Circulating trimethylamine N-oxide in association with diet and cardiometabolic biomarkers: an international pooled analysis

Abstract

Background: Trimethylamine N-oxide (TMAO), a diet-derived, gut microbial-host cometabolite, has been linked to cardiometabolic diseases. However, the relations remain unclear between diet, TMAO, and cardiometabolic health in general populations from different regions and ethnicities.

Objectives: To examine associations of circulating TMAO with dietary and cardiometabolic factors in a pooled analysis of 16 population-based studies from the United States, Europe, and Asia.

Methods: Included were 32,166 adults (16,269 white, 13,293 Asian, 1247 Hispanic/Latino, 1236 black, and 121 others) without cardiovascular disease, cancer, chronic kidney disease, or inflammatory bowel disease. Linear regression coefficients (β) were computed for standardized TMAO with harmonized variables. Study-specific results were combined by random-effects meta-analysis. A false discovery rate <0.10 was considered significant.

Results: After adjustment for potential confounders, circulating TMAO was associated with intakes of animal protein and saturated fat (β = 0.124 and 0.058, respectively, for a 5% energy increase) and with shellfish, total fish, eggs, and red meat (β = 0.370, 0.151, 0.081, and 0.056, respectively, for a 1 serving/d increase). Plant protein and nuts showed inverse associations (β = -0.126 for a 5% energy increase from plant protein and -0.123 for a 1 serving/d increase of nuts). Although the animal protein-TMAO association was consistent across populations, fish and shellfish associations were stronger in Asians (β = 0.285 and 0.578), and egg and red meat associations were more prominent in Americans (β = 0.153 and 0.093). Besides, circulating TMAO was positively associated with creatinine (β = 0.131 SD increase in log-TMAO), homocysteine (β = 0.065), insulin (β = 0.048), glycated hemoglobin (β = 0.048), and glucose (β = 0.023), whereas it was inversely associated with HDL cholesterol (β = -0.047) and blood pressure (β = -0.030). Each TMAO-biomarker association remained significant after further adjusting for creatinine and was robust in subgroup/sensitivity analyses.

Conclusions: In an international, consortium-based study, animal protein was consistently associated with increased circulating TMAO, whereas TMAO associations with fish, shellfish, eggs, and red meat varied among populations. The adverse associations of TMAO with certain cardiometabolic biomarkers, independent of renal function, warrant further investigation.

Keywords: Consortium of Metabolomics Studies; biomarker; cardiovascular disease; diet; trimethylamine N-oxide.

FIGURE 1

Circulating trimethylamine N-oxide (TMAO) in relation to demographics, lifestyle, and medical history. Linear regression coefficients (β) and 95% CIs were adjusted for age, sex, race and ethnicity, education, fasting time, obesity, central obesity, smoking status, alcohol consumption, physical activity, use of multivitamins, menopausal status and hormone therapy in women, intakes of red meat, egg, and fish, and history of diabetes, hypertension, dyslipidemia, and nonalcoholic fatty liver disease. β indicates the increase or decrease in SD units of TMAO on the log-scale. Q-values represent corrected P values for multiple comparisons by controlling the false discovery rate. I² represents the degree of heterogeneity. NAFLD, nonalcoholic fatty liver disease; WHR, waist-to-hip ratio.

FIGURE 2

Circulating trimethylamine N-oxide (TMAO) in relation to dietary factors. Linear regression coefficients (β) and 95% CIs were adjusted for age, sex, race and ethnicity, education, fasting time, obesity, central obesity, smoking status, alcohol consumption, physical activity, use of multivitamins, menopausal status and hormone therapy in women, intakes of red meat, egg, and fish, and history of diabetes, hypertension, dyslipidemia, and nonalcoholic fatty liver disease. β indicates the increase or decrease in SD units of log-TMAO by dietary changes. Q-values represent corrected P values for multiple comparisons by controlling the false discovery rate. I² represents the degree of heterogeneity.

FIGURE 3

Circulating trimethylamine N-oxide (TMAO) in relation to cardiometabolic biomarkers. Linear regression coefficients (β) and 95% CIs were adjusted for age, sex, race and ethnicity, education, fasting time, obesity, central obesity, smoking status, alcohol consumption, physical activity, use of multivitamins, menopausal status and hormone therapy in women, intakes of red meat, egg, and fish, and history of diabetes, hypertension, dyslipidemia, and nonalcoholic fatty liver disease. β indicates the increase or decrease in SD units of log-biomarkers by per SD change in log-TMAO. Q-values represent corrected P values for multiple comparisons by controlling the false discovery rate. I² represents the degree of heterogeneity. DBP, diastolic blood pressure; HbA1c, glycated hemoglobin; SBP, systolic blood pressure.