Enhanced neuron–glia network in the submucosa and increased neuron outgrowth into the mucosa are associated with distinctive expressions of neuronal factors in the colon of rat IBS model

Abstract Background Neuronal attraction and repulsion factors regulate neuron network formation. In the colon of irritable bowel syndrome (IBS), neuron network and enteric glial cells (EGCs) in the submucosa, neuronal outgrowth in the mucosa, and expressions of neuronal factors remain unknown. Methods IBS models were prepared by intracolonic injections of acetic acid to Wistar Kyoto (WKY) rats. Using whole‐mount submucosal plexus tissue stripped from the distal colon, we examined neuron network, EGC morphology, and localization of both attraction factor (nerve growth factor: NGF) and repulsion factor (semaphorin3A: Sema3A). We evaluated mRNA expressions of NGF and Sema3A in the mucosa and submucosa and neuron outgrowth into the mucosa. Key Results In IBS models, nerve fibers were thickened and densely increased in the submucosa remarkably from the outer toward the inner plexus. Submucosal EGCs exhibited process hyperplasia and bulbous swelling of terminals. NGF was predominantly expressed in EGCs than neurons in the submucosa. NGF mRNA expressions were increased in the submucosa in WKY, and their expressions were increased in the mucosa after the injection. Sema3A mRNA expressions were increased in both layers of WKY but tended to be decreased in the mucosa alone after the injection. Neuron outgrowth was increased into the mucosa. NGF was localized at EGCs in the lamina propria mucosae but not mucosal mast cells. Conclusions & Inferences Neuron network enhancement in the submucosa and neuron outgrowth into the mucosa may be associated with axon guidance factors expressed in hyperplastic EGCs in the colonic submucosa of IBS models.