Gut Neurons Linked to Allergy Response

By Integrative Practitioner Staff 

Regulation of the intestinal epithelium has long been understood as a coordinated process involving epithelial, stromal, and immune cells. New research now identifies a fourth, critical regulator: vasoactive intestinal peptide (VIP), a neuropeptide that acts directly on gut stem cells to restrain an allergy-like immune response. The findings, reported recently in Nature Immunology (DOI: 10.1038/s41590-025-02325-1), reveal an unexpected neuro-epithelial mechanism that helps maintain intestinal balance. 

The study, led by Manuel Jakob, M.D., a clinician-scientist and abdominal surgeon based in Bern and a Ph.D. candidate at Charité – Universitätsmedizin Berlin, emerged from an unbiased exploration of gut immune regulation. Contrary to the team’s initial hypothesis, VIP does not primarily regulate the epithelium through VIP receptor 2 (VIPR2) on immune cells. Instead, VIP acts via VIP receptor 1 (VIPR1) on epithelial cells to suppress stem cell differentiation into secretory lineages. 

Using mouse models with either germline or neuron-specific deletion of VIP, the researchers observed a dramatic expansion of “secretory lineages.” The cell types—tuft, goblet, Paneth, and stem cells—collectively mimic a type 2, allergy-like immune response. These cell types originate from a common progenitor and are responsible for producing substances such as mucus and antimicrobial peptides. Their overabundance suggested that VIP normally acts as a brake for this process. 

Type 2 immune responses in the gut are known to be tightly regulated, often involving a feedback loop between tuft cells and innate lymphoid cells type 2 (ILC2s). Tuft cells produce interleukin-25 (IL-25), which activates ILC2s and triggers the release of cytokines such as IL-13. Previous models assumed VIP would amplify this response by acting directly on immune cells through VIPR2. Instead, Jakob’s team found the opposite: deletion of VIP indirectly initiated the response by allowing excessive tuft cell differentiation and IL-25 production. 

This unexpected pathway highlights the role of the enteric nervous system (often called the “gut brain”) as a higher-order regulator of immune balance. Although part of the peripheral nervous system, the enteric nervous system operates semi-autonomously and communicates closely with both the immune system and the central nervous system. The study provides evidence that neurons use VIP to integrate environmental cues, including dietary signals, to fine-tune immune reactions in the gut. 

The findings open new possibilities for treating diseases driven by type 2 immunity, including food allergies, irritable bowel syndrome, and conditions associated with excessive mucus production or diarrhea. Notably, the allergy-like response in mice could be mitigated by switching from solid to liquid diets, suggesting that food composition and physical properties influence neuro-immune signaling. 

To read the full story written by Deborah Borfitz, head over to Bio-IT World.