Mucus Barriers to Microparticles and Microbes are Altered in Hirschsprung's Disease

Abstract

Mucus forms a protective hydrogel layer over the intestinal epithelium, presenting a selective and robust barrier to the uptake of particulates and microbe invasion. Disease can alter mucus production and composition, thus potentially modifying mucosal barrier properties. Hirschsprung’s disease (HD) is a developmental abnormality of the nervous system often complicated by intestinal infection. An investigation of colonic mucus barrier properties in an HD animal model, endothelin receptor B mutant mice, revealed significantly reduced microsphere (passive) and microbe (active) transport rates (7-fold and 3.6-fold, respectively, in proximal colonic mucus) relative to wild-type. Transport differences were evident in both the ganglionic and aganglionic colon segments, in agreement with the risk of Hirschsprung’s disease-associated enterocolitis after surgery to remove aganglionic colon segments. The development of therapies aimed at altering colonic mucus barrier properties could be explored towards preventing the onset of enterocolitis in Hirschsprung’s disease.

Guidelines for the diagnosis and management of Hirschsprung-associated enterocolitis

“…These include dysbiosis of the intestinal microbiome[3-6], impaired mucosal barrier function[4, 7, 8], altered innate immune responses[9, 10], and bacterial translocation[4, 11]. …”

Established and emerging concepts in Hirschsprung’s-associated enterocolitis

“…Murine models of EdnrB mutation display aganglionosis of the distal hindgut, mimicking the most common clinical finding in HSCR patients[26, 27]. For this reason, mutation of EdnrB in mice, both in the whole animal ( EdnrB −/− )[28–34] and specifically in neural crest cells only ( EdnrB NCC−/− )[35, 36], has been used to study the pathogenesis of HAEC, with 9 publications using these models over the last five years.…”

“…Finally, they noted decreased amounts of membrane-bound Mucin 4 (Muc4), but not secreted Muc2, in the distal colons of EdnrB −/− animals. Further, functional studies have been performed in the same animal model[34]. In these studies, reduced rates of transport of microparticles and bacteria, both active and passive, were observed in the aganglionic and ganglionated bowel.…”

Mucus models to evaluate the diffusion of drugs and particles

“…3)[62]. MPT was also used to demonstrate that stimuli associated with food ingestion can impact the diffusion of model drug carriers in mucus[63]. Increased lipid and Ca 2+ concentrations, and decreased pH affected the local mucus microenvironment, decreasing amine-, carboxylate-, and sulfate-modified 200 nm particle transport rates and altered porcine intestinal mucus structure[59].…”

“…Studies are often performed using animal models due to limited availability of human tissues. Human samples are mainly obtained during surgical procedures (e.g., corrective gastro-intestinal surgeries to resect diseased tissue or to reduce stomach volume); however, these diseased tissues likely have altered barrier properties[63, 126]. Human samples from the trachea and nasal mucosa are less readily available but can be obtained from transplant rejections[127], airway biopsies[128], fetal tissue[129], nasal septum surgery[130], or nasal turbinate removal[131].…”