Arlene Licudine

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.

Childhood Trauma Is Associated With Hypothalamic-Pituitary-Adrenal Axis Responsiveness in Irritable Bowel Syndrome

BACKGROUND & AIMS A history of early adverse life events (EALs) is associated with a poorer outcome and higher levels of distress in adult patients with functional gastrointestinal disorders. An EAL is thought to predispose individuals to develop a range of chronic illnesses by inducing persistent changes in the central stress response systems, including the hypothalamic-pituitary-adrenal (HPA) axis. We sought to determine if EALs affect the HPA axis response to a visceral stressor in irritable bowel syndrome (IBS) patients and healthy controls, and to determine if this is affected by sex or related to symptoms or quality of life. METHODS Forty-four IBS patients (25 women, 19 men) and 39 healthy controls (21 women, 18 men) were assessed for gastrointestinal and psychological symptoms and EALs by validated questionnaires and interview. All subjects underwent a visceral stressor (sigmoidoscopy). Salivary cortisol was collected at baseline and serially for 1 hour poststressor. RESULTS Twenty-one IBS patients and 18 controls had EALs. In subjects with and without IBS, an EAL was associated with higher mean (+/-SD) cortisol levels (0.32 +/- 0.2 vs 0.20 +/- 0.1 microg/dL; P = .003) and higher area under the curve (28.1 +/- 17 vs 18.6 +/- 13 microg x min/dL; P = .005) after the stressor compared with subjects without EALs. In IBS, a faster resolution of cortisol to basal values corresponded to lower symptom severity (r = -0.36, P < .05) and better disease-specific quality of life (r = 0.33, P < .05). CONCLUSIONS HPA axis hyperresponsiveness to a visceral stressor is related more to a history of EALs than to the presence of IBS. However, HPA axis reactivity has a moderating effect on IBS symptoms.

Serum and Colonic Mucosal Immune Markers in Irritable Bowel Syndrome

OBJECTIVES:Low-grade colonic mucosal inflammation has been postulated to have an important role in the pathophysiology of irritable bowel syndrome (IBS). The objectives of this study were (i) to identify serum and tissue-based immunological and neuroendocrine markers associated with mucosal inflammation in male (M) and female (F) patients with non-post-infectious IBS (non-PI-IBS) compared with healthy controls and (ii) to assess possible correlations of such markers with IBS symptoms.METHODS:Sigmoid mucosal biopsies were obtained from 45 Rome II positive IBS patients without a history of PI-IBS (26 F, 35.5% IBS-C, 33.3% IBS-D, 31.1% IBS-A/M) and 41 healthy controls (22 F) in order to measure immunological markers (serum cytokine levels, colonic mucosal mRNA levels of cytokines, mucosal immune cell counts) and neuroendocrine markers associated with mucosal inflammation (corticotropin releasing factor- and neurokinin (NK)-related ligands and receptors, enterochromaffin cells). Symptoms were measured using validated questionnaires.RESULTS:Of all the serum and mucosal cytokines measured, only interleukin-10 (IL-10) mRNA expression showed a group difference, with female, but not male, patients showing lower levels compared with female controls (18.0±2.9 vs. 29.5±4.0, P=0.006). Mucosal mRNA expression of NK-1 receptor was significantly lower (1.15±0.19 vs. 2.66±0.56, P=0.008) in female, but not male, patients compared with healthy controls. No other significant differences were observed.CONCLUSIONS:Immune cell counts and levels of cytokines and neuropeptides that are associated with inflammation were not significantly elevated in the colonic mucosa of non-PI-IBS patients, and did not correlate with symptoms. Thus, these findings do not support that colonic mucosal inflammation consistently has a primary role in these patients. However, the finding of decreased IL-10 mRNA expression may be a possible biomarker of IBS and warrants further investigation.

Autonomic Response to a Visceral Stressor is Dysregulated in Irritable Bowel Syndrome and Correlates with Duration of Disease

Previous studies reported altered autonomic nervous system (ANS) responses in irritable bowel syndrome (IBS) at baseline and to colonic balloon distension. This study examined heart rate variability (HRV) and plasma catecholamines as an index of ANS responsiveness in IBS during flexible sigmoidoscopy (FS) and explored associations of HRV with clinical measures.

Irritable Bowel Syndrome and Early Life Trauma Are Associated With an Enhanced HPA Axis Response to Hormone Stimulation

G A A b st ra ct s group. Only 37% of the PPI group had documented indication for PPI use. Conclusions: SBP is common problem with cirrhotic patients. There are many risk factors associated with developing SBP, and one of these may be the use of PPIs. Our study found that the use of PPIs and lower ascitic albumin level may predispose patients to more severe infections and increase mortality. This is an important consideration when prescribing PPIs in cirrhotic patients.

T2072 Colonic Mucosal Inflammation is Unlikely to Play a Primary Role in Irritable Bowel Syndrome

Introduction: An enhanced mucosal immune or inflammatory response has been postulated to play a key role in the pathophysiology of IBS. Previous studies have reported an increase in serum cytokines and colonic mucosal lymphocyte and mast cell counts in IBS patients vs. healthy controls (HCs), but data are inconsistent and limited. Aims: 1) To compare inflammatory markers in the blood and colonic mucosa in IBS and HCs, 2) To determine if these measures are affected by sex, and 3) To explore if these measures are related to IBS symptoms.Methods: Male (M) and female (F) Rome positive IBS patients with stable disease activity and HCs underwent a sigmoidoscopy with colon biopsies (taken at 30 cm from the anal verge). Blood samples were also collected. The following was measured: 1) serum levels of cytokines (IL-1β, IL-6, IL-8, IL-10, and TNF-α), 2) mucosal mRNA levels of the same cytokines, CRF, and CRF1 receptor using real-time PCR, and 3) lymphocyte and mast cell counts per total biopsy area using an automated system. All subjects completed questionnaires assessing GI and non-GI symptoms. Results: 45 IBS patients (26F, 19M) and 41 agematched HCs (22F, 19M) were studied. IBS subtypes were 34% IBS-C, 34% IBS-D, and 32% IBS-M/A. None of the IBS patients had documented post-infectious IBS. Overall, there were no statistically significant differences in any of the measured inflammatory markers between IBS patients and HCs. However, group differences were seen amongst female subjects. Compared to healthy women, female IBS had a small but significant mean increase in serum level of the pro-inflammatory cytokine TNF-α (4.4±0.08 vs. 4.1±0.06 pg/ml, p= 0.046). They also had lower mucosal mRNA levels of the anti-inflammatory cytokine IL-10 compared to HCs (4.9±0.1 vs. 5.5±0.2, p=0.02). However, neither finding maintained statistical significance when corrected for multiple comparisons. Serum cytokine levels did not correlate with their respective mucosal cytokine mRNA levels (p=NS). There were no significant differences in CRF colonic mucosal expression or cell counts between IBS and controls. Serum IL-10 levels (r=-0.44, p = 0.006) and colonic mucosal CRF expression (r=0.45, p=0.003) negatively correlated with current symptom ratings. Conclusion: Taken together, the lack of strong and significant differences in mucosal and serum immune markers between IBS andHCs argues against the presence of a predominant proinflammatory response within the colonic mucosa in IBS. Further studies are needed to determine if an immune disturbance plays a more significant role in women with IBS, and if immune markers are associated with symptom flares in IBS.