Location: Obesity and Metabolism Research
Project Number: 2032-51530-025-049-R
Project Type: Reimbursable Cooperative Agreement
Start Date: Apr 20, 2020
End Date: Feb 28, 2023
Our recent studies have identified a novel mechanism for atherosclerosis where high circulating levels of trimethylamine N-oxide (TMAO), which is generated from dietary choline and L-carnitine by gut microbiome and hepatic-mediated enzymatic reactions, promote atherogenesis in mice and are associated with elevated risk of cardiovascular disease (CVD) in humans. Our data now further indicate that plasma TMAO levels are regulated through complex interactions between host genetic, gut bacterial, and dietary factors in multiple organ systems, such as the liver and kidney. The Objective is to dissect the relationships between genetic, dietary, and gut bacterial factors that regulate plasma TMAO levels using Systems Genetics.
To accomplish our objective of dissecting the relationships between genetic, dietary, and gut bacterial factors that regulate plasma TMAO levels we will perform a series of experiments and analysis. These include the following: 1. We propose a nutrigenetics study with the Hybrid Mouse Diversity Panel (HMDP) where ~100 inbred mouse strains will be fed diets supplemented with and without choline. Several analyses will be performed in this large experiment: a) We will carry out a gene-diet genome-wide association study (GWAS) in the HMDP and identify loci associated with plasma and urinary TMAO levels in response to a choline challenge. b) We will determine compositional changes in the gut microbiome as a result of choline feeding in the HMDP, identify genomic loci associated with changes in microbial composition, and determine whether these loci are also associated with plasma and urinary TMAO levels. c) We will determine whether dietary supplementation affects expression of hepatic and renal genes that regulate TMAO at the level of production and excretion, respectively. d) We will determine whether TMAO-associated loci exhibit nutrigenetic interactions in humans from a controlled dietary trial and whether the genetic determinants of TMAO are shared between mice and humans.