TY  - JOUR
AU  - Jakob, Manuel O
AU  - Sterczyk, Nele
AU  - Boulekou, Sotiria
AU  - Forster, Patrycja M
AU  - Barleben, Luisa
AU  - Alzain, Nadra
AU  - Jarick, Katja J
AU  - Pirzgalska, Roksana M
AU  - Raposo, Bruno
AU  - Hansson, Karl
AU  - Nyström, Elisabeth E L
AU  - Gondrand, Aurelia
AU  - González-Acera, Miguel
AU  - Leclère, Pierre S
AU  - Lapson, Marlen S
AU  - Poggenseier, Sarah
AU  - Deshpande, Divija
AU  - Velleman, Laura
AU  - Breiderhoff, Tilman
AU  - Brunkhorst, Max Felix
AU  - Schüle, Anton M
AU  - Guerra, Gabriela M
AU  - Durek, Pawel
AU  - Mashreghi, Mir-Farzin
AU  - Kühl, Anja A
AU  - Chu, Coco
AU  - Schneider, Christoph
AU  - Weidinger, Carl
AU  - Siegmund, Britta
AU  - Nordmann, Thierry M
AU  - Voehringer, David
AU  - Patankar, Jay V
AU  - Becker, Christoph
AU  - Birchenough, George M H
AU  - Veiga-Fernandes, Henrique
AU  - Ronchi, Francesca
AU  - Kolesnichenko, Marina
AU  - Diefenbach, Andreas
AU  - Klose, Christoph S N
TI  - Enteric nervous system-derived VIP restrains differentiation of LGR5+ stem cells toward the secretory lineage impeding type 2 immune programs.
JO  - Nature immunology
VL  - 26
IS  - 12
SN  - 1529-2908
CY  - London
PB  - Springer Nature Limited
M1  - DZNE-2025-01321
SP  - 2227 - 2243
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Vasoactive Intestinal Peptide: metabolism
KW  - Vasoactive Intestinal Peptide: immunology
KW  - Enteric Nervous System: immunology
KW  - Enteric Nervous System: metabolism
KW  - Cell Differentiation: immunology
KW  - Mice
KW  - Receptors, G-Protein-Coupled: metabolism
KW  - Cell Lineage
KW  - Intestinal Mucosa: immunology
KW  - Intestinal Mucosa: metabolism
KW  - Lymphocytes: immunology
KW  - Immunity, Innate
KW  - Mice, Inbred C57BL
KW  - Stem Cells: immunology
KW  - Stem Cells: metabolism
KW  - Mice, Knockout
KW  - Homeostasis
KW  - Vasoactive Intestinal Peptide (NLM Chemicals)
KW  - Receptors, G-Protein-Coupled (NLM Chemicals)
KW  - Lgr5 protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41286457
DO  - DOI:10.1038/s41590-025-02325-1
UR  - https://pub.dzne.de/record/282558
ER  -