Lay Summary

Proposal No.    IBD-0093R2
Principal Investigator:  Jonathan Braun, M.D., Ph.D.
Applicant Organization:  University of California, Los Angeles (U.S.A.)
Project Title:  The intestinal fungi:  role in microbial consortia and mucosal immune homeostasis
Period of Award:  October 1, 2004 - March 31, 2006
 
An important but perplexing insight over the past decade is the critical role of bacteria in inflammatory bowel disease.  Intestinal bacteria are required both to stimulate the occurrence of colitis in susceptible individuals and probably to activate regulatory cells that can protect against colitis.  What has been perplexing is the difficulty in identifying which bacterial species and which of their products are predominant in the microbial-immune interaction.  In this project, we present two ideas that may bridge this gap.  First, we report here the surprising finding that fungi are a major, unappreciated component of the intestinal microorganisms.  Analogous to bacteria, fungi and their products could have an important direct influence on intestinal immune function.  Second, we propose that the enteric microorganisms should be understood as a community whose composition, abundance, and products are governed by intimately interacting sets of microorganisms, which we term “microbial consorts.”  In particular, we want to determine if sets of fungal and bacterial species work together to control their abundance and the molecules they produce that affect the intestinal immune system.  This simple idea - that microbial consorts are the basic biologic units in microbial-immune interaction - may give new clarity to the manner by which microorganisms confer colitis risk and open fresh strategies to how they should be therapeutically controlled.

We address these hypotheses with three aims.  First, we will test for the existence and make-up of microbial consorts in mice, by assessing the colonization patterns of bacteria and fungi after microbial inoculation.  Second, we will evaluate mice bearing different microbial communities for their susceptibility to immune-mediated colitis (induced by CD4 T cells), to evaluate which microbial consorts confer colitis risk.  Third, we will determine the composition of fungal species in the human intestine.  If successful, these aims will provide the first systematic description of fungal species colonizing the intestine; the first formal demonstration of intestinal microbial consorts; and, the identification of consorts associated with two important microbial-immune interactions: activation of colitis-forming CD4 T cells.