image: The gut brain influences the composition of the intestinal barrier via the messenger molecule VIP. When it is absent, certain cell types appear more frequently at the gut surface, as this tissue section (mouse model) shows: tuft cells (red), mucus-producing goblet cells (yellow), Paneth cells (pink), and stem cells (green). © Charité | Luisa Barleben
Credit: © Charité | Luisa Barleben
An international research team led by scientists from Charité – Universitätsmedizin Berlin and Bern has identified a previously unknown function of the intestinal nervous system. As the team now reports in the journal Nature Immunology*, the intestinal nervous system plays a key role in regulating both the composition and stability of the intestinal barrier. Disruption of this protective mechanism can lead to the development of allergies. These findings open new avenues for advancing therapies for allergies, chronic inflammatory bowel diseases and irritable bowel syndrome.
The intestinal nervous system, often referred to as the "gut brain", is essential in controlling digestion and maintaining the intestinal barrier. This protective layer, made up of the intestinal mucosa, immune cells and the microbiome, shields the body from contents of the gut. Its effectiveness depends on the delicate balance among these components. If this balance is disrupted, inflammation, allergies or chronic intestinal diseases can arise. The intestinal mucosa serves as the body’s primary defense against pathogens. While previous studies have shown that the intestinal nervous system is involved in immune responses in addition to digestion, its role in the development of intestinal epithelial cells has remained largely unclear until now.
An international research team led by Charité, the University of Bern, and Inselspital Bern, Bern University Hospital, has now shown for the first time that the intestinal nervous system acts as a central regulator of the intestinal barrier. By releasing a specific molecule, it directs the development of different cell types in the intestinal wall and in this way shapes immune responses in the intestine that can promote allergies.
The intestinal nervous system as a "conductor" between stem cells and immune cells
In their study, the researchers investigated how specific nerve cells in the gut interact with intestinal stem cells. They focused on the vasoactive intestinal peptide (VIP), a messenger molecule produced by the intestinal nervous system. The findings show for the first time that intestinal nerve cells use VIP to communicate directly with intestinal stem cells, ensuring that these cells do not multiply too rapidly nor develop excessively into certain cell types. When this regulatory mechanism breaks down and VIP is absent, an excess of so-called tuft cells occurs. These cells then release signals that activate an allergy-like response in the intestine.
"Our findings show that the intestinal nervous system is a decisive factor in preserving a healthy intestinal mucosa, regulating immune responses, and ultimately maintaining an intact intestinal barrier," explains Dr. Manuel Jakob from the Department of Visceral Surgery and Medicine at Inselspital, research associate at the Department for BioMedical Research (DBMR) at the University of Bern and scientist at Charité. The study’s first author adds: "Our 'gut brain' is far more than a facilitator of digestion. It acts as a central hub for health, immunity and potentially for conditions that affect large parts of the population. Interestingly, the results suggest that the effect may be shaped by the diet, i.e. the formulation of the food".
New approaches for inflammatory and allergic gut diseases
A healthy gut microbiome and a balanced immune response are vital for protecting the body from disease, making research on the intestinal nervous system increasingly significant. "The mechanism we have uncovered may help explain why some individuals are particularly sensitive in the gut and how we might intervene more precisely in the future," explains Prof. Christoph Klose, head of the Neuroimmune Interaction research group at Charité's Institute of Microbiology, Infectious Diseases and Immunology and senior author of the study. "By deepening our understanding of how nerves, cells and immune responses interact in the gut, we can develop more targeted and personalized therapies - for example for allergies, irritable bowel syndrome or chronic inflammatory bowel diseases." The findings also suggest that these reactions might be directly influenced through diet. As a next step, the team plans to investigate how nutrition can be strategically used to support the nerve-gut axis and support intestinal health
*Jakob MO et al. Enteric nervous system-derived VIP restrains differentiation of LGR5+ stem cells toward the secretory lineage impeding type 2 immune program. Nat Immunol 2025 Nov 24. doi: 10.1038/s41590-025-02325-1
Journal
Nature Immunology