Dysregulation of Epithelial Metabolism and Regeneration by Sulfite Exposure in Pediatric Ulcerative Colitis

PROJECT SUMMARY The prevalence of ulcerative colitis (UC) in children continues to increase yearly. Recent evidence in pediatric UC patients showed significant mitochondrial impairment in the colon tissues. This is important as optimal mitochondrial activity is required for the solemn function of colonic stem cells that replenish the physical barrier of the colon epithelium. Since patients are constantly exposed to environmental factors such as diet, it is critical to reveal the dietary factors that influence mitochondrial function in the colon epithelium as they would be vital in the management of UC in children. Sulfites are endogenous products of several sulfur-containing compounds, and they are also ubiquitous in our diets as preservatives. My preliminary data in colon organoids derived from pediatric patients showed a detrimental role of sulfite on mitochondrial metabolism and differentiation, with worse metabolic outcomes in samples from pediatric UC patients. My analysis of transcriptomic data from 206 children with UC showed that the Mocs1 gene required for downstream clearance of sulfites in the mitochondria is downregulated in the colon of UC patients, suggesting a potential for inefficient sulfite detoxification in the colon. In this study, I will use patient-derived colon organoids to define how sulfites regulate mitochondrial metabolism and differentiation in health and in UC (Aim 1), reveal the sulfite-induced and sulfite susceptibility chromatin sites in the pediatric colon that explains these metabolic and differentiation anomalies (Aim 2), and how sulfites and the loss of epithelial Mocs1 shape colon biology in the complex gut environment in vivo using physiological relevant models (Aim 3). This award will advance my training in disease models of IBD, epithelial biology, and epigenomics as I work toward establishing an innovative career in regenerative nutrition with a focus on pediatric digestive diseases and continue efforts to enhance diverse representation in the biomedical sciences.