Targeting the Gut Mycobiome in Ulcerative Colitis - Project Summary/Abstract This K23 Mentored Patient-Oriented Research Career Development Award proposal will provide experiential training, cohesive mentorship, and a fantastic research environment facilitating Dr. Sushrut Jangi’s development as an independent clinician scientist. His long-term career goal is to deliver personalized microbiome-directed treatments to improve outcomes in patients with ulcerative colitis (UC). A disabling disease, UC affects 1 million patients nationally, leading to gastrointestinal symptoms, recurrent relapses, and reduced quality of life. Current management is limited to biologic therapies with an efficacy of only ~30-50%. There is a dire need for more efficacious treatments, including those targeting the microbiome. Optimizing these treatments has called for considering microbes beyond bacteria, including fungi (the mycobiome). Recent evidence strongly supports that the fungal microbe Candida albicans is implicated in perpetuating colonic inflammation and in UC relapse. However, assessing and directly targeting C. albicans in UC remains unexplored. The current proposal will address this knowledge gap. The overall objectives are to 1) evaluate the mycobiome as a predictor of biologic-treatment failure 2) identify competitive interactions between the bacteriome and C. albicans in vitro 3) test the feasibility and preliminary efficacy of adjunctive fluconazole to alter the mycobiome and improve UC outcomes. To achieve these aims, 40 active UC patients initiating biologic-therapies will be prospectively recruited. Longitudinal fecal samples will be collected to determine if persistent elevations in C. albicans are associated with biologic-treatment failure. Second, the growth of patient stool-derived C. albicans strains will be tested in the presence of bacterial strains, to identify if specific bacteria or their metabolites may regulate C. albicans growth in vitro. Finally, in a pilot randomized controlled trial, 36 patients with active UC will receive 14 days of 200 mg of fluconazole or placebo, in addition to standard immunosuppression. Primary outcomes of feasibility of this intervention, and secondary outcomes of microbial changes and clinical outcomes will be assessed. This proposal’s outcomes are expected to determine if C. albicans may predict biologic-treatment failure, to identify bacteria that antagonize C. albicans, and to test if targeting the mycobiome may reduce C. albicans and improve UC outcomes. Dr. Jangi is a gastroenterologist with a background in clinical research. However, he requires advanced training in mixed-effect models to assess the dynamic microbiome alongside patient covariates, assessment of microbial functions and communities through shotgun metagenomics and co-abundance measures, translational research, and in clinical trial design and execution. He has assembled a strong mentorship team led by Dr. Dominique Michaud, spanning national experts in microbiology, inflammatory bowel disease, the microbiome, and clinical trial development. This approach, combined with the outstanding resources available at Tufts Medical Center and Tufts University, will ensure Dr. Jangi’s success in his transition to an independent investigator.
