P145 Phagocyte responses to gut-derived C. albicans are modified in inflammatory bowel disease

Abstract

Abstract Background Fungi are a key component of the human gut microbiota and have been strongly implicated in the pathogenesis of inflammatory bowel disease (IBD). Candida albicans typically exists as a commensal yeast within healthy hosts but can form tissue-invasive filaments that secrete Candidalysin (CLYS) toxin to disrupt epithelial barriers. Dynamics of this morphological switch are influenced by genotypic and phenotypic variation of gut-resident C. albicans strains, which may impact host response and extent of mucosal inflammation. Methods C. albicans isolates were derived from healthy control (HC) and IBD gut biopsies. Phenotypic, genomic, and proteomic analyses were conducted on these isolates. To further understand host interplay with intestinal C. albicans under physiologically relevant conditions, a human ‘gut-on-a-chip’ system was developed to assess tissue invasion potential in vitro. Results IBD-derived isolates were more readily able to form filaments, displayed altered cell wall composition, and modulated expression of adhesion-associated genes including IHD1. Subsequent innate leukocyte responses to these strain-dependent profiles were investigated to understand impact on host immunity. When exposed to IBD-derived C. albicans strains, blood neutrophils from healthy donors displayed increased swarming behaviour and NETosis induction, whereas monocyte-derived macrophages released greater amounts of pro-inflammatory IL-1b. These responses were substantially diminished in neutrophils and macrophages from IBD patients, suggesting altered reactivity to fungal stimuli in disease settings. The gut-on-a-chip model system confirmed that IBD-derived strains display increased adhesion and translocation in a dynamic human gut environment. Conclusion Gut-adapted C. albicans strains from HC and IBD donors exhibit distinct biological profiles that impact on host immune responses and shape interactions with the gut barrier in a novel organ chip model.