Lay Summary
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
It is believed that abnormal interactions between gut resident bacteria and gut local immune system play a key role in initiation and development and development of IBD. Because studies in humans rely on the evaluation of IBD patients with long standing disease, i.e., the disease had already occurred, these studies are in fact investigating the “after-effects” and they have a significant limitation to identification of triggering events of the disease.
The ileal pouch and its inflammatory condition (i.e., pouchitis) will serve as an ideal human model for IBD. With the increasing application of restorative proctocolectomy (surgical removal of whole colon and rectum) with ileal pouch-anal anastomosis (formation of a reservoir using 30 cm of last segment of the small intestine to maintain bowel continuity and fecal continence) as the surgical treatment of choice for patients with ulcerative colitis, 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 one to study prospectively the events that might eventually lead to the development of intestinal inflammation. Etiology and pathogenesis of pouchitis are not known, 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 the ileal pouch and pouchitis can be prospectively monitored as a way to study IBD from the beginning of disease until it evolves into its chronic form.
We will study pathogenesis of mucosal inflammation by assessing bacteria-host interactions. 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, we plan to conduct a series of experiments to measure gut bacteria and levels of immune cells, anti-bacterial substances, and inflammatory mediators in the tissue specimens at different stages of pouch diseases, i.e., before, during, and after formation of the pouch, before and after the development of pouchitis, and before and after treatment. Comparisons of these parameters may help identify agents responsible for triggering, initiating, and maintaining disease process of pouchitis and IBD. This proposal will be critical for us to generate substantial pilot data for our future application for larger longitudinal and more definitive studies.