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

Abstract

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.

Objectives: The purpose of this study was 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 to 1990) and the second (2000 to 2002) blood collections; 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 collection were significantly associated with an increased risk of CHD (relative risk [RR] in the top tertile: 1.58 [95% confidence interval (CI): 1.05 to 2.38]; RR per 1-SD increment: 1.33 [95% CI: 1.06 to 1.67]). Participants with elevated TMAO levels (the top tertile) at both time points showed the highest RR of 1.79 (95% CI: 1.08 to 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 (p interaction = 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.

Keywords: coronary heart disease; diet; gut-microbial metabolites; prospective cohort study; risk factors.

Figure 1:. Dose-response relationship between TMAO levels at the second collection and the risk of coronary heart disease (CHD).

Reference: a minimum value. Dotted lines indicate lower and upper 95% confidence intervals. Pink line (Plinear =0.01) shows the relative risk (RR) in a model adjusted for matched factors (age, smoking habit, fasting status, and date of blood collection), family history of myocardial infarction, postmenopausal hormone use, aspirin use, alcohol, physical activity, and the Alternative Healthy Eating Index (without alcohol). All covariates were based on assessments at the second time point. Blue line (Plinear =0.07) shows the RR in a model with an additional adjustment of BMI, hypertension, dyslipidemia, and diabetes at the second time point.

Figure 2:. Risk of CHD incidence according to TMAO changes stratified by adherence to healthy dietary habits.

Risk of coronary heart disease (CHD) according to tertile (T) categories of changes (∆) in trimethylamine N-oxide (TMAO) or per 1 SD increment of ∆TMAO among women with lower or higher adherence to healthy dietary habits assessed by the Alternative Healthy Eating Index (panel A), or adherence to plant-based diet (panel B). Relative risks (RRs) were adjusted for total energy intake and the same covariates (including matched factors, demographic/lifestyle factors, obesity, and metabolic risk factors at the first time point and concurrent changes between two time points) in model 3 of Table 1 (details of covariates in the model in the Supplemental Appendix). Higher or lower adherence to dietary habits was based on the median value of the Alternative Healthy Eating Index (panel A) or the plant-based diet index (panel B). Test for interactions between ∆TMAO and diet: Pinteraction=0.008 in panel A; Pinteraction=0.04 in panel B.

Central Illustration:. Risk for coronary heart disease (CHD) by changes (Δ) in trimethylamine N-oxide (TMAO).

Reference: no change. Dotted lines indicate lower and upper 95% confidence intervals. RRs and 95% CIs were adjusted for the same covariates of model 3 in Table 1. P value of testing for linear association (Plinear)=0.016. Abbreviation: Trimethylamine N-oxide, TMAO; Reference, Ref.; Relative risk, RR.