Impact of Enteric Neuronal Loss on Intestinal Cell Composition

Abstract

AbstractHirschsprung disease (HSCR) is a congenital disorder characterized by the absence of an enteric nervous system (ENS) in the distal gut, causing obstruction and constipation. Despite the known importance of the ENS for normal gut function due to its interaction with other intestinal cells, the impact of ENS loss on intestinal homeostasis remains largely unexplored. In this manuscript, we investigate changes in intestinal composition associated with loss of an ENS, by performing single cell RNA sequencing on zebrafish intestines collected from 5 days post-fertilization wildtype zebrafish and aretmutant HSCR model. Significant findings were validated through immunofluorescence and fluorescencein situhybridization in zebrafish and human tissues. Notable shifts included a reduction in enterocytes and enterochromaffin cells, alongside an increase in immune and endothelial cells, as well as BEST4+ enterocytes, in the HSCR model. These discoveries elucidate significant changes in the intestinal cellular composition in HSCR, highlighting potential pathways to secondary complications and offering insights into new therapeutic possibilities aimed at enhancing patient outcomes.