Brain sciencesAug 27, 2026

Injected α-Synuclein in the Small Intestine May Cause Vagus Nerve-Linked Gut-to-Brain Disease in Normal and Mutant Mice

Gut-Brain Axis Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Aug 28, 2026

Abstract

At 4 months post-injection, p-α-synuclein deposition was observed in both the duodenal muscular layer and the striatum of C57BL/6J mice.

Gut microbiota alterations and motor behavioral deficits were noted in C57BL/6J mice alongside p-α-synuclein deposition.
Truncal vagotomy was associated with reduced p-α-synuclein levels in the brain and changes in gut microbiota.
In A53T transgenic mice, p-α-synuclein pathology and neurodegenerative changes were observed following α-synuclein preformed fibril injection.
The lack of a genetically matched wild-type control in A53T mice limits definitive attribution of observed changes to the transgene.
Findings support the Braak hypothesis, indicating that gut-derived p-α-synuclein pathology may propagate to the brain via vagal pathways.

Simplified

Background: The Braak hypothesis proposes that α-synuclein (α-syn) pathology may originate in the gastrointestinal tract and propagate to the central nervous system along the gut-brain axis; however, the precise propagation routes and the factors influencing this process remain controversial. Methods: A gut-originating Parkinson's disease model was established by injecting α-syn preformed fibrils (PFF) into the duodenal muscularis of C57BL/6J and A53T transgenic mice. Phosphorylated α-synuclein (p-α-syn) pathology, motor behavior, and gut microbiota were assessed, with truncal vagotomy included to evaluate its association with gut-to-brain propagation. Results: In C57BL/6J mice, at 4 months post-injection, p-α-syn deposition was observed in both the duodenal muscular layer and the striatum, accompanied by gut microbiota alterations and motor behavioral deficits. Truncal vagotomy was associated with reduced p-α-syn levels in the brain and alterations in the gut microbiota. In A53T transgenic mice, p-α-syn pathology and neurodegenerative changes were also observed following α-syn PFF injection, though the lack of a genetically matched wild-type control precludes definitive attribution of these phenotypes solely to the A53T transgene. Conclusions: These results align with the Braak hypothesis, showing that gut-derived p-α-syn pathology and associated functional impairments are intimately linked to vagal pathways during their propagation to the brain. Additionally, this gut-origin PD mouse model may serve as a useful tool for future mechanistic investigations.