Serotonergic regulation of gut physiology and homeostasis in Drosophila

Serotonin (5-HT) is a key neurotransmitter regulating mood, appetite, and sleep. Although 5-HT is synthesized within the central nervous system, the majority is produced by enterochromaffin cells in the intestinal epithelium, underscoring its central role in gastrointestinal physiology. While altered serotonergic signaling is linked to disorders such as Irritable Bowel Syndrome and Crohn’s disease, the underlying cellular and molecular mechanisms remain poorly defined. Preliminary findings from our laboratory demonstrate that the Drosophila gut is innervated by serotonergic neurons and that altering 5-HT levels impacts both food intake and defecation frequency. Here, we mapped the expression of serotonin receptors across fly gut epithelial cells and evaluated their role in gastrointestinal homeostasis. We found that 5-HT7r loss of function flies exhibit increased food intake and defecation frequency, indicating that this receptor mediates the serotonergic regulation of gut function and establishing 5-HT as a critical modulator of intestinal homeostasis.