Regulation of trimethylamine metabolism

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Background: The long-term goal of my NSERC Discovery program is to understand the role of dietary choline, and related nutrients, on mammalian physiology. Choline is an essential nutrient required for phospholipid synthesis, membrane signaling, lipoprotein secretion, acetylcholine biosynthesis, and one-carbon metabolism. Emerging research has determined that dietary choline can be metabolism by intestinal bacteria to produce trimethylamine (TMA), which is oxidized in the liver to produce trimethylamine-oxide (TMAO).  We have developed a new analytical method for assessing these TMA and TMAO in plasma. Furthermore, we have shown that dietary choline supplementation increases plasma TMAO levels; however, this relationship is dependent on the animal model, length of feeding, and level of dietary supplementation. For this NSERC Discovery grant, my laboratory will focus on factors that regulate trimethylamine metabolism and will investigate the physiological role of TMAO within various cells/tissues. To date, only dietary choline has been implicated in the production of TMA from intestinal bacteria; however, we hypothesize that choline from the diet (both source and amount) and bile (i.e. PC synthesized in liver) can contribute to TMA/TMAO production. Specific Objective 1: To understand the dietary and physiological factors that modulate trimethylamine/trimethylamine-oxide production. Specific Objective 2. To understand how altering PC metabolism de novo PC supply modulates trimethylamine/trimethylamine-oxide production. Specific Objective 3: To determine physiological consequences of modulating TMAO in regulating lipid metabolism and cellular stress using in vivo and in vitro models. Impact of Research Program: The training of HQPs is a central component of this research program. HQP will develop both their scientific (animal handling, bioassays, cell culture, experimental design) and professional (verbal and written communication, leadership, community interaction) skills. Trainees will be encouraged to think beyond their comfort level to ensure scientific growth and to develop a passion for scientific theory and discovery. The research atmosphere is strengthened by collaboration with local NSERC Discovery funded laboratories (Drs. Richard, Willing, Field, Curtis) with convergent expertise. My HQP have equal opportunity to participate and lead collaborative projects. This NERSC Discovery program will continue to provide novel contributions to our fundamental knowledge of choline nutrition, biochemistry, physiology and metabolism across the lifespan. This project will use a multidisciplinary approach (including Molecular, Biochemical, and Physiological techniques), dietary manipulation, novel animal models, and cell culture to elucidate the biological effects of TMAO, and to understand the complex relationship between choline metabolism and TMAO production.