Abstract The commensal microbiota has important impacts on host physiology and health that are only beginning to be elucidated. Most current studies, however, have focused only on the bacterial microbiota despite the presence of fungal, archaeal and viral members. The presence of anti-Saccharomyces cerevisiae (ASCA) antibodies serves as a diagnostic tool for Crohn’s disease (CD) and suggests that fungal members of the microbiota contribute to disease severity. Moreover, common genetic polymorphisms identified in individuals with IBD, such as Nod2, Dectin-1, and Card9 are known to recognize fungal cell wall components. We have recently demonstrated that one of the most prominent members of the mycobiota, S. cerevisiae, can exacerbate intestinal colitis through upregulation of host purine metabolism in the gut. The end product of purine metabolism in humans is uric acid. Recent studies have demonstrated that uric acid can have significant impacts on autophagy. Coincidentally, many of the genes associated with IBD in humans, impact autophagic processes. There is a significant body of clinical literature that links autophagy, yeast, and uric acid production, yet these relationships have yet to be explored. Here we propose to identify how fungal members of the microbiota induce purine metabolism from intestinal epithelia and determine how purine metabolism influences intestinal immunity to worsen disease. We have brought together an inter-disciplinary team of investigators with combined expertise in autophagy, fungal genetics and mucosal immunology to explore how yeast can functionally influence intestinal disease.

! Project Narrative The types of microbes that reside on the body are critical to the development of the immune system and maintenance of intestinal homeostasis. Most studies to date have focused on the bacterial members of this community despite the presence of fungi, archaea and viral species. This proposal will seek to understand how individual fungal species influence metabolism and immunity of the host and that dictate intestinal disease. These experiments have the potential to impact diagnostic and therapies to treat intestinal maladies.