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Elevated Human β-Defensin-2 Levels Indicate an Activation of the Innate Immune System in Patients With Irritable Bowel Syndrome

Langhorst, Jost, MD1; Junge, Angela1; Rueffer, Andreas, MD2; Wehkamp, Jan, MD3; Foell, Dirk, MD4; Michalsen, Andreas, MD1; Musial, Frauke, PhD1; Dobos, Gustav J., MD1

American Journal of Gastroenterology: February 2009 - Volume 104 - Issue 2 - p 404–410
ORIGINAL CONTRIBUTIONS: FUNCTIONAL GIDISORDERS
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OBJECTIVES: Irritable bowel syndrome (IBS) is a highly prevalent functional disorder. According to the Rome criteria, macroscopic and histological inflammation is a crucial exclusion criterion for IBS. Human defensins appear to be part of the innate immune system in the gastrointestinal tract. Human β-defensin-2 (HBD-2) was the first inducible human antimicrobial protein discovered. The expression is induced by probiotic microorganisms and proinflammatory cytokines. Recent results imply that HBD-2 is expressed in active intestinal inflammation, especially in ulcerative colitis (UC). Our aim was to evaluate fecal measurements of HBD-2 in patients with active UC and IBS, and in healthy controls (HCs).

METHODS: Fecal specimens were collected from a total of 100 participants (30 with active UC, 46 IBS, and 24 HCs). Exclusion criteria were the current use of probiotics and antibiotics. Furthermore, IBS patients with elevated C-reactive protein or leukocytes, a history of bacterial overgrowth or infectious gastrointestinal disease over the last 6 month were excluded. Disease status was addressed in all participating subjects by medical history and current symptoms. In addition, each IBS and UC patient underwent ileocolonoscopy with histopathology. Fecal inflammation markers lactoferrin (Lf) and calprotectin (Cal) were measured by enzyme-linked immunosorbent assay (ELISA) and reported as μg/g. Fecal HBD-2 was measured by ELISA and reported as ng/g feces. In addition, immunoblots were performed for fecal HBD-2. Paraffin-embedded tissue from colonic biopsies was tested for HBD-2 peptides by immunohistochemistry.

RESULTS: Lf as well as Cal was elevated in active UC (mean: 152.1±s.d. 374.7 μg/g; 103.5±87.1 μg/g), compared with IBS (8.3±19.4 μg/g; 18.6±23.3 μg/g), and HCs (0.4±0.5 μg/g; 7.1±7.9 μg/g). Scheffepost hoctests revealed significant differences (P=0.006; P<0.001) between active UC vs. IBS and HC. In contrast, HBD-2 levels were highest in active UC (mean: 106.9±s.d. 91.5 ng/g), almost as high in IBS (pts 76.0±67.9ng/g), and lowest for HCs (29.9±16.1 ng/g). Scheffepost hoctests revealed significant differences (P< 0.001) between the groups of patients (UC and IBS) vs. HCs. Immunohistochemical investigation was consistent with fecal secretion data and demonstrated the presence of β-defensin 2 peptides in colonic epithelial enterocytes in UC as well as IBS patients with elevated fecal HBD-2.

CONCLUSIONS: The results indicate significantly elevated levels of HBD-2 in patients with IBS compared with HCs and similar to those with active UC. The results support an activation of the mucosal innate defense system toward a proinflammatory response in IBS patients in the absence of macroscopic signs of inflammation.

Am J Gastroenterol 2009; 104:404-410; doi:10.1038/ajg.2008.86; published online 20 January 2009

1Department of Internal Medicine, University of Duisburg-Essen, Kliniken Essen-Mitte, Essen, Germany;

2Laboratory L+S AG, Bad Bocklet-Groβenbrach, Germany;

3Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology and Department of Internal Medicine I, Robert Bosch Hospital, Stuttgart, Germany;

4Department of Pediatrics, University of Muenster, Germany.

Correspondence: Jost Langhorst, MD, Department of Internal Medicine, University of Duisburg-Essen, Kliniken Essen-Mitte, Am Deimelsberg 34a, Essen D-45276, Germany. E-mail: jost.langhorst@gmx.de

Received 3 March 2008; accepted 16 September 2008

© The American College of Gastroenterology 2009. All Rights Reserved.
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