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| Item Type: | Article |
|---|---|
| Title: | Enteric nervous system-derived VIP restrains differentiation of LGR(5)(+) stem cells toward the secretory lineage impeding type 2 immune programs |
| Creators Name: | 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., Voehringer, David, Patankar, Jay V., Becker, Christoph, Birchenough, George M.H., Veiga-Fernandes, Henrique, Ronchi, Francesca, Kolesnichenko, Marina, Diefenbach, Andreas and Klose, Christoph S.N. |
| 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. |
| Keywords: | Cell Differentiation, Cell Lineage, Enteric Nervous System, G-Protein-Coupled Receptors, Homeostasis, Inbred C57BL Mice, Innate Immunity, Intestinal Mucosa, Knockout Mice, Lymphocytes, Stem Cells, Vasoactive Intestinal Peptide, Animals |
| Source: | Nature Immunology |
| ISSN: | 1529-2908 |
| Publisher: | Nature Publishing Group |
| Volume: | 26 |
| Number: | 12 |
| Page Range: | 2227-2243 |
| Date: | December 2025 |
| Official Publication: | https://doi.org/10.1038/s41590-025-02325-1 |
| PubMed: | View item in PubMed |
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