Abstract
BACKGROUND: Chronic intestinal pseudo-obstruction (CIPO) is a severe gastrointestinal motility disorder that may be idiopathic or associated with systemic disease. In idiopathic cases, the pathophysiological mechanisms remain poorly defined. Although mutations in angiogenic factors have been reported in mitochondrial forms of CIPO, their role in non-mitochondrial cases is still unclear. OBJECTIVE: To investigate genetic and molecular contributors to CIPO, with a specific focus on intestinal microvasculature. METHODS: Jejunal samples from patients with CIPO were analysed by whole exome sequencing (WES) and mitochondrial DNA (mtDNA) profiling. Morphometric and immunohistochemical studies assessed collagen remodelling, vascular architecture, neuromuscular integrity and hypoxia. Expression of angiogenic factors, including thymidine phosphorylase (TP) and vascular endothelial growth factor (VEGF), was evaluated. RESULTS: WES did not identify known CIPO-causing variants, but rare mutations in collagen-related genes were detected in a subset of patients. Tissue analysis revealed higher fibrosis, vascular remodelling with a predominance of very small vessels, thinning of the longitudinal muscle and neuronal loss. TP and VEGF expression were significantly reduced, whereas hypoxia-inducible factor-1α (HIF-1α) was markedly upregulated. mtDNA integrity and copy number were preserved, whereas haplogroup J was overrepresented. Multivariate analysis linked these alterations to a higher frequency of sub-occlusive episodes. CONCLUSIONS: Vascular dysfunction and collagen abnormalities emerge as key contributors to neuromuscular degeneration in CIPO. These findings provide novel mechanistic insights into disease pathophysiology and support further exploration of vascular-targeted therapeutic strategies.