Gut microbe–generated metabolite trimethylamine N‐oxide and the risk of diabetes: A systematic review and dose‐response meta‐analysis

Summary Elevated circulating concentrations of the gut bacteria choline metabolite trimethylamine N ‐oxide (TMAO) were found in patients with type 2 diabetes mellitus (T2DM). However, whether a high level of TMAO is related to the risk of diabetes has not been studied. We aimed to synthesize the evidence on the relation between TMAO levels and the risk of diabetes mellitus (DM) and to investigate the association further in a dose‐response meta‐analysis. PubMed, Web of Science, and Scopus databases were searched for studies from inception to June 2018. A total of 12 clinical studies were included in this study, and 15 314 enrolled subjects were included. A meta‐analysis of two‐class variables and continuous variables were used to obtain pooled effects. Dose‐response meta‐analysis was used to investigate the dose‐response relationship between TMAO concentrations and the risk of DM. Meta‐regression and subgroup analyses were applied to identify the source of heterogeneity in this study. High levels of circulating TMAO were associated with an increased risk of DM (odds ratio [OR] = 1.89) using the two‐class meta‐analysis. Plasma levels of TMAO in patients with diabetes were higher than in subjects without diabetes (standardized mean difference [SMD]: 0.36) using a meta‐analysis of continuous variables. The OR for DM prevalence increased by 54% per 5 μmol L −1 increment of plasma TMAO (OR = 1.54) according to the dose‐response meta‐analysis. This is the first systematic review and meta‐analysis to demonstrate a positive dose‐dependent association between circulating TMAO levels and increased diabetes risk.