Gut-derived bacterial components (LPS, MDP) provide Signal 1 for NLRP3 inflammasome priming via TLR4/TLR2/NOD2, inducing pro-IL-1β and NLRP3 transcription. Signal 2 activation occurs through mitochondrial dysfunction from SCFA deficiency, causing ROS release and potassium efflux. Active caspase-1 cleaves pro-IL-1β and gasdermin D, executing pyroptotic cell death. Released IL-1β acts on neuronal IL-1R1 to promote complement C1q/C3-mediated synaptic pruning. SCFAs interrupt at both signals via GPR109A-mediated mitochondrial biogenesis and NF-κB inhibition.
Curated pathway from expert analysis
flowchart TD
A["NLRP3 Inflammasome<br/>Activation"]
B["CASP1-mediated<br/>Pro-GSDMD Cleavage"]
C["GSDMD Pore Formation<br/>Pyroptosis"]
D["IL1B Release<br/>Pro-inflammatory Cytokine"]
E["Complement C3<br/>Activation"]
F["C1QA-mediated<br/>Synaptic Pruning"]
G["GPR109A (HCAR2)<br/>Anti-inflammatory Signal"]
H["Microglial<br/>Activation"]
I["Neuroinflammation<br/>Cognitive Decline"]
A --> B
B --> C
C --> D
D --> H
E --> F
F --> I
G --> D
G --> H
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style I fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
Median TPM across 13 brain regions for NLRP3, CASP1, GSDMD, IL1B, IL1R1, C3, C1QA, GPR109A (HCAR2) 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 NLRP3, CASP1, GSDMD, IL1B, IL1R1, C3, C1QA, GPR109A (HCAR2).
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 adult C57BL/6 mice are fed a diet lacking fermentable fiber (SCFA-depleted diet) for 4 weeks, THEN hippocampal complement proteins C1q and C3 will increase by >50% and synaptic density (measured by | Significant increase in C1q/C3 protein expression and increased colocalization of complement with synaptic markers; reduced dendritic spine density and synaptic | — no observation — | pending | 0.65 |
| IF NLRP3 knockout mice receive chronic SCFA depletion, THEN there will be no significant increase in hippocampal IL-1β or complement-mediated synaptic pruning compared to wild-type SCFA-depleted mice, | NLRP3 knockout mice will be protected from SCFA depletion-induced synaptic pruning, with hippocampal IL-1β and C1q levels remaining at baseline despite SCFA dep | — no observation — | pending | 0.58 |