ABSTRACT The gut serves as a nexus that connects and integrates organ systems throughout the body, with far-reaching consequences in health and disease. The biological function of the gut as an organ is the result of complex interactions between dynamic and heterogeneous cell types. Any pathological insult to the gut, such as barrier breach or infection, must be met with a response that is appropriate and proportional to the insult, such that homeostasis is re-established. In this application, we propose novel single-cell genomic approaches to decipher heterogeneous cellular responses to inflammatory challenge. Through a series of functional genetics studies, we aim to elucidate the molecular basis of mucosal immunity in the context of pathological inflammation. Towards this end, we propose the following specific aims: Aim 1. Comprehensively define all cell lineages and dynamic functional states in intestinal inflammation. Aim 2. Delineate intercellular communication networks that coordinate intestinal inflammation. Aim 3. Identify disease modifier pathways in human biopsies and integrate with intercellular communication networks.