Stress Impairs Murine Intestinal Barrier Function: Improvement by Glucagon-Like Peptide-2

Abstract

Stress-induced intestinal barrier dysfunction may be involved in chronic intestinal disorders. Glucagon-like peptide-2 (GLP-2) is an intestinotrophic growth hormone that can rapidly improve intestinal epithelial barrier function. Here, we investigated whether mouse intestine is responsive to chronic psychological stress and whether pretreatment with GLP-2 can ameliorate stress-induced changes. Mice were subjected to water avoidance stress (WAS; 1 h/day for 10 days) with GLP-2 or saline administered 4 h before each WAS session. After the final stress period, the intestine was removed for assessment of physiological/morphological changes. Compared with controls (sham-stressed mice), stressed mice demonstrated enhanced ion secretion and permeability in the jejunum, ileum, and colon. In addition, increased numbers of bacteria were observed adhering to and/or penetrating the epithelium, associated with infiltration of mononuclear cells into the mucosa. GLP-2 treatment improved intestinal barrier function in stressed mice and ameliorated other aspects of impaired host defense. Our study extends previous findings in rats of stress-induced intestinal dysfunction and provides insights into potential novel therapeutics.

In Vitro Diffusion Barriers of the Mouse Jejunum in Ussing Chambers

“…Perdue's group (10,11) have reported for the mouse jejunum that Gt was 20-25 mS/cm 2 , a value similar to the one obtained in this present work, although Perdue did not examine the characteristics of Gt or the morphology. Fromm's group (12) have estimated Gt of the subepithelial lamina propria-submucosa to be 25 mS/ cm 2 in the rat jejunum.…”

Role of Corticotropin-releasing Factor in Gastrointestinal Permeability

“…In rodents, acute or subchronic stressors, including restraint stress, cold restraint stress, WAS, mild noise stress, and mixed restraint and acoustic stress, increased tissue conductance, and the fluxes of 3 H mannitol, 51 Cr-labeled EDTA, horseradish peroxidase, in the jejunum, ileum, and colon. 32,50,54,[69][70][71][72] These results indicate the ability of stress to modulate paracellular and transcellular transport of ions, and small and large macromolecules. Multiple mechanisms have been invocated to explain stress-mediated transport abnormalities.…”

“…53 Several other studies using various stress models have reproduced the elevation of Isc in the colon and ileum of rodents and showed the involvement of CRF receptors. 24,33,45,50,[54][55][56] Both the acute intraperitoneal administration of CRF and chronic peripheral administration of CRF, the selective CRF 1 receptor agonist stressin-1 and the selective CRF 2 receptor ligand, Ucn3, increase the basal rat colonic Isc. 33,57 Therefore, a role for both CRF receptor subtypes in this alteration is suggested, although the response is not reduced by the selective CRF 2 receptor antagonist antisauvagine.…”

Glucocorticoids and the Intestinal Environment

“…However, the duration and repetition of stressors may influence severity, and the alterations may be temporary or permanent [34,58]. Generally, intestinal ion secretion [40,59], macromolecular permeability [60,61], inflammation [40,59], visceral hypersensivity and colonic motility increased [40], while gastric motility decreased in various animal models of stress [62][63][64]. These stress responses have been also described in IBD patients and involve dysregulation of HPA axis [12,15,17].…”

“…In humans, the jejunal net water and sodium chloride absorption decreased during both psychological (induced by dichotomous listening) [78] and physical stress (induced by cold pain) [79], and also ion absorption is changed toward secretion in psychological form [78]. Both acute and chronic stress inductions increased short circuit current (an in vitro technique used for measuring the secretory response of intestines) in several parts of rodent intestines [36,41,59,80]. In addition, the peripheral non-selective CRF antagonists astressin or -helical CRF9-41 abolished stress-induced alterations [41,80,81].…”