A human multilineage gut organoid model for Parkinson disease

Hosseini Bondarabadi, M.; Xu, M.; de Leeuw, J.; Slingerland, S.; van der Zee, S.; Sommer, I. E. C.; Harmsen, H. J. M.; van Laar, T.; van Ijzendoorn, S. C. D.

doi:10.64898/2025.12.16.694313

bioRxiv · 10.64898/2025.12.16.694313

A human multilineage gut organoid model for Parkinson disease

Hosseini Bondarabadi, M.·Xu, M.·de Leeuw, J.·Slingerland, S.·van der Zee, S.·Sommer, I. E. C.·Harmsen, H. J. M.·van Laar, T.·van Ijzendoorn, S. C. D.

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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.

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Hosseini Bondarabadi, M., Xu, M., de Leeuw, J., Slingerland, S., van der Zee, S., Sommer, I. E. C., Harmsen, H. J. M., van Laar, T., van Ijzendoorn, S. C. D.. 2025-12-18. A human multilineage gut organoid model for Parkinson disease. https://doi.org/10.64898/2025.12.16.694313

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