Figure 1.

The mechanism by which chronic psychological stress aggravates IBD. (A) Stress activates the HPA axis: Stress induces the hypothalamus to release CRH, which triggers the release of ACTH from the hypophysis. ACTH subsequently initiates GC over-synthesis and release in the adrenal cortex. CRH reaches the colon through the blood and binds to CRHRs on the surface of MCs to promote degranulation and the production of proinflammatory cytokines IL-1β and TNF-α, which, in turn, increase the permeability of the colonic epithelial barrier. Furthermore, the overproduction of GC reduces tight junction protein expression between colonocytes, impairing the intestinal barrier function. (B) Stress activates the SNS but inhibits the vagus nerve: The sympathetic nervous system is stimulated by stress, which causes the adrenal medulla to secrete excessive AD and NE, promoting the activation of NF-κB signaling and mediating higher secretion of inflammatory cytokines in peripheral tissues. The inhibition of the anti-inflammatory effect of the vagus nerve promotes macrophage-induced TNF-α production, which aggravates the progress of colitis. (C) Stress is involved in innate and adaptive immune dysfunction by regulating specific immune cells and cytokine production: Stress induces macrophages to infiltrate the colon and polarize into an M1 phenotype. Additionally, stress promotes intestinal DCs to secrete IL-6 and IL-23, which induces Tregs to differentiate into a Foxp3⁺IL17⁺TNF-α⁺T cell phenotype. M1 macrophages and Foxp3⁺IL17⁺TNF-α⁺T cells secrete corresponding inflammatory cytokines to aggravate the colonic inflammatory response. (D) Stress induces microbiome community dysbiosis: Stress causes dysbiosis by increasing intestinal pathogens and decreasing SCFA-producing bacteria in the intestine. Intestinal pathogens can cause and exacerbate colitis by impairing the intestinal barrier and activating intestinal immunity. Decreased SCFAs lead to reduced tight junction protein expression and goblet cell numbers, which in turn lead to impaired intestinal barrier function and aggravated colonic inflammation. HPA axis, hypothalamic-pituitary-adrenal axis; CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; GC, glucocorticoids; CRHRs, CRH receptors; ANS, autonomic nervous system; SNS, sympathetic nervous system; AD, adrenaline; NE, noradrenaline; VS, vagus nerve; MCs, mast cells; SCFAs: short-chain fatty acids; MLN, mesenteric lymph node; ENS, enteric nervous system.