ID: h-583535bb
Hypothesis
Gut-BBB Axis: Tributyrin/Butyrate HDAC Inhibition Epigenetically Restores Claudin-5 at the BBB
Gut dysbiosis-driven butyrate deficit causes HDAC-mediated silencing of CLDN5 in brain endothelial cells; tributyrin prodrug restores CLDN5 expression via H3K27ac enrichment at the CLDN5 promoter, re-sealing the BBB in a virtuous cycle l.
neurodegeneration
EvidencePending (0%)📖 5 cit🗣 1 debates✓ 5 support✗ 2 oppose
✓ All Quality Gates Passed
🧪 Overview
Gut dysbiosis-driven butyrate deficit causes HDAC-mediated silencing of CLDN5 in brain endothelial cells; tributyrin prodrug restores CLDN5 expression via H3K27ac enrichment at the CLDN5 promoter, re-sealing the BBB in a virtuous cycle linking gut microbiome to neurovascular integrity.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["Gut Butyrate Deficit<br/>Dysbiosis-Driven SCFA Loss"]
B["HDAC Activity in Endothelium<br/>Chromatin Deacetylation"]
C["CLDN5 Promoter Silencing<br/>Reduced Claudin-5 Expression"]
D["Tight Junction Weakening<br/>BBB Permeability Increase"]
E["Neuroinflammatory Ingress<br/>Peripheral Mediator Entry"]
F["Tributyrin/Butyrate Rescue<br/>HDAC Inhibition"]
G["CLDN5 Re-expression<br/>Barrier Resealing"]
A --> B
B --> C
C --> D
D --> E
F --> G
G -.->|"reverses"| C
G --> D
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style G fill:#1b5e20,stroke:#81c784,color:#81c784⚖️ Evidence
⚖️ Evidence Matrix5 supports0 contradicts
Supports
Social stress induces neurovascular pathology promoting depression.
Supports
Development, maintenance and disruption of the blood-brain barrier.
Supports
The blood-brain barrier in aging and neurodegeneration.
Supports
Regulation of blood-brain barrier integrity by Dmp1-expressing astrocytes through mitochondrial transfer.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — CLDN5
No curated PDB or AlphaFold mapping for CLDN5 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for CLDN5 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 CLDN5.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
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🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF adult mice with gut dysbiosis (antibiotic-treated) receive oral tributyrin (300 mg/kg/day) for 14 days, THEN brain endothelial H3K27ac enrichment at the CLDN5 promoter will increase ≥2-fold (measur | H3K27ac levels at CLDN5 promoter will increase from baseline (vehicle) to ≥2-fold change, and CLDN5 mRNA will increase ≥1.5-fold in brain microvessel isolations | — no observation — | pending | 0.72 |
| IF tributyrin restores CLDN5 expression in gut-dysbiotic mice, THEN hippocampal BBB permeability (measured by Evans Blue extravasation) will decrease by ≥40% within 21 days post-treatment compared to | Evans Blue concentration in hippocampus will decrease to ≤60% of vehicle-treated dysbiotic controls (normalized to brain weight) | — no observation — | pending | 0.68 |
🔮 Falsifiable Predictions (2)
pendingconf 72%
IF adult mice with gut dysbiosis (antibiotic-treated) receive oral tributyrin (300 mg/kg/day) for 14 days, THEN brain endothelial H3K27ac enrichment at the CLDN5 promoter will increase ≥2-fold (measured by ChIP-qPCR) compared to vehicle-treated dysbiotic controls.
Predicted outcome: H3K27ac levels at CLDN5 promoter will increase from baseline (vehicle) to ≥2-fold change, and CLDN5 mRNA will increase ≥1.5-fold in brain microvessel
Falsification: H3K27ac enrichment at CLDN5 promoter shows no statistically significant increase (p>0.05) or decreases; CLDN5 expression remains unchanged or decreases
pendingconf 68%
IF tributyrin restores CLDN5 expression in gut-dysbiotic mice, THEN hippocampal BBB permeability (measured by Evans Blue extravasation) will decrease by ≥40% within 21 days post-treatment compared to untreated dysbiotic mice.
Predicted outcome: Evans Blue concentration in hippocampus will decrease to ≤60% of vehicle-treated dysbiotic controls (normalized to brain weight)
Falsification: Hippocampal Evans Blue extravasation shows no statistically significant decrease (p>0.05); BBB permeability remains elevated or increases; CLDN5 protein levels in brain endothelial cells do not increa
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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