Fig. 1: Chronic stress leads to excessive activation of the HPA axis, causing harm to the immune and physiological systems, and eventually contributing to the onset of depression.

a Chronic psychological stress induces hyperactivation of the HPA axis, resulting in the release of glucocorticoids (GCs), which disrupt circuits responsible for regulating the stress response and maintaining physiological balance. CRH corticotropin-releasing hormone, ACTH adrenocorticotropic hormone, GCs glucocorticoids. b GCs are synthesized and released by the adrenal glands during HPA activation, can cross the blood-brain barrier (BBB) via P-glycoprotein (P-gp) transporters on endothelial cells, and bind to GC receptors on brain cells, including microglia and neurons. Prolonged binding of GCs to microglia receptors may induce a pro-inflammatory state in these resident immune cells of the central nervous system (CNS). P-gp: P-glycoprotein. c Prolonged and sustained stress also triggers the overactivation of various effector cells in the immune system, resulting in harmful effects. d Chronically elevated glucocorticoid levels promote the development of an inflammatory subset of enteric glia and cause transcriptional immaturity in enteric neurons, leading to gut dysmotility. The illustration was created using resources from Biorender.com.