Scientific Abstract

Proposal No.  IBD-0086R2
Principal Investigator:  Robin Spiller, M.D.
Applicant Organization:  University of Nottingham (United Kingdom)
Project Title:  Altered enteric nerve phenotype and visceral sensation in inflammatory bowel disease
Period of Award:  August 1, 2005 – January 1, 2007

Aim:  To test the hypothesis that patients with symptomatic quiescent ulcerative colitis demonstrate visceral hypersensitivity that is related to overexpression of neuropeptides and markers of enteric nerve damage.

Background:  Chronic recurrent short-lived abdominal pain similar to irritable bowel syndrome is a frequent but poorly understood clinical problem in quiescent inflammatory bowel disease (IBD).  Current treatments for these symptoms, principally based on dietary manipulation, antispasmodics and possibly surgery, are largely ineffectual. Although active IBD is invariably associated with abdominal pain, these chronic symptoms occur without evidence of ongoing inflammation, suggesting that visceral hypersensitivity may be important.

We have recently shown that such symptoms can also persist following recovery from an episode of acute diverticulitis, a condition which causes widespread damage and hyperproliferation within the enteric nervous system leading to the altered expression of Substance P, NPK and galanin.  Similar alterations in neuropeptides are also seen in IBD, although the exact functional consequences of these changes both in this and other forms of colitis is not known.  However, animal models of inflammation suggest that these changes, which can be manipulated pharmacologically, can lead to visceral hypersensitivity and it is this link that we aim to explore in this study.
 
Method:  Asymptomatic and symptomatic patients with quiescent ulcerative colitis will be studied.  Age and sex matched controls will be used.  Patients will be interviewed regarding their current bowel habit and undergo a rigid sigmoidoscopy examination. Biopsies will be taken from the rectum and assessed for inflammatory infiltrate, nerve morphology, neuropeptide staining and receptor density.  Patients will undergo visceral sensitivity testing, analyzing two sensory modalities (stretch and chemical sensitivity).

Endpoints:  Primary outcome measure will be differences in sensory thresholds between symptomatic and asymptomatic patients.  Secondary endpoints will be neuropeptide immunoreactivity and receptor density and their correlation to sensory thresholds.

Rationale and relevance to IBD:  This research would be regarded as a major step in the development of effective therapeutic strategies in IBD, as it allows the problem of persisting symptoms during remission of inflammation to be approached from an original angle.  Similar research in patients with hypersensitive bladders has resulted in the successful therapeutic use of novel analgesic agents, including resiniferatoxin.