Commensal fungal communities in the regulation of immunity and intestinal inflammation

Abstract Decades of research have revealed that intestinal bacteria are critical for regulating homeostatic and protective immune responses. However, recent studies suggest that additional players such as fungi and viruses have high potential to influence these processes. While important trans-kingdom relationships between gut fungi (mycobiota) and bacteria have been recently unveiled, how fungi influence intestinal homeostasis, states of inflammation and responses to therapeutic interventions for Inflammatory Bowel Disease (IBD) is still less clear. In prior works, we defined profound effects of gut mycobiota on local and gut distal immunity through interaction with CX3CR1+ mononuclear phagocyte or by shaping host antibody repertoires that influence fungal commensalism. We defined that these processes are affected in IBD. In a multicenter placebo-controlled clinical trial of fecal microbiota transplantation (FMT) in Ulcerative colitis (UC) we recently determined that fungal clearance and blunted immune activation against Candida albicans correlates with a response to therapy. These findings suggest a possible role of gut mycobiota in efficacy of and response to therapeutic interventions. In preliminary studies we demonstrate the presence of rich genetic and phenotypic diversity of opportunistic Candida strains that dominated the colonic mucosa of IBD patients. We found that these isolates differ by their ability to cause host cell damage and are functionally diverse across individuals. In this competitive renewal we propose studies aiming to decipher the processes on inflammation caused by patient-associated strains. We hypothesize that these organisms influence inflammation and response to therapy through the production of factors that are regulated at strain-specific level. The results of this study will map the human gut mycobiota functionally and might provide a basis for targeted novel therapies and co-therapies for inflammatory diseases.