Immune Activation in Patients With Irritable Bowel Syndrome

Liebregts, Tobias; Adam, Birgit; Bredack, Christoph; Röth, Alexander; Heinzel, Susanne; Lester, Sue; Downie–Doyle, Sarah; Smith, Eric; Drew, Paul; Talley, Nicholas J.; Holtmann, Gerald

doi:10.1053/j.gastro.2007.01.046

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Volume 132, Issue 3 , Pages 913-920, March 2007

Immune Activation in Patients With Irritable Bowel Syndrome

Presented in part at Digestive Disease Week 2006, Los Angeles, California, May 20-25, 2006.

Tobias Liebregts
- Department of Gastroenterology and Hepatology, University of Adelaide, Royal Adelaide Hospital, South Australia
- Nerve-Gut Research Laboratory, Hanson Institute, Adelaide, SA, Australia
Birgit Adam
- Department of Gastroenterology and Hepatology, University of Adelaide, Royal Adelaide Hospital, South Australia
- Nerve-Gut Research Laboratory, Hanson Institute, Adelaide, SA, Australia
Christoph Bredack
- Department of Gastroenterology and Hepatology, University of Adelaide, Royal Adelaide Hospital, South Australia
- Nerve-Gut Research Laboratory, Hanson Institute, Adelaide, SA, Australia
Alexander Röth
- Department of Internal Medicine, Division of Hematology, University of Essen, Germany
Susanne Heinzel
- Department of Surgery, University of Adelaide, Royal Adelaide Hospital, South Australia
Sue Lester
- Arthritis Research Laboratory, Hanson Institute, Adelaide, SA, Australia
Sarah Downie–Doyle
- Arthritis Research Laboratory, Hanson Institute, Adelaide, SA, Australia
Eric Smith
- Department of Surgery, University of Adelaide, Royal Adelaide Hospital, South Australia
Paul Drew
- Department of Surgery, University of Adelaide, Royal Adelaide Hospital, South Australia
Nicholas J. Talley
- Mayo Clinic, College of Medicine, Rochester, Minnesota
- Department of Medicine, University of Sydney, New South Wales, Australia
Gerald Holtmann
- Department of Gastroenterology and Hepatology, University of Adelaide, Royal Adelaide Hospital, South Australia
- Nerve-Gut Research Laboratory, Hanson Institute, Adelaide, SA, Australia
- Address requests for reprints to: Gerald Holtmann, MD, FRACP, Professor of Medicine, Royal Adelaide Hospital, Department of Gastroenterology and Hepatology, University of Adelaide, North Terrace, Adelaide SA 5000, Australia. fax: (61) 8-8222-2414.

Received 5 April 2006; accepted 7 December 2006. published online 31 January 2007.

Background & Aims: We set out to test the hypothesis that irritable bowel syndrome (IBS) is characterized by an augmented cellular immune response with enhanced production of proinflammatory cytokines. We further aimed to explore whether symptoms and psychiatric comorbidity in IBS are linked to the release of proinflammatory cytokines. Methods: We characterized basal and Escherichia coli lipopolysaccharide (LPS)-induced cytokine production in peripheral blood mononuclear cells (PBMCs) from 55 IBS patients (18 mixed-, 17 constipation-, 20 diarrhea-predominant) and 36 healthy controls (HCs). PBMCs were isolated by density gradient centrifugation and cultured for 24 hours with or without (1 ng/mL) LPS. Cytokine production (tumor necrosis factor [TNF]-α, interleukin [IL]-1β, and IL-6) was measured by enzyme-linked immunosorbent assay. Abdominal symptoms and psychiatric comorbidities were assessed by using the validated Bowel Disease Questionnaire and the Hospital Anxiety and Depression Scale. Results: IBS patients showed significantly (P < .017) higher baseline TNF-α, IL-1β, IL-6, and LPS-induced IL-6 levels compared with HCs. Analyzing IBS subgroups, all cytokine levels were significantly (P < .05) higher in diarrhea-predominant IBS (D-IBS) patients, whereas constipation-predominant IBS patients showed increased LPS-induced IL-1β levels compared with HCs. Baseline TNF-α and LPS-induced TNF-α and IL-6 levels were significantly higher in patients reporting more than 3 bowel movements per day, urgency, watery stools, and pain associated with diarrhea compared with patients without these symptoms (all P < .05). LPS-induced TNF-α production was associated significantly (r = 0.59, P < .001) with anxiety in patients with IBS. Conclusions: Patients with D-IBS display enhanced proinflammatory cytokine release, and this may be associated with symptoms and anxiety.

Abbreviations used in this paper: C-IBS, constipation-predominant irritable bowel syndrome, D-IBS, diarrhea-predominant irritable bowel syndrome, HCs, healthy controls, HPA, hypothalamic-pituitary-adrenal, IBS, irritable bowel syndrome, IL, interleukin, LPS, lipopolysaccharide, M-IBS, mixed IBS, PBMCs, peripheral blood mononuclear cells, PI-IBS, postinfectious IBS, TNF, tumor necrosis factor