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

Center for Neurobiology of Stress, David Geffen School of Medicine, University of California, Los Angeles, CA 90073, USA.
Neurogastroenterology and Motility (Impact Factor: 3.59). 09/2008; 21(2):149-59. DOI: 10.1111/j.1365-2982.2008.01171.x
Source: PubMed


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.

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Available from: Emeran A Mayer, Mar 11, 2014
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    • "mechanical allodynia and thermal hyperalgesia (Zhang et al., 2012), and (b) a mouse model of chronic psychosocial stress along with visceral hiperalgesia (Tramullas et al., 2012). This evidence highlights that changes in both the HPA axis activity and the immune function are involved in chronic stress-induced hyperalgesia (Blackburn- Munro and Blackburn-Munro, 2001; Fries et al., 2005; Chang et al., 2009; Sominsky et al., 2013). Yet, it is not completely clear the way the HPA axis, immune and nociceptive functions are connected as to lead to the development of enduring cutaneous pain after repeated exposure to stress. "
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    ABSTRACT: Although it is widely known that immunological, hormonal and nociceptive mechanisms are altered by exposure to repeated stress, the interplaying roles of each function in the development of post-stress hyperalgesia are not completely clear. Thus, we wanted to establish how interleukin 1-beta (IL-1β), corticosterone and microglia interact to contribute in the development of hyperalgesia following repeated forced swim. Rats were subjected to either forced swim, sham swim or non-conditioned. Each group was then treated with minocycline, ketoconazole, or saline. Thermal nociception was measured via the hot plate test, before and after the behavioral conditioning, whereas blood and lumbar spinal cord tissue samples were obtained at the end of the protocol. Serum levels of corticosterone, spinal tissue concentration of IL-1β and spinal OX-42 labeling (microglial marker) were determined. Rats exposed to forced swim stress developed thermal hyperalgesia along with elevated spinal tissue IL-1β, increased OX-42 labeling and relatively diminished serum corticosterone. Pre-treatment with minocycline and ketoconazole prevented the development of thermal hyperalgesia and the increase in IL-1β, without significantly modifying serum corticosterone. These results suggest that the development of forced swim-induced thermal hyperalgesia requires the simultaneous presence of increased spinal IL-1β, microglial activation, and relatively decreased serum corticosterone.
    Brain research bulletin 12/2013; 100. DOI:10.1016/j.brainresbull.2013.11.003 · 2.72 Impact Factor
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    • "A relationship between ELA and the development of IBS in adulthood has been described in clinical literature and animal models. Furthermore, both ELA and IBS are characterized by female predominance and dysregulation of the HPA axis (Drossman et al., 1997; Whitehead et al., 2002; Dinan et al., 2006; Tarullo and Gunnar, 2006; Hyman et al., 2008; Chang et al., 2009). Therefore, the mechanisms by which ELA induces visceral hypersensitivity likely involve ovarian hormones and signaling within the HPA axis. "
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    ABSTRACT: A history of early life adversity (ELA) has health-related consequences that persist beyond the initial maltreatment and into adulthood. Childhood adversity is associated with abnormal glucocorticoid signaling within the hypothalamic-pituitary-adrenal (HPA) axis and the development of functional pain disorders such as the irritable bowel syndrome (IBS). IBS and many adult psychopathologies are more frequently diagnosed in women, and ovarian hormones have been shown to modulate pain sensitivity. Therefore, the sexually dimorphic effects of ELA and the role of ovarian hormones in visceral pain perception represent critical research concepts to enhance our understanding of the etiology of IBS. In this review, we discuss current animal models of ELA and the potential mechanisms through which ovarian hormones modulate the HPA axis to alter nociceptive signaling pathways and induce functionally relevant changes in pain behaviors following ELA.
    Frontiers in Neuroscience 02/2013; 7(7):13. DOI:10.3389/fnins.2013.00013 · 3.66 Impact Factor
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    • "Stress and episodes of anxiety are strongly implicated in the pathophysiology of irritable bowel syndrome (IBS), a chronic functional gastrointestinal (GI) disorder characterized by abdominal pain and abnormal bowel habits (Longstreth et al., 2006; Lydiard, 2001; Mayer et al., 2009; Posserud et al., 2004). This comorbidity of stress with the exacerbation of IBS symptomatology is supported by an abnormal hypothalamic-pituitary-adrenal (HPA) axis in IBS patients (Chang et al., 2009; Dinan et al., 2006). Further supporting the link between stress and IBS, the symptoms of IBS persist long after a stressful event and are exacerbated by subsequent stress (Blanchard et al., 2008). "
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    ABSTRACT: Epigenetic molecular mechanisms, which include DNA methylation and histone deacetylation, are implicated in the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Previously, we demonstrated that repeated water avoidance stress (WAS), a validated model of chronic psychological stress, induces heightened visceral pain behaviors in rodents that resemble irritable bowel syndrome (IBS) sequelae. However, the involvement of epigenetic molecular mechanisms in the pathophysiology of stress-induced visceral pain has not been explored. Our hypothesis is that epigenetic mechanisms within the central nervous system (CNS) are important to chronic stress-induced visceral hypersensitivity. Adult male F-344 rats with intracerebroventricular (i.c.v.) cannulae were exposed to 7 days of repeated WAS. Controls received a SHAM stress. Following the daily 1h stressor, trichostatin A (TSA; 100ng/ml), a potent histone deacetylase inhibitor, or vehicle (VEH; 0.1% DMSO/saline,) as control was administered via the i.c.v. cannula. Visceral sensitivity was assessed 24h after the final WAS and quantified the visceromotor response (VMR) by recording the number of abdominal contractions in response to graded pressures (20-60mmHg) of colorectal distensions (CRD). From a separate group of rats that were exposed to repeated WAS or SHAM stress, the amygdala was isolated to assess the methylation status of glucocorticoid receptor (GR) and corticotropin releasing-factor (CRF) genes via bisulfite sequencing and verified by pyrosequencing. GR and CRF gene expression was quantified via qRT-PCR. Stressed rats exhibited visceral hypersensitivity that was significantly attenuated by TSA. Compared to SHAM controls, methylation of the GR gene was increased following WAS while expression of the GR gene was decreased. Methylation of the CRF promoter was decreased with WAS with a concomitant increase in CRF expression. This study demonstrates the involvement of central epigenetic mechanisms in regulating stress-induced visceral hypersensitivity and provides a foundation for exploring the epigenetic mechanisms that may contribute to IBS-like symptomatology.
    Psychoneuroendocrinology 10/2012; 38(6). DOI:10.1016/j.psyneuen.2012.09.016 · 4.94 Impact Factor
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