Background: Trimethylamine N-oxide (TMAO), a diet-derived, gut microbial-host co-metabolite, has been linked to cardiometabolic diseases. However, the relationships remain unclear between diet, TMAO, and cardiometabolic health in general populations from different regions and ethnicities.
Objective: To examine associations of circulating TMAO with dietary and cardiometabolic factors in a pooled analysis of 16 population-based studies from the US, Europe, and Asia.
Design: Included were 32,166 adults (16,269 White, 13,293 Asian, 1,247 Hispanic/Latino, and 1,236 Black) 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. 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 5%-energy increase) and with shellfish, total fish, eggs, and red meat (β=0.370, 0.151, 0.081, and 0.056, respectively, for 1-serving/day increase). Plant protein and nuts showed inverse associations (β=-0.126 for 5%-energy increase from plant protein and -0.123 for 1-serving/day of nuts). Although the animal protein-TMAO association was consistent across populations, fish and shellfish associations were stronger among Asians (β=0.285 and 0.578), and egg and red meat associations were more prominent among Americans (β=0.153 and 0.093). Besides, circulating TMAO was positively associated with creatinine (β=0.131 per standard deviation increase in log-TMAO), homocysteine (β=0.065), insulin (β=0.048), HbA1c (β=0.048), and glucose (β=0.023), while 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 robust in subgroup/sensitivity analyses.
Conclusions: In an international, consortium-based study, animal protein was consistently associated with increased circulating TMAO, while 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.