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Gene Expression Profiles of Ileal Inflammatory Bowel Disease Correlate with Disease Phenotype and Advance Understanding of Its Immunopathogenesis

Ben-Shachar, Shay MD*,†; Yanai, Henit MD†,‡; Baram, Liran MSc†,‡; Elad, Hofit MSc†,‡; Meirovithz, Elhanan PhD; Ofer, Amos PhD†,‡; Brazowski, Eli MD†,§; Tulchinsky, Hagit MD†,‖; Pasmanik-Chor, Metsada PhD; Dotan, Iris MD†,‡

doi: 10.1097/01.MIB.0000437045.26036.00
Original Basic Science Articles

Background: Pouchitis may develop in patients with ulcerative colitis undergoing pouch surgery. We aimed to evaluate the de novo inflammation developing in the ileal pouch, hypothesizing that it may be similar to ileitis in Crohn's disease (CD).

Methods: Patients with ulcerative colitis pouch were prospectively recruited, stratified according to disease behavior into normal pouch, chronic pouchitis, and Crohn's-like disease of the pouch groups, and compared with controls. Gene expression analysis was performed using microarrays, validated by real-time polymerase chain reaction. Gene ontology and clustering were evaluated using bioinformatic tools.

Results: Sixty-six subjects were recruited. Although in ulcerative colitis ileum there were no significant gene expression alterations, patients with normal pouch had 168 significant alterations (fold change ≥ 2, corrected P ≤ 0.05). In chronic pouchitis and Crohn's-like disease of the pouch, 490 and 1152 alterations were detected, respectively. High degree of overlap in gene expression alterations between the pouch subgroups was demonstrated. The magnitude of change correlated with pouch disease behavior. Gene expression profiles were more reflective of disease behavior compared with inflammatory indices. CD ileitis had 358 alterations, with a 90% overlap with pouchitis. Gene ontology analyses revealed multiple biological processes associated with pouch inflammation, including response to chemical stimulus, small molecule metabolic and immune system processes, and specific infection-related pathways such as Staphylococcus aureus, leishmaniasis, and tuberculosis.

Conclusions: Gene alterations in pouch inflammation and CD overlap, suggesting that inflammatory bowel diseases is a spectrum, rather than distinct diseases. Pouchitis may serve as a model of CD. The novel pathways associated with inflammatory bowel diseases may decipher pathophysiology and suggest targets for intervention.

Article first published online 8 October 2013

*Genetics Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel;

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;

IBD center, Department of Gastroenterology and Liver Diseases, Tel Aviv Medical Center, Tel Aviv, Israel;

Departments of §Pathology, and

Surgery, Tel Aviv Medical Center, Tel Aviv, Israel; and

Bioinformatics Unit, G.S.W. Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

Reprints: Iris Dotan, MD, IBD center, Department of Gastroenterology and Liver Diseases, Tel Aviv Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel (e-mail: irisd@tlvmc.gov.il).

Partially supported by a grant from the Leona M. and Harry B. Helmsley Charitable Trust.

The authors have no conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.ibdjournal.org).

Received July 13, 2013

Accepted August 26, 2013

© Crohn's & Colitis Foundation of America, Inc.
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