Enteric nervous system-derived VIP restrains differentiation of LGR5+ stem cells toward the secretory lineage impeding type 2 immune programs
Jakob MO, Sterczyk N, Boulekou S, Forster PM, Barleben L, Alzain N, Jarick KJ, Pirzgalska RM, Raposo B, Hansson K, Nyström EE, Gondrand A, González-Acera M, Leclère PS, Lapson MS, Poggenseier S, Deshpande D, Velleman L, Breiderhoff T, Brunkhorst MF, Schüle AM, Guerra GM, Durek P, Mashreghi MF, Kühl AA, Chu C, Schneider C, Weidinger C, Siegmund B, Nordmann TM, Vöhringer D, Patankar J, Becker C, Birchenough GM, Veiga-Fernandes H, Ronchi F, Kolesnichenko M, Diefenbach A, Klose CS (2025)
Publication Type: Journal article
Publication year: 2025
Journal
Book Volume: 26
Pages Range: 2227-2243
Journal Issue: 12
DOI: 10.1038/s41590-025-02325-1
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.
Authors with CRIS profile
David Vöhringer
Department of Infection Biology
Jay Patankar
Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology
Christoph Becker
Professur für Molekulare Gastroenterologie
Involved external institutions
Max-Planck-Institut für Biochemie / Max Planck Institute of Biochemistry
Germany (DE)
University of Gothenburg / Göteborgs universitet
Sweden (SE)
Champalimaud Foundation / Fundação Champalimaud
Portugal (PT)
Charité - Universitätsmedizin Berlin
Germany (DE)
University of Zurich / Universität Zürich (UZH)
Switzerland (CH)
Tsinghua University
China (CN)
Deutsches Rheuma-Forschungszentrum (DRFZ)
Germany (DE)
Germany (DE)
University of Gothenburg / Göteborgs universitet
Sweden (SE)
Champalimaud Foundation / Fundação Champalimaud
Portugal (PT)
Charité - Universitätsmedizin Berlin
Germany (DE)
University of Zurich / Universität Zürich (UZH)
Switzerland (CH)
Tsinghua University
China (CN)
Deutsches Rheuma-Forschungszentrum (DRFZ)
Germany (DE)
How to cite
APA:
Jakob, M.O., Sterczyk, N., Boulekou, S., Forster, P.M., Barleben, L., Alzain, N.,... Klose, C.S. (2025). Enteric nervous system-derived VIP restrains differentiation of LGR5+ stem cells toward the secretory lineage impeding type 2 immune programs. Nature Immunology, 26(12), 2227-2243. https://doi.org/10.1038/s41590-025-02325-1
MLA:
Jakob, Manuel O., et al. "Enteric nervous system-derived VIP restrains differentiation of LGR5+ stem cells toward the secretory lineage impeding type 2 immune programs." Nature Immunology 26.12 (2025): 2227-2243.
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