PROJECT SUMMARY
An obesogenic Western-style (HF) diet causes low-grade intestinal inflammation, intestinal microbiota
imbalance, and an increased risk of cardiovascular disease. However, our knowledge about the pathways
producing each of these different disease manifestations is incomplete, making it difficult to see connections.
Experiments proposed in this application are aimed at addressing this critical gap in knowledge. Our long-range
goal is to elucidate molecular mechanisms that make the gut microbiota a liability during non-communicable
diseases. This application aims to study the mechanisms through which HF diet drives gut dysbiosis and
determine whether the resulting imbalance escalates the production of microbial metabolites that increase the
risk for cardiovascular disease. Our central hypothesis is that mitochondrial dysfunction induced by an
obesogenic HF diet activates epithelial repair responses (e.g., crypt hyperplasia), which in turn drives an
expansion of facultative anaerobic Enterobacteriaceae, a taxon known to produce metabolites that accelerate
atherosclerosis. To test our hypothesis, we will determine whether mitochondrial dysfunction-induced monocyte
recruitment promotes colonic epithelium repair responses (specific aim 1). We will identify the role of colonic
epithelium repair responses in driving HF diet-induced Enterobacteriaceae expansion (specific aim 2). We will
also elucidate the mechanism by which HF diet-induced Enterobacteriaceae expansion increases circulating
trimethylamine N-oxide (TMAO) levels and promotes cardiovascular disease (specific aim 3). By defining the
complex order of events that links these disease manifestations, we expect the completion of the proposed
experiments to usher in a decisive conceptual advance to understand how HF diet increases cardiovascular
disease risk.
