Inflammatory Bowel Disease (IBD) is characterized by inflammation along the gastrointestinal tract that causes diarrhea, cramping, weight loss, and fatigue. IBD has been associated with the loss of function of the Protein Tyrosine Phosphatase non-receptor Type 2 (Ptpn2) gene. Our group has reported that whole-body Ptpn2-knockout (KO) mice have decreased numbers and functionality of specialized small intestinal epithelial cells called Paneth cells, increased gut barrier permeability, and a dysregulated gut microbiome, all of which are factors in IBD development. Intestinal epithelial cells (IECs) directly maintain gut microbiome homeostasis, control gut permeability, create the mucus layer, and absorb nutrients, thus Ptpn2 deletion could directly influence multiple IEC functions. Moreover, whole-body Ptpn2 deletion causes a hyperactive immune response in mice, which significantly compromises the differentiation and function of IECs. Here, we investigated whether intrinsic epithelial Ptpn2 loss affects the function and differentiation of IEC subtypes in vitro and in vivo. Methods: Enteroids were generated from small intestinal crypts isolated from Ptpn2-wildtype (WT) and global Ptpn2-KO mice (BALB/c). In addition, tamoxifen-inducible epithelial-specific Ptpn2-KO mice (Ptpn2?IEC) and Ptpn2 controls (Ptpn2fl/fl; C57Bl/6J) had IECs isolated for total RNA isolation followed by qPCR analysis of gene targets associated with function and differentiation of IEC subtypes. Results: In undifferentiated enteroids, the expression of IEC subtype-associated genes Lyz1, Defa5, and Defa6 (Paneth cells), Muc2 and Tff3 (goblet cells), c-Maf (enterocytes), and Sucnr1 and Pou2f3 (tuft cells), showed no significant difference in Ptpn2-WT versus KO enteroids. In addition, there was no change in the expression of the same targets in ileal IECs of Ptpn2?IEC versus Ptpn2fl/fl mice (n>5), except for Paneth cell markers that were all downregulated as reported by the McCole lab in a previous publication. However, immunostaining for Dclk1, a tuft cell marker, revealed higher numbers of tuft cells in the ileum of Ptpn2?IEC vs. Ptpn2fl/fl mice (n=6), while alcian blue staining revealed elevated number of goblet cells in the colon of Ptpn2?IEC vs. controls (n=8). Conclusion: Epithelial Ptpn2 deletion does not impact the expression of IEC markers in vitro, but it does increase the number of tuft and goblet cells in vivo. This implies a requirement for non-epithelial cell types in epithelial Ptpn2 regulation of IEC differentiation.