Intestinal stem cells (ISCs) are the regenerative force of the gut epithelium. Lgr5+-ISC have been shown to respond to changes in their microenvironment by coping with different metabolites, adapting to caloric changes, and recovering from injury and inflammation. However, how pathogenic bacteria affect adult stem cell regeneration and, as a consequence, the overall tissue adaption to infection has yet to be explored in depth. Here, we interrogated early Lgr5+ ISC responses to an enteric intracellular pathogen by profiling individual IECs from the mouse small intestine. Utilizing GFP-labeled Salmonella enterica, we isolated intracellular invaded cells to elucidate invasion programs of epithelial cell subsets. In particular, we identified a Salmonella-specific infection signature comprised of antimicrobial peptide (AMP) genes, including the Defensin gene family. Our findings demonstrate that Salmonella enterica targets differentiated Paneth, enterocytes, and stem/progenitor cells at these early stages of infection. In response, a rapid Lg5+ ISC-driven cellular remodeling to enterocyte and Paneth lineages expressing AMP genes is initiated to combat the intruders. Importantly, we uncovered an ISC differentiation program via inflammasome activation to protect the crypt environment, while eliminating infected stem cells from the overall stem cell pool. This novel Lgr5+ stem cell defense mechanism not only protects the gut epithelium from persistent bacterial infection but also promotes tissue regeneration. We propose epithelial remodeling to AMP-secreting cells as a novel innate immune response to handle different gut stresses mediated by Lgr5+ ISCs to maintain organizational principles of gut homeostasis and physiology.
