STAT3 is a transcription factor involved in cytokine signaling and plays a key role in regulating immune homeostasis in the gut. This study shows that STAT3 activity in intestinal epithelial cells (IECs) is induced during colitis and is essential for mucosal wound healing. The researchers used genetically engineered mice to demonstrate that STAT3 activation in IECs is dependent on IL-22, not IL-6. IL-22 is secreted by colonic CD11c+ cells in response to Toll-like receptor stimulation. Conditional knockout mice with an IEC-specific deletion of STAT3 activity were highly susceptible to experimental colitis, indicating that epithelial STAT3 regulates gut homeostasis. STAT3LEC-KO mice showed a defect in epithelial restitution during colitis. Gene chip analysis indicated that STAT3 regulates the cellular stress response, apoptosis, and wound healing pathways in IECs. Both IL-22 and epithelial STAT3 were found to be important in wound-healing experiments in vivo. The study also shows that IL-22 is specifically induced by CD11c+ cells during acute experimental colitis. IL-22 activates STAT3 in IECs, which promotes mucosal wound healing. The findings suggest that STAT3 signaling in IECs is crucial for maintaining intestinal homeostasis and that IL-22 is an important regulator of mucosal wound healing via STAT3 activation in IECs. The study highlights the role of innate immune cells, such as CD11c+ cells, in producing IL-22, which is essential for maintaining gut homeostasis and promoting wound healing. The results indicate that STAT3 is dispensable for gut homeostasis under steady-state conditions but is activated upon challenge to drive tissue regeneration and protection in situations of increased demand, such as during colitis and injury.STAT3 is a transcription factor involved in cytokine signaling and plays a key role in regulating immune homeostasis in the gut. This study shows that STAT3 activity in intestinal epithelial cells (IECs) is induced during colitis and is essential for mucosal wound healing. The researchers used genetically engineered mice to demonstrate that STAT3 activation in IECs is dependent on IL-22, not IL-6. IL-22 is secreted by colonic CD11c+ cells in response to Toll-like receptor stimulation. Conditional knockout mice with an IEC-specific deletion of STAT3 activity were highly susceptible to experimental colitis, indicating that epithelial STAT3 regulates gut homeostasis. STAT3LEC-KO mice showed a defect in epithelial restitution during colitis. Gene chip analysis indicated that STAT3 regulates the cellular stress response, apoptosis, and wound healing pathways in IECs. Both IL-22 and epithelial STAT3 were found to be important in wound-healing experiments in vivo. The study also shows that IL-22 is specifically induced by CD11c+ cells during acute experimental colitis. IL-22 activates STAT3 in IECs, which promotes mucosal wound healing. The findings suggest that STAT3 signaling in IECs is crucial for maintaining intestinal homeostasis and that IL-22 is an important regulator of mucosal wound healing via STAT3 activation in IECs. The study highlights the role of innate immune cells, such as CD11c+ cells, in producing IL-22, which is essential for maintaining gut homeostasis and promoting wound healing. The results indicate that STAT3 is dispensable for gut homeostasis under steady-state conditions but is activated upon challenge to drive tissue regeneration and protection in situations of increased demand, such as during colitis and injury.