Christoph S. N. Klose课题组提出了肠神经系统衍生的血管活性肠肽（VIP）抑制LGR5⁺干细胞向分泌细胞系分化，从而阻碍2型免疫程序。相关论文于2025年11月24日发表于国际顶尖学术期刊《自然—免疫学》杂志上。

该研究组发现了一个神经上皮回路，其中血管活性肠肽（VIP）阳性的肠神经元作用于VIPR1⁺上皮干细胞，抑制其增殖和分泌谱系分化。这一途径的破坏导致簇状细胞的扩增，白细胞介素(IL)-25的产生增强，2组先天淋巴样细胞（ILC2s）的激活，并诱导类似蠕虫驱逐的2型免疫反应。这种表型独立于微生物群发生，但受IL-25R-ILC2-IL-13轴和膳食固体食物摄入量的调节。他们的发现揭示了肠神经系统作为上皮命运决定和免疫平衡的关键调节器，补充了保护屏障完整性和粘膜稳态的既定机制。

据介绍，屏障内稳态依赖于免疫系统、上皮细胞和共生微生物群之间精细调节的相互作用。除了这些调节因子外，肠神经系统最近成为协调肠道免疫反应的中心枢纽，尽管其在上皮分化中的作用在很大程度上仍未被探索。

附：英文原文

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

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

Issue&Volume: 2025-11-24

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.

DOI: 10.1038/s41590-025-02325-1

Source: https://www.nature.com/articles/s41590-025-02325-1