Scientific Abstract

Proposal No.   IBD-0105R
Principal Investigator:  Klaus Michel, Ph.D. (replacement PI);
Anne Rühl, M.D., Ph.D. (original PI)
Applicant Organization:  Technische Universität München (Freising-Weihenstephan, Germany)
Project Title:  Enteric glia in intestinal inflammation
Period of Award:  July 1, 2004 – June 30, 2006

The etiology of the human inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis, remains unknown.  While there is a huge body of evidence establishing a central role of the mucosal immune system in the etiopathogenesis of IBD, little is known about the contribution of the enteric nervous system (ENS).  However, it has been repeatedly demonstrated that the ENS is affected in IBD, and in turn the ENS has been implicated in the pathogenesis of inflammatory diseases of the gut.

Similar to the organisation of the central nervous system, the ENS is made up from two major cell populations: enteric neurons and enteric glial cells.  Recently, it has been demonstrated that ablation of enteric glial cells results in mucosal disintegration and, consecutively, severe intestinal inflammation.  From these findings it was concluded that enteric glia may be essential to maintain the integrity of the intestinal mucosa.

The aim of this project is to investigate glial-epithelial interactions in the intestinal mucosa, employing in vitro and in situ techniques in human tissue.  In vitro, we will co-culture isolated and purified human enteric glial cells with human epithelial cells, and we will assess epithelial barrier function and glial expression of neurotrophins, neurotrophic factors and/or epithelial growth factors in this system.  Further, we will investigate if proinflammatory cytokines affect glial synthesis of trophic factors.  These studies will be complemented by ex vivo identification of the presence and cellular source for previously identified trophic factors, employing immunohistochemistry in whole mount preparations of inflamed and non-inflamed Crohn’s disease intestinal tissue.

We expect that improving the insight into glial-epithelial interactions and identifying mediators of these interactions will significantly further our understanding of the pathophysiologic mechanisms in the multiple stages of gastrointestinal inflammation.  We hope that such an understanding will ultimately allow for novel therapeutic approaches to IBD targeting enteric glial cells and their products.