Role of Corticotropin-releasing Factor in Gastrointestinal Permeability

Abstract

The interface between the intestinal lumen and the mucosa is the location where the majority of ingested immunogenic particles face the scrutiny of the vast gastrointestinal immune system. Upon regular physiological conditions, the intestinal microflora and the epithelial barrier are well prepared to process daily a huge amount of food-derived antigens and non-immunogenic particles. Similarly, they are ready to prevent environmental toxins and microbial antigens to penetrate further and interact with the mucosal-associated immune system. These functions promote the development of proper immune responses and oral tolerance and prevent disease and inflammation. Brain-gut axis structures participate in the processing and execution of response signals to external and internal stimuli. The brain-gut axis integrates local and distant regulatory networks and supersystems that serve key housekeeping physiological functions including the balanced functioning of the intestinal barrier. Disturbance of the brain-gut axis may induce intestinal barrier dysfunction, increasing the risk of uncontrolled immunological reactions, which may indeed trigger transient mucosal inflammation and gut disease. There is a large body of evidence indicating that stress, through the brain-gut axis, may cause intestinal barrier dysfunction, mainly via the systemic and peripheral release of corticotropin-releasing factor. In this review, we describe the role of stress and corticotropin-releasing factor in the regulation of gastrointestinal permeability, and discuss the link to both health and pathological conditions. (J Neurogastroenterol Motil 2015;21:33-50)

Chronic Early-life Stress in Rat Pups Alters Basal Corticosterone, Intestinal Permeability, and Fecal Microbiota at Weaning: Influence of Sex

“…6,34 Glucocorticoids play a role in the increased intestinal permeability induced by a short acute maternal separation stress in PND10 pups 17 but not in adult rats subjected to repeated maternal separation. 36,37 In the present study, we found no correlation between corticosterone plasma levels and intestinal permeability at weaning, either in LNS or BMS models, suggesting that glucocorticoids are not involved in the mechanisms contributing to the altered permeability. Peripheral corticotropin-releasing factor receptors and nerve growth factors have been identified as major underlying mechanisms of the enhanced intestinal permeability in adult rats exposed to intermittent maternal separation post-natally.…”

“…Peripheral corticotropin-releasing factor receptors and nerve growth factors have been identified as major underlying mechanisms of the enhanced intestinal permeability in adult rats exposed to intermittent maternal separation post-natally. 36,37 Whether similar mechanisms are implicated in the increased permeability during the developmental period at weaning need to be further investigated. Intestinal barrier disruption has been described to occur in IBS patients, [38][39][40][41] although the link between early adverse life events and increased intestinal permeability needs to be evaluated based on the present experimental data.…”

Corticotropin-releasing Factor Changes the Phenotype and Function of Dendritic Cells in Mouse Mesenteric Lymph Nodes

“…22,23 In contrast, activation of CRF-R2 by administration of CRF-R2 agonist can prevent visceral pain induced by colorectal distention. 24 With respect to the relationship between these two receptors, it has been reported that CRF-R1 is the primary receptor involved in stress-induced alterations of lower gut secretomotor and pain sensations, whereas CRF-R2 regulates the CRF-R1-mediated stimulation of intestinal motor function.…”

Irritable Bowel Syndrome: Is It Really a Functional Disorder? A New Perspective on Alteration of Enteric Nervous System

“…For example, the corticotrophin-releasing factor, a key modulator of stress response in the brain, has been extensively investigated and the present role in the gastrointestinal tract such as decreasing gastric emptying, increasing colonic motility, and inducing visceral hypersensitivity are established. [2][3][4] Psychological comorbidities such as depression and anxiety are also more prevalent in patients with IBS compared to healthy controls and is thought to play an important role in IBS.…”

“…For example, the corticotrophin-releasing factor, a key modulator of stress response in the brain, has been extensively investigated and the present role in the gastrointestinal tract such as decreasing gastric emptying, increasing colonic motility, and inducing visceral hypersensitivity are established. [2][3][4] Psychological comorbidities such as depression and anxiety are also more prevalent in patients with IBS compared to healthy controls and is thought to play an important role in IBS.1 However, latest medical and scientific developments have led to further investigation of organic changes in patients with IBS such as inflammatory cell infiltration, increased permeability, and changes in neuroendocrine system in the gut. 5,6 The enteric nervous system (ENS) is one of the candidates for a possible organic cause of underlying IBS pathophysiology.…”