Specific butyrate-producing gut bacteria (e.g., Faecalibacterium, Roseburia) generate systemic butyrate that crosses the blood-brain barrier and inhibits hippocampal microglial HDAC2, leading to hyperacetylation of transcription factors that upregulate TREM2-independent phagocytic pathways. This enhances microglial amyloid-beta uptake and lysosomal degradation while suppressing NLRP3 inflammasome activation. Testable prediction: Germ-free AD mice colonized with butyrate-producing bacteria or treated with sodium butyrate will show reduced amyloid plaque burden, increased microglial amyloid phagocytosis rates ex vivo, and decreased IL-1β and caspase-1 levels, compared to controls.
Curated pathway from expert analysis
flowchart TD
A["Gut Butyrate Deficiency<br/>HDAC2 Dysregulation"]
B["Microglial Amyloid<br/>Clearance Impairment"]
C["HDAC2 Inhibition<br/>Microglial Reprogramming"]
D["Butyrate Restoration<br/>Epigenetic Reset"]
E["HDAC2-Butyrate Axis<br/>as AD Prevention Target"]
F["Microglial<br/> epigenetic Therapy"]
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.
No curated PDB or AlphaFold mapping for HDAC2 yet. Search RCSB →
Median TPM across 13 brain regions for HDAC2 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 HDAC2.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF 5xFAD germ-free mice receive daily intraperitoneal sodium butyrate (300 mg/kg) for 8 weeks starting at 4 months of age, THEN hippocampal amyloid plaque burden will decrease by ≥30% compared to vehi | ≥30% reduction in hippocampal amyloid plaque burden after 8 weeks of sodium butyrate treatment, with increased co-localization of IBA1+ microglia with thioflavi | — no observation — | pending | 0.65 |
| IF germ-free APP/PS1 mice are colonized with human-derived Faecalibacterium prausnitzii (butyrate-producer) vs. Escherichia coli (non-butyrate-producer) via oral gavage for 6 weeks, THEN microglial HD | ≥40% reduction in microglial HDAC2 activity (nuclear extraction + fluorometric assay) and ≥60% increase in Aβ42 uptake by cultured hippocampal microglia isolate | — no observation — | pending | 0.55 |