Enteric nervous system-derived VIP restrains differentiation of LGR5+ stem cells toward the secretory lineage impeding type 2 immune programs
Year: 2025
Type: article
Abstract: Barrier homeostasis relies on a finely tuned interplay between the immune system, epithelial cells and commensal microbiota. Beyond these regulators, the enteric nervous system has recently emerged as a central hub coordinating intestinal immune responses, although its role in epithelial differentiation has remained largely unexplored. Here, we identify a neuroepithelial circuit in which vasoactive intestinal peptide (VIP)-positive enteric neurons act on VIPR1 epithelial stem cells to restrain both their proliferation and secretory lineage differentiation. Disruption of this pathway leads to an expansion of tuft cells, enhanced interleukin (IL)-25 production, activation of group 2 innate lymphoid cells (ILC2s) and induction of a type 2 immune response resembling worm expulsion. This phenotype occurs independently of the microbiota but is modulated by the IL-25R-ILC2-IL-13 axis and dietary solid food intake. Our findings expose the enteric nervous system as a critical regulator of epithelial fate decisions and immune balance, complementing established mechanisms that safeguard barrier integrity and mucosal homeostasis.
DOI: 10.5167/uzh-290931
Authors: Jakob, Manuel O., Sterczyk, Nele, Boulekou, Sotiria, Forster, Patrycja M., Barleben, Luisa, Alzain, Nadra, Jarick, Katja J., Pirzgalska, Roksana M., Raposo, Bruno, Hansson, Karl, Nyström, Elisabeth E. L., Gondrand, Aurelia, González-Acera, Miguel, Leclère, Pierre S., Lapson, Marlen S., Poggenseier, Sarah, Deshpande, Divija, Velleman, Laura, Breiderhoff, Tilman, Brunkhorst, Max Felix, Schüle, Anton M., Guerra, Gabriela M., Durek, Pawel, Mashreghi, Mir-Farzin, Kühl, Anja A., Chu, Coco, Schneider, Christoph, Weidinger, Carl, Siegmund, Britta, Nordmann, Thierry M., et al
Language: English
Topic: IL-33, ST2, and ILC Pathways
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7128031306
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