%0 Journal Article
%A Jakob, Manuel O
%A Sterczyk, Nele
%A Boulekou, Sotiria
%A Forster, Patrycja M
%A Barleben, Luisa
%A Alzain, Nadra
%A Jarick, Katja J
%A Pirzgalska, Roksana M
%A Raposo, Bruno
%A Hansson, Karl
%A Nyström, Elisabeth E L
%A Gondrand, Aurelia
%A González-Acera, Miguel
%A Leclère, Pierre S
%A Lapson, Marlen S
%A Poggenseier, Sarah
%A Deshpande, Divija
%A Velleman, Laura
%A Breiderhoff, Tilman
%A Brunkhorst, Max Felix
%A Schüle, Anton M
%A Guerra, Gabriela M
%A Durek, Pawel
%A Mashreghi, Mir-Farzin
%A Kühl, Anja A
%A Chu, Coco
%A Schneider, Christoph
%A Weidinger, Carl
%A Siegmund, Britta
%A Nordmann, Thierry M
%A Voehringer, David
%A Patankar, Jay V
%A Becker, Christoph
%A Birchenough, George M H
%A Veiga-Fernandes, Henrique
%A Ronchi, Francesca
%A Kolesnichenko, Marina
%A Diefenbach, Andreas
%A Klose, Christoph S N
%T Enteric nervous system-derived VIP restrains differentiation of LGR5+ stem cells toward the secretory lineage impeding type 2 immune programs.
%J Nature immunology
%V 26
%N 12
%@ 1529-2908
%C London
%I Springer Nature Limited
%M DZNE-2025-01321
%P 2227 - 2243
%D 2025
%X 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.
%K Animals
%K Vasoactive Intestinal Peptide: metabolism
%K Vasoactive Intestinal Peptide: immunology
%K Enteric Nervous System: immunology
%K Enteric Nervous System: metabolism
%K Cell Differentiation: immunology
%K Mice
%K Receptors, G-Protein-Coupled: metabolism
%K Cell Lineage
%K Intestinal Mucosa: immunology
%K Intestinal Mucosa: metabolism
%K Lymphocytes: immunology
%K Immunity, Innate
%K Mice, Inbred C57BL
%K Stem Cells: immunology
%K Stem Cells: metabolism
%K Mice, Knockout
%K Homeostasis
%K Vasoactive Intestinal Peptide (NLM Chemicals)
%K Receptors, G-Protein-Coupled (NLM Chemicals)
%K Lgr5 protein, mouse (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41286457
%R 10.1038/s41590-025-02325-1
%U https://pub.dzne.de/record/282558