Scientists Discover Allergy-Triggering Role of Peptide in the Gut

By Deborah Borfitz  

December 18, 2025 | It has been firmly established in recent years that regulation of the intestinal epithelium relies heavily on signaling from epithelial, stromal, and immune cells. But there’s also a fourth player, a “very important peptide” known as VIP, which acts directly on stem cells in the gut to restrain an allergy-like response, according to Manuel Jakob, M.D., a clinician-scientist and abdominal surgeon based in Bern, Switzerland and a Ph.D. candidate at Charité -- Universitätsmedizin Berlin. 

The discovery was a happy incident born out of an “unbiased look” at the control mechanisms that refuted a hypothesis that VIP (vasoactive intestinal peptide) regulates epithelial cells via VIP receptor 1 (VIPR1), he says. In fact, VIP suppresses stem cell differentiation into the secretory epithelial cells, as reported in a study that was published recently in Nature Immunology (DOI: 10.1038/s41590-025-02325-1). 

After making either a germline or neuron-specific deletion of VIP, the research team observed that four “secretory lineages” were highly abundant, “mimicking an allergy-like response in the mouse,” says Jakob. These are the cell types—tuft, goblet, Paneth, and stem cells—which develop from a common progenitor cell in the gut and whose primary function is producing and releasing substances. 

It has been established over the last 20 years that signaling received by the gut epithelium determines cell fate, but the crosstalk between cells involved in gut immune pathways is not fully understood, he explains. This is largely because the communication is incredibly complex, ongoing, and bidirectional. 

Recent research has focused on the interplay of interleukin-13 (IL-13), nuclear factor kappa B (NF-κB), and Wnt signaling pathways. Jakob and his team were interested in learning how type 2 immune reactions (allergy-like response) are regulated, making no assumptions about who the molecular actors might be. 

Thwarted Hypothesis 

Type 2 immune responses are tightly regulated within a living system, in this case a mouse, says Jakob. These control processes can be either direct via innate lymphoid cells type 2 (ILC2s)/T helper 2 cells or indirect via the epithelium. 

Earlier studies have shown that tuft cells are the primary source of interleukin-25, which engages on a receptor expressed on ILC2s and initiates the tuft cell-ILC2 circuit triggering an allergy-like response. But in the latest modeling by Jakob and his colleagues, this response (evidenced by a high abundance of tufts and goblet cells) was initiated indirectly with the deletion of VIP.  

“This was a striking finding because we expected quite the opposite,” Jakob says. “Studies have shown that VIP can signal two receptors [VIPR1 and VIPR2] and VIP receptor 2 is expressed on ILC2s and induces the release of type 2 cytokines, such as IL-13 and IL-5, the beginning of an allergy-like response.”  

That gave birth to the thwarted hypothesis that the type 2 immune reaction was being directly triggered, enlisting other immune cells to engage in the fight. “But then we observed that it’s the other receptor [VIPR1] that is expressed on the epithelium and induces this response.” 

Jakob works in the lab of Christoph Klose, who generated the knockout model used in the study where VIP was deleted. His segue into the allergy field was a result of his fascination with the genetically engineered mouse, Jakob adds, noting both that neurons were his first love and the serendipity of turning on the VIPR1 circuit in a type 2 immune lab.  

Clinical Implications 

The enteric nervous system, the network of nerve cells within the walls of the gastrointestinal tract that controls digestive functions, has been largely overlooked for the past few decades, says Jakob. But scientists are starting to appreciate the importance of neurons in the “gut brain” in terms of both immune regulation and epithelial control. 

While a major part of the peripheral nervous system, the enteric nervous system can operate autonomously like a brain in the gut to independently control digestion, he says. It is also deeply connected to the central nervous system (brain and spinal cord) through the gut-brain axis.  

The network linking the brain and digestive system is of enormous research interest, given how the immune response is coordinated, says Jakob. Immune cells can function independently but still need a hierarchical system to keep those immune responses in check and neither over- nor under-reacting.  

Study findings presented in the Nature Immunology paper provide supporting evidence that the enteric nervous system acts as a sophisticated interface between the body's internal environment, the gut microbiome, and the central nervous system. This may help explain why some people have a sensitive gut and find new avenues to intervene in the future, he says.  

The pathway describing this neuro-epithelial-immune circuit—i.e., how VIP inhibits ILC2s indirectly via VIPR1-mediated suppression of tuft cell differentiation and IL-25 production—warrants further investigation, continues Jakob. But the fact that VIP can suppress an allergy-like response suggests its potential utility in treating many diseases involving type 2 immune responses, a list that includes irritable bowel syndrome as well as food allergies whose symptoms include diarrhea.  

“If you could suppress that type of immune reaction by applying a ligand such as VIP, directly via a pill, that would be fantastic,” says Jakob. On the other hand, having observed how VIP launches a cascade of molecular events that enhance mucus thickness and maturation, future directions might also include leveraging VIP in the treatment of people with bowel leakage.  

Food Therapy 

Jakob is particularly interested in the role of food, pointing to the study finding that the allergy-like response in mice could be remedied with a liquid rather than a solid diet. “That means that a ligand [or] several ligands in the food are required for the promotion of this entire activation of the type 2 immune reaction,” he says. “Food consistency, formulation, and applying direct ligands [that bind directly to a receptor] would be extremely interesting ways to treat patients in the future.”  

“Neurons play an important part here because they may sense many different cues, so they can send signals from the immune system but also send out signals directly to immune cells—not only VIP, but also others such as CGRP [calcitonin gene-related peptide], acetylcholine and noradrenaline,” says Jakob. “I think if we can better understand how an immune response is coordinated on a top level, we can probably in the future tackle many diseases.”  

Jakob’s next steps include looking at how nutrition might be strategically used to support intestinal health. “Food ... is an extremely easy way to manipulate certain things without harm to the patient,” he says. 

This will require a more detailed understanding of how food influences neuron activation or inhibition, as well as how exactly VIP works on the cellular and molecular level—and what VIP does in other organs beyond the intestines, Jakob adds. These studies will use knockout rodent models of different neuropeptides as well as intestinal organoid cultures derived from human biopsy samples, as was the case with the latest investigation.