Circulating trimethylamine N-oxide and cardiovascular, cerebral, and renal diseases including mortality: Umbrella review of published systematic reviews and meta-analyses

Abstract

Aims Several systematic reviews/meta-analyses of observational studies have demonstrated associations between circulating trimethylamine-N-oxide (TMAO) and cardiovascular, cerebral, and renal diseases, including mortality. However, causal roles for TMAO in these diseases are controversial. Interventions are lacking to show whether lowering TMAO in clinical trials could reduce the risks of these diseases. TMAO could still serve as a prognostic marker for the mentioned outcomes, but investigating this potential role requires robust methodologies. We conducted a systematic search and critical evaluation of published systematic reviews/meta-analyses in the field. Data synthesis We identified 27 systematic reviews/meta-analyses on the association between TMAO and stroke (n = 7), cardiovascular disease including cause-specific and/or all-cause mortality (n = 14), and other related outcomes (n = 6). The majority of the systematic reviews/meta-analyses found higher blood TMAO concentrations in patients who were positive for the outcomes. Primary studies included populations with multiple risk factors for the given outcomes and did not sufficiently account for potential confounders. Prospective studies examining associations between baseline TMAO and subsequent disease outcomes in healthy populations were entirely absent. Furthermore, we identified serious flaws in methods, conduct and reporting in the majority of the published systematic reviews/meta-analyses, thus leading to critically low confidence in the results. Conclusions High quality systematic reviews/meta-analyses examining the associations between TMAO and cardiovascular or cerebral disease are needed to examine potential causal and/or predictive roles of TMAO in these diseases. This study is registered at the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42024534940).