Hirschsprung disease (HSCR) is a life-threatening birth defect in which the distal colon is devoid of enteric neural ganglia. HSCR is treated by surgical removal of aganglionic bowel, but many children continue to have severe problems after surgery. We studied whether administration of glial cell derived neurotrophic factor (GDNF) induces enteric nervous system regeneration in mouse models of HSCR. We performed studies with four mouse models of HSCR: Holstein (Hol^Tg/Tg, a model for trisomy 21-associated HSCR), TashT (TashT^Tg/Tg, a model for male-biased HSCR), Piebald-lethal (Ednrb^s-l//s-l, a model for EDNRB mutation-associated HSCR), and Ret^9/- (with aganglionosis induced by mycophenolate). Mice were given rectal enemas containing GDNF or saline (control) from postnatal days 4 through 8. We measured survival times of mice, and colon tissues were analyzed by histology, immunofluorescence, and immunoblots. Neural ganglia regeneration and structure, bowel motility, epithelial permeability, muscle thickness, and neutrophil infiltration were studied in colon tissues and in mice. Stool samples were collected, and microbiomes were analyzed by 16S rRNA gene sequencing. Time-lapse imaging and genetic cell-lineage tracing were used to identify a source of GDNF-targeted neural progenitors. Human aganglionic colon explants from children with HSCR were cultured with GDNF and evaluated for neurogenesis. GDNF significantly prolonged mean survival times of Hol^Tg/Tg mice, Ednrb^s-l//s-l mice, and male TashT^Tg/Tg mice, compared with control mice, but not Ret^9/- mice (which had mycophenolate toxicity). Mice given GDNF developed neurons and glia in distal bowel tissues that were aganglionic in control mice, had a significant increase in colon motility, and had significant decreases in epithelial permeability, muscle thickness, and neutrophil density. We observed dysbiosis in fecal samples from Hol^Tg/Tg mice compared with feces from wild-type mice; fecal microbiomes of mice given GDNF were similar to those of wild-type mice except for Bacteroides. Exogenous luminal GDNF penetrated aganglionic colon epithelium of Hol^Tg/Tg mice, inducing production of endogenous GDNF, and new enteric neurons and glia appeared to arise from Schwann cells within extrinsic nerves. GDNF application to cultured explants of human aganglionic bowel induced proliferation of Schwann cells and formation of new neurons. GDNF prolonged survival, induced enteric neurogenesis, and improved colon structure and function in 3 mouse models of HSCR. Application of GDNF to cultured explants of aganglionic bowel from children with HSCR induced proliferation of Schwann cells and formation of new neurons. GDNF might be developed for treatment of HSCR.

Hirschsprung’s disease (HSCR) is a severe congenital anomaly of the enteric nervous system (ENS) characterized by functional intestinal obstruction due to a lack of intrinsic innervation in the distal bowel. Distal innervation deficiency results from incomplete colonization of the bowel by enteric neural crest cells (eNCCs), the ENS precursors. Here, we report the generation of a mouse model for HSCR — named Holstein — that contains an untargeted transgenic insertion upstream of the collagen-6α4 (Col6a4) gene. This insertion induces eNCC-specific upregulation of Col6a4 expression that increases total collagen VI protein levels in the extracellular matrix (ECM) surrounding both the developing and the postnatal ENS. Increased collagen VI levels during development mainly result in slower migration of eNCCs. This appears to be due to the fact that collagen VI is a poor substratum for supporting eNCC migration and can even interfere with the migration-promoting effects of fibronectin. Importantly, for a majority of patients in a HSCR cohort, the myenteric ganglia from the ganglionated region are also specifically surrounded by abundant collagen VI microfibrils, an outcome accentuated by Down syndrome. Collectively, our data thus unveil a clinically relevant pathogenic mechanism for HSCR that involves cell-autonomous changes in ECM composition surrounding eNCCs. Moreover, as COL6A1 and COL6A2 are on human Chr.21q, this mechanism is highly relevant to the predisposition of patients with Down syndrome to HSCR.

The development of the neonatal gastrointestinal tract microbiota remains a poorly understood process. The interplay between neonatal (gestational age, genetic background), maternal (mode of delivery, nutritional status) and environmental factors (antibiotic exposure, available nutrition) are thought to influence microbial colonization, however, the exact mechanisms are unclear. Derangements in this process likely contribute to various gastrointestinal diseases including necrotizing enterocolitis and inflammatory bowel disease. As such, enhanced understanding of microbiota development may hold the key to significantly reduce the burden of gastrointestinal disease in the pediatric population. The most debatable topics during microbial seeding and possible future treatment approaches will be highlighted in this review.

Background: The COVID-19 pandemic is a global issue which affects the entire population’s mental health. This study evaluates how restrictions to curtail this pandemic change parenting self-efficacy, depressive symptoms, couple satisfaction and health-related quality of life in parents after delivery of a newborn. Methods: In this prospective single center evaluation of parental self-efficacy and quality of life, four validated questionnaires were used to repeatedly assess parenting self-efficacy (Tool to measure Parental Self-Efficacy, TOPSE), depressive symptoms (Edinburgh Postnatal Depression Scale, EPDS), couple satisfaction (Couple Satisfaction Index, CSI) and health-related quality of life (short form 12, SF12). Fifty-three parents of 50 infants answered a total number of 63 questionnaires during the lockdown period to limit the spread of COVID-19. These questionnaires were matched with 63 questionnaires of 58 other parents that had answered them before or after strong pandemic related measures. Results: Parents experienced lower parenting self-efficacy during the strict pandemic measures as compared to before and after (p = 0.04). In terms of age, socioeconomic, marital status and duration of hospitalization we detected no significant difference between both groups. On univariate linear regression, TOPSE scores were associated with gestational age (p = 0.044, parameter estimate: 1.67, 95% CI: 0.048 to 3.301), birth weight (p = 0.035, parameter estimate: 0.008, 95% CI: 0.001 to 0.015), number of newborns’ siblings (p = 0.0554, parameter estimate: 7.49, 95% CI: −0.174 to 15.145) and distance of home from hospital (p = 0.043, parameter estimate: −0.38, 95% CI: −0.745 to −0.011). Interestingly, there was a positive correlation between quality of life and TOPSE scores, suggesting that those who experience a higher self-efficacy also have a higher quality of life. Conclusions: When implementing a lock-down period psychological effects such as lower experience of parental self-efficacy have to be considered.

Esophageal dysmotility is almost universal after esophageal atresia repair and is mainly related to the developmental anomaly of the esophagus. Esophageal dysmotility is involved in the pathophysiology of numerous symptoms and co-morbidities associated with esophageal atresia such as gastroesophageal reflux disease, aspiration and respiratory complications and symptoms of dysphagia and feeding disorders. High resolution esophageal manometry (HREM) has facilitated the characterization of the dysmotility but there is an incomplete correlation between symptoms and manometrical patterns. Impedance coupled to HREM should help to predict the clinical outcome and therefore personalize patient management. Nowadays, the management of esophageal dysmotility in patients with esophageal atresia is essentially based on treatment of associated inflammation related to peptic or eosinophilic esophagitis.