Gut Dysbiosis and the Vagal Pathway to Parkinson's Disease: Modeling LPS-Driven Alpha-Synuclein Misfolding from the Gastrointestinal Tract to the Brain
Samantha Denko, Hailey Holestine, Anaya Ishtiaq, Daniel Johnson, Esther Jung, Alani Pino, Zoe Powell-Maignan, Andrew Wise
Research proposal · Advanced Medical Neuroscience Internship, Leadership Initiatives at Georgetown University · July 31, 2026
Status: under review for publication
Abstract
Parkinson's disease is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and the buildup of misfolded alpha-synuclein in Lewy bodies, though the cause of the misfolding is unknown. We propose that gut dysbiosis-driven inflammation, specifically inflammatory metabolites and lipopolysaccharide (LPS) from the gut microbiome, causes alpha-synuclein misfolding in enteric neurons that travels to the brain through the vagus nerve.
To test this, we propose using human induced pluripotent stem cell-derived Gut-Brain Vagal Pathway Assembloids, a connected enteric organoid and hindbrain organoid, exposed to factors derived from Parkinson's patients' gut microbiota under four conditions: a vehicle control, LPS alone, inflammatory metabolites (IPA and DCA) alone, and all three combined. We expect the combined condition to produce the most misfolding and inflammation, and expect pathology to propagate from the enteric organoid to the hindbrain organoid.
These findings would help clarify whether gut inflammation meaningfully contributes to Parkinson's pathology and could inform early intervention through the gut microbiome.
Presented To
A panel including Dr. James Giordano (Chief, Georgetown Neuroethics Studies) and Dr. Rachel Wurzman.