Abstract
Hirschsprung disease-associated enterocolitis (HAEC) leads to significant mortality and morbidity, but its pathogenesis remains unknown. Changes in the colonic epithelium related to goblet cells and the luminal mucus layer have been postulated to play a key role. Here we show that the colonic epithelium of both aganglionic and ganglionic segments are altered in patients and in mice with Hirschsprung disease (HSCR). Structurally, goblet cells were altered with increased goblet cell number and reduced intracellular mucins in the distal colon of biopsies from patients with HSCR. Endothelin receptor B (Ednrb) mutant mice showed increased goblet cell number and size and increased cell proliferation compared to wild-type mice in aganglionic segments, and reduced goblet cell size and number in ganglionic segments. Functionally, compared to littermates, Ednrb−/− mice showed increased transepithelial resistance, reduced stool water content and similar chloride secretion in the distal colon. Transcript levels of goblet cell differentiation factors SPDEF and Math1 were increased in the distal colon of Ednrb−/− mice. Both distal colon from Ednrb mice and biopsies from HSCR patients showed reduced Muc4 expression as compared to controls, but similar expression of Muc2. Particle tracking studies showed that mucus from Ednrb−/− mice provided a more significant barrier to diffusion of 200 nm nanoparticles as compared to wild-type mice. These results suggest that aganglionosis is associated with increased goblet cell proliferation and differentiation and subsequent altered surface mucus properties, prior to the development of inflammation in the distal colon epithelium. Restoration of normal goblet cell function and mucus layer properties in the colonic epithelium may represent a therapeutic strategy for prevention of HAEC.
Highlights
Hirschsprung disease (HSCR) is a congenital disorder of the intestinal tract that is characterized by variable lengths of colorectal aganglionosis resulting from the failure of neural crestderived cells to form the distal enteric nervous system (ENS) [1], [2]
In this study we looked at the colonic epithelium from Ednrb2/2 mice and from biopsies obtained from HSCR patients without active inflammation, to investigate epithelial changes associated with aganglionosis
Histological grading of inflammation in the biopsies showed no inflammation in HSCR colon, and none had any clinical evidence of Hirschsprung-associated enterocolitis (HAEC)
Summary
Hirschsprung disease (HSCR) is a congenital disorder of the intestinal tract that is characterized by variable lengths of colorectal aganglionosis resulting from the failure of neural crestderived cells to form the distal enteric nervous system (ENS) [1], [2]. Studies of the mucus layer in HSCR have shown changes in both mucins and secreted immunoglobulin in patients with HAEC [8], [9], [10]. Goblet cell differentiation factors are altered in chronic inflammatory bowel diseases different patterns of expression have been reported in Crohn’s disease versus ulcerative colitis. Increases in goblet cell number have been found in quiescent Crohn’s disease epithelium in contrast to a number of studies that show decreased goblet cell numbers in active Crohn’s disease and in ulcerative colitis [21], [22], [23]. The goal of this study was to determine how goblet cell and mucus layer structure and function are altered in aganglionic colon from mice and humans
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