Differentiating the role and underlying mechanisms of serotonin in the gut epithelium to develop targeted therapeutic strategies for disorders of gut-brain interaction and mood dysfunction.

• Applicant: Dr. Franziska Carolin Lammert
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Gastroenterology ; Pediatric and Adolescent Medicine
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 574690439

Disorders of gut-brain interaction (DGBIs) frequently co-occur with affective disorders, such as anxiety and depression, yet current treatments typically address only one of these conditions. In children, however, DGBIs are the most common cause of chronic gastrointestinal (GI) symptoms such as functional abdominal pain, irritable bowel syndrome, or constipation. Emerging evidence highlights the role of epithelial serotonin (5-HT) and vagal signaling as key mediators of gut-brain communication. The overall objective of this project is to investigate how intestinal 5-HT influences the central nervous system (CNS), with a particular focus on affective disorders, cognitive function, GI motility, and visceral pain regulation - with the long-term aim of developing novel, gut-targeted therapies. Aim 1 explores the anatomical basis of vagal signaling under conditions of altered intestinal 5-HT signaling. Using transgenic mouse models with modified intestinal or systemic 5-HT production, vagotomy will be employed to selectively modulate vagal pathways. Immunohistochemistry will be used to map neuronal activation patterns and the distribution of 5-HT-positive cells in key brain regions involved in vagal afferent processing. Combined with neuronal tracing, this approach will anatomically characterize serotonergic projections and enable the identification and spatial mapping of activated neuronal networks in the CNS. Aim 2 investigates the functional consequences of peripheral 5-HT alterations on CNS activity and behavior. Using fiber photometry and optogenetics, we will monitor and manipulate neuronal activity in real-time with high specificity. The genetically encoded fluorescent 5-HT biosensor, sLight1.3, will be injected into CNS regions involved in pain and emotion regulation using an adeno-associated virus, and optic fibers will be implanted. The 5-HT release will be measured as a tonic signal; stress-induced suppression will serve as a functional readout. In parallel, standardized behavioral and cognitive testing in transgenic mouse models will assess the impact on mood and anxiety-like behavior. This will enable us to link intestinal 5-HT manipulations to central and behavioral outcomes. Aim 3 evaluates how epithelial 5-HT modulates GI motility and visceral pain. We will perform GI transit, motility, and visceromotor reflex testing in transgenic mouse models to determine how peripheral serotonin affects gut function and how these effects depend on vagal signaling. Finally, we will translate our mechanistic findings into a therapeutic approach by further developing a gut-specific, microbur-nanoparticle-based delivery system containing fluoxetine. This system targets intestinal 5-HT signaling locally, offering a promising strategy for treating DGBIs without systemic side effects.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Kara Margolis