In Parkinson's disease, elevated H2S-producing Desulfovibrio species and depleted butyrate-producing Faecalibacterium prausnitzii create a metabolite imbalance that simultaneously disrupts gut barrier integrity and increases systemic LPS translocation. The resulting TLR4 activation on enteric neurons triggers NF-κB-mediated neuroinflammation, promoting local alpha-synuclein misfoldling and aggregation. This enteric pathology then propagates bidirectionally along the vagus nerve to the dorsal motor nucleus and from autonomic ganglia to peripheral neurons, representing the gut-first progression of PD. Fecal transplant to germ-free α-synuclein transgenic mice will test whether disease-specific microbial communities are sufficient to induce enteric protein aggregation and whether Desulfovibrio colonization alone reproduces the pathological phenotype.
Curated pathway from expert analysis
flowchart TD
A["H2S/Butyrate<br/>Imbalance"]
B["Gut Barrier<br/>Dysfunction"]
C["TLR4 Signaling<br/>Neuroinflammation"]
D["SNCA Expression<br/>Alpha-Synuclein"]
E["Enteric Alpha-Synuclein<br/>Pathology"]
F["Gut-Brain TLR4 Axis<br/>as Therapeutic Target"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for SNCA from GTEx v10.
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for SNCA.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No resource usage or linked notebooks recorded for this hypothesis yet.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF germ-free α-synuclein transgenic (Thy1-αSyn) mice are colonized with H2S-producing Desulfovibrio vulgaris ATCC 29579, THEN intestinal p-S129 α-synuclein accumulation will increase by ≥50% in enteri | Increased p-S129 α-synuclein immunoreactivity (≥50% change) in myenteric and submucosal plexuses, measured by quantitative immunohistochemistry with stereologic | — no observation — | pending | 0.72 |
| IF butyrate-producing Faecalibacterium prausnitzii A2-165 is co-administered with Desulfovibrio vulgaris to germ-free α-synuclein transgenic mice, THEN fecal LPS activity and intestinal TLR4 downstrea | Fecal LPS activity reduced by ≥60% and ileal p-NF-κB p65/β-actin ratio reduced to baseline (germ-free) levels, measured by Limulus amebocyte lysate assay and we | — no observation — | pending | 0.68 |