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 also the potential to influence these processes. It is unknown how gut fungal communities, so called ?mycobiota?, can be influenced by intestinal pathologies, antibiotic treatment, immune and dietary changes that have been reported to lead to ?bacterial dysbiosis?. We have shown that a polymorphism in the human gene encoding the anti-fungal receptor Dectin-1 (CLEC7A) is strongly associated with the severity of ulcerative colitis (UC) and that, in a mouse model of colitis, the overgrowth of opportunistic fungi such as Candida and Trichosporon spp. contribute to intestinal inflammation. This suggests that disturbances in the healthy fungal community (?mycobiota dysbiosis?) may be an important factor in the development or progression of intestinal disease. In this proposal, we will explore the hypothesis that gut mycobiota dysbiosis might affect intestinal inflammation by promoting aberrant interaction of ?dysbiotic? fungi with the host mucosal immune system and with intestinal bacteria. Our preliminary data show that mycobiota dysbiosis induced with the commonly used antifungal drug fluconazole can affect the severity of lung allergy (house dust mite allergy model) and intestinal inflammation (DSS and T cell transfer mouse models). Oral supplementation with three dysbiotic filamentous fungi (Aspergillus amstelodami, Epicoccum nigrum, and Wallemia sebi) that expanded during fluconazole treatment recapitulated the detrimental effects of fluconazole on inflammation, while fungi unrelated to dysbiosis (S. fibuligera) did not. We found that, in addition to influencing the mycobiota, drug-induced dysbiosis affects gut bacterial communities. In a novel ?mycobiota defined? model that lacks indigenous fungi, introduction of a single intestinal fungus led to distinctive changes in the intestinal bacteria, suggesting that fungi and bacteria can influence each other in the gut. Employing new in vivo tools, high-throughput platforms and computational pipelines, we will focus on delineating: (1) the mechanisms by which fungal dysbiosis affects gut mycobiota and intestinal inflammation, (2) the relative contribution of Dectin-1 and adaptor molecule CARD9 on the inflammatory effects of mycobiota dysbiosis, (3) the specific interactions of dysbiotic fungi with bacteria and with the host in a novel ?mycobiota defined? mouse model. It is currently unknown whether gut microbiota dysbiosis, which is solely viewed as ?bacterial dysbiosis?, is actually a collective feature of more complex interactions between prokaryotic and eukaryotic communities. We anticipate defining how common antifungal drugs and dysbiotic fungi lead to intestinal inter-kingdom community dysbiosis that affect immunity and contribute to intestinal disease. The results of this study will map mycobiota profiles associated with fungal dysbiosis and will be a further step towards defining aberrant inter-kingdom interactions in the gut which can be the basis for targeted novel therapies for inflammatory diseases.

Public Health Relevance

The intestines are home to a community of bacteria, but also of viruses and fungi. As intestinal pathologies and antibiotics promote a process of unhealthy bacterial changes in the gut known as ?dysbiosis?, we hypothesized that antifungal medication might not only target some dangerous fungal pathogens, but also affect healthy fungal communities in the gut, promoting ?fungal dysbiosis?. In this proposal, we will study the effects of fungal dysbiosis on intestinal disease, and will define aberrant interactions between ?dysbiotic fungi?, the host and bacteria in the gut that can be targeted to tailor novel therapies for inflammatory bowel diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Perrin, Peter J
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Weill Medical College of Cornell University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Leonardi, Irina; Li, Xin; Semon, Alexa et al. (2018) CX3CR1+ mononuclear phagocytes control immunity to intestinal fungi. Science 359:232-236
Leonardi, Irina; Li, Xin; Iliev, Iliyan D (2018) Macrophage interactions with fungi and bacteria in inflammatory bowel disease. Curr Opin Gastroenterol 34:392-397
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Li, Xin; Leonardi, Irina; Semon, Alexa et al. (2018) Response to Fungal Dysbiosis by Gut-Resident CX3CR1+ Mononuclear Phagocytes Aggravates Allergic Airway Disease. Cell Host Microbe 24:847-856.e4
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