The role of dietary cholesterol in Nonalcoholic fatty liver disease through the action of gut microbiota - PROJECT SUMMARY
The prevalence of Nonalcoholic fatty liver disease (NAFLD) is increasing worldwide, affecting a quarter of
the global population. NAFLD may progress to its more severe form, Nonalcoholic steatohepatitis (NASH), which
will become the number one indication for liver transplant. While there are over 400 ongoing NAFLD-related
clinical trials, there are no FDA-approved therapies. There is an immediate need for strategies to counteract
NAFLD/NASH development and progression throughout the world. However, little is known about its
pathophysiology. Western diet contributes to disease pathogenesis, mediated in part by the gut microbiome.
Epidemiological studies indicate dietary cholesterol closely associates with the incidence of late-stage NAFLD.
However, the influences of Western dietary components, such as cholesterol, on gut microbiota are largely
unknown. There is a considerable gap in knowledge regarding the mechanistic relationships between
discrete Western dietary components, gut microbiota, and the development of NAFLD/NASH. Preliminary
studies show Western diets containing high levels of cholesterol induce gut microbial imbalances that precede
and are a prerequisite for NAFLD/NASH in Specific pathogen-free (SPF) mice, yet germ-free (GF) mice that lack
a gut microbiome are protected from disease. Bifidobacteria are key commensal organisms that are beneficial
to the host and are commonly downregulated in metabolic disorders such as NAFLD/NASH. However,
environmental cues that drive a loss of Bifidobacteria remain elusive. Preliminary studies show they are lost from
the gut upon high-cholesterol feeding in a dose-dependent manner and their relative abundance is negatively
correlated with liver damage. These data strongly suggest diet drives a loss of Bifidobacteria which compromises
the host and contributes to NAFLD/NASH pathogenesis. It is critical to define the underlying mechanisms if
microbiome-based therapeutic strategies against NAFLD/NASH are to be developed. The goal of this proposal
is to define the role of dietary cholesterol in driving gut microbial imbalances in NAFLD/NASH pathogenesis. I
hypothesize dietary cholesterol drives gut Bifidobacteria elimination which promotes a proinflammatory microbial
milieu during the pathogenesis of NAFLD/NASH. To test this hypothesis, I will utilize a combination of in vitro, in
vivo, and bioinformatics techniques to 1) Determine critical functional elements that impact Bifidobacteria’s
capacity to sustain a niche in the presence of high dietary cholesterol alone vs. within a complex gut microbiota
community in NAFLD/NASH development and 2) Elucidate the indirect effect of dietary cholesterol mediated
through altered bile acid profile on loss of Bifidobacteria from a complex gut microbiota community in
NAFLD/NASH development. By exposing me to central aspects of microbiome research, these studies provide
the perfect vehicle for my training and will propel me toward achieving my goal of becoming a Principal
Investigator studying interactions between diet, gut microbes, and metabolic disease at a R1 institution.
