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Peer-reviewedCC BY 4.0PLOS Biology

Fungal suppression by bacterial metabolite-activated human intestinal γδT-cells is disrupted in Crohn’s disease

  • Liya Mathew1
  • Sean L. Carlson2
  • Michael Savage3
  • Claire Pardieu4
  • Megan B. O’Brien5
  • Ellie Crawley6
  • Paul Harrow7
  • Ann-Kristin Kaune8
  • Edward Devlin9
  • Emily L. Priest
  • Marilena Crescente
  • Kimberly Martinod
12 more authors
  • James Boot
  • SoFong Cam Ngan
  • Marco Gasparetto
  • Klaartje Kok
  • James O. Lindsay
  • Jonathan P. Richardson
  • Julian R. Naglik
  • Andrew J. Stagg
  • Matthias Eberl
  • Siu Kwan Sze
  • Carol A. Munro
  • Neil E. McCarthy
9 affiliations
  1. 1Centre for Immunobiology and Infection, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
  2. 2Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, United Kingdom
  3. 3Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London, United Kingdom
  4. 4School of Pharmacy, University of Reading, Reading, United Kingdom
  5. 5Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America
  6. 6Faculty of Applied Health Sciences, Brock University, St. Catharines, Ontario, Canada
  7. 7Department of Paediatric Gastroenterology, The Royal London Children’s Hospital, Barts Health NHS Trust, London, United Kingdom
  8. 8Department of Gastroenterology, Barts Health NHS Trust, London, United Kingdom
  9. 9Division of Infection and Immunity, School of Medicine, and Systems Immunity Research Institute, Cardiff University, Cardiff, United Kingdom
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Abstract

Gut symbionts condition mucosal immunity to resist infection by enteropathogens, but the specific microbes and mechanisms involved differ significantly between host species. In higher primates, bacterial metabolite HMB-PP is sensed by a specialized population of Vγ9Vδ2+T-cells, which we now report can potently suppress growth of endogenous fungi in human intestinal organ cultures. In healthy intestine, HMB-PP-stimulated Vδ2+ T-cells restricted outgrowth of keystone fungus Candida albicans via a mechanism that required IL-22. In Crohn’s disease (CD), Vδ2+ T-cells were poorly responsive to HMB-PP and permitted outgrowth of C. albicans strains that formed toxin-producing filaments, triggered neutrophil extracellular traps, and induced macrophage IL-1β release ex vivo. Genomic and proteomic analysis of the Candida isolates suggested increased tissue adhesion of CD-derived strains, which rapidly invaded the gut barrier in an ‘intestine-on-a-chip’ model. These data reveal that bacterial activation of Vδ2+ T-cells suppresses fungal pathobionts in human gut via an IL-22-dependent mechanism that is dysregulated in CD.

Fungi are common members of the gut microbiome, but inflammation can tip them toward harmful forms. This study shows that bacterial signals activate gut γδ T cells to suppress fungi and limit invasive strains and that this defense is disrupted in Crohn’s disease.

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Cite

BibTeXRIS
BibTeX
@article{mathew2026fungal,
  title = {{Fungal suppression by bacterial metabolite-activated human intestinal γδT-cells is disrupted in Crohn’s disease}},
  author = {Liya Mathew and Sean L. Carlson and Michael Savage and Claire Pardieu and Megan B. O’Brien and Ellie Crawley and Paul Harrow and Ann-Kristin Kaune and Edward Devlin and Emily L. Priest and Marilena Crescente and Kimberly Martinod and James Boot and SoFong Cam Ngan and Marco Gasparetto and Klaartje Kok and James O. Lindsay and Jonathan P. Richardson and Julian R. Naglik and Andrew J. Stagg and Matthias Eberl and Siu Kwan Sze and Carol A. Munro and Neil E. McCarthy},
  journal = {PLOS Biology},
  year = {2026},
  month = nov,
  doi = {10.1371/journal.pbio.3004080},
  url = {https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004080},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Fungal suppression by bacterial metabolite-activated human intestinal γδT-cells is disrupted in Crohn’s disease
AU  - Liya Mathew
AU  - Sean L. Carlson
AU  - Michael Savage
AU  - Claire Pardieu
AU  - Megan B. O’Brien
AU  - Ellie Crawley
AU  - Paul Harrow
AU  - Ann-Kristin Kaune
AU  - Edward Devlin
AU  - Emily L. Priest
AU  - Marilena Crescente
AU  - Kimberly Martinod
AU  - James Boot
AU  - SoFong Cam Ngan
AU  - Marco Gasparetto
AU  - Klaartje Kok
AU  - James O. Lindsay
AU  - Jonathan P. Richardson
AU  - Julian R. Naglik
AU  - Andrew J. Stagg
AU  - Matthias Eberl
AU  - Siu Kwan Sze
AU  - Carol A. Munro
AU  - Neil E. McCarthy
PY  - 2026
DA  - 2026/11/02
JO  - PLOS Biology
DO  - 10.1371/journal.pbio.3004080
UR  - https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004080
AB  - Gut symbionts condition mucosal immunity to resist infection by enteropathogens, but the specific microbes and mechanisms involved differ significantly between host species. In higher primates, bacterial metabolite HMB-PP is sensed by a specialized population of Vγ9Vδ2+T-cells, which we now report can potently suppress growth of endogenous fungi in human intestinal organ cultures. In healthy intestine, HMB-PP-stimulated Vδ2+ T-cells restricted outgrowth of keystone fungus Candida albicans via a mechanism that required IL-22. In Crohn’s disease (CD), Vδ2+ T-cells were poorly responsive to HMB-PP and permitted outgrowth of C. albicans strains that formed toxin-producing filaments, triggered neutrophil extracellular traps, and induced macrophage IL-1β release ex vivo. Genomic and proteomic analysis of the Candida isolates suggested increased tissue adhesion of CD-derived strains, which rapidly invaded the gut barrier in an ‘intestine-on-a-chip’ model. These data reveal that bacterial activation of Vδ2+ T-cells suppresses fungal pathobionts in human gut via an IL-22-dependent mechanism that is dysregulated in CD.  Fungi are common members of the gut microbiome, but inflammation can tip them toward harmful forms. This study shows that bacterial signals activate gut γδ T cells to suppress fungi and limit invasive strains and that this defense is disrupted in Crohn’s disease.
SN  - 1545-7885
ER  -