Enteric nervous system-derived VIP restrains differentiation of LGR5+ stem cells toward the secretory lineage impeding type 2 immune programs
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
- Thierry M. Nordmann (ORCID: https://orcid.org/0000-0002-3702-815X)
- Luisa Barleben
- Aurelia Gondrand (ORCID: https://orcid.org/0009-0004-9989-4899)
- Britta Siegmund
- Sotiria Boulekou (ORCID: https://orcid.org/0000-0001-5520-4164)
- Max Brunkhorst
- Manuel O. Jakob (ORCID: https://orcid.org/0000-0003-3638-3114)
- Anja A. Kühl (ORCID: https://orcid.org/0000-0003-2293-5387)
- Nadra Alzain
- Bruno Raposo (ORCID: https://orcid.org/0000-0003-4734-7207)
- Tilman Breiderhoff (ORCID: https://orcid.org/0000-0002-1676-7498)
- Pawel Durek (ORCID: https://orcid.org/0000-0002-6179-0670)
- Roksana M. Pirzgalska (ORCID: https://orcid.org/0000-0003-2314-0439)
- Elisabeth Nyström (ORCID: https://orcid.org/0000-0002-6970-7894)
- Miguel González-Acera (ORCID: https://orcid.org/0009-0008-9445-5650)
- Gabriela Maria Guerra (ORCID: https://orcid.org/0000-0002-9773-4929)
- Katja J. Jarick (ORCID: https://orcid.org/0000-0001-5162-7266)
- Pierre S. Leclère (ORCID: https://orcid.org/0000-0002-1794-9461)
- Patrycja M. Forster
- Anton M Schüle (ORCID: https://orcid.org/0009-0003-3094-9778)
- Laura Velleman (ORCID: https://orcid.org/0009-0002-7347-8067)
- Marlen S. Lapson
- Sarah Poggenseier (ORCID: https://orcid.org/0009-0001-5343-9987)
- Christoph Schneider
- Karl Hansson
- et al
- Nele Sterczyk
- Coco Chu
- Divija Deshpande
Publication Details
- Journal
- Universität Zürich, ZORA
- Published
- 2025-11-24
- DOI
- https://doi.org/10.5167/uzh-290931
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00