Butyrate acts as a pan-HDAC inhibitor suppressing microglial HDAC3 activity. In dysbiosis, butyrate deficiency permits HDAC3 to deacetylate histones at the TREM2 promoter, downregulating TREM2 expression. This exacerbates the TREM2 loss-of-function AD risk phenotype (rs75932628), leading to impaired phagocytosis of Aβ/α-synuclein and metabolic microglial dysfunction (enhanced glycolysis, mitochondrial fragmentation). Undegraded aggregates further stimulate TLR pathways, completing a feedforward inflammatory loop.
Curated pathway from expert analysis
flowchart TD
A["HDAC3 Inhibition<br/>Histone Deacetylase"]
B["PGC-1alpha Activation<br/>Mitochondrial Biogenesis"]
C["NLRP3 Inflammasome<br/>Suppression"]
D["HIF1A Stabilization<br/>Hypoxic Response"]
E["TREM2 Microglial<br/>Metabolic Reprogramming"]
F["Neuroinflammation<br/>Resolution"]
G["Metabolic<br/>Protection"]
H["Synaptic<br/>Integrity"]
A --> B
B --> G
A --> C
C --> F
D --> E
E --> F
F --> H
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style H fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for HDAC3, TREM2, PGC-1α, NLRP3, HIF1α 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 HDAC3, TREM2, PGC-1α, NLRP3, HIF1α.
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 primary human iPSC-derived microglia from TREM2 rs75932628 variant carriers are treated with vehicle vs. HDAC3-selective inhibitor (RGFP966, 500nM) for 72 hours under inflammatory (IFNγ/LPS) primin | Reduced ECAR (glycolysis) and restored mitochondrial aspect ratio in HDAC3-inhibited TREM2-variant microglia | — no observation — | pending | 0.55 |
| IF germ-free C57BL/6 mice colonized with a defined consortium of butyrate-producing bacteria (Clostridium spp.) are compared to germ-free controls for 4 weeks during ongoing Aβ deposition (APP/PS1 bac | Significant increase in microglial TREM2 protein (measured by flow cytometry/IHC) and 30% reduction in cortical Thioflavin-S+ plaque area | — no observation — | pending | 0.65 |