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Background Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite produced from dietary nutrients. Many studies have discovered that circulating TMAO levels are linked to a wide range of health outcomes. Objectives This study aimed to summarize health outcomes related to circulating TMAO levels. Methods We searched Embase, Medline, Web of Science and Scopus databases from inception to 15 February 2022 to identify and update meta-analyses examining the associations between TMAO and multiple health outcomes. For each health outcome, we estimated the summary effect size, 95% prediction confidence interval (CI), between-study heterogeneity, evidence of small-study effects, and evidence of excess-significance bias. These metrics were used to evaluate the evidence credibility of the identified associations. Results This umbrella review identified 24 meta-analyses that investigated the association between circulating TMAO levels and health outcomes including all-cause mortality, cardiovascular diseases, diabetes mellitus, cancer, and renal function. We updated these meta-analyses by including a total of 82 individual studies in 18 unique health outcomes. Among them, 14 associations were nominally significant. After evidence credibility assessment, we found six (33%) associations (i.e., all-cause mortality, cardiovascular disease mortality, major adverse cardiovascular events, hypertension, diabetes mellitus, and glomerular filtration rate) to present highly suggestive evidence. Conclusions TMAO might be a novel biomarker related to human health conditions including all-cause mortality, hypertension, cardiovascular disease, diabetes, cancer and kidney function. Further studies are needed to investigate whether circulating TMAO levels could be an intervention target for chronic disease.

OBJECTIVE We conducted a Mendelian randomization (MR) study to examine the associations of type 2 diabetes and glycemic traits with gastrointestinal diseases (GDs). RESEARCH DESIGN AND METHODS Uncorrelated genetic variants associated with type 2 diabetes (n = 231), fasting insulin (n = 38), fasting glucose (n = 71), and hemoglobin A1c (n = 75) at the genome-wide significance were selected as instrument variables. Genetic associations with 23 common GDs were obtained from the FinnGen and UK Biobank studies and other large consortia. RESULTS Genetic liability to type 2 diabetes was associated with the risk of 12 GDs. Per 1-unit increase in the log-transformed odds ratio (OR) of type 2 diabetes, the OR was 1.06 (95% CI, 1.03–1.09) for gastroesophageal reflux disease, 1.12 (95% CI, 1.07–1.17) for gastric ulcer, 1.11 (95% CI, 1.03–1.20) for acute gastritis, 1.07 (95% CI, 1.01–1.13) for chronic gastritis, 1.08 (95% CI, 1.03–1.12) for irritable bowel syndrome, 1.04 (95% CI, 1.01–1.07) for diverticular disease, 1.08 (95% CI, 1.02–1.14) for acute pancreatitis, 1.09 (95% CI, 1.05–1.12) for cholelithiasis, 1.09 (95% CI, 1.05–1.13) for cholelithiasis with cholecystitis, 1.29 (95% CI, 1.17–1.43) for nonalcoholic fatty liver disease, 1.12 (95% CI, 1.03–1.21) for liver cirrhosis, and 0.93 (95% CI, 0.89–0.97) for ulcerative colitis. Genetically predicted higher levels of fasting insulin and glucose were associated with six and one GDs, respectively. CONCLUSIONS Associations were found between genetic liability to type 2 diabetes and an increased risk of a broad range of GDs, highlighting the importance of GD prevention in patients with type 2 diabetes.