Neuronal regulation of epithelial differentiation controls type 2 immunity at barrier surfaces

• Applicant: Professor Dr. Christoph Siegfried Niki Klose
• Subject Area: Gastroenterology ; Immunology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 567148419

At barrier surfaces, such as the intestine, a delicate balance between a single layer of epithelial cells, tissue-resident immune cells, and commensal microbiota is a prerequisite for maintaining mucosal homeostasis. It is well established that disturbances in any of these components shift the balance towards inflammation, often resulting in chronic diseases. Likewise, the enteric nervous system (ENS) innervates the gut by integrating a plethora of intrinsic and extrinsic stimuli. Although the primary function of the ENS is to mediate peristalsis of the intestine, an immunoregulatory function of the ENS is emerging. However, the different regulatory pathways by which the ENS controls mucosal homeostasis are largely unexplored. This interdisciplinary proposal aims to narrow this vital scientific gap by establishing the ENS as a crucial regulator of epithelial differentiation and, consequently, type 2 immune responses. For this purpose, the ENS might serve as a signaling hub integrating signals generated by feeding and nutrient sensing, which we will explore as well. Based on a strong foundation of preliminary data demonstrating that gene targeting in the ENS provokes disturbances in epithelial differentiation, commensal microbiota, and mucus formation, resulting in an overshooting type 2 immune response, we will dissect the neuro-epithelial-immune interactions using genetics, organoids, gnotobiotic models and single-cell transcriptomics in combination with in vivo barcode labeling. We propose a proof-of-principle study aiming to establish neuro-epithelial-immune crosstalk as a signaling hub for the maintenance of mucosal immune-homeostasis relevant to chronic inflammation and therapy. Therefore, our research constitutes not only a critical conceptual advance in neuroimmunology but also has the potential to discover novel molecular pathways that can be harnessed for the prevention or treatment of chronic inflammation and allergic diseases.

• DFG Programme: Reinhart Koselleck Projects