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Downregulation of Expression of Xenobiotic Efflux Genes is Associated with Pelvic Pouch Inflammation in Ulcerative Colitis

Kabakchiev, Boyko PhD*; Tyler, Andrea PhD*; Stempak, Joanne M. MSc*,†; Milgrom, Raquel MD; Silverberg, Mark S. MD, PhD*,‡

doi: 10.1097/MIB.0000000000000078
Original Basic Science Articles

Background: As many as 50% of patients with ulcerative colitis who have undergone ileal pouch-anal anastomosis develop de novo inflammation in the ileal pouch after surgery. With the use of microarray technology, we investigated what gene expression changes occur in the pelvic pouch after surgery for ulcerative colitis and how these changes vary by pouch outcome.

Methods: Patients who had undergone ileal pouch-anal anastomosis and closure of ileostomy had biopsy specimens from the pouch and pre-pouch ileum prospectively collected. The subjects were allocated into 4 outcome groups: no pouchitis, pouchitis, Crohn's disease–like phenotype, and familial adenomatous polyposis controls. RNA was extracted and transcriptomes were analyzed using a genome-wide approach. The statistical significance of each gene was assessed, and raw P values were corrected for multiple comparisons.

Results: The expression levels of 2733 transcripts in the pouch were significantly associated with outcome. These genes could be classified into 3 categories: regulation of the immune system, modification of the extracellular matrix, and xenobiotic activity. Contrary to the first 2 categories, genes involved in xenobiotic activity, such as ABCB1, had lower expression in the pouchitis and Crohn's disease–like groups compared with the no pouchitis and familial adenomatous polyposis groups.

Conclusions: Transporters of compounds including xenobiotics are downregulated in recurrent disease after ileal pouch-anal anastomosis, whereas inflammatory pathways are upregulated. These findings corroborate the hypothesis that changes in barrier function could contribute to development of intestinal inflammation.

Article first published online 28 May 2014.Supplemental Digital Content is Available in the Text.

*Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada;

Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada; and

Division of Gastroenterology, University of Toronto, Toronto, ON, Canada.

Reprints: Boyko Kabakchiev, PhD, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 60 Murray Street, Room L3-004, Toronto, ON M5T 3L9, Canada (e-mail: kabakchiev@lunenfeld.ca); or Mark S. Silverberg, MD, PhD, 600 University Avenue, Room 441, Toronto, ON M5G 1X5, Canada (e-mail: msilverberg@mtsinai.on.ca).

Supported by the Crohn's and Colitis Foundation of Canada.

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 March 18, 2014

Accepted April 15, 2014

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