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Immune regulation by fungal strain diversity in inflammatory bowel disease.

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 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 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 (T_H17 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.

SUBMITTER: Li XV

PROVIDER: S-EPMC9166917 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Immune regulation by fungal strain diversity in inflammatory bowel disease.

Li Xin V XV Leonardi Irina I Putzel Gregory G GG Semon Alexa A Fiers William D WD Kusakabe Takato T Lin Woan-Yu WY Gao Iris H IH Doron Itai I Gutierrez-Guerrero Alejandra A DeCelie Meghan B MB Carriche Guilhermina M GM Mesko Marissa M Yang Chen C Naglik Julian R JR Hube Bernhard B Scherl Ellen J EJ Iliev Iliyan D ID

Nature 20220316 7902

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<sup>1-6</sup>. Although aberrant changes in the mycobiota have been linked to several diseases, including inflammatory bowel disease<sup>3-9</sup>, it is currently unknown whether fungal species captured by deep sequencing represent living organisms and whether specific fungi have functional consequenc ...[more]

PMID: 35296857

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Project description:The molecular processes linked to the development and progression of Crohn's disease (CD) and ulcerative colitis (UC) are not completely understood. MicroRNAs (miRNAs) regulate gene expression and are indicated as diagnostic, prognostic, and predictive biomarkers in chronic degenerative diseases. Our objectives included the identification of global miRNA expression in CD and UC, as well as miRNA target genes, miRNA-mRNA interaction networks, and biological functions associated with these different forms of inflammatory bowel disease (IBD).MethodsBy performing a comprehensive meta-analysis, we integrated miRNA expression data from nine studies in IBD. We obtained detailed information on significantly deregulated miRNAs (fold change, FC ≥ 2 and p < 0.05), sample type and number, and platform applied for analysis in the training and validation sets. Further bioinformatic analyses were performed to identify miRNA target genes, by using the microRNA Data Integration Portal tool. We also sought to identify statistically enriched pathways of genes regulated by miRNAs using ToppGene Suite. Additional analyses were performed to filter for genes expressed in intestinal tissue using the European Bioinformatics Institute (EBI) database.ResultsOur findings showed the upregulation of 15 miRNAs in CD and 33 in UC. Conversely, six miRNAs were downregulated in CD, while seven were downregulated in UC. These results indicate a greater deregulation of miRNAs in UC compared to CD. Of note, miRNA target genes were enriched for immune system regulation pathways. Among significantly deregulated miRNAs with a higher number of miRNA-target gene interactions, we identified miR-199a-5p and miR-362-3p altered in CD, while among UC case patients, miRNA-target gene interactions were higher for miR-155-5p.ConclusionsThe identified miRNAs play roles in regulating genes associated with immune system regulation and inflammation in IBD. Such miRNAs and their target genes have the potential to serve as clinically relevant biomarkers. These findings hold promise for enhancing the accuracy of diagnoses and facilitating the development of personalized treatment strategies for individuals with various forms of IBD.

Dataset Information

Immune regulation by fungal strain diversity in inflammatory bowel disease.

Publications

Immune regulation by fungal strain diversity in inflammatory bowel disease.

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