Long-Term Changes in Gut Microbial Metabolite Trimethylamine N-Oxide and Coronary Heart Disease Risk

Background: A gut-microbial metabolite, trimethylamine N-oxide (TMAO) has been associated with coronary atherosclerotic burden. No previous prospective study has addressed associations of long-term changes in TMAO with coronary heart disease (CHD) incidence. Objective: To investigate whether 10-year changes in plasma TMAO levels were significantly associated with CHD incidence. Methods: This prospective nested case-control study included 760 healthy women at baseline. Plasma TMAO levels were measured both at the first (1989–90) and the second blood collections (2000–02); 10-year changes (Δ) in TMAO were calculated. Incident cases of CHD (n=380) were identified after the second blood collection through 2016 and were matched to controls (n=380). Results: Regardless of the initial TMAO levels, 10-year increases in TMAO from the first to second blood collections were significantly associated with an increased risk of CHD (relative risk [RR] in the top tertile: 1.58 [95% CI: 1.05, 2.38]; RR per 1 SD increment: 1.33 [1.06, 1.67]). Participants with elevated TMAO levels (the top tertile) at both time points showed the highest RR of 1.79 (1.08, 2.96) for CHD as compared with those with consistently low TMAO levels. Further, we found that the ΔTMAO-CHD relationship was strengthened by unhealthy dietary patterns (assessed by the Alternate Healthy Eating Index) and was attenuated by healthy dietary patterns (Pinteraction=0.008). Conclusions: Long-term increases in TMAO were associated with higher CHD risk, and repeated assessment of TMAO over 10 years improved the identification of people with a higher risk of CHD. Diet may modify the associations of ΔTMAO with CHD risk.