Lay Summary

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

Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that results in a significant impairment of a patient’s quality of life. While the exact cause of CD remains unclear, it is apparent that genetics plays an important role. It is well established that first-degree relatives of patients with CD are at increased risk for developing the disease. A variety of genes have been identified that contribute to this risk.

Under normal circumstances, the human intestine is a tightly regulated barrier between the external environment, open to the outside world, and the tissues and organs that lie inside the body. The intestine allows the transfer of water and important nutrients across its membranes while keeping unwanted materials and bacteria inside the gut, leading to the formation of waste as stool. This gut barrier process is regulated by tight junctions and transporter proteins that line the intestine and is supervised by the immune system. In CD, patients develop a leaky gut, which is referred to as increased intestinal permeability. As CD becomes more active, the intestine becomes more leaky and as CD is treated, this leakiness resolves. We are able to measure intestinal permeability by feeding patients safe substances that are not normally absorbed across the gut barrier and then collecting their urine to look for the presence of these substances that have been subsequently filtered out of the bloodstream. When the urine contains excessive amounts of these substances, we know that a patient has increased intestinal permeability.

A consistent and unexplained observation is that 10-20% of first-degree relatives of CD patients have leaky guts in the apparent absence of any clinical disease. This is interesting because first-degree relatives are the group of people at greatest risk for developing CD. An even more interesting discovery is that a particular genetic mutation, known to increase the risk of small intestinal CD called CARD15, has been linked to this leaky gut in relatives. What is not known is whether these at-risk individuals have increased intestinal permeability because they have already developed early small bowel CD that has not yet caused them any symptoms or if they have leaky guts to begin with and this abnormal leak causes the development of CD. Our study will answer this important question by examining the small bowel of these patients to look for ulcers and erosions that would be evidence of early CD. This can be accomplished by having relatives with abnormal permeability swallow a special camera the size of a pill that records images of their gut barrier as it passes through the small intestine. The images are transmitted by harmless radio waves to a recorder outside the body. We will also test for CARD15 and other mutations to determine the relationship between specific genetic mutations, leaky guts and early CD.
 
This is a very important question to answer in the field of inflammatory bowel disease research and will provide crucial information that will benefit future CD patients and their relatives who are at greatest risk of developing the disease. If the leaky gut in first-degree relatives represents very early CD, then it provides us a screening tool to identify these patients at an early stage when we may have the greatest chance to prevent them from getting sick. Conversely, if the leaky gut is associated with normal small bowel mucosa, it may represent an identifiable risk factor for the future development of CD that will allow for studies of new and innovative therapies aimed at preventing IBD. Finally, characterizing the contributory role of CARD15 and other genetic mutations in the development of a leaky gut and of CD may provide valuable markers that can help identify patients at risk for the disease in the future.