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The Intestinal Mycobiome and IBD

Award Number: K01DK125526
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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The Intestinal Mycobiome and IBD - PROJECT SUMMARY Crohn’s disease (CD) represents a significant public health challenge with more than 1 million individuals affected by this condition in the US. To date, a complete cure of CD is not available. CD has a multifactorial etiology, characterized by a complex interplay between environmental and genetic factors, particularly an inappropriate inflammatory response to commensal microbes in genetically affected individuals. Fungal infection represents one of the most serious health hazards, especially for immuno-compromised patients. C andidiasis has dramatically increased worldwide, especially in neutropenic patients or patients with altered gut microbiome due to increased antibiotic use. Recent studies performed by our group have demonstrated that the abundance C. tropicalis is significantly higher in patients with CD compared to their non-diseased first-degree relatives. C. tropicalis and C. albicans have been recognized as the most common pathogenic fungi and are part of the human commensal flora. C. tropicalis and C. albicans are commonly found in the gastrointestinal tract. However, the role of Candida infections in intestinal inflammation in patients with CD has not been fully elucidated. Therefore, there is a need for mechanistic studies aimed at delineating the molecular mechanisms by which Candida infection may result in exacerbation of CD. Studies proposed herein take advantage of a unique resource, a spontaneous murine model of CD-like ileitis (SAMP1/YitFc or SAMP), to decipher the mechanistic role of candidiasis in experimental ileitis. Strong preliminary data from our group have demonstrated that C57BL/6 (B6) mice infected with C. tropicalis are significantly more susceptible to develop dextran sodium sulfate (DSS)- induced colitis compared to uninfected littermates, with increased gene expression of key Th1 response- associated genes, such as Tnf and Ifn, and decreased expression of Th2 response-associated genes, such as Il4 and Il13. 16S rRNA analysis of fecal samples from infected and uninfected mice have shown that C. tropicalis significantly altered the microbiome population of B6 mice, with increased abundance of mucin degrading bacteria, such as Akkermansia (A.) muciniphila and Ruminococcus (R.) gnavus. Based on its biological effects, we hypothesized that Candida infection may alter the gut microbiome community resulting in dysbiosis that, in turn, increases the susceptibility of the host to develop IBD, or triggers flare in CD patients. The goals of this proposal are: (1) demonstrate that Candida infections contribute to worsen experimental intestinal inflammation; and (2) identify the specific microbes and mechanisms responsible for the increased intestinal inflammation in B6 and SAMP mice. Understanding the mechanisms by which candidiasis affects the gut microbiome is essential to maintain remission in CD patients and the design of novel antimicrobial therapies with increased efficacy and decreased side-effects.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $121,770 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/27/2025	NON-COMPETING CONTINUATION	$121,770
														Subtotal = $121,770

Issue Date FY: 2024 ( Subtotal = $121,770 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/23/2024	NON-COMPETING CONTINUATION	$121,770
														Subtotal = $121,770

Issue Date FY: 2023 ( Subtotal = $121,770 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/23/2023	NON-COMPETING CONTINUATION	$121,770
														Subtotal = $121,770

Issue Date FY: 2022 ( Subtotal = $121,770 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/25/2022	NON-COMPETING CONTINUATION	$121,770
														Subtotal = $121,770

Issue Date FY: 2021 ( Subtotal = $123,270 )
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/1/2021	NEW	$123,270
														Subtotal = $123,270

Grand Total All Awards = $610,350

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The Intestinal Mycobiome and IBD

Award Number: K01DK125526

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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