Scientific Abstract

Proposal No. IBD-0218
Principal Investigator:   Bo Shen, M.D., M.S.
Applicant Organization:  The Cleveland Clinic Foundation (Ohio, U.S.A.)
Project Title:  Pouchitis: a human model for bacteria-host interaction in inflammatory bowel disease
Period of Award:  November 1, 2007 – April 30, 2010

With the increasingly common use of restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) as the surgical treatment of choice for patients with ulcerative colitis (UC) a new form of IBD has emerged, i.e., pouchitis, the inflammation of the ileal pouch reservoir. Since the time of the pouch creation is known, this allows to prospectively study the events that might eventually lead to the development of intestinal inflammation. Etiology and pathogenesis of pouchitis are not clear, but this new entity can cause substantial morbidity as its annual incidence is as high as 40%, and its management can be challenging. Using this "man-made” disease model our long-term goal is to take advantage of the fact that IPAA/pouchitis can be prospectively monitored as a way to study IBD from the beginning of disease until it evolves into its chronic form, as it happens in IBD. We will study pathogenesis of mucosal inflammation by assessing bacteria-host interactions and will acquire unique knowledge that can be applied for prevention and therapeutic intervention in IBD. We speculate that alterations in the pouch flora and the associated immune abnormalities are mechanistically linked. However, no formal and objective proof has been obtained so far to establish this link. Therefore, based on these premises, this proposal will test the following central hypothesis: The altered recognition of pouchitis microflora by the local mucosal immune system results in inflammation-mediated tissue damage. This hypothesis will be tested by two specific aims:

AIM 1.  To assess composition of the microflora in normal and inflamed pouches at different stages of evolution of the disease. a) luminal bacteria; and b) mucosa-associated bacteria.

AIM 2. To evaluate innate and adaptive immune responses in normal and inflamed pouches at different stages of evolution of the disease. a) dendritic cells; b) toll-like receptors; c) Paneth cell defensins; and d) tissue cytokines.

To achieve our long-term goal it is necessary to study longitudinally a large cohort of patients undergoing IPAA before, during, and after creation of the pouch, before and after development of pouchitis, and before and after treatment.  Therefore, the purpose of this application is to gather cross-sectional information on the microbiology and immunology of pouchitis to be used as preliminary data for a subsequent larger longitudinal study.