Friday, May 9, 2025
5/9/2025
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).