Gut-to-brain spread in mice

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Sangjune Kim, Han Seok Ko (senior author), Ted Dawson, Valina Dawson, Pankaj Pasricha and colleagues, Johns Hopkins.

What happened

Pathological alpha-synuclein fibrils were injected into the duodenal and pyloric muscle layers of mice. Phosphorylated alpha-synuclein appeared first in the dorsal motor nucleus of the vagus, then the lower hindbrain including the locus coeruleus, and much later the basolateral amygdala, dorsal raphe nucleus and substantia nigra pars compacta. Dopamine neuron loss and motor and non-motor symptoms followed the same timeline. Cutting the vagus nerve (truncal vagotomy) or removing alpha-synuclein blocked the spread, neuron loss and behavioural deficits. Neuron 2019;103:627–641. Three commentaries were published; I found no correction or retraction.

Why it moved us toward a cure

It gave experimental support to Braak's gut-to-brain route (landmark 6) and to prion-like spread (landmark 8). It suggests there may be a window to block spread early.

An earlier rat study had already traced synuclein injected in the gut wall to the brainstem (landmark 259).

Outcome

Open; the debate is unsettled.

• A Danish registry study (Svensson 2015) found a hazard ratio of 0.85 (95% CI 0.63–1.14, not significant) after full (truncal) vagotomy, and 0.53 (0.28–0.99) when follow-up passed 20 years, against the general population. A Swedish study of 9,430 vagotomised patients (Liu 2017) found no overall association (HR 0.96, 0.78–1.17), with a suggestion of lower risk after truncal vagotomy at least 5 years earlier (HR 0.59, 0.37–0.93).
• Imaging work (Horsager 2020, landmark 130) supported "body-first" and "brain-first" subtypes; Beach et al. 2021 studied vagus nerve and stomach at autopsy (111 normal elderly, 33 incidental Lewy body disease, 53 Parkinson's) and argued the pathology pattern counts against a body-first route.
• 2024–26 papers on gastric and duodenal seeding activity and gut-brain immune cells add evidence but did not settle it.
• Direct human proof that Parkinson's starts in the gut is still lacking.

Sources

• Kim et al., Neuron 2019, DOI 10.1016/j.neuron.2019.05.035 (PMC6706297)
• Svensson et al., Ann Neurol 2015;78:522–529, DOI 10.1002/ana.24448
• Liu et al., Neurology 2017;88:1996–2002, DOI 10.1212/WNL.0000000000003961
• Beach et al., J Parkinsons Dis 2021, DOI 10.3233/JPD-212733 (abstract via medRxiv preprint)
• Horsager et al., Brain 2020;143:3077–3088, DOI 10.1093/brain/awaa238
• Munoz-Pinto et al. 2024, Mol Neurodegener 19:78
• Not yet verified: the Beach 2021 published abstract (preprint summary only); the 2025 gastric-seeding, duodenal-seeding and intestinal-macrophage papers were not read in full; Alzforum's Masliah dossier list was not checked (none of the authors is Masliah).