RESEARCH

We are broadly interested in how environmental cues (dietary components and therapies) shape intestinal epithelial metabolism and regeneration in health and disease.

We use patient-derived organoids and animal models to elucidate the pathogenesis of pediatric digestive diseases, particularly inflammatory bowel diseases (IBD). Our overall goal is to understand potential links to preventing disease onset and progression and enhancing patient-centered treatment strategies.

Current areas of interest include:

Epithelial metabolic dysregulation is a hallmark of disease in IBD. We believe that capturing these epithelial metabolic anomalies of human IBD on the bench may advance our understanding of the disease, determine the contribution of the epithelium to inflammation, and support the discovery of epithelial-directed management practices for clinical applications. Patient-derived epithelial organoids may serve as long term models of disease, making them a critical pre-clinical tool to further understand the polygenic nature of IBD. Our recent report shows apparent lipid-induced hypermetabolism in colon epithelial organoids obtained from pediatric ulcerative colitis (UC) patients, in association with increased chemoattractive proteins. Ongoing work will (a) continue to elucidate how mitochondrial metabolism contributes to inflammation during epithelial colonoid differentiation in UC (b) explore small molecule inhibitors and nutritional factors that may regulate hypermetabolic phenotypes in UC colon epithelium, and (c) define the characteristic cellular metabolic phenotypes in biopsy-derived enteroids from pediatric Crohn’s patients.

1. Epithelial Metabolic Regulation in IBD

2. Impact of Food Additives on Epithelial Metabolism and Regeneration

IBD (Crohn’s disease and ulcerative colitis) is increasing disproportionately in children and adolescents. The polygenic nature of the disease is strongly linked to environmental exposures. Children may have a greater exposure to food additives (per kg body weight), which include food preservatives and coloring agents. Sulfites are ubiquitous preservatives with a GRAS status and our current single cell data suggests an impact of sulfite exposure on stem cell clusters. Our ongoing NIH-funded work in this area seeks to (a) define how sulfite-based preservatives may impact intestinal epithelial metabolism and regeneration, (b) understand the role of the microbiome in sulfite-induced epithelial phenotypes in IBD, (c) determine whether certain genes critical for sulfite detoxification contribute to IBD pathogenesis, and (d) understand the crosstalk between the epithelium and lamina propria lymphocytes upon sulfite exposure in health and disease.

Research tools used in the lab include:

  • Development of patient biopsy-derived intestinal organoids (from adult stem cells)
  • Animal models: genetically engineered and gnotobiotic mice
  • Primary tissue culture (cells and organoids)
  • Genomic techniques (bulk RNA sequencing, ATAC-seq, single-cell RNA sequencing mainly using split-pool combinatorial barcoding)
  • Molecular biology (PCR, western blot, RNA-immunoprecipitation, lentivirus-mediated gene transduction)
  • Flow cytometry, immunofluorescence, and immunohistochemistry
  • Light and Confocal microscopy