Gut Microbiota‐Derived Trimethylamine N‐Oxide and the Risk of Diabetes: An Updated Systematic Review and Meta‐Analysis

ABSTRACT Recent studies have discovered higher levels of circulating trimethylamine N‐oxide, a metabolite produced by gastrointestinal microbiota, among patients diagnosed with diabetes. This study presents an updated systematic review and meta‐analysis examining the association between trimethylamine N‐oxide levels and the risk of developing diabetes. PubMed and Scopus databases were searched for the studies published up to April 2024. Observational (cross‐sectional, case–control, and cohort) studies examining the relationship between TMAO levels and diabetes were included in our systematic review and meta‐analysis, excluding non‐original research, non‐human studies, and non‐English publications. Out of 1538 publications, 32 studies focusing on type 2 and gestational diabetes were included. We conducted two distinct meta‐analyses investigating the association between TMAO levels and type 2 diabetes. First, we found significantly elevated TMAO levels in diabetic patients compared to non‐diabetics (standardized mean difference [SMD]: 1.21, 95% confidence interval [CI]: 0.13–2.28). Second, we observed that elevated TMAO levels were associated with 49% increased odds of diabetes (odds ratio [OR]: 1.49, 95% CI: 1.06–2.10). However, the pooled hazard ratio (HR) analysis did not reveal a statistically significant association (HR: 1.00, 95% CI: 0.62, 1.61). Moreover, the included studies showed a higher type 2 diabetes prevalence in the elevated TMAO group. Regarding gestational diabetes, we also detected a positive correlation with TMAO levels. Our study indicates that individuals with type 2 diabetes have notably higher TMAO levels compared to non‐diabetics. Furthermore, our systematic review suggests an elevated risk of developing both type 2 diabetes and gestational diabetes in individuals with higher TMAO levels.