Gut microbiota have been associated with many different disorders, including
cardiovascular disease. One common mechanism involves the production, from dietary
components, of metabolites that enter the circulation and affect physiologic functions such as
inflammation. We propose to perform a comprehensive screen of gut microbiota-derived
metabolites that contribute to cardio-metabolic disorders. Using a panel of genetically diverse
inbred strains of mice, we will identify microbes and microbiota-derived metabolites that
associate with atherosclerosis, followed by validation in human cohorts and mechanistic studies
in germ-free mice. The work will be done in three laboratories with complimentary skills: A.
Lusis (genetics), F. Rey (microbiology), and Z. Wang (metabolomics). All of the investigators
have worked together for several years.
The proposal represents an extension of a screen we previously performed using a
panel of 100 inbred strains of mice for atherosclerosis (900 mice total). In that screen, we
observed over a 200-fold range of lesion development. We now propose to analyze the
microbiomes (Aim 1) and plasma metabolomes (Aim 2) of the mice and to relate these to
atherosclerosis traits. We will then prioritize the significant associations by studying these in an
atherosclerosis case-control human population (Aim 3). Finally, we will study the mechanisms
by which the metabolites affect disease using germ-free mouse models (Aim 4). In preliminary
studies, the levels of trimethylamine-N-oxide, another microbe-derived molecule shown to
contribute to human atherosclerosis, were significantly correlated with lesion development.
And, using a subset of the panel, we identified two microbes (A. muciniphila and R. intestinalis)
associated with cardiometabolic traits and showed that these exhibited the predicted effects
when used to colonize mice.
These preliminary studies provide strong validation for the overall approach. We
anticipate identifying several novel metabolites associated with atherosclerosis and related
traits, and exploring the underlying mechanisms. This should pave the way for novel therapies
that target the microbiome.