Dysbiosis compromises intestinal tight junctions (occludin, claudin-1, ZO-1) and reduces α-defensin production, permitting Gram-negative bacteria and LPS translocation into systemic circulation. Circulating LPS engages TLR4 on Kupffer cells and bone marrow monocytes, establishing chronic endotoxemia. MyD88-dependent signaling induces CCL2 (MCP-1), recruiting CCR2+ pro-inflammatory monocytes across the compromised blood-brain barrier into CNS parenchyma, where they amplify neurodegeneration.
Curated pathway from expert analysis
flowchart TD A["Gut Dysbiosis"] -->|"disrupts"| B["Intestinal tight junction downregulation"] B -->|"allows"| C["Gram-negative bacteria and LPS translocation"] C -->|"engages"| D["TLR4 activation on Kupffer cells and monocytes"] D -->|"recruits"| E["MyD88-dependent signaling cascade"] E -->|"activates"| F["IRAK4 kinase activation"] F -->|"induces"| G["CCL2 production"] G -->|"recruits"| H["CCR2-positive inflammatory monocytes"] H -->|"traffic across"| I["Compromised blood-brain barrier"] I -->|"infiltration"| J["CNS monocyte-driven inflammation"]
No linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for TLR4, MyD88, IRAK4, CCL2, CCR2, ZO-1 (TJP1) 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 TLR4, MyD88, IRAK4, CCL2, CCR2, ZO-1 (TJP1).
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 CCR2-deficient (Ccr2-DTR or Ccr2-/-) mice are colonized with high-fat diet-induced dysbiosis or春晚FMT from LPS-challenged donors for 8 weeks, THEN despite persisting gut barrier dysfunction (reduced | >80% reduction in CNS CCR2+CD11b+Ly6Chigh monocytes despite elevated serum LPS and gut barrier compromise | — no observation — | pending | 0.58 |
| IF IRAK4 kinase activity is pharmacologically inhibited with an IRAK4 inhibitor (e.g., mesenimb or AS2444497) in a 5xFAD or APP/PS1 mouse model for 4 weeks starting at 6 months of age, THEN CNS CCR2+C | ≥40% reduction in CNS CCR2+CD11b+Ly6Chigh monocytes and ≥50% reduction in cortical CCL2 mRNA | — no observation — | pending | 0.65 |