Chronic constipation is a common worldwide health problem affecting 1 in 6 people. Yet the underlying causes of this condition are still poorly defined. Consequently, common treatment options are restricted to diet and lifestyle changes or use of osmotic laxatives, which frequently produce unsatisfactory results. Preclinical studies in this field are hampered by the lack of well-described mouse models and often rely on the administration of non-specific drugs delaying intestinal transit. In this project we will make use of a novel genetic mouse model of intestinal dysmotility that we have generated. Based on multiple preliminary data, we hypothesize that dysregulated signalling in specific intestinal epithelial cells disturbs the gut hormone expression profile, which subsequently impact neuromuscular function and delays intestinal transit. This will be investigated using a mix of approaches such as LC-MS secretome analysis, single cell and spatial transcriptomics, computational modelling, CRISPR-Cas9 genome editing, mouse and human intestinal organoids, and organ bath experiments. The findings of this study will contribute to a better mechanistic understanding of intestinal dysmotility, which may eventually help to develop novel therapeutic strategies for at least a fraction of constipation disorders.