Pathways involved in gut mucosal barrier dysfunction induced in adult rats by maternal deprivation: corticotrophin‐releasing factor and nerve growth factor interplay

Abstract

Neonatal maternal deprivation (NMD) increases gut paracellular permeability (GPP) through mast cells and nerve growth factor (NGF), and modifies corticotrophin-releasing factor (CRF) and corticosterone levels. CRF, corticosterone and mast cells are involved in stress-induced mucosal barrier impairment. Consequently, this study aimed to specify whether corticosteronaemia and colonic expression of both preproCRF and CRF are modified by NMD, and to determine if altered expression may participate in the elevated GPP in connection with NGF and mast cells. Male Wistar rat pups were either separated from postnatal days 2-14, or left undisturbed with their dam. At 12 weeks of age, adult rats were treated with mifepristone (an antagonist of corticoid receptors), α-helical CRF (9-41) (a non-specific CRF receptor antagonist), or SSR-125543 (CRF-R 1 receptor antagonist). We also determined corticosteronaemia and both colonic preproCRF and CRF expression. Then, control rats were treated by CRF, doxantrazole (mast cell stabilizer), BRX-537A (a mast cell activator) and anti-NGF antibody. NMD did not modify colonic CRF level but increased colonic preproCRF expression and corticosteronaemia. Peripheral CRF, via CRF-R 1 receptor, but not corticosterone, was involved in the elevated GPP observed in these rats, through a mast-cell-mediated mechanism, since the increase of GPP induced by exogenous CRF was abolished by doxantrazole. Anti-NGF antibody treatment also reduced the elevated GPP induced by CRF or BRX-537A. CRF acts through CRF-R 1 receptors to stimulate NGF release from mast cells, which participates in the elevated GPP observed in NMD adult rats. This suggests that early traumatic experience induced neuro-endocrine dysfunction, involved in alterations of gut mucosal barrier.

Role of Corticotropin-releasing Factor in Gastrointestinal Permeability

“…79 Stress-induced enhancement of colonic permeability was mimicked by exogenous administration of CRF, 33 and abolished by pretreatment with the peripheral administration of the non-selective CRF antagonists astressin or -helical CRF 9-41 . 37,55,80 Likely, the selective CRF 1 receptor agonist, cortagine, 48 the selective CRF 1 receptor antagonist, SSR-125543, 80 and the selective CRF 2 receptor antagonist, antisauvagine-30, 78 reduced the response, supporting the participation of both CRF receptors in the modulation of colonic permeability.…”

“…76 A subsequent study from the same group showed that CRF, acting through its receptor CRF 1 receptor, stimulated NGF release from mast cells, which in turn increased gut paracellular permeability. 80 Dendritic cells are relevant for the regulation of intestinal immune function and permeability through CRF production, a process augmented by commensal bacteria. 107 Similarly, CRF 1 and CRF 2 receptor agonists exert a biphasic effect on macrophages.…”

Nerve growth factor and diarrhea-predominant irritable bowel syndrome (IBS-D): a potential therapeutic target?

“…2), psychophysiological stress (such as adverse life events, catching cold, and intestinal infection) activates the hypothalamic-pituitary-adrenal (HPA) axis (Mayer, 2000;Chang et al, 2009;Kennedy et al, 2014). The central and intestinal corticotropin releasing factor (CRF) increases and activates intestinal MCs (Barreau et al, 2007;Overman et al, 2012). Activated MCs degranulate and release mediators such as NGF and tryptase.…”

New Insights in the Etiology and Pathophysiology of Irritable Bowel Syndrome: Contribution of Neonatal Stress Models

“…Indeed, treating (i.p. route) animals with either nonselective CRF-R1/2 (␣-helical CRF 9-41) or selective CRF-R1 (NBI-35965, CP-154, 526 and SSR-125543) receptor antagonists abolishes the effects of NMD on gut permeability, bacterial translocation, and visceral hypersensitivity (29,54,56,63,64). It is established that CRF-R1 mediates stress-induced gut disturbances in adult animals (64 -66); these results confirm that CRF-R1 is likewise involved in NMD-induced gut dysfunctions in newborn rat.…”