Mopelola Adeyemo

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.

Differences in Gastrointestinal Symptoms According to Gender in Rome II Positive IBS and Dyspepsia in a Latin American Population

OBJECTIVES:Irritable bowel syndrome (IBS), constipation, and bloating are more prevalent in women than men, but gender differences associated with dyspepsia are inconsistent.The aim of this study was to determine gender differences in the prevalence of symptoms diagnostic for functional gastrointestinal disorders (FGIDs) in subjects with IBS and dyspepsia, as well as in controls in Mexico.METHODS:A database of 1,021 subjects (61% women) who completed the Rome II Modular Questionnaire (RIIMQ) in Spanish Mexico was analyzed. Gender differences in the frequency of all symptoms included in the RIIMQ between those fulfilling criteria for IBS (28.9%), dyspepsia (4.0%) and controls without any FGIDs (38.2%) were studied. Subjects fulfilling criteria only for other FGIDs were excluded.RESULTS:There were higher proportions of women with IBS (67.8%) and dyspepsia (85.4%) compared with the control group (55.9%) (P<0.001). In IBS, women more frequently reported changes in the number of bowel movements (BMs) associated with the onset of abdominal discomfort/pain, fewer than three BMs/week and abdominal fullness/bloating/swelling than men. Men with IBS more frequently reported swallowing air to belch and abdominal pain that improved after a BM than women. In controls, burping and hard or lumpy stools were both more frequent in men.CONCLUSIONS:In Mexico, gender differences in FGIDs exist, with both IBS and dyspepsia being more common in women than men. In IBS, symptoms related to constipation and bloating were more common in women, but the dyspepsia group was too small to draw any conclusions. Finally, this is the first study to report that belching is more common in men than women controls not fulfilling criteria for any FGID.

New Treatments for Irritable Bowel Syndrome in Women

The estimated prevalence of irritable bowel syndrome (IBS) in Western countries is 7–15%, with a female:male ratio of 2–2.5:1 in IBS patients who seek healthcare services; however, the female predominance is lower in the general population. IBS has a significant impact on health-related quality of life and is associated with a significant healthcare and economic burden. Management of IBS is comprised of general measures and pharmacologic and nonpharmacologic treatment. However, there are ongoing efforts to find more effective therapeutic approaches. As advancements in the understanding of the pathophysiology of IBS continue to grow, new and effective treatments with novel mechanisms of action that have the potential to improve relief of IBS symptoms over current treatments are likely to be developed. This article provides an overview of current and emerging therapies for IBS and also highlights sex and gender differences in clinical trials and treatment response.

The effect of sex and irritable bowel syndrome on HPA axis response and peripheral glucocorticoid receptor expression

BACKGROUND AND AIMS Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in irritable bowel syndrome (IBS). Enhanced HPA axis response has been associated with reduced glucocorticoid receptor (GR) mediated negative feedback inhibition. We aimed to study the effects of IBS status, sex, or presence of early adverse life events (EAL) on the cortisol response to corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH), and on GR mRNA expression in peripheral blood mononuclear cells (PBMCs). METHODS Rome III+ IBS patients and healthy controls underwent CRF (1μg/kg ovine) and ACTH (250μg) stimulation tests with serial plasma ACTH and cortisol levels measured (n=116). GR mRNA levels were measured using quantitative PCR (n=143). Area under the curve (AUC) and linear mixed effects models were used to compare ACTH and cortisol response measured across time between groups. RESULTS There were divergent effects of IBS on the cortisol response to ACTH by sex. In men, IBS was associated with an increased AUC (p=0.009), but in women AUC was blunted in IBS (p=0.006). Men also had reduced GR mRNA expression (p=0.007). Cumulative exposure to EALs was associated with an increased HPA response. Lower GR mRNA was associated with increased pituitary HPA response and increased severity of overall symptoms and abdominal pain in IBS. CONCLUSION This study highlights the importance of considering sex in studies of IBS and the stress response in general. Our findings also provide support for PBMC GR mRNA expression as a peripheral marker of central HPA response.

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.