A diverse community of commensal bacteria colonizes the mammalian gut. Interactions between the commensal microflora and the gut immune system are critical for establishing a proper balance between immune host defense mechanisms and tissue health. Although a few studies have reported the presence of fungal DNA in human and murine feces, gut fungi have been largely overlooked and their interactions with the gut immune system have not been investigated. We have recently reported an abundant and highly diverse population of fungal species (gut mycobiome) to be a significant component of the murine intestinal microbiota. We found that gut fungi interact with the immune system through the innate immune receptor Dectin-1 and that mice lacking Dectin-1 exhibit increased susceptibility to chemically-induced colitis, which is a result of altered responses to indigenous fungi. However not all fungi are "bad". We found that a mouse commensal strain of Saccharomycopsis fibuligera (S. fibuligera ID1) was protective against intestinal inflammation in a DSS- induced model of colitis. Certain species of commensal bacteria have long been known to modulate mucosal immune responses, dictate the balance between Th1, Th2, Th17 and Treg cells and have been widely used for prevention and treatment of intestinal disorders. Only a few studies have reported that fungi can have similar protective properties, although the mechanism behind such "protection" is largely unknown. This proposal focuses on defining protective gut fungi and their mechanisms of protection by studying their interaction with bacteria and the intestinal epithelium as well as with the innate and adaptive immune systems in the gut. We hypothesize that commensal fungi interact with gut bacteria and with the mucosal immune system to induce tolerogenic mechanisms, leading to suppression of intestinal inflammation and colitis. We will test our hypothesis in three specific aims.
In Specific Aim 1 we will evaluate commensal and related fungi for protective properties using a mouse model of DSS induced colitis.
In Specific Aim 2 we will extend the analysis to look at protection by S. fibuligera ID1 and other fungi in models targeting different arms of colitis etiology including T cell-mediated and infectious microbe-mediated disease.
In Specific Aim 3 we will explore mechanisms of protection including fungal-induced alterations in the bacterial microbiome, interaction of gut fungi with the intestinal epithelium and the innate immune system, and regulation of T cell bias in the intestine.

Public Health Relevance

Proper interactions between our immune systems and microorganisms living in our guts are critical for healthy intestines. The vast majority of studies on these interactions have focused on gut bacteria. In this proposal, we will define the specific molecular mechanisms coordinating immune recognition of fungi in the gut, and especially on how good fungi in the gut can be protective against intestinal inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Career Transition Award (K99)
Project #
1K99DK098310-01A1
Application #
8635702
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hamilton, Frank A
Project Start
2014-04-04
Project End
2016-03-31
Budget Start
2014-04-04
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$90,000
Indirect Cost
$6,667
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Underhill, David M; Iliev, Iliyan D (2014) The mycobiota: interactions between commensal fungi and the host immune system. Nat Rev Immunol 14:405-16