Final Progress Report

Proposal No.  IBD-0148R
Principal Investigator:  Michael Zasloff, M.D., Ph.D.
Applicant Organization:  Georgetown University (Washington, District of Columbia, U.S.A.)
Project Title:  Antimicrobial peptide expression and its relationship to commensal bacteria in the transplanted small bowel
Period of Award:  July 25, 2005 – July 31, 2008

Lay Summary of Final Report:

It is remarkable that normally we live in harmony with microbes. In the small intestine a delicate single layer of epithelial cells serves as the “skin” separating the organ from the vast numbers and species of intestinal bacteria. In conditions like Crohn’s disease and ulcerative colitis this harmony breaks down and an immunologic battle ensues between the immune defenses of our bowel and the microbes that reside within. A similar breakdown in host-microbial harmony arises in the setting of human small bowel transplantation. Small intestinal transplantation is performed in individuals who have lost a functional bowel, and can no longer be fed intravenously. About 60 % of the recipients are infants and children younger than 15 years for whom the allograft provides the only remaining means to deliver adequate nutritional support required for growth. Our institution is one of the leading intestinal transplant centers worldwide. Although remarkable progress has been made in this procedure over the past 15 years, with over 600 transplants performed worldwide, organ rejection is still a significant problem, with graft failure occurring within 3-4 years in about 30% of patients.1

With support from the Broad Medical Research Program, we conducted studies designed to help us better understand the process of intestinal rejection, a condition which shares many clinical similarities with Crohn’s disease.

We discovered that a high percentage of transplant recipients unexpectedly carry specific genetic mutations in the NOD2 gene, which codes for a microbe sensor that plays an important role in the immune health of the small intestine, and which is known to be defective in a large percentage of individuals with Crohn’s disease.2 When an otherwise “healthy” donor intestine is transplanted into an individual who carries a NOD2 mutation, the risk of rejection was almost 100-fold greater than observed when the bowel was transplanted into an individual with “normal” NOD2 genes. Within weeks of transplantation into a NOD2 mutant recipient, a “normal” donor small intestine loses its capacity to sustain the production of key antimicrobial substances required to protect the bowel wall from assault by its own normal resident bacteria. We believe these studies will help us improve the practice of intestinal transplantation and perhaps help elucidate processes that go awry in inflammatory bowel diseases, such as Crohn’s disease. We are currently exploring how mutations in the recipient’s NOD2 gene leads to a failure of the allograft’s microbial defenses.