Lay Summary

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 underlying cause of the human inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis, remains unknown.  While there is a plethora of studies addressing the mucosal immune system in IBD, little is known about the contribution of the enteric nervous system (ENS).  The ENS can be conceived as a little brain in the gut and it regulates almost all vital functions of the gastrointestinal tract.  It has been repeatedly demonstrated that the ENS is affected by intestinal inflammation, and consequently, it was suggested that the ENS may also be involved in the development of IBD.  However, little is known about precise mechanisms by which the ENS may impact upon intestinal inflammation.

In order to study interactions between the ENS and intestinal inflammation, it is most promising to focus on a specific cell type of the ENS, namely the glial cells (enteric glia).  There are indications derived from genetically modified animal models that the glial cells in the ENS may play a central role to preserve the intestinal mucosal barrier:  If mice are born without enteric glia, the normal architecture of the intestinal mucosa disintegrates, resulting in serious intestinal inflammation and death of the animals.  These observations suggested that enteric glia may be essential to maintain mucosal defence mechanisms, and that a loss of the glial support may be involved in the processes that underlie the changes seen in the inflamed bowel.

In this project we will address the factors mediating glial-mucosal interactions and their regulation.  We will use a unique tissue culture system in which we combine isolated enteric glial cells from human intestine with human epithelial cells, and in this system we will evaluate how the presence or absence of enteric glia changes the functional properties of the epithelial cells.  We will then analyze which glial factors are needed to effect the observed changes.  These studies will be complemented by microscopic analyses of inflamed and non-inflamed specimens from Crohn’s disease patients to assess if the patterns identified in tissue culture can also be seen in tissue samples from patients.

We expect that improving insight into glial-epithelial interactions and identifying factors involved in these interactions will significantly further our understanding of the mechanisms underlying the multiple stages of gastrointestinal inflammation.  We hope that such an understanding will ultimately allow for novel therapeutic approaches to IBD.