Project Details
Projekt
Targeting intestinal yeasts and pathogenic yeast-responsive CD4+ T cells in Crohn’s disease
Subject Area
Gastroenterology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 426660215
Inappropriate CD4+ T cell responses against gut microbiota are considered to be a major factor in the pathophysiology of inflammatory bowel diseases (IBD). Despite extensive research on microbiome alterations in IBD, the disease-relevant microorganisms are still largely unknown. Most studies to date have focused on changes in bacterial species in IBD, while fungi have been largely ignored. We identified intestinal and dietary yeasts as triggers of altered inflammatory CD4+ T-cell reactivity in patients with Crohn's disease (MC), but not in patients with ulcerative colitis (UC). Such T-cell responses were characteristic for a subpopulation of CD patients positive for anti-Saccharomyces cerevisiae antibodies (ASCA), suggesting fundamentally different host-fungal interactions in this subgroup of patients. While these data provide the first strong correlative evidence for the involvement of yeasts and yeast-reactive CD4+ T cells in CD, further investigations are needed to determine their direct contribution to disease pathophysiology. In this project, we aim to identify the precise yeast-responsive T-cell receptors and antigenic peptides to provide the basis for developing new treatment strategies that target altered yeast-specific T cells. We will further investigate fungal strain variability in the gut microbiome and anti-fungal antibodies in IBD patients, to gain insights into the underlying mechanisms of the altered host-fungal interaction in ASCA positive CD patients. Finally, we will investigate the role of nutritional intervention with selective removal of yeast antigens, which, if effective, would be an attractive treatment strategy to support the efficacy of other anti-inflammatory therapies or of remission maintenance. Overall, this project aims to set the stage for the development of new treatment approaches for IBD patients by targeted modulation of the microbiome or the pathogenic T cells.
DFG Programme
Research Units
