A single-cell survey of the small intestinal epithelium reveals extensive diversity in cell types and their gene signatures. The study profiles 53,193 individual epithelial cells from mouse small intestine and organoids, identifying novel subtypes and their molecular characteristics. It highlights unexpected diversity in hormone-secreting enteroendocrine cells and distinguishes two tuft cell subtypes, one of which expresses the epithelial cytokine TSLP and CD45, a pan-immune marker not previously associated with non-hematopoietic cells. The study also characterizes how cell-intrinsic states and proportions respond to bacterial and helminth infections. Salmonella infection increases Paneth and enterocyte abundance and activates an antimicrobial program, while Heligmosomoides polygyrus expands goblet and tuft cell populations. The survey uncovers new markers, programs, and principles of gut homeostasis and pathogen response. The study identifies key transcription factors, GPCRs, and leucine-rich repeat proteins for each major cell type, and defines a novel taxonomy for enteroendocrine cells. It also distinguishes two novel tuft cell subsets, Tuft-1 and Tuft-2, with distinct gene expression profiles. The study further characterizes microfold (M) cells, which are rare in the small intestine and were not detected in the initial survey. The results provide a detailed reference dataset and specific hypotheses for follow-up studies, including cell-type-specific markers, TFs, and GPCRs, which may lead to novel interventions in inflammatory, metabolic, and proliferative gut pathologies.A single-cell survey of the small intestinal epithelium reveals extensive diversity in cell types and their gene signatures. The study profiles 53,193 individual epithelial cells from mouse small intestine and organoids, identifying novel subtypes and their molecular characteristics. It highlights unexpected diversity in hormone-secreting enteroendocrine cells and distinguishes two tuft cell subtypes, one of which expresses the epithelial cytokine TSLP and CD45, a pan-immune marker not previously associated with non-hematopoietic cells. The study also characterizes how cell-intrinsic states and proportions respond to bacterial and helminth infections. Salmonella infection increases Paneth and enterocyte abundance and activates an antimicrobial program, while Heligmosomoides polygyrus expands goblet and tuft cell populations. The survey uncovers new markers, programs, and principles of gut homeostasis and pathogen response. The study identifies key transcription factors, GPCRs, and leucine-rich repeat proteins for each major cell type, and defines a novel taxonomy for enteroendocrine cells. It also distinguishes two novel tuft cell subsets, Tuft-1 and Tuft-2, with distinct gene expression profiles. The study further characterizes microfold (M) cells, which are rare in the small intestine and were not detected in the initial survey. The results provide a detailed reference dataset and specific hypotheses for follow-up studies, including cell-type-specific markers, TFs, and GPCRs, which may lead to novel interventions in inflammatory, metabolic, and proliferative gut pathologies.