Immune regulation by fungal strain diversity in inflammatory bowel disease

Article

关键词: ANTI-SACCHAROMYCES-CEREVISIAE;    CANDIDA-ALBICANS;    COLONIZATION;    ANTIBODIES;    MICROBIOTA;    EVOLUTION;    ALIGNMENT;    PATHOGEN;    COLITIS;    FLORA;   

DOI  :  10.1038/s41586-022-04502-w

来源: SCIE

【 摘 要 】

The fungal microbiota (mycobiota) is an integral part of the complex multikingdom microbial community colonizing the mammalian gastrointestinal tract and has an important role in immune regulation(1-6). Although aberrant changes in the mycobiota have been linked to several diseases, including inflammatory bowel disease(3-9), it is currently unknown whether fungal species captured by deep sequencing represent living organisms and whether specific fungi have functional consequences for disease development in affected individuals. Here we developed a translational platform for the functional analysis of the mycobiome at the fungal-strain- and patient-specific level. Combining high-resolution mycobiota sequencing, fungal culturomics and genomics, a CRISPR-Cas9-based fungal strain editing system, in vitro functional immuno reactivity assays and in vivo models, this platform enables the examination of host-fungal crosstalk in the human gut. We discovered a rich genetic diversity of opportunistic Candida albicans strains that dominate the colonic mucosa of patients with inflammatory bowel disease. Amongthese human-gut-derived isolates, strains with high immune-cell-damaging capacity (HD strains) reflect the disease features of individual patients with ulcerative colitis and aggravated intestinal inflammation in vivo through IL-1 beta-dependent mechanisms. Niche-specific inflammatory immunity and interleukin-17A-producing T helper cell (T(H)17 cell) antifungal responses by HD strains in the gut were dependent on the C. albicans-secreted peptide toxin candidalysin during the transition from a benign commensal to a pathobiont state. These findings reveal the strain-specific nature of host-fungal interactions in the human gut and highlight new diagnostic and therapeutic targets for diseases of inflammatory origin.

【 授权许可】

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