UCSF

Sensory enteroendocrine cells in the intestinal epithelium detect and relay information about the lumenal environment to other cells within and outside the gut. Serotonergic enterochromaffin (EC) cells are a subset of enteroendocrine cells that detect noxious stimuli within the gut lumen, such as chemical irritants and microbial byproducts, and transduce this information to sensory nerve fibers to elicit defensive responses such as nausea and visceral pain. While much has recently been learned about the pharmacological and biophysical characteristics of EC cells, a more broadscale investigation of their properties has been hindered by their relatively low prevalence and sparse anatomical distribution within the gut epithelium. Furthermore, whether EC cells in crypts and villi detect different stimuli or produce distinct physiological responses is unknown. Here we address these questions by developing a reporter mouse model to quantitatively measure the release and propagation of serotonin from EC cells in live intestines. Crypt EC cells exhibit a tonic low-level mode that activates epithelial serotonin 5-HT4 receptors to modulate basal ion secretion and a stimulus-induced high-level mode that activates 5-HT3 receptors on sensory nerve fibers. Both these modes can be initiated by the irritant receptor TRPA1, which is confined to crypt EC cells. The activation of TRPA1 by luminal irritants is enhanced when the protective mucus layer is compromised. We also introduce an in vitro method for large-scale parallel analysis of individual EC cell activity within a physiologically relevant epithelial context. Using this approach, we identify somatostatin-28 (SST28) as a potent inhibitor of both basal and stimulus-evoked serotonin release from EC cells and delineate the signaling pathway that underlies this modulatory response. Our analysis suggests that targeting this inhibitory signaling pathway may offer novel therapeutic avenues for treating gastrointestinal disorders associated with EC cell function and dysregulated serotonin signaling. Together with the ongoing development of specific biosensors, this platform provides a template for the efficient characterization of other rare sensory cell types and their pharmacological modulators.