Abstract 19174: Gut Microbial Utilization of Choline Significantly Alters Host Lipid, DNA Methylation, and Hepatic Gene Expression Profiles

Choline is an essential nutrient necessary for several biological functions in the human body; in addition to being the precursor to acetylcholine, choline is required for the formation of phosphatidylcholine and the universal methyl donor SAM (S-adenosyl methionine). Gut microbial metabolism of dietary choline results in the production of trimethylamine (TMA), a compound that is absorbed by the host and further converted to trimethylamine N-oxide (TMAO) in the liver. While the role of the gut microbiota as a modulator of choline bioavailability has been poorly explored, it is well established that both choline deficiency and TMAO accumulation are associated with cardiovascular disease. We used germ-free mice colonized with defined synthetic communities of bacteria that differ only in their ability to convert choline to TMA to evaluate the impact of microbial choline utilization on host physiology. We found that bacterial utilization of choline significantly reduces the bioavailability of choline to the host as well as significantly alters (i) host gene expression (in liver and adipose tissue), (ii) lipid profiles, and (iii) serum and hepatic metabolomes. Furthermore, conversion of choline to TMA and TMAO results in changes in gene expression consistent with increased fatty acid oxidation, apoptosis, reactive oxygen species generation, fibrin deposition, vasoconstriction and adipogensis concomitant with a decrease in oxidative stress tolerance and clearance of thrombi from the vasculature. Many of the differentially expressed genes are known targets of the nuclear receptors PPAR and FXR. Lastly, colonization with a choline consuming TMAgenic community resulted in significant alterations in global DNA methylation patterns in multiple tissues in as little as two-weeks post colonization.