Journal Article

DZNE-2025-01321

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Enteric nervous system-derived VIP restrains differentiation of LGR5+ stem cells toward the secretory lineage impeding type 2 immune programs.

Jakob, M. O. ; Sterczyk, N. ; Boulekou, S. ; Forster, P. M. ; Barleben, L. ; Alzain, N. ; Jarick, K. J. ; Pirzgalska, R. M. ; Raposo, B. ; Hansson, K. ; Nyström, E. E. L. ; Gondrand, A. ; González-Acera, M. ; Leclère, P. S. ; Lapson, M. S. ; Poggenseier, S. ; Deshpande, D. ; Velleman, L. ; Breiderhoff, T.DZNE* ; Brunkhorst, M. F. ; Schüle, A. M. ; Guerra, G. M. ; Durek, P. ; Mashreghi, M.-F. ; Kühl, A. A. ; Chu, C. ; Schneider, C. ; Weidinger, C. ; Siegmund, B. ; Nordmann, T. M. ; Voehringer, D. ; Patankar, J. V. ; Becker, C. ; Birchenough, G. M. H. ; Veiga-Fernandes, H. ; Ronchi, F. ; Kolesnichenko, M. ; Diefenbach, A. ; Klose, C. S. N.

2025
Springer Nature Limited London

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Please use a persistent id in citations: 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.

Keyword(s): Animals (MeSH) ; Vasoactive Intestinal Peptide: metabolism (MeSH) ; Vasoactive Intestinal Peptide: immunology (MeSH) ; Enteric Nervous System: immunology (MeSH) ; Enteric Nervous System: metabolism (MeSH) ; Cell Differentiation: immunology (MeSH) ; Mice (MeSH) ; Receptors, G-Protein-Coupled: metabolism (MeSH) ; Cell Lineage (MeSH) ; Intestinal Mucosa: immunology (MeSH) ; Intestinal Mucosa: metabolism (MeSH) ; Lymphocytes: immunology (MeSH) ; Immunity, Innate (MeSH) ; Mice, Inbred C57BL (MeSH) ; Stem Cells: immunology (MeSH) ; Stem Cells: metabolism (MeSH) ; Mice, Knockout (MeSH) ; Homeostasis (MeSH) ; Vasoactive Intestinal Peptide ; Receptors, G-Protein-Coupled ; Lgr5 protein, mouse

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Contributing Institute(s):

1. Genome Engineering (AG Wurst)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 30 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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