Gnotobiotic Core

PROJECT SUMMARY Intestinal fungi, including Candida species, are normal components of the human intestinal microbiota that can escape the intestinal niche and trigger autoimmunity or inflammatory disease. There is a significant knowledge gap in the understanding of how fungi colonize the intestine and the factors that limit their colonization and

translocation across the intestinal barrier. The goal of this Program Project Grant (P01) is to identify factors that regulate Candida intestinal colonization. Published and preliminary data from the Project Leaders suggest that fungal, bacterial, and host factors all interact to regulate Candida colonization of the intestine. Dissection of these

complex interkingdom interactions requires in vivo experimental systems that allow for controlled manipulation of fungal colonizers, the bacterial microbiota, and the host immune system. Gnotobiotic mouse models, involving the use of germ-free mice, provide a platform for developing such experimental systems. The mission of the

Gnotobiotic Core is therefore to provide gnotobiotic mouse models to each of the three projects in this P01. Germ-free mice will be used to create defined experimental models where we introduce a single bacterial or fungal species, defined species mixtures, or complex communities transplanted from other experimental animals

or humans. Further, these experiments will be conducted in germ-free genetically modified mice to explore the contributions of host factors. The Gnotobiotic Core builds on extensive existing gnotobiotic infrastructure and the long-standing expertise of Core Leader Hooper’s lab in developing and using gnotobiotic models to study many

different aspects of host-microbiota interactions in the intestine. The Aims of the Gnotobiotic Core will be to 1) provide germ-free or selectively colonized wild-type or mutant mice to test hypotheses about how the bacterial microbiota regulates Candida colonization of the intestinal tract; and 2) derive additional germ-free immune-

deficient mouse strains to test hypotheses about how host immunity and its interactions with the bacterial microbiome impact Candida colonization. Pursuit of these goals will allow us to build gnotobiotic mouse models that enable experimental dissection of the fungal, bacterial, and host factors that regulate Candida colonization.

These studies in gnotobiotic mice will provide novel insights into interactions among intestinal fungi, bacteria, and the host immune system, thus revealing fundamental principles about fungal colonization of the intestine.