WIP 77 - Nutrigenomic Program of Pediatric Intestinal Stem Cell Development

Poster Number: WIP 77
Publication Number: WIP 77.687

Background: Tissue-resident stem cells play a critical role in tissue maintenance by responding to dietary cues. Many connections between nutrition and inflammatory bowel disease (IBD) have been proposed, but mechanistic ties remain elusive. Recent studies in developmental biology suggest that alterations of intestinal stem cells (ISCs) during pediatric development determine the susceptibility to childhood IBD.
We have recently developed a nutrigenomic screening system showing that metabolites and nutrients directly alter specific gene expression (i.e. nutrigenomics) to modulate adult ISC function. This screening system has shown that adult ISCs have altered lineage fates, from a self-renewal/regenerative fate to a secretory fate, when exposed to a high glucose diet as opposed to a high-fat ketogenic diet. Here, we will use similar tactics to investigate the regulatory role of the nutrigenomic program in the development of pediatric ISCs.
Our research takes advantage of novel understanding in stem cell nutrigenomics and will allow us to study disease, such as the developmental origin of IBD.

Objective: We will use an in-vivo mouse and in-vitro organoid model to begin establishing the nutrigenomic program critical for ISC function in pediatric gut development. We will perform perturbation and rescuing experiments to pinpoint the regulatory nutrients and metabolites critical for ISC function in gut development. This project will establish the early steps of creating a new experimental platform.

Design/Methods: IRB approval is not required. We will use a published database to identify metabolic genes that appear to be key to pediatric gut development. Once identified, we will induce target gene deletion (using CreER-loxP technology) both in-vitro (ISC mouse organoid) and in-vivo (mouse) to determine changes in gut development. We will look for gross changes in organoid development in the in-vitro model and will identify histological changes to the dissected gut in-vivo. Target genes have been identified and experiments are currently underway with results expected prior to April 2024.