INTESTINAL EPITHELIAL CELL-SPECIFIC DELETION OF JAK2 DISRUPTS GUT HOMEOSTASIS AND INCREASES INTESTINAL PERMEABILITY

Abstract BACKGROUND The intestinal epithelium is essential for barrier integrity and mucosal immune regulation. While Janus kinase (JAK)–STAT signaling is implicated in inflammatory bowel disease (IBD) and JAK inhibitors are increasingly used, the endogenous role of JAK2 in intestinal epithelial cells (IECs) remains poorly defined. Aim To define the in vivo role of epithelial JAK2 in barrier function, immune regulation, and colitis susceptibility. METHODS IEC-specific Jak2 knockout (vJak2 KO) mice were generated using the Villin-Cre/loxP system. Barrier function was assessed by FITC-dextran permeability assay. Tight junction, cytokine, and cell cycle gene expression were measured by RT-PCR. Histopathology and neutrophil infiltration were evaluated in H&E-stained sections. Colitis susceptibility was tested using dextran sodium sulfate (DSS). RESULTS vJak2 KO mice were born at expected ratios and maintained normal body weight. When examined at 12 weeks of age, they had developed shortened colons and mild small intestinal inflammation. vJak2 KO mice showed increased intestinal permeability, reduced tight junction gene expression, elevated Il13 and Il17, and reduced Il1b and Il6. Histology revealed neutrophil infiltration, villous blunting, and higher pathology scores in the small intestine without overt colitis. In a model of DSS-induced colitis, vJak2 KO mice exhibited modest, and dose-dependent exacerbation of weight loss. CONCLUSION Epithelial Jak2 supports barrier integrity and regulates expression of genes involved in mucosal immune state and integrity under steady-state conditions. These findings indicate that broad JAK inhibition may compromise epithelial function in IBD, highlighting the need to clarify the specific roles of JAKs and STATs in gut homeostasis and disease towards optimal therapeutic targeting.