Gut microbiota–derived metabolite trimethylamine-N-oxide and multiple health outcomes: an umbrella review and updated meta-analysis

Trimethylamine-N-oxide (TMAO) is a gut microbiota–derived metabolite produced from dietary nutrients. Many studies have discovered that circulating TMAO concentrations are linked to a wide range of health outcomes. This study aimed to summarize health outcomes related to circulating TMAO concentrations. We searched the 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 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. This umbrella review identified 24 meta-analyses that investigated the association between circulating TMAO concentrations and health outcomes including all-cause mortality, cardiovascular diseases (CVDs), diabetes mellitus (DM), cancer, and renal function. We updated these meta-analyses by including a total of 82 individual studies on 18 unique health outcomes. Among them, 14 associations were nominally significant. After evidence credibility assessment, we found 6 (33%) associations (i.e., all-cause mortality, CVD mortality, major adverse cardiovascular events, hypertension, DM, and glomerular filtration rate) to present highly suggestive evidence. TMAO might be a novel biomarker related to human health conditions including all-cause mortality, hypertension, CVD, DM, cancer, and kidney function. Further studies are needed to investigate whether circulating TMAO concentrations could be an intervention target for chronic disease. This review was registered at www.crd.york.ac.uk/prospero/ as CRD42021284730. ▪