Gut microbiota-derived trimethylamine N-oxide is associated with the risk of all-cause and cardiovascular mortality in patients with chronic kidney disease: a systematic review and dose-response meta-analysis

BACKGROUND: Trimethylamine N-oxide (TMAO) derived from gut microbiota causes kidney-heart damage in chronic kidney disease (CKD) patients. However, it is controversial whether CKD patients with higher TMAO are associated with a higher risk of death. We aimed to assess the correlation between circulating TMAO concentration and the risk of all-cause and cardiovascular death in CKD patients of different dialysis statuses and different races by dose-response analyses, and the underlying mechanisms were also explored by analyzing the correlations of TMAO with glomerular filtration rate (GFR) and inflammation. METHOD: PubMed, Web of Science, and EMBASE were systematically searched up to 1 July 2022. A total of 21 studies involving 15,637 individuals were included. Stata 15.0 was used to perform the meta-analyses and dose-response analyses with extracted data. Subgroup analyses were conducted to recognize possible sources of heterogeneity. RESULTS: The risk of all-cause mortality was increased in non-dialysis CKD patients (RR = 1.26, 95%CI = 1.03–1.54, p = 0.028) and non-black dialysis patients (RR = 1.62, 95%CI = 1.19–2.22, p = 0.002) with the highest circulating TMAO concentration, and the association was confirmed to be linear. In addition, an increased risk of cardiovascular mortality was also found in non-black dialysis patients with the highest circulating TMAO concentration (RR = 1.72, 95%CI = 1.19–2.47, p = 0.004), likewise, a linear association was identified. However, for dialysis patients including blacks with high TMAO concentrations, there was no significant increase in either all-cause mortality (RR = 0.98, 95%CI = 0.94-1.03, p = 0.542) or cardiovascular mortality (RR = 0.87, 95% CI = 0.65–1.17, p = 0.362). Meanwhile, we verified strong correlations between TMAO and both GFR (r= −0.49; 95% CI= −0.75, −0.24; p < 0.001) and inflammatory markers (r = 0.43; 95% CI= 0.03, 0.84; p = 0.036) in non-dialysis patients. CONCLUSIONS: Increased circulating TMAO concentrations increase the risk of all-cause mortality in non-dialysis and non-black dialysis CKD patients. Moreover, elevated TMAO levels raise the cardiovascular mortality risk in non-black dialysis patients. KEY MESSAGES: 1. Non-dialysis and non-black dialysis CKD patients with higher circulating TMAO concentrations are associated with an increased risk of all-cause mortality. 2. Non-black dialysis patients with higher concentrations of TMAO are associated with an increased risk of cardiovascular mortality. 3. Circulating TMAO concentrations have a strong negative correlation with GFR and a positive correlation with inflammation biomarkers in non-dialysis CKD patients.