Trimethylamine N-oxide is associated with long-term mortality risk: the multi-ethnic study of atherosclerosis

Abstract

Aims: Little is known about associations of trimethylamine N-oxide (TMAO), a novel gut microbiota-generated metabolite of dietary phosphatidylcholine and carnitine, and its changes over time with all-cause and cause-specific mortality in the general population or in different race/ethnicity groups. The study aimed to investigate associations of serially measured plasma TMAO levels and changes in TMAO over time with all-cause and cause-specific mortality in a multi-ethnic community-based cohort.

Methods and results: The study included 6,785 adults from the Multi-Ethnic Study of Atherosclerosis. TMAO was measured at baseline and year 5 using mass spectrometry. Primary outcomes were adjudicated all-cause mortality and cardiovascular disease (CVD) mortality. Secondary outcomes were deaths due to kidney failure, cancer, or dementia obtained from death certificates. Cox proportional hazards models with time-varying TMAO and covariates assessed the associations with adjustment for sociodemographics, lifestyles, diet, metabolic factors, and comorbidities. During a median follow-up of 16.9 years, 1704 participants died and 411 from CVD. Higher TMAO levels associated with higher risk of all-cause mortality [hazard ratio (HR): 1.12, 95% confidence interval (CI): 1.08-1.17], CVD mortality (HR: 1.09, 95% CI: 1.00-1.09), and death due to kidney failure (HR: 1.44, 95% CI: 1.25-1.66) per inter-quintile range, but not deaths due to cancer or dementia. Annualized changes in TMAO levels associated with higher risk of all-cause mortality (HR: 1.10, 95% CI: 1.05-1.14) and death due to kidney failure (HR: 1.54, 95% CI: 1.26-1.89) but not other deaths.

Conclusion: Plasma TMAO levels were positively associated with mortality, especially deaths due to cardiovascular and renal disease, in a multi-ethnic US cohort.

Keywords: Cardiovascular disease; Microbiome; Mortality; Red meat; Trimethylamine N-oxide.

Structured Graphical Abstract

Plasma TMAO levels are positively associated with mortality, especially deaths due to cardiovascular and renal disease, in a multi-ethnic US cohort. CI, confidence interval; CVD, cardiovascular disease; HR, hazard ratio; IQR, inter-quintile range, the difference between the midpoint of the first and fifth quintile; TMA, trimethylamine; TMAO, trimethylamine N-oxide.

Figure 1

Dose–response relationships of serial measures of plasma TMAO levels with the risk of all-cause mortality (left) and cardiovascular mortality (right). Relationships were evaluated using restricted cubic splines with three knots at the 10^th, 50^th, and 90^th percentiles. Dotted vertical lines represent, from left to right, the 10^th, 25^th, 50^th, 75^th, and 90^th percentiles of TMAO levels. Variables adjusted were the same as Model 3 (primary model) in Table 2. The top 1% of the TMAO distribution was not shown for better visualization.

Figure 2

Risk of all-cause mortality associated with serial measures of plasma TMAO levels (per IQR): subgroup analysis. Variables adjusted were the same as Model 3 (primary model) in Table 2. HRs were obtained from the beta coefficients of TMAO and the interaction terms. After Bonferroni’s correction for multiple comparisons, statistical significance was defined as a two-sided P value of <0.005. AHEI was dichotomized based on median value at baseline (low: < 40.4, high ≥ 40.4). IQR: inter-quintile range, comparing the midpoints of the first and fifth quintiles (7.5 µmol/L). AHEI, alternate healthy eating index, with higher score indicating better diet quality. eGFR, estimated glomerular filtration rate, with higher values indicating better renal function.