Diverse infections transcriptionally reprogram the intestinal epithelium and epithelial–immune cell interactions

The distal small intestine has a vital role in host physiology through its regulation of nutrient and fluid homeostasis. Despite being affected in Crohn’s disease and serving as a major target for a range of infections, we know relatively little about the complexity of cellular responses and cell–cell communication in the ileum during infection. Here we present GutPath, an atlas of over 500,000 single cells with RNA and protein expression profiles for 91 cell states in the ileum across diverse infectious archetypes. We show that GutPath accurately captures established immune responses to infection while revealing pathogen-specific responses in enterocytes. To highlight the discovery potential of this atlas, we identify a new enterocyte transcriptional state present during Yersinia pseudotuberculosis infection that is spatially linked to bacterial load and tissue pathology. GutPath establishes a much-needed resource for the immunology community that will accelerate the study of transcriptional diversity in the cellular landscapes of the small intestine. In this Resource, Beiting and colleagues provide an atlas of the mouse ileum and mesenteric lymph nodes under homeostatic conditions and during enteric infection. They also present GutPath, a tool that enables interrogation of the dataset.