Gastroenterology

Gastroenterology

Volume 130, Issue 2, February 2006, Pages 304-311
Gastroenterology

Clinical–alimentary tract
Hypothalamic-Pituitary-Gut Axis Dysregulation in Irritable Bowel Syndrome: Plasma Cytokines as a Potential Biomarker?

https://doi.org/10.1053/j.gastro.2005.11.033Get rights and content

Background & Aims: Irritable bowel syndrome (IBS) is a functional disorder with an etiology that has been linked to both psychological stress and infection. The primary aim of this study was to examine the hypothalamic-pituitary-adrenal axis in patients with IBS and to relate such response to plasma cytokine profiles. Methods: A total of 151 subjects, 76 patients and 75 controls, were recruited. The patients with IBS were diagnosed according to Rome II criteria. Forty-nine patients and 48 matched controls had cytokine levels measured, and a subset of 21 patients and 21 controls also underwent a corticotropin-releasing hormone (CRH) stimulation test with plasma levels of adrenocorticotropic hormone (ACTH) and cortisol measured. The remaining 27 patients and 27 controls underwent a dexamethasone (1 mg) challenge. Results: Cortisol and the proinflammatory cytokines interleukin (IL)-6 (together with its soluble receptor) and IL-8 were elevated in all IBS subgroups (diarrhea predominant, constipated, and alternators), although the elevation was most marked in the constipated subgroup. There was no alteration in the anti-inflammatory cytokine IL-10. Following CRH infusion, an exaggerated release of both ACTH and cortisol was observed in patients with IBS. There was a significant correlation between the ACTH response (δACTH) and the IL-6 levels. A similar relationship existed between the δACTH/δcortisol ratio and the IL-6 levels. Dexamethasone suppression of cortisol was similar in patients and controls. Conclusions: IBS is characterized by an overactivation of the hypothalamic-pituitary-adrenal axis and a proinflammatory cytokine increase.

Section snippets

Study Population

Patients were recruited from gastroenterology clinics at St James’s Hospital (Dublin, Ireland). Individuals aged between 18 and 55 years who satisfied Rome II criteria for the diagnosis of IBS3 and in whom organic gastrointestinal diseases, including inflammatory bowel disease, and clinically significant systemic diseases had been excluded were considered for inclusion in the study. Pregnant women, individuals with known lactose intolerance or immunodeficiency, and individuals who had undergone

Baseline Characteristics

Classification of subjects at baseline by predominant symptom indicated that 30 were alternators, 36 diarrhea predominant, and 10 constipation predominant. Patients and control subjects were well matched in terms of alcohol use; however, 18 of the patients were cigarette smokers, whereas only 8 healthy controls smoked.

Differences in plasma cytokine levels were established. Levels of IL-6 (mean ± SEM) (Figure 1) in patients with IBS were 2.45 ± 0.19 pg/mL compared with 1.07 ± 0.10 pg/mL in

Discussion

Our results indicate that patients with IBS have an exaggerated stress response, as evidenced by the enhanced release of both ACTH and cortisol following CRH infusion. Such patients also showed increased levels of the proinflammatory cytokines IL-6 and IL-8. The former is known to be a potent activator of the HPA, and our analysis suggests that the HPA hyperresponsivity is related to elevation of IL-6 levels. We measured free plasma cytokine levels because these will reflect the biologic

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    Supported in part by Science Foundation Ireland in the form of a centre grant (Alimentary Pharmabiotic Centre), the Health Research Board of Ireland, the Higher Education Authority of Ireland, and the Wellcome Trust.

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