The intestinal mucosa is a complex and dynamic interface in which host genetics interact with environmental factors to maintain a delicate homeostatic balance. Breakdown in intestinal homeostasis may lead to inflammatory bowel disease (IBD), an incurable disease which affects millions of people worldwide. Therapeutic promotion of mucosal healing holds great promise; however, it comes with the risk of fueling tumor growth. Thus, we hypothesize that a comprehensive understanding of the cell circuitry involved in regeneration and tumorigenesis can lead to novel disease-specific therapeutic approaches. However, in-depth spatial and functional characterization of these processes at the single-cell resolution is lacking. To fill this gap, this we aim to explore the cellular and molecular landscape of intestinal tissues, including the microbiome, during mucosal healing following distinct environmental challenges. Using single cell and spatial transcriptomics and proteomics, we will map a high-resolution atlas of murine and human intestinal tissues at steady-state/normal conditions and in the setting of IBD. Moreover, using recently developed technologies that integrate tissue imaging and RNA sequencing of host (eukaryotic) and bacterial (microbiota) cells, we will uncover for the first time the host-microbiota niches in healthy and disease states.