Status: Funded - Open
A personalized model of the gut epigenome and microbiome in pediatric inflammatory bowel disease
Elizabeth Radford, BA, MB BChir, PhD
BACKGROUND: Inflammatory bowel diseases can have a devastating effect on children’s physical, social, emotional and academic development; there is an urgent need to better understand the etiology of these diseases in order to improve treatment. There is good evidence that environmental factors, particularly the gut microbiome, play a major role in the pathogenesis of IBD. Epigenetic marks are a strong candidate for being the mechanism through which the environment alters the phenotype and developmental trajectory of an individual, and gut bacteria have been shown to alter the epigenetic profile of intestinal stem cells.
GAP: It is not known whether altered gut bacteria in IBD patients cause epigenetic changes in the gut epithelium which contribute to the development of IBD.
HYPOTHESIS: We hypothesize that patients newly diagnosed with IBD have an altered gut microbiota. We hypothesize that the DNA methylation profile of the gut epithelium of patients newly diagnosed with IBD is altered, and that this correlates with the altered microbiome. We hypothesize that alterations in the gut microbiome result in altered gut epithelial DNA methylation, and that this contributes to the pathogenesis of inflammatory bowel disease.
METHODS: We will generate genome wide DNA methylation profiles of purified intestinal epithelium using Illumina K450 methylation arrays and assess the composition of adjacent gut microbiomes through 16S sequencing; in parallel intestinal biopsy-derived epithelial organoids will be generated for both patients and controls and co-cultured with disease specific patient-derived microbiota and subsequent changes in DNA methylation and cellular function assessed.
IMPACT: If successful our results will provide a first step towards the development of a clinically applicable biomarker as well as to further our understanding of how the gut microbiota modulates the host cell epigenome in children with IBD, lending support to efforts to therapeutically alter the microbiome of IBD patients.