Little is known about the role of gut fungi in regulating a healthy gut microflora and in contributing to inflammatory disorders. Most studies of gut microflora focus on commensal bacteria which make up the majority of microbes in the gut. Numerous studies have documented effects of intestinal bacteria on tuning mucosal immunity and in instructing tissue development and repair. Antibiotic use, host genetics, and diet influence the bacterial microbiota and susceptibility to intestinal inflammatory disease. What about fungi? Our overall hypothesis is that intestinal fungal dysbiosis influences the immune system in ways that can increase susceptibility to inflammatory disease and that can be targeted to increase resistance to inflammatory disease. In this renewal proposal, we document that disruption of the ?normal? mycobiome in mice causes increased susceptibility to colitis and to allergic asthma. We propose studies aimed at understanding how antibiotic use, host genetics, and diet influence the intestinal fungal microbiota (?mycobiota?) in the near and long-term. We will characterize how common (Candida and Saccharomyces) and less well-known (Wallemia, Epicoccum) fungi influence susceptibility to intestinal inflammatory disease.

Public Health Relevance

Growing evidence suggests that fungi in the gut (the fungal microbiota, or ?mycobiome?) influence health and susceptibility to disease. We have previously observed that fungi and immune responses to fungi can influence severity of colitis in mouse models and in patients with inflammatory bowel disease. In this project we will characterize how antibiotic, genetic, and dietary perturbation of the mycobiome influence colitis and investigate how changes in gut fungal populations persist.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK093426-07
Application #
9929568
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Perrin, Peter J
Project Start
2012-07-01
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
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Wheeler, Matthew L; Limon, Jose J; Bar, Agnieszka S et al. (2016) Immunological Consequences of Intestinal Fungal Dysbiosis. Cell Host Microbe 19:865-73
Underhill, David M; Pearlman, Eric (2015) Immune Interactions with Pathogenic and Commensal Fungi: A Two-Way Street. Immunity 43:845-58
Tang, Jie; Iliev, Iliyan D; Brown, Jordan et al. (2015) Mycobiome: Approaches to analysis of intestinal fungi. J Immunol Methods 421:112-121
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Iliev, Iliyan D; Funari, Vincent A; Taylor, Kent D et al. (2012) Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis. Science 336:1314-7