Abstract P205: Long-term Changes in Microbiota-dependent Metabolite Trimethylamine N-oxide and Risks of Hypertension and Coronary Heart Disease, and Their Modulation by Diet: The Nurses' Health Study and the POUNDS Lost Trial

Introduction: A gut microbiota-related metabolite, trimethylamine N-oxide (TMAO) has been related to risks of cardiovascular events, however, whether changes in TMAO may contribute to the incidence of hypertension remains unknown. Gut microbiome may be affected by sodium intake and dietary patterns linked to blood pressure control, while little is known about whether these dietary factors may modify associations between TMAO changes and risks of hypertension and cardiovascular events. Hypothesis: To test whether long-term changes in TMAO are associated with increased risks of hypertension and coronary heart disease (CHD), and whether sodium intake and adherence to the DASH (Dietary Approaches to Stop Hypertension) dietary pattern may modulate these associations. Methods: A prospective nested case-control study was performed in 730 women (including 362 incident cases of fatal CHD and nonfatal myocardial infarction). We measured blood levels of TMAO at 2 time points (in 1989-90 and 2000-01), and prospectively examined associations of 10-year changes in TMAO with CHD events after the date of the second blood collection (through 2016). For the hypertension outcome, we assessed prevalent hypertension at 2nd time point among total participants, as well as the incidence of hypertension over 10 years (between 1989-90 and 2000-01) among people who were initially free of hypertension (n=410). In overweight and obese participants (n=429) from a randomized dietary intervention, we also investigated whether diet-induced changes in TMAO were related to blood pressure changes considering 24-hr urinary sodium excretion as a marker of sodium intake. Results: Elevated TMAO levels were significantly associated with hypertension at the 2nd time point (relative risk (RR): 1.30 (95% CI: 1.09, 1.56) per 1 SD increment). Also, greater 10-year increases in TMAO were significantly associated with increased risks of incident hypertension and CHD, with evidence of significant modification by adherence to the DASH diet (P-interaction =0.02 for hypertension; P-interaction =0.01 for CHD). Among people with lower adherence to the DASH diet (i.e., having unhealthy dietary patterns and higher sodium intake), every 1 SD increase in TMAO was associated with a RR of 2.13 (1.30, 3.49) for hypertension, and a RR of 2.03 (1.42, 2.89) for CHD. Such significantly increased risks of hypertension and CHD by TMAO increases were not found for women with higher adherence to the DASH diet. In a dietary intervention, we also found similar associations; diet-induced changes in TMAO levels with blood pressure changes were modified by urinary sodium excretion. Conclusion: Increases in TMAO, an atherogenic microbial metabolite, were associated with higher risks of hypertension and CHD among women, and heart-healthy dietary patterns and sodium intake modified the unfavorable associations of TMAO with the risks of these diseases.