Unbiased molecular definition of epithelial barrier formation and defects driving inflammatory bowel disease

The intestinal epithelial barrier is one of the body’s largest mucosal surfaces. The cells involved reflect the numerous functions the epithelium must perform. The barrier requires time critical co-ordination with other intestinal cell compartments in utero for normal development. In maturity, dysregulation of the barrier or cross-talk can lead to disease such as inflammatory bowel disease (IBD). Despite the importance of the intestinal epithelium in development and health, characterisation of the origins of dysregulation are lacking. Questions also remain about the full spectrum of epithelial cell diversity and its mutualistic relationship with other intestinal compartments. This project characterises the development of the epithelial and mesenchymal cross talk in utero, in health and in IBD at high resolution using single cell RNA-sequencing (scRNAseq). Studying intestinal epithelial diversity in health and disease, isolating epithelial cells from IBD and controls and mapping over 11,000 cells from health and UC inflammation, mapped cell diversity through the maturation of epithelium. This identified a hitherto unappreciated BEST4/OTOP2 cell that sensed pH and was dysregulated in inflammation and cancer. Furthermore, a second project mapped human intestinal development from 8-22 post conceptual weeks. This charted 101 cell types across developmental time and through spatial transcriptomics (ST) could map these to tissue revealing origins of diverse cellular compartments along with fibroblast and intestinal stem cells across space and time. These results provide a platform that maps the human intestinal epithelium and previously unappreciated resolution and from which the normal developmental cues can be established and allow identification of the drivers of dysregulation in IBD.