Intestinal epithelial cell-specific deletion of Jak2 disrupts gut homeostasis

Disruption of the intestinal epithelial barrier is recognized as a driver of inflammatory bowel disease (IBD) pathogenesis, yet the signaling pathways that govern epithelial integrity remain incompletely defined. Among these, Janus kinase (JAK)-mediated signaling plays a role in intestinal epithelial cells (IECs), coordinating barrier function and host defense. However, the role of JAK2 in IECs remains poorly understood. To investigate the in vivo role of epithelial JAK2, we generated mice with IEC-specific Jak2 deletion using the Villin-Cre system. These mice were born at expected Mendelian ratios and normal body weights. By 12 weeks of age, they developed shortened colons and exhibited mild small intestinal inflammation under homeostatic conditions. Histological analysis revealed increased neutrophilic infiltration and epithelial damage in the small intestine, without overt colitis. JAK2 deficiency led to increased intestinal permeability, with altered expression of genes that determine tight junctions, and a skewed cytokine gene expression profile marked by elevated Il13 and Il17 and reduced Il1-β and Il6. When subjected to dextran sodium sulfate (DSS)-induced colitis, Jak2-deficient mice exhibited sex-dependent weight loss. These findings show that IEC-specific JAK2 promotes barrier integrity and constrains low-grade inflammation under homeostatic conditions, highlighting a previously underappreciated role for epithelial JAK2 in mucosal regulation.