Lay Summary

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 inflammation of the colon in ulcerative colitis (UC) remain poorly understood.  One clue to the etiology of ulcerative colitis is the observation that pouches created from the distal small bowel (ileum) following total colectomy for UC frequently become inflamed, a condition called pouchitis.  In contrast, pouches created following colectomy for familial adenomatous polyposis (FAP) almost never become inflamed.  While UC is commonly considered to be a disease limited to the colon, it is clear that when the colon is removed and the ileum is converted into a pouch to store fecal material, the small bowel of the UC subject becomes susceptible to an inflammatory process that previously was limited to the large intestine.  This inflammation usually responds to treatment with antibiotics suggesting a bacterial origin, although no abnormal bacteria have been identified in the pouch contents.  Thus, when fecal stagnation occurs in an ileal pouch, the small intestine of the UC subject is uniquely susceptible to damage from some product(s) produced by what appears to be normal fecal bacteria.  We believe that if this injurious fecal agent could be elucidated, one would gain insight not only into the etiology of pouchitis, but possibly into the etiology of UC as well.

Previous workers have proposed that hydrogen sulfide (H₂S), an extremely toxic gas produced by normal intestinal bacteria, could play a role in UC.  We have recently carried out studies showing markedly increased H₂S production in the pouches of subjects with UC versus those of subjects with FAP.  While the production of H₂S was highest in subjects studied during an active pouchitis episode, H₂S production was higher in UC versus FAP subjects, independent of the activity of their pouchitis.  Thus, there appears to be a fundamental abnormality in UC that results in an overproduction of H₂S.  A better understanding of why there is excessive H₂S production might provide insights into the etiology of pouchitis and UC.  We propose to utilize subjects with ileal pouches as an innovative, simple means of elucidating the origin of the abnormality that causes excessive H₂S production in UC subjects.  To this end, we will determine if this excess H₂S production results from a bacterial flora that is particularly adept at converting fecal contents into H₂S and/or from an excess of material in the feces that can be metabolized to H₂S by the fecal bacteria.  The results of these studies should provide information that will provide direction for future studies designed to reduce H₂S production in the gut, which, in turn, will make it possible to assess the role of H₂S as a causative or aggravating agent in UC.