Psychological Stress-Induced Systemic Corticosterone Directly Sabotages Intestinal Stem Cells Activity

Stress exerts profound impacts on the gastrointestinal tract, yet its effects on intestinal stem cells (ISCs) have not been fully explored. Here, we unveiled a notable reduction in both the quantity and proliferative capacity of ISCs under chronic stress condition, which was mediated by elevated corticosterone levels resulting from the activation of the hypothalamic-pituitary-adrenal (HPA) axis. Mechanistically, corticosterone directly impairs ISCs by interacting with its receptor, nuclear receptor subfamily 3 group c member 1 (NR3C1), which promoted FKBP prolyl isomerase 5 (FKBP5) expression to negatively regulate the AKT activation by mediating the dephosphorylation at the Ser473, thus enhancing the nuclear translocation of the forkhead box O (FoxO) to inhibit the proliferative activity. Collectively, these findings provide a novel mechanistic insight into the deleterious effects of psychological stress on gut, and underscore corticosterone as a key mediator linking stress to ISCs dysfunction. Overall design: To deeply deciphered the molecular mechanisms that drives the deleterious effect of stress on ISCs via corticosterone, we conducted RNA-seq on Lgr5-GFPhi ISCs purified by fluorescence-activated cell sorting (FACS) from mice subjected to once exposure to either restraint stress or corticosterone injection. We then performed gene expression profiling analysis using data obtained from RNA-seq of 12 different ISCs. Comparative gene expression profiling analysis of RNA-seq data for Ctrl versus CRS ISCs, and Vehicle versus CORT ISCs.