Scientific Abstract
Proposal No. IBD-0151
Principal Investigator: Michael D. Levitt, M.D.
Applicant Organization: Minnesota Veterans Research Institute (Minneapolis, U.S.A.)
Project Title: Cause of the increased hydrogen sulfide production observed in inflamed ileal pouches of subjects with ulcerative colitis
Period of Award: July 1, 2005 – January 14, 2007
Despite extensive research, the factors that cause and maintain the mucosal inflammation of ulcerative colitis (UC) remain speculative. A possible clue to the source of the mucosal inflammation in UC is provided by the complications observed with ileal pouches constructed following total colectomy. In UC subjects, these pouches frequently become inflamed, a condition termed pouchitis. In contrast, pouchitis virtually never occurs following colectomy for familial adenomatous polyposis (FAP). Pouchitis rapidly responds to antibiotic therapy, although no abnormal flora have been identified. Thus, the seemingly normal fecal flora of UC subjects, when stagnated in a pouch, produce a metabolite that causes pouch inflammation. Identification of this abnormality would enhance our understanding of pouchitis, but, more important, could provide insights into the pathogenesis of UC.
The normal colonic flora releases hydrogen sulfide (H2S), and we observed that H2S is released in 10-fold greater quantity by the pouch contents of UC subjects with acute pouchitis versus FAP subjects. UC subjects with pouchitis in the distant past also had greater H2S production than did FAP subjects. In vitro and in vivo studies have shown that experimental exposure to sulfide alters the metabolism of colonic mucosa. Interaction of sulfide with products of inflammatory cells (nitric oxide, hydrogen peroxide) enhanced colonocyte toxicity and intestinal lymphocytes have been shown to produce highly reactive free radicals during exposure to sulfide metabolites. The concept driving the present proposal is that increased fecal H2S production (probably in conjunction with an abnormal mucosal response to sulfide or a sulfide metabolite) plays an etiological role in the mucosal inflammation of pouchitis and, by extrapolation, in UC.
The studies to be performed have the following goals:
1. Determine if the increased H2S production observed in acute pouchitis results from an unusually active sulfide-producing flora and/or an excess of substrate that can be used by a “normal” flora for sulfide production.
2. If an increased activity of the flora is observed, determine if this activity can be attributed to organisms known as sulfate reducing bacteria (SRB).
3. If excess sulfide-releasing substrate is observed, obtain preliminary data that will assist in the subsequent identification of this substrate.
Innovative aspects of this study: While H2S has received attention as a potential etiological agent in UC, attempts to identify a potential luminal toxin are complicated by the presence of the diseased colon. The present study is the first to focus on pouchitis as a simple model (free of the potential complicating effects of the diseased colon) with which to study the increased H2S production in UC subjects. Understanding the origin of this increased H2S production will provide direction for therapies to reduce this production, with the final goal being studies to determine if reduction of H2S production is beneficial in UC.