Abstract
This study proposed to determine global microRNA (miRNA) expression and miRNA-regulated pathways in Intestinal Neuronal Dysplasia type B (IND-B). Fifty patients (0–15 years old) with IND-B were included in the study. Peripheral blood samples were collected from all 50 patients and from 10 healthy asymptomatic children (controls). Rectal biopsies were collected from 29/50 patients; biopsy tissues were needle microdissected to isolate the different intestinal layers, for molecular analysis. Global miRNA expression was determined using TaqMan arrays. Correlation analysis between miRNA expression in plasma and biopsy samples as well as among tissues derived from the distinct intestinal layers was performed. Computational approaches were used for miRNA target prediction/identification of miRNA-regulated genes and enriched pathways biologically relevant to IND-B pathogenesis. miRNAs were statistically significantly deregulated (FC ≥ 2 and p ≤ 0.05) in submucosal and muscular layers: over-expressed (miR-146a and miR-146b) and under-expressed (miR-99a, miR-100, miR-130a, miR-133b, miR-145, miR-365, miR-374-5p, miR-451). Notably, let-7a-5p was highly over-expressed in patient plasma compared to healthy controls (FC = 17.4). In addition, miR-451 was significantly under-expressed in both plasma and all biopsy tissues from the same patients. Enriched pathways (p < 0.01) were axon guidance, nerve growth factor signalling, NCAM signalling for neurite out-growth, neuronal system and apoptosis. miRNA expression is deregulated in the submucosa and muscular layers of the rectum and detected in plasma from patients with IND-B. Biologically enriched pathways regulated by the identified miRNAs may play a role in IND-B disease pathogenesis, due to the activity related to the neurons of the enteric nervous system.
Highlights
Intestinal neuronal dysplasia type B (IND-B) is a pathological entity of the group of gastrointestinal neuromuscular diseases characterized by complex alterations in the intestinal submucosal nerve plexuses[1]
Rectal tissue samples were pooled according to their location in the distinct layers of the intestinal wall. miRNA expression in intestinal submucosa and submucosa plus muscular layers was compared to the mucosal layer, since ganglion cells of the nerve plexus, which are affected in Intestinal Neuronal Dysplasia type B (IND-B), are not www.nature.com/scientificreports present in this layer
IND-B is a rare disease that remains surrounded by several controversies ranging from its definition as a real disease to the different criteria for its diagnosis and treatment options[2,7,30]
Summary
Intestinal neuronal dysplasia type B (IND-B) is a pathological entity of the group of gastrointestinal neuromuscular diseases characterized by complex alterations in the intestinal submucosal nerve plexuses[1]. IND-B can be understood as a primary disease in which genetic alterations directly influence the embryological development of the enteric nervous system[2,9] This theory is supported by in vivo studies demonstrating that certain mutations may play a role on migration and development of neural crest cells, determining megacolon and hyperplasia of neuroenteric plexuses[10,11]. These findings remain to be identified in human studies. We identified biologically enriched pathways containing a large number of miRNA-target genes with roles related to the neurons of the enteric nervous system Such pathways may play a role in IND-B disease pathogenesis
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