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<p>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<sup>+</sup> 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.</p>

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Enteric nervous system-derived VIP restrains differentiation of LGR5+ stem cells toward the secretory lineage impeding type 2 immune programs

  • 期刊论文

  • 发表日期：

    2025年11月24日

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  • Manuel O. Jakob,
  • Nele Sterczyk,
  • Sotiria Boulekou,
  • Patrycja M. Forster,
  • Luisa Barleben,
  • Nadra Alzain,
  • Katja J. Jarick,
  • Roksana M. Pirzgalska,
  • Bruno Raposo,
  • Karl Hansson,
  • Elisabeth E. L. Nyström,
  • Aurelia Gondrand,
  • Miguel González-Acera,
  • Pierre S. Leclère,
  • Marlen S. Lapson,
  • Sarah Poggenseier,
  • Divija Deshpande,
  • Laura Velleman,
  • Tilman Breiderhoff,
  • Max Felix Brunkhorst,
  • Anton M. Schüle,
  • Gabriela M. Guerra,
  • Pawel Durek,
  • Mir-Farzin Mashreghi,
  • Anja A. Kühl,
  • Coco Chu,
  • Christoph Schneider,
  • Carl Weidinger,
  • Britta Siegmund,
  • Thierry M. Nordmann,
  • David Voehringer,
  • Jay V. Patankar,
  • Christoph Becker,
  • George M. H. Birchenough,
  • Henrique Veiga-Fernandes,
  • Francesca Ronchi,
  • Marina Kolesnichenko,
  • Andreas Diefenbach,
  • Christoph S. N. Klose

摘要

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.