Scientific Abstract

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 enteric bacteria in mucosal immune homeostasis. Important, because enteric bacteria are required for colitis formation and its resistance, and provide the stimuli for both colitigenic and protective immune (adaptive or innate) function. Perplexing, because neither monoassociation microbial studies nor antigen-specific immunologic studies have yielded a coherent picture of the bacterial species or products predominating the enteric microbial-immune interaction.

In this project, we present two ideas that may bridge this gap. First, we report the surprising finding that fungi comprise a diverse enteric microflora and hence a major, unappreciated component of the intestinal microbiota.  Analogous to bacteria, fungal species and their products may emerge as an important direct influence on intestinal immune function.  Second, we propose that the enteric microbiota should be understood as a community—whose composition, abundance, and products are governed by intimately interacting microbial consorts.  The awareness of bacteria-bacteria consorts provides the conceptual basis for emerging areas like probiotics.  However, we believe that consorts may also include heterologous fungal-bacterial interaction.  The existence of microbial consorts predicts that the microbial products influencing enteric immune functions are equally dependent on the species producing the definitive bioactive molecules, and the enabling species that guide the abundance and biosynthetic activity of the producing species.  This simple idea—that microbial consorts are the basic biologic units in microbial-immune interaction—may account for the perplexities in the existing monoassociation experimental studies.
 
We address these hypotheses with three aims.  First, we will test for the existence and make-up of microbial consorts by inoculating newborn mice with diversely fractionated enteric microbial populations, and analyzing the resultant enteric microbial communities by high-throughput phylogenetic analysis.  Second, we will evaluate the effect of these different microbial communities on the susceptibility of mice to colitigenic CD4+ T cell activity. Third, we will test for the existence and composition of fungal microflora within the commensal enteric microflora of the human colon.  If successful, these aims will provide the first systematic description of the enteric fungal microflora in mouse and human; the delineation of enteric bacterial-bacterial and fungal-bacterial consorts; and, the association of certain consorts with colitigenic CD4+ T cell activity.