Chronic psychological stress-orchestrated glial-ILC3 circuit exacerbates intestinal inflammation and depression

Chronic psychological stress can exacerbate intestinal inflammation both in patients with inflammatory bowel disease (IBD) and animal models of experimental colitis, but the underlying mechanism remains poorly understood. Here, we identified a chronic stress-orchestrated intestinal glia-Group 3 innate lymphoid cell (ILC3) circuit that impairs innate interleukin (IL)-22-mediated immune protection. We found that stress promoted the release of excessive amounts of glucocorticoid (GC) by the adrenal cortex through activation of the hypothalamic-pituitary-adrenal axis. Subsequently, chronically elevated level of GC dysregulated the phenotype and function of enteric glial cells (EGCs) through binding to the glucocorticoid receptor on EGCs, thereby weakening glial-derived neurotrophic factor production. These lead to the deficiency of innate IL-22 and impairment of gut defense. Simultaneously, we demonstrated that exacerbation of intestinal inflammation further unleashes the progression of neuroinflammation and anxiety/depression-like behaviors. Our work sheds light on a novel mechanism by which chronic psychological stress exacerbates intestinal inflammation, expanding the understanding of ILC3 biology and ILC3-mediated mucosal immunity. We proposed an innate IL-22-based therapeutic strategy for IBD patients with psychological comorbidities, and suggested stress management as a valuable component of IBD care in the context of bidirectional brain-gut communication.