.

Methods: PubMed, Scopus, Cochrane and ProQuest search engines were systematically searched up to 18 June 2019. All of the studies that evaluated the relationship between TMAO and stroke were included in the systematic review and eligible studies were included into the meta-analysis. Meta-regression and subgroup analysis were also employed to find the source of heterogeneity.

Results: Eight studies (two cross-sectional studies, two cohort studies, three case-control studies and one nested case-control study) with a total of 6150 participants were included in the meta-analysis. The overall result showed that being in the highest category of TMAO increased the odds of stroke by 68% (OR: 1.675; CI: 0.866-3.243; P = 0.047) and mean TMAO concentrations was 2.201 μmol/L higher in patients with stroke rather than non-stroke controls (weighted mean difference (WMD): 2.20; CI: 1.213-3.188; P < 0.001). Furthermore, we observed revealed a non-linear association between increased TMAO levels and increased odds of stroke (P- for nonlinearity < 0.001). In addition, visual inspection of the funnel plot revealed a significant asymmetry among studies examining the differences in TMAO in patients with stroke versus control group.

Conclusion: This is the first meta-analysis to show positive dose-dependent relations between circulating TMAO concentration and stroke risk. However, further interventional studies and long-term studies are needed to better explain causality.

Keywords: Dose-response analysis; Gut microbiota metabolite; Observational studies; Risk factor; Stroke; Trimethylamine N-oxide (TMAO).