Abstract Background Suppressing JAK/STAT signaling can reduce inflammation in patients with inflammatory bowel disease (IBD). However, its exact role in intestinal epithelial components and its impact on mucosal healing remain unclear. This study aims to investigate the effects and regulation of JAK/STAT signaling inhibition on intestinal epithelial cells (IECs) and stem cells (ISCs) during acute intestinal inflammation using mouse and organoid models. Methods For mice with dextran sodium sulfate (DSS)-induced acute enteritis, JAK/STAT signaling was inhibited using JAK inhibitors. Enteritis severity, intestinal barrier integrity, and tight junction proteins were evaluated, as well as the expression, proliferation, and apoptosis of IECs and ISCs. In vitro, mouse intestinal organoids were developed to explore the effects of JAK/STAT inhibition on organoids, IECs, and ISCs during TNF-a-induced injury. Results Inhibiting overactivated JAK/STAT signaling reduced enteritis severity and inflammation in mice, while enhancing epithelial integrity by improving mucosal permeability and restoring tight junction protein expression. The JAK inhibitor also restored the expression of IECs and ISCs, promoted proliferation, and inhibited apoptosis in the epithelium, thereby supporting epithelial homeostasis and regeneration during acute inflammation. In vitro, inhibition of JAK/STAT signaling significantly improved organoid growth, proliferation, and differentiation under rmTNF-α-induced injury. In addition to reducing inflammation, it also restored IECs and ISCs in organoids by facilitating their proliferation and differentiation and suppressing apoptosis. Conclusion Overactivated JAK/STAT signaling during acute inflammation disrupts intestinal epithelial homeostasis. Inhibiting JAKISTAT signaling promotes IEC and ISC proliferation and differentiation while suppressing inflammation, ultimately facilitating mucosal homeostasis and repair during acute inflammation. Conflict of interest: Liu, Haoying: No conflict of interest Wang, Lijia: No conflict of interest Xu, Jiaxin: No conflict of interest Shen, Yinxian: No conflict of interest Huang, Shangzhan: No conflict of interest Zhou, Qi: No conflict of interest Liao, Jiazhi: No conflict of interest Dr. Xiao, Fang: No conflict of interest
Liu et al. (Thu,) studied this question.