Scientific Abstract

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

Inflammatory bowel diseases (IBD) involve an inappropriate host inflammatory response to gut lumen microbes.  However, it is unclear whether IBD patients’ microbiota are more proinflammatory than those of healthy individuals, or whether disease results from patients’ altered interactions with their microbiota.

We have developed zebrafish as a model to study interactions among host GI tissues and the gut microbiota.  Zebrafish have experimental attributes that make them ideally suited for examining mechanisms underlying human diseases such as IBD.  For example, the GI tracts of zebrafish and mammals are very similar, but unlike mice, zebrafish produce hundreds of embryos that develop rapidly, allowing analysis of parameters that influence gut physiology on a different scale than is possible with mouse models.  In zebrafish we can readily manipulate both host genetics and the gut microbial community, including rearing animals germ free, mono-associating them with specific microbial species, or colonizing them with complex microbiota from different donors. The transparency of developing zebrafish, as well as the availability of transgenic zebrafish lines expressing fluorescent proteins in particular cell populations, allows the study of interactions between host cells and gut microbes in real time in vivo.  Finally, zebrafish are emerging as an excellent model for drug discovery because they are amenable to high throughput small molecule screens.

We hypothesize that loss of gut motility causes changes in the composition of the gut microbiota that lead to gut inflammation. This hypothesis arose from our analysis of a zebrafish mutant that exhibits loss of enteric neurons, gut hypomotility, and intestinal inflammation. This and other hypomotile mutants we have identified will allow us to dissect the causal relationships between gut motility, gut microbial ecology, and pathologic intestinal inflammation. We propose that changes in motility that alter the composition of the gut microbiota initiate the inflammatory processes associated with IBD.  By transplanting microbiota from normal and inflamed guts into germ free wild type and hypomotile mutant recipients, we will be able to distinguish whether the microbiota themselves or the hosts’ response to the microbial community are responsible for promoting inflammation.  Because of the similarities between the zebrafish and mammalian GI tracts, our results should provide new insights into the etiology of human IBD, which will have direct implications for current diagnostic and treatment practices.  In addition, the establishment of a zebrafish model of IBD will allow us in the future to screen for small molecules that prevent gut inflammation, which holds enormous promise for discovering new therapies for IBD patients.