Defining Determinants of Intestinal Barrier Health and Disease (360G-Wellcome-219523_Z_19_Z)

IBD affects over 1.5 million and 2 million people in North America and Europe respectively. A significant proportion fail to respond to current treatments. In IBD genetic, environmental and intestinal barrier defects combine to precipitate dysregulated immune responses in the mucosa that manifest in disease. Recently we have utilized single cell technologies to chart the behaviour of diverse cell types making up the mucosal barrier in health and early diagnosis IBD. This has demonstrated the nature of cellular remodeling occurring in the human colon in inflammation revealing trajectories of differentiation, the connectedness of different cell states together with describing novel epithelial, mesenchymal, T, B and myeloid cell states that hallmark disease. In this work we will build on these findings to explore functional pathways and barrier cell relationships revealed by this analysis that maintain commensal symbiosis in health but lead to breakdown in tolerance driving inflammation in IBD. Specifically, we will focus on defining how the colonic epithelia remodels to lose cell intrinsic barrier protective function, how the supporting mesenchyme fuels inflammation and how heterogenous colonic myeloid cells handle commensal bacteria in health and IBD to drive aberrant adaptive responses.