Dysregulation of the hypothalamic‐pituitary‐adrenal (HPA) axis in irritable bowel syndrome

Abstract

Enhanced stress responsiveness has been implicated as a potential mechanism contributing to the pathophysiology of irritable bowel syndrome (IBS), and should be reflected in altered function of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Both of these systems can modulate mucosal immune function. The aims of this study were: (i) to characterize the basal circadian rhythm of adrenocorticotropin hormone (ACTH) and cortisol in IBS vs healthy controls; (ii) to compare stimulated ACTH, cortisol and noradrenaline responses to a pelvic visceral stressor (sigmoidoscopy) in IBS and controls; and (iii) to correlate neuroendocrine responses with colonic mucosal cytokine expression and symptoms in IBS. Two separate studies were conducted in women. In Study 1, basal cortisol levels were analysed in 41 IBS and 25 controls using 24-h collections of plasma ACTH and cortisol (q10 min sampling). In Study 2, 10 IBS patients with diarrhoea (IBS-D) and 10 controls underwent sigmoidoscopy with measurements of stimulated neuroendocrine responses and cytokine mRNA expression in colonic tissue. Basal ACTH levels were significantly blunted (P < 0.05), while basal and stimulated plasma cortisol levels were higher in patients. Basal cortisol levels prior to an experimental visceral stressor positively correlated with anxiety symptoms (P < 0.004), but not IBS symptoms. Irritable bowel syndrome patients with diarrhoea had significantly decreased mRNA expression of mucosal cytokines [interleukin (IL)-2, IL-6] in the sigmoid colon vs controls (P < 0.05). Although dysregulations in stress-responsive systems such as the HPA axis and mucosal immune function are demonstrated in IBS, they do not appear to have a primary role in modulating IBS severity and abdominal pain.

Importance of CRF Receptor-Mediated Mechanisms of the Bed Nucleus of the Stria Terminalis in the Processing of Anxiety and Pain

“…Corticotropin-releasing factor (CRF) is a neuromodulator involved in the behavioral and physiological response to stress and is often linked to adversity associated with anxiety and pain disorders, including irritable bowel syndrome (IBS; Chang et al, 2009;Dinan et al, 2006;Fukudo, 2013). In support, our previous studies and others have investigated the effects of repeated psychological stress in a preclinical model that reproduces the hallmark traits of IBS (Bradesi et al, 2005;Myers and Greenwood-Van Meerveld, 2012;Tran et al, 2013;Venkova et al, 2010).…”

Review article: associations between immune activation, intestinal permeability and the irritable bowel syndrome

“…Overall, most studies reported altered cytokine expression levels. Pro-inflammatory cytokines known to be associated with activated mononuclear cells (IL-1b, IL-6, IL-8, IL-12) and activated lymphocytes (IL-2, IFN-c) were found to be either down-regulated 76,[101][102][103] or up-regulated. 25,76 Increased TNFa 76 and NO 41 levels were observed in rectal and colonic mucosa.…”

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).…”