Gut-Brain Axis in Parkinson's Disease Pathogenesis

Parkinson’s disease is characterised by progressive loss of dopaminergic neurons in the substantia nigra and accumulation of misfolded α-synuclein aggregates known as Lewy bodies. Increasing evidence supports a pivotal role for the gut–brain axis in disease onset and progression. Aberrant α-synuclein species first appear within the enteric nervous system and may propagate via the vagus nerve to the central nervous system in a prion-like manner. This bidirectional communication network encompasses neuronal pathways, immune cell trafficking and microbial metabolites that together modulate neuroinflammation, gut motility and barrier integrity. Gastrointestinal symptoms frequently precede motor deficits by years, emphasising the potential of peripheral biomarkers and early interventions. Age-related changes in proteolytic enzymes, immune signalling and microbiota composition further influence α-synuclein aggregation and spread. A comprehensive understanding of these interconnections is essential for developing disease-modifying therapies and for stratifying global risk.

Research from Nature Portfolio

Recent studies have demonstrated that microglia-like CD11c+ cells transport aggregated α-synuclein from the brain to the ileum in a mouse model. Using single-cell RNA sequencing, these cells were shown to share activation profiles in both sites, and photo-labelling techniques confirmed their migration along neural and vascular routes. This work elucidates a cellular mechanism for bidirectional α-synuclein trafficking and highlights immune surveillance within the gut–brain axis as a potential therapeutic target.

Gut-Brain Axis in Parkinson's Disease Pathogenesis publication trend

The graph below shows the total number of articles in gut-brain axis in parkinson's disease pathogenesis across all publications each year (not limited to Nature Index journals).

Technical terms

α-Synuclein: Presynaptic protein whose misfolding and aggregation form Lewy bodies in Parkinson’s disease.

Enteric nervous system: Intrinsic network of neurons controlling gastrointestinal motility and secretion.

Vagus nerve: Major cranial nerve conveying sensory and motor signals between gut and brain.

CD11c+ cells: Integrin-expressing immune cells with microglia-like properties that can traffic between brain and gut.

Toll-like receptor 2 (TLR2): Innate immune receptor triggering MyD88/NF-κB signalling and inflammatory responses.

MyD88: Adaptor protein that couples TLR2 activation to downstream NF-κB-mediated transcription.

NF-κB: Transcription factor regulating genes involved in inflammation and cell survival.

Asparagine endopeptidase (AEP): Lysosomal protease that cleaves α-synuclein and promotes its aggregation.

C/EBPβ: Transcription factor that upregulates AEP expression under oxidative stress and ageing.

References

1. Brain-to-gut trafficking of alpha-synuclein by CD11c+ cells in a mouse model of Parkinson’s disease. Nature Communications (2023).
2. α-Synuclein induces prodromal symptoms of Parkinson’s disease via activating TLR2/MyD88/NF-κB pathway in Schwann cells of vagus nerve in a rat model. Journal of Neuroinflammation (2023).
3. C/EBPβ/AEP is age-dependently activated in Parkinson’s disease and mediates α-synuclein in the gut and brain. npj Parkinson's Disease (2023).
4. Parkinson mice show functional and molecular changes in the gut long before motoric disease onset. Molecular Neurodegeneration (2021).