Spatial and temporal resolution to dissect cellular circuits controlling intestinal physiology, immunity, and inflammatory pathologies

PROJECT SUMMARY As a critical barrier tissue, the intestinal mucosa must balance complex environmental stimuli — including dietary components, microbes, metabolites, and xenobiotics — to fine-tune immune development and tolerance. In health, homeostasis is maintained via a constellation of specialized cell types that connect host physiology to these external signals. Disruption of intestinal physiology results in numerous diseases, including inflammatory conditions such as Crohn’s disease and ulcerative colitis. Here, we propose a framework to dissect the cellular mechanisms underlying the homeostatic and inflamed states in the small intestine and colon at unprecedented spatial and temporal resolution. In Aim 1, we will spatially profile gene and protein expression across human gut samples in health and disease, developing the necessary computational tools to identify critical disruptions in cell-cell communication networks that result from inflammation. Computational tools developed in this context will have broad application in studying tissue biology. Additionally, we will make cross-disease comparisons (e.g., Crohn’s disease, celiac disease, and eosinophilic gastroenteritis) to identify common inflammatory mechanisms independent of tissue type. In Aim 2, we will leverage experimental mouse models to spatially profile the dynamics of inflammation (from homeostasis through induction and resolution of inflammation) and dietary stress in the mouse gut — generating temporally resolved maps of these processes. In Aim 3, we will use organoid and cell-cell coculture models to determine how chemosensory pathways are translated into the coordinated cellular responses that maintain homeostasis.