Impairment of Gut Motility and Colon Pathology in SOD1G93A Mice

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by motor nervous system dysfunction and non-motor symptoms. Constipation is a common non-motor symptom affecting approximately 50%–70% of ALS patients. However, the underlying pathophysiological mechanism remains poorly understood. Notably, intestinal structure and function abnormalities have been observed in multiple neurodegenerative disorders. Thus, this study aimed to investigate potential pathological alterations contributing to intestinal dysmotility of ALS. Methods: In this study, we utilized mutant superoxide dismutase 1^G93A (SOD1^G93A) transgenic mice models of ALS to elucidate the possible pathophysiological mechanisms of constipation in ALS. We examined alterations in structures related to intestinal movement, including enteric neurons, enteric glial cells, muscularis macrophages (MMs), interstitial fibroblast-like cells, MMs- bone morphogenetic protein-2 (BMP2) - bone morphogenetic protein receptor (BMPR) pathway, and the autonomic nervous system, including the vagal, thoracolumbar spinal cord and lumbosacral spinal cord, using immunofluorescence and western blot analyses. Results: SOD1^G93A mice exhibited a significant delay in bowel movement compared to wild-type mice at 90 days of age (p = 0.013) and 120 days of age (p < 0.001). Histopathological analyses revealed substantial alterations in the intestinal structure of SOD1^G93A mice, including a reduction in cholinergic neurons (p = 0.002) and an upregulation of glial fibrillary acidic protein in the myenteric ganglion. Additionally, the number of MMs was reduced (p = 0.003) and the MMs-BMP2-BMPR pathway was abnormal. Conclusions: In SOD1^G93A mice, pathological alterations in the structural components responsible for intestinal movement may contribute to delayed bowel movement frequently observed in SOD1^G93A mice and in individuals with ALS who experience increased constipation. Furthermore, this study provides novel insights into the potential involvement of the gut-brain axis in ALS.