The Metabolic Fate of Isotopically‐Labeled Trimethylamine‐ N ‐oxide (TMAO) in Humans

Although trimethylamine‐ N ‐oxide (TMAO) is associated with chronic disease risk, little is known about the metabolic fate of orally consumed TMAO. As part of a randomized, controlled cross‐over study, healthy young men (n=40) consumed 50 mg deuterium‐labeled methyl‐d9‐TMAO (d9‐TMAO) and TMAO metabolites were measured in plasma, urine, stool and muscle. Plasma d9‐TMAO comprised ~75% of total TMAO at 2 h and remained elevated after 6 h. d9‐trimethylamine (d9‐TMA) and d6‐dimethylamine (d6‐DMA) became enriched in plasma with averages of 52% and 3% of total TMA and DMA, respectively, at 6 h. d9‐TMAO was excreted more rapidly during 0–6 h than 6–24 h, comprising 67% and 52%, respectively, of urinary TMAO. No d9‐TMAO was detected in feces. Interestingly, d9‐TMAO and d9‐TMA were detected in skeletal muscle (n=6) at 6 h, and the enrichment ratio of d9‐TMAO:d9‐TMA was influenced by a genetic variant in flavin‐containing monooxygenase ( FMO3 G472A). The heterozygous GA genotype had lower muscle d9‐TMAO:d9‐TMA than the homozygous wildtype GG genotype. In conclusion, orally consumed TMAO is rapidly absorbed, is metabolized in part to TMA and DMA, and is taken up by skeletal muscle, where evidence of impaired conversion of TMA to TMAO among carriers of the FMO3 472A variant allele is observed. Support or Funding Information Egg Nutrition Center, Beef Checkoff through the National Cattlemen's Beef Association, Canadian Institutes of Health Research Postdoctoral Fellowship.