Immune regulation by fungal strain diversity in inflammatory bowel disease

Xin V. Li, Irina Leonardi, Gregory G. Putzel, Alexa Semon, William D. Fiers, Takato Kusakabe, Woan-Yu Lin, Iris H. Gao, Itai Doron, Alejandra Gutierrez-Guerrero, Meghan B. DeCelie, Guilhermina M. Carriche, Marissa Mesko, Chen Yang, Julian R. Naglik, Bernhard Hube, Ellen J. Scherl and Iliyan D. Iliev ()
Additional contact information
Xin V. Li: Cornell University
Irina Leonardi: Cornell University
Gregory G. Putzel: Cornell University
Alexa Semon: Cornell University
William D. Fiers: Cornell University
Takato Kusakabe: Cornell University
Woan-Yu Lin: Cornell University
Iris H. Gao: Cornell University
Itai Doron: Cornell University
Alejandra Gutierrez-Guerrero: Cornell University
Meghan B. DeCelie: Cornell University
Guilhermina M. Carriche: Cornell University
Marissa Mesko: Cornell University
Chen Yang: Yale University
Julian R. Naglik: King’s College London
Bernhard Hube: Hans Knoell Institute
Ellen J. Scherl: Cornell University
Iliyan D. Iliev: Cornell University

Nature, 2022, vol. 603, issue 7902, 672-678

Abstract: Abstract 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 regulation1–6. Although aberrant changes in the mycobiota have been linked to several diseases, including inflammatory bowel disease3–9, 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 immunoreactivity 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. Among these 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-1β-dependent mechanisms. Niche-specific inflammatory immunity and interleukin-17A-producing T helper cell (TH17 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.

Date: 2022
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DOI: 10.1038/s41586-022-04502-w

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