Lay Summary

Proposal No. IBD-0102
Principal Investigator:  Andrew T. Gewirtz, Ph.D.
Applicant Organization:  Emory University (Atlanta, Georgia, U.S.A.)
Project Title:  Adaptive immunity to flagellin in inflammatory bowel disease
Period of Award:  May 1, 2004 – April 30, 2006

The symptoms of active flares of inflammatory bowel disease (IBD) are generally similar to those of persons who have been infected with food-borne bacteria such as Salmonella, even though extensive laboratory testing on samples from IBD patients consistently fail to detect the presence of any known food-borne infectious agents.  Whether occurring in Salmonellosis or IBD, these symptoms result in large part from the recruitment/actions of cells of the immune system.  When occurring in response to salmonella, this immune response is a health-promoting event as it clears the infection.  However, similar immune responses seem to occur in IBD even though appropriate triggers appear not to be present. 

It has been observed that, in mouse models of IBD, disease does not develop if mice are kept in germ-free housing, leading to the theory that IBD results from an aberrant immune response to the bacteria that normally live in the human intestine.  While a substantial amount of research supports this hypothesis, the reasons underlying how and/or why the immune system might so respond to normal intestinal bacteria remains largely unknown.

Our approach has been to try to understand the mechanisms that control the healthy immune response to Salmonella in the hope that it might allow for insight into how things go awry in IBD.  Our research has indicated that an important means by which the immune system normally recognizes Salmonella is by detecting a protein called flagellin that is released by these bacteria.  Although both normal intestinal bacteria and Salmonella make flagellin, only Salmonella can get flagellin across the lining of the intestine where it must be to triggers an immune response.  However, if intestinal barrier function is decreased, as is known to occur in IBD, flagellin from normal bacteria may be able to trigger and immune response and thus may be a trigger for active flares of IBD.  In this proposal, we plan to test this hypothesis by examining immune responses to flagellin in humans with IBD as well as in mouse models of this disorder.