Plasma trimethylamine N-oxide concentration is associated with choline, phospholipids, and methyl metabolism

Background: Elevated plasma concentrations of the gut bacteria choline metabolite trimethylamine N-oxide (TMAO) are associated with atherosclerosis. However, the determinants of TMAO in humans require additional assessment. Objective: We examined cardiometabolic risk factors and pathways associated with TMAO concentrations in humans. Design: A total of 283 individuals (mean +/- SD age: 66.7 +/- 9.0 y) were included in this observational study. Plasma concentrations of trimethylamine, TMAO, choline, lipids, phospholipids, and methyl metabolites were measured. Results: Study participants were divided into 4 groups by median concentrations of TMAO and choline (4.36 and 9.7 mu mol/L, respectively). Compared with the group with TMAO and choline concentrations that were less than the median (n = 82), the group with TMAO and choline concentrations that were at least the median (n = 83) was older and had lower high-density lipoprotein (HDL) cholesterol, phospholipids, and methylation potential, higher creatinine, betaine, S-adenosylhomocysteine (SAH), and S-adenosylmethionine (SAM), and higher percentages of men and subjects with diabetes. The difference in plasma TMAO concentrations between men and women (7.3 +/- 10.0 compared with 5.4 +/- 5.6 mu mol/L, respectively) was NS after adjustment for age and creatinine (P = 0.455). The TMAO:trimethylamine ratio was higher in men (P < 0.001). Diabetes was associated with significantly higher plasma TMAO concentration (8.6 +/- 12.2 compared with 5.4 +/- 5.2 mu mol/L) even after adjustments. Sex and diabetes showed an interactive effect on trimethylamine concentrations (P = 0.010) but not on TMAO concentrations (P = 0.950). Positive determinants of TMAO in a stepwise regression model that applied to the whole group were SAH, trimethylamine, choline, and female sex, whereas plasma phosphatidylcholine was a negative determinant. Conclusions: High TMAO and choline concentrations are associated with an advanced cardiometabolic risk profile. Diabetes is related to higher plasma TMAO concentrations but also to alterations in interrelated pathways such as lipids, phospholipids, and methylation. Elevated plasma TMAO concentrations likely reflect a specific metabolic pattern characterized by low HDL and phospholipids in addition to hypomethylation. This trial was registered at clinicaltrials.gov as NCT02586181 and NCT02588898.