AI Insight
Researchers discovered that in healthy human intestines, a specialized immune cell type called Vγ9Vδ2+ T-cells can suppress fungal growth when activated by a bacterial metabolite called HMB-PP, using an IL-22-dependent mechanism. In patients with Crohn's disease, these T-cells respond poorly to bacterial signals, allowing harmful Candida albicans fungi to overgrow, form tissue-damaging filaments, and trigger inflammatory responses. Candida strains isolated from Crohn's disease patients showed enhanced ability to adhere to and invade the intestinal barrier compared to strains from healthy individuals.
Why it matters
This finding reveals a previously unknown link between bacterial metabolites, immune cells, and fungal control in the human gut, and identifies a specific immune defect in Crohn's disease. Understanding this mechanism could lead to new therapeutic approaches for inflammatory bowel disease that target the bacterial-fungal-immune axis rather than simply suppressing inflammation.
by Liya Mathew, Sean L. Carlson, Michael Savage, Claire Pardieu, Megan B. O’Brien, Ellie Crawley, Paul Harrow, Ann-Kristin Kaune, Edward Devlin, Emily L. Priest, Marilena Crescente, Kimberly Martinod, 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
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.