Scientific Abstract
Proposal No. IBD-0243
Principal Investigator: Levinus Dieleman, M.D., Ph.D.
Applicant Organization: University of Alberta (Edmonton, Canada)
Project Title: Capsule endoscopy for the assessment of abnormal intestinal permeability in Crohn’s disease relatives
Period of Award: November 1, 2008 – February 28, 2012
Aims: To determine if healthy, asymptomatic first-degree relatives of Crohn’s disease (CD) patients with increased small intestinal permeability are more likely to have endoscopically abnormal small bowel mucosa as determined by capsule endoscopy, as compared to age and sex-matched first-degree relatives with normal intestinal permeability. Our hypothesis is that the prevalence of mucosal small bowel lesions is significantly greater in first-degree relatives with abnormal permeability. Our secondary goal is to study the relationship between impaired intestinal permeability, endoscopic small bowel lesions and CARD15 3020insC mutations to determine whether abnormal intestinal permeability and small bowel lesions are associated with a greater prevalence of this mutated CARD15 gene.
Background: Increased small intestinal permeability is seen in patients with CD and in 10-20% of their first-degree relatives. CD etiology has a significant genetic component and first-degree relatives have a significantly increased risk of developing the disease. Although its clinical relevance is unknown, abnormal small intestinal permeability among first-degree relatives has been linked to the 3020insC mutation in the CARD15 gene, a gene already implicated in small bowel CD. However, it is unclear whether the first-degree relatives with abnormal permeability have early, asymptomatic, subclinical CD or whether they have an inherent abnormality in small intestinal permeability without any mucosal inflammation. Capsule endoscopy is our most effective means of imaging the small intestine and will identify whether patients with increased small intestinal permeability have mucosal erosions and ulcerations, suggestive of subclinical CD, or whether they have an endoscopically normal small bowel.
Significance of Study: We believe that this is a pivotal question that needs to be answered in the field of IBD research. Most theoretical constructs regarding the pathogenesis of CD postulate a defect in mucosal barrier function as a critical and early step. The evidence for this comes from observations made in animal models and extrapolations made from human studies. However, there is a very real confounding factor involved in this paradigm. Abnormal permeability is a marker of abnormal function of the intestinal tight junction. Unfortunately, it can also be a marker of mild intestinal disease. Thus, observing increased small intestinal permeability in a population at high risk of contracting CD can be explained by either hypothesis. It is critically important to answer this question.
If increased permeability simply represents very early disease this will enable us to identify these patients and initiate early intervention trials. It may provide us an opportunity to intervene at a time when there may be the greatest chance to change the natural course of CD. Conversely, if increased permeability represents a risk factor for the development of CD, it opens the door to explore new and innovative therapies to prevent IBD, which may include altering the intestinal microflora or regulating the functional state of epithelial tight junctions.
This is an innovative study that will address a fundamentally important question in Crohn’s disease research, the results of which may lead to improved understanding of disease pathogenesis, may result in earlier disease detection, and possibly may provide opportunities for earlier treatment and/or disease prevention. This study will generate preliminary data that may lead to long-term follow-up of the genetic predisposition to CD, the predictive value of intestinal permeability in the later development of CD, and possibly to early intervention trials in at-risk Crohn’s first-degree relatives.