Lay Summary

Proposal No.  IBD-0209
Principal Investigator:  Karen Guillemin, Ph.D.
Applicant Organization:  University of Oregon (Eugene, U.S.A.)
Project Title: Do changes in gut motility promote gut inflammation by altering the composition of gut microbiota?
Period of Award:  August 1, 2007 - December 31, 2009

The human gut harbors a large diversity of bacteria that are important for normal digestion of the food we eat.  In IBD, human gut cells react to gut bacteria in ways that result in inflammation.  A key question is whether the types of bacteria in the guts of IBD patients differ from those of people who are disease free because there are types that specifically promote inflammation, or whether the inflammation results from alterations in the gut cells that cause them to respond inappropriately to normal bacteria.

These questions are difficult to address in human patients and in animal studies using mammals.  Therefore, we have begun to address these questions in zebrafish.  The benefit of the zebrafish system is that the gut is very similar to that of mammals, but because young zebrafish are nearly transparent, grow very quickly, and develop outside the mother, we can observe interactions between gut cells and bacteria in living animals in real time.  In addition, we can perform many types of manipulations, such as rearing zebrafish without any gut bacteria and then reintroducing specific types of bacteria we suspect may be involved in inflammation.  Also, we have collections of mutant zebrafish with altered gut properties that will allow us to test how bacteria differ between normal and defective guts.

We propose that when the gut does not undergo the normal motility that propels food and bacteria through it, the types of bacteria that live in the gut change, favoring ones that promote inflammation.  We will test this idea by manipulating gut motility and learning whether this causes an increase in gut inflammation.  If it does, we will then transplant bacteria from zebrafish with altered gut motility and inflamed guts into zebrafish that have normal guts, to learn whether these bacteria cause gut inflammation.  If this manipulation does cause inflammation, it will suggest that it is an alteration in the types of bacteria that are important in causing gut inflammation.  If this manipulation does not cause inflammation, it will suggest that inflammation results from an inappropriate response to normal bacteria, rather than to changes in the types of bacteria that are present.

Our proposed experiments will allow us to distinguish whether it is the composition of the gut bacteria that causes gut inflammation, or if gut inflammation results from an inappropriate response to normal bacteria.  Because of the similarities between the guts of zebrafish and mammals, including humans, these results will provide new insights into the cause of gut inflammation in IBD.  In the future, we will use our zebrafish model to screen for small molecules that prevent gut inflammation with the goal of discovering new therapies for IBD patients.