Mice with Neural Crest Conditional Deletion of EdnrB Model Neonatal Hirschsprung’s Associated Enterocolitis

Hirschsprung’s disease (HSCR) is a common cause of intestinal obstruction in the newborn and is characterized by absence of the enteric nervous system in the distal hindgut. Up to 40% of infants develop potentially life-threatening Hirschsprung’s-Associated Enterocolitis (HAEC) prior to definitive surgery. Clinical series have suggested that abnormal goblet cell function, decreased secretory IgA secretion, leukocyte dysfunction, altered microbiota, and bowel obstruction may all contribute to the pathogenesis of HAEC. We have characterized mice with a neural crest conditional deletion of endothelin receptor B (EdnrB), which display distal colonic aganglionosis and develop HAEC in the fourth post-natal week. Our investigations reveal decreased luminal SIgA and impaired SIgA transport (polymeric immunoglobulin receptor), alterations in goblet cell numbers and morphology, alterations in splenic and Peyer’s Patch lymphocyte populations, and persistence of primarily anaerobic species (Bacteroides, Tanerella, Clostridium, Paludibacter) in the colonic microbiota during HAEC. These findings mimic the human condition and provide targets for understanding the multifactorial pathogenesis of HAEC.