This study provides a comprehensive single-cell transcriptomic analysis of the mouse small intestinal epithelium, profiling 53,193 individual epithelial cells. The authors identified novel subtypes and characterized their gene signatures, including two distinct tuft cell subtypes and unexpected diversity in hormone-secreting enteroendocrine cells. They also constructed a new taxonomy for these cells. The study revealed that Salmonella infection increased the abundance of Paneth and enterocytes and activated antimicrobial programs, while Heligmosomoides polygyrus infection expanded goblet and tuft cell populations. The research highlights new markers and programs, associates sensory molecules with specific cell types, and provides insights into gut homeostasis and responses to pathogens.This study provides a comprehensive single-cell transcriptomic analysis of the mouse small intestinal epithelium, profiling 53,193 individual epithelial cells. The authors identified novel subtypes and characterized their gene signatures, including two distinct tuft cell subtypes and unexpected diversity in hormone-secreting enteroendocrine cells. They also constructed a new taxonomy for these cells. The study revealed that Salmonella infection increased the abundance of Paneth and enterocytes and activated antimicrobial programs, while Heligmosomoides polygyrus infection expanded goblet and tuft cell populations. The research highlights new markers and programs, associates sensory molecules with specific cell types, and provides insights into gut homeostasis and responses to pathogens.