Dysbiosis permits overgrowth of SIBO species and opportunistic fungi (Candida albicans, Malassezia) whose cell wall components (D-alanyl-LTA, zymosan) are potent TLR2 ligands. TLR2/MyD88 signaling in astrocytes triggers PLA2-dependent arachidonic acid release, upregulating COX-2/PGE2 and NFAT dephosphorylation. This astrocyte 'priming' converts astrocytes from neurotrophic to neurotoxic, producing complement C3 that tags neurons for phagocytosis by hyperactive microglia.
Curated pathway from expert analysis
flowchart TD
A["TLR2 Activation<br/>Pattern Recognition"]
B["MyD88<br/>Adaptor Protein"]
C["NFATC1<br/>Transcription Factor"]
D["PTGS2 (COX-2)<br/>Prostaglandin Synthesis"]
E["PTGER2 (EP2)<br/>Prostanoid Receptor"]
F["Complement C3<br/>Activation"]
G["Neuroinflammatory<br/>Response"]
H["Synaptic<br/>Dysfunction"]
A --> B
B --> C
C --> D
D --> E
E --> G
F --> G
G --> H
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for TLR2 yet. Search RCSB →
Median TPM across 13 brain regions for TLR2, MyD88, NFATC1, PTGS2 (COX-2), PTGER2 (EP2), C3 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 TLR2, MyD88, NFATC1, PTGS2 (COX-2), PTGER2 (EP2), C3.
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 astrocyte-specific MyD88 is genetically deleted (Cx45-Cre;MyD88fl/fl) in adult mice with antibiotic-induced dysbiosis and Candida albicans colonization, THEN astrocyte COX-2 (PTGS2) protein levels | COX-2 (PTGS2) protein expression in GFAP+ astrocytes will be ≥50% lower; nuclear NFATc1+ astrocytes will be ≥40% reduced; cortical C3aR1+ neurons will be ≥35% m | — no observation — | pending | 0.65 |
| IF germ-free C57BL/6J mice are monocolonized with Enterococcus faecalis OG1RF (wild-type, D-alanyl-LTA+) compared to isogenic ΔdltA deletion mutant (lacking D-alanylation), THEN mice colonized with D- | Hippocampal C3 concentration by ELISA will be ≥2-fold elevated; microglial phagocytic index (CD68+/IBA1+ area fraction) will be ≥40% higher; CA1 NeuN+ neuron co | — no observation — | pending | 0.55 |