Gut butyrate deficiency impairs microglial amyloid clearance via HDAC2-mediated epigenetic dysregulation
🧪 Overview
Gut dysbiosis in Alzheimer's disease reduces butyrate-producing bacteria (Faecalibacterium prausnitzii, Roseburia intestinalis), causing systemic butyrate deficiency. Butyrate normally acts as an endogenous histone deacetylase (HDAC) inhibitor; decreased butyrate allows HDAC2 to suppress histone acetylation at promoters of anti-inflammatory genes in microglia, impairing their ability to phagocytose and clear amyloid-beta plaques. This HDAC2-mediated epigenetic silencing reduces expression of genes encoding phagocytic receptors (TREM2, CR3) and lysosomal enzymes, creating a feed-forward loop where accumulated amyloid further disrupts gut barrier integrity and exacerbates dysbiosis. Oral supplementation with butyrate or butyrate-producing bacterial consortia would restore microglial epigenetic regulation and enhance amyloid clearance.
🧬 Mechanism
Curated pathway from expert analysis
flowchart TD
A["HDAC2 Activity<br/>Histone Deacetylase"]
B["Microglial Epigenetic<br/>Regulation"]
C["Phagocytosis<br/>Gene Expression"]
D["Microglial Amyloid<br/>Clearance Capacity"]
E["HDAC-Dependent<br/>Epigenetic Dysregulation"]
F["HDAC2 as<br/>Microglial Reprogramming Target"]
A --> B
B --> C
C --> D
D --> E
E --> F
style A fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style F fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — HDAC2
No curated PDB or AlphaFold mapping for HDAC2 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for HDAC2 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 HDAC2.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
📊 Market Indicators
💾 Resource Usage
🔮 Predictions
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF adult 5xFAD mice with established amyloid pathology are given oral sodium butyrate supplementation (150 mg/kg/day) for 8 weeks, THEN hippocampal amyloid plaque burden will decrease by at least 25% | Hippocampal amyloid plaque burden reduced by ≥25% (Thioflavin-S stereology or 11C-PiB PET SUVR) after 8 weeks of butyrate supplementation | — no observation — | pending | 0.65 |
| IF butyrate supplementation restores microglial phagocytic capacity, THEN butyrate-treated 5xFAD mice will show at least 2-fold increase in TREM2 and CR3 gene expression and enhanced in vivo amyloid p | TREM2 and CR3 mRNA expression ≥2-fold higher; in vivo phagocytosis assay shows ≥2-fold increased amyloid internalization by microglia in butyrate-treated mice | — no observation — | pending | 0.55 |
▸Metadatasource: v1_phase_c_backfill · origin_type: audit_hypothesis_generator
| source | v1_phase_c_backfill |
| origin_type | audit_hypothesis_generator |
| _schema_version | 1 |