A human multilineage gut organoid model for Parkinson disease

Abstract

Emerging evidence links gut dysfunction to Parkinson disease (PD) pathogenesis, yet human models to study gut-related mechanisms are lacking. We developed a human intestinal organoid model incorporating PD-relevant cell types. Using control and PD patient-derived pluripotent stem cells, we generated intestinal epithelial organoids and vagal neural crest cells, then co-cultured them into assembloids. The resultant structures featured lumen-forming polarized epithelial monolayers with enteroendocrine cells, contractile subepithelial myofibroblast-like layers, and neuroglial networks containing dopaminergic and cholinergic enteric neurons. Notably, assembloids from a PD patient carrying the GBA1-E326K variant exhibited progressive -synuclein accumulation in non-enteroendocrine epithelial cells. This model recapitulates key gut architecture and PD-associated phenotypes, offering a physiologically relevant platform for mechanistic studies and therapeutic discovery targeting gut-brain pathways in PD.