Reduced SCFA-producing bacteria (Lachnospiraceae, Ruminococcaceae, Faecalibacterium) in PD leads to microglial dysfunction, impaired α-synuclein clearance, and increased pro-inflammatory cytokine production. Butyrate deficiency reduces tight junction expression. Critical translational barriers: butyrate has poor CNS bioavailability (~5% crosses BBB), fecal SCFA is heavily confounded by diet, and SCFA effects may be secondary to prodromal dietary changes. Optimal strategy: high-dose resistant starch (45g/day) rather than direct butyrate supplementation.
Curated pathway from expert analysis
flowchart TD
A["HDAC3 Class I<br/>Histone Deacetylase 3"]
B["NCoR/SMRT Complex<br/>Transcriptional Co-repressor"]
C["H3K9 Deacetylation<br/>Chromatin Condensation"]
D["Inflammatory Gene Repression<br/>NFKB Pathway Suppression"]
E["Microglial Activation<br/>Pro-inflammatory Response"]
F["TREM2 Downregulation<br/>DAM Transition Impaired"]
G["Phagocytic Capacity<br/>Amyloid Clearance Reduced"]
H["Synaptic Dysfunction<br/>Memory-Related Gene Expression"]
I["Cognitive Decline<br/>Neurodegeneration Progression"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
G --> H
H --> I
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style I fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aMedian TPM across 13 brain regions for HDAC3/GPR43 (FFAR2)/IL10/TREM2/OCLN from GTEx v10.
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 HDAC3.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF patients with early-stage Parkinson's disease consume high-dose resistant starch (45g/day) for 12 weeks, THEN fecal SCFA concentrations (particularly butyrate and propionate) will increase by ≥50% | ≥50% increase in fecal SCFA; ≥30% reduction in inflammatory cytokines; ≥25% reduction in nigral microglial PET signal | — no observation — | pending | 0.65 |
| IF germ-free or antibiotic-depleted α-synuclein transgenic (ASO) mice receive fecal microbiota transplantation from Parkinson's disease patients (vs. healthy controls), THEN colonic HDAC3 activity and | ≥40% increase in microglial TREM2+ cells; ≥50% increase in IL-10+ microglia; ≥30% reduction in pS129 α-synuclein; ≥20% improvement in motor performance | — no observation — | pending | 0.55 |