Proximal ganglionic intestine in Hirschsprung Disease is fibrotic and stiff

Hirschsprung disease (HSCR) is a congenital intestinal disorder characterized by the absence of ganglia in the distal intestine. Despite surgical resection of the aganglionic intestine and pull-through surgery, patients with HSCR still experience bowel dysfunction, indicating that latent abnormalities may also exist in the proximal ganglionic intestine. To elucidate possible causes of postoperative bowel dysfunction in HSCR, we investigated differences in the proximal ganglionic intestine using an animal model of HSCR (Ednrb-null mice) and validated our findings in tissue from patients with HSCR. We found that the proximal ganglionic colon of HSCR mice exhibited greater stiffness and fibrosis than their WT littermates. Similarly, submucosal fibrosis was significantly greater in the proximal ganglionic intestine of patients with HSCR than in intestinal tissue from age- and site-matched controls. Furthermore, we observed dysregulated expression of extracellular matrix-related (ECM-related) genes in the proximal ganglionic intestine of HSCR mice compared with controls. We conclude that increased fibrosis, stiffness, and alterations in ECM composition may contribute to persistent dysfunction of the ganglionic intestine in HSCR. These findings add to the growing body of literature that describe abnormalities in the proximal ganglionic intestine of HSCR and suggest that HSCR is not limited to the aganglionic intestine alone.