Gut dysbiosis depletes butyrate-producing commensals (Faecalibacterium prausnitzii, Clostridium XIVa, Akkermansia muciniphila), reducing SCFA-mediated activation of microglial GPR43/GPR41 receptors and HDAC inhibition. This removes inhibitory checkpoints on NF-κB, permitting unchecked pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6). The pathway integrates receptor-mediated G-protein signaling with epigenetic regulation through histone deacetylase inhibition, creating a dual braking mechanism on microglial activation that is compromised in neurodegeneration.
Curated pathway from expert analysis
flowchart TD A["Gut Dysbiosis"] --> B["Depleted butyrate-producing commensals"] B --> C["Reduced SCFA production"] C --> D["Loss of GPR43 and GPR41 signaling"] D --> E["Loss of HDAC3 inhibition"] E --> F["NF-kappaB activation"] F --> G["Unchecked pro-inflammatory cytokines"] G --> H["Neurodegeneration"] style A fill:#ef5350,color:#0d0d1a style B fill:#ef5350,color:#0d0d1a style C fill:#4fc3f7,color:#0d0d1a style D fill:#4fc3f7,color:#0d0d1a style E fill:#4fc3f7,color:#0d0d1a style F fill:#4fc3f7,color:#0d0d1a style G fill:#ef5350,color:#0d0d1a style H fill:#ffd54f,color:#0d0d1a
No linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for GPR43 yet. Search RCSB →
Median TPM across 13 brain regions for GPR43 (FFAR2), GPR41 (FFAR3), HDAC3, RELA (NF-κB p65) 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 GPR43 (FFAR2), GPR41 (FFAR3), HDAC3, RELA (NF-κB p65).
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 germ-free mice are colonized with butyrate-producing Faecalibacterium prausnitzii and Clostridium XIVa to restore SCFA levels, THEN microglial GPR43/NF-κB signaling will normalize (reduced NF-κB p6 | Normalized NF-κB activity (phospho-RELA/RELA ratio reduced to <1.5) and restored HDAC activity (HDAC3 deacetylase activity ≥80% of specific-pathogen-free baseli | — no observation — | pending | 0.68 |
| IF GPR43 (FFAR2) is selectively deleted in microglia using Cx3cr1-Cre;FFAR2-flox mice, THEN microglial hyperactivation and neurodegeneration will occur spontaneously (elevated IL-1β ≥2-fold, Iba-1+ ce | Increased density of Iba-1+ amoeboid microglia in hippocampus (≥50% vs. FFAR2-WT littermates), elevated IL-1β and TNF-α in hippocampal tissue lysates (≥2-fold i | — no observation — | pending | 0.72 |