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The intestinal epithelium acts as a physical barrier between the luminal microbes and the immune cells in the lamina propria while also coordinating a very delicate equilibrium to maintain mucosal homeostasis. Dysregulation in the physical barrier leads to inflammatory conditions like inflammatory bowel disease (IBD). Single nucleotide polymorphism (SNPs) in the gene protein tyrosine phosphatase non-receptor type 2 (PTPN2) has been implicated in IBD. These SNPs cause loss-of-function in the protein product of PTPN2 – T-cell protein tyrosine phosphatase (TCPTP). Along with genetic susceptibilities, alterations in the gut microbiota and expansion of pathobionts such as adherent-invasive Escherichia coli (AIEC) have also been associated with IBD. Our previous work showed, mice deficient for the expression of the IBD risk gene, Ptpn2, exhibit a microbial shift and pronounced expansion of a novel murine adherent-invasive Escherichia coli (mAIEC) strain. In this dissertation, we aimed to investigate how PTPN2 expression in intestinal epithelial cells (IEC) maintains equilibrium between the commensal bacteria and restricts invading pathobionts like mAIEC. To do so, we used, tamoxifen-inducible, IEC-specific knockout mice (Ptpn2∆IEC) and control floxed (Ptpn2fl/fl ) mice. We also used, Caco-2 BBe colonic IECs which were genetically modified by CRISPR-Cas9 to carry the SNP rs1893217 (PTPN2-KI) or a complete knockout of PTPN2 gene (PTPN2-KO). Overall, in this dissertation we have demonstrated a critical role of intestinal epithelial PTPN2 in mucosal immunity at it promotes anti-microbial peptide defenses and enhances barrier function during infection from pathobionts like mAIEC. Additionally, we also revealed that epithelial PTPN2 is crucial for maintaining immune-cytokine regulatory landscape of the gut to withstand pathobiont colonization. We also demonstrate a role for PTPN2 in regulating host proteins that mediate AIEC entry into host cell. These finding provide an essential cell-specific role for this clinically relevant gene in the maintenance of multiple aspects of mucosal barrier defenses against harmful bacteria.