Molecular mechanisms of sensory transduction in the gut
David Julius, Ph.D.
Gastrointestinal (GI) disorders are among the most common medical comorbidities in individuals with autism spectrum disorder (ASD)1. The gut produces the majority of the neurotransmitter serotonin, which is elevated in several forms of ASD and has been implicated in visceral pain syndromes. Enterochromaffin (EC) cells constitute <1 percent of the total intestinal epithelium, yet produce >90 percent of the body's serotonin. EC cells have been suggested to detect numerous chemical changes in the gut lumen that are associated with visceral pain, including irritants, endogenous inflammatory molecules and microbiota-derived metabolites2.
Despite growing interest in the gut-neural axis, relatively little is known about the molecular mechanisms underlying chemosensory transduction by the gut epithelium, such as how signals are detected and transduced by EC cells, and how this information is transmitted to the nervous system. To gain greater insights into these mechanisms, David Julius and his collaborators at the University of California, San Francisco, (Nicholas Bellono, James Bayrer and Holly Ingraham) generated intestinal organoids from a transgenic mouse in which EC cells are marked with a fluorophore, enabling them to carry out detailed functional and genetic profiling of these cells in the context of a native tissue environment. Their initial studies have shown that EC cells are electrically excitable, polymodal chemosensors within the gut that engage in direct synaptic interactions with sensory nerve fibers3. In collaboration with the Brierley lab (University of Adelaide, Australia), they have also shown that activation of this pathway enhances mechanical sensitivity of the gut.
Julius and colleagues now propose to further define intrinsic EC cell functional properties and utilize this information to investigate the physiological effects of EC activation on associated neural pathways. They will use chemogenetic tools in mice to examine the contribution of EC cells and serotonergic signaling pathways to visceral pain. Together, these studies will provide a molecular foundation for uncovering basic mechanisms underlying pain syndromes of the gut and provide potential mechanistic insights to explain the high comorbidity of gastrointestinal dysfunction with ASD.
1.McElhanon et al. Pediatrics 133, 872-883 (2014) PubMed
2.Furness et al. Nat. Rev. Gastroenterol. Hepatol. 10, 729–740 (2013) PubMed
3.Bellono et al. Cell 170, 185–198 (2017) PubMed
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