H2S/butyrate imbalance drives enteric alpha-synuclein pathology via TLR4 signaling
🧪 Overview
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.
🧬 Mechanism
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:#a5d6a7⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — SNCA
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for SNCA from GTEx v10.
💉 Clinical Trials
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.
🏆 Tournament
🏆 Arenas / Elo
📊 Market Indicators
💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
🔮 Predictions
| 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 |
▸Metadatasource: v1_phase_c_backfill · origin_type: audit_hypothesis_generator
| source | v1_phase_c_backfill |
| origin_type | audit_hypothesis_generator |
| _schema_version | 1 |