Lay Summary

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

Despite the presence of microbes on the surfaces of our intestine, most of the time we show no signs of a battle raging between these microbes and our immune system.  The wall of the small and large intestine is normally free of any of the signs of inflammation.  This freedom is due, in part, to the production of powerful antimicrobial peptides that create a defensive shield.  Indeed, these substances are sufficient to provide the tools needed to defend the intestine against microbes.

In conditions like Crohn’s disease and ulcerative colitis (otherwise known as inflammatory bowel disease (IBD)), it is possible that the inflammation characteristic of these diseases occurs because the “front-line” innate antimicrobial defenses fail.  A better understanding of how the bowel normally is in contact with microbes without resorting to inflammation might provide insights into more effectively treating or preventing IBD.

We will study patients who are undergoing small intestinal transplantation.  This procedure is performed in individuals who have lost functional bowel and can no longer absorb sufficient nutrients.  As part of the care provided to these patients, endoscopy and biopsy sampling are routinely conducted on a daily to weekly basis to assess the health of transplant.  By applying “gene-chip” technology, we will examine the activity of the many genes that are expressed in the cells that line the bowel wall as the transplanted bowel begins to function in its new setting.  In human small intestinal transplantation, the bowel is initially sterilized with an antibiotic wash and patients dosed with broad spectrum antibiotics.  We would like to know which antimicrobial genes are turned on as oral feeding begins and as microbes come to repopulate the bowel.  We wish to know the types of bacteria that first inhabit the transplanted bowel, which of these bacteria are recognized by the bowel’s defenses as either “harmful” or “friendly,” and how the subsequent production of antimicrobial peptides affects the population of bowel bacteria.

In our experience, we expect that some of our patients will experience “acute rejection.”  In this state, certain intestinal cells that are known to produce antimicrobial peptides are destroyed.  We would like to study whether this loss of antimicrobial peptide production leads to the appearance of bacterial species that were not capable of subsisting in the “normal” protected bowel.  In addition, as we treat these patients with drugs to suppress rejection, we would like to follow the changes in the population of gut microbial species that ensues.  These studies will provide insights into the antimicrobial defenses used by the human bowel to permit harmonious existence with certain types of bacteria, and permit us to understand how this system fails in IBD.  In addition, should antimicrobial defenses be defective in IBD, we believe that it might be possible to develop therapeutic agents that could stimulate production of endogenous antimicrobial peptides by “bypassing” defective circuits.