A role for corticotropin-releasing factor in functional gastrointestinal disorders

Abstract

Functional gastrointestinal disorders (FGIDs), which include irritable bowel syndrome (IBS), encompass a heterogeneous group of diseases identified by chronic or recurrent symptom-based diagnostic criteria. Psychosocial factors are key components in the outcome of clinical manifestations of IBS symptoms. Anxiogenic and endocrine responses to stress are mediated by the corticotropin-releasing factor (CRF)–CRF1 receptor pathway. Preclinical studies show that activation of the CRF1 receptor by exogenous CRF or stress recapitulates many functional symptoms of IBS diarrhea-predominant patients as related to anxiogenic/hypervigilant behavior, autonomic nervous system alterations, induction of diarrhea, visceral hyperalgesia, enhanced colonic motility, mucus secretion, increased permeability, bacterial translocation, and mast cell activation, which are all alleviated by selective CRF1 receptor antagonists. Clinical studies also support that CRF administration can induce IBS-like symptoms in healthy subjects and heighten colonic sensitivity in IBS patients. Yet to be ascertained is whether CRF1 receptor antagonists hold promise as a new therapy in IBS treatment.

Mast Cells and Irritable Bowel Syndrome: From the Bench to the Bedside

“…51 Abnormal small intestinal and colonic permeability, which facilitates enhanced antigen exposure that may activate the intestinal immune system, has been implicated in the pathogenesis of IBS. 61,62 Numerous evidence showed a positive relationship between the number of mucosal MCs and intestinal permeability, 61 and the MC-derived tryptase was well identified as a key factor disrupts the intestinal barrier. 63 MC tryptase cleaves PAR2 on colonocytes to increase paracellular permeability by acting on intercellular apical junction complex, which mainly consists of the tight junctions such as claudins, occludin, zonula occludens, junctional adhesion molecule, and the adherens junction such as E-cadherin.…”

“…82,83 Acute or chronic stress exposure has widely impacted on intestinal functions and MC activation. 62,84 Plenty of work has been done to verify the concept that MCs contribute to stress induced gut dysfunction. For example, MCs mediate stress induced intestinal barrier disruption [85][86][87] and visceral hypersensitivity 82,88,89 due to the release of tryptase, TNF-α, 86 and histamine.…”

“…91 Recently, evidence supported that stress induced CRF, acting on the CRF1 and CRF2 receptors, should be the key factors in MCs degranulation. 62,85,86 Stress triggers the increase in intestinal paracellular permeability via mast cell dependent release of proteases, which could be reproduced by peripheral administration of CRF, and blocked by CRF 1/2 receptor antagonist, mast cell stabilizers, and protease inhibitors. 86 …”

A preliminary investigation of the effects of cognitive behavioral therapy for panic disorder on gastrointestinal distress in patients with comorbid panic disorder and irritable bowel syndrome

“…Corticotrophin-releasing factor (CRF) is a neuropeptide which plays a central role in mediating the stress response, fear and arousal, immune function, GI function, and chronic pain. [6][7][8] CRF dysregulation plays an important role in the pathophysiology of anxiety and mood disorders, IBS, and others commonly co-occurring conditions. [3,9] Across these commonly co-occurring disorders, there is accruing evidence for disruption of the normal inhibitory feedback in the HPA axis.…”

Biological interaction of stress and irritable bowel syndrome

“…CRF plays a crucial role in the stress-related stimulation of the hypothalamo-pituitary-adrenal axis and, in association with urocortins, acts as a neuromodulator to coordinate the behavioural, autonomic, and visceral efferent limbs of the stress response. [23][24][25][26] These peptides act as messengers and interact with CRF receptors (CRF1 and CRF2) located, among other sites, both in the gut and brain regions linked with digestive function, emotional behaviour, and autonomic nervous system activity. [16] It is increasingly recognized that CRF1 receptors activated by CRF and urocortin 1 in brain stress network increase the anxiety-like behaviour along with changes in endocrine function and in gut these peptides change the colon functions, such as muscle contractions or motility, secretion and pain sensitivity leading to abdominal pain and development of watery stool or diarrhea.…”