Aryl hydrocarbon receptor (AhR), expressed in microglia, astrocytes, and neurons, normally ligates tryptophan catabolites from gut bacteria (indole, indole-3-propionate). Dysbiosis depletes tryptophan-metabolizing commensals, reducing AhR ligand availability. Simultaneously, chronic neuroinflammation elevates IDO1, shunting tryptophan toward kynurenine pathway, producing quinolinic acid (NMDAR agonist) and ROS. SCFAs normally suppress IDO1 via GPR41/GPR43-STAT3 signaling, creating a protective deficit.
Curated pathway from expert analysis
flowchart TD
A["Tryptophan<br/>Metabolism"]
B["AHR Activation<br/>Transcription Factor"]
C["IDO1 / KYNU<br/>Kynurenine Pathway"]
D["KYNA Synthesis<br/>Neuroprotective Metabolite"]
E["QUIN Synthesis<br/>Neurotoxic Metabolite"]
F["GRIN2A Activation<br/>Excitotoxicity"]
G["STAT3<br/>Pro-inflammatory Signaling"]
H["Neuronal<br/>Excitotoxicity"]
A --> B
B --> C
C --> D
C --> E
D --> F
E --> F
B --> G
G --> H
F --> H
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style D fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7
style E fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style H fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for AHR yet. Search RCSB →
Median TPM across 13 brain regions for AHR, IDO1, KYNU, HAAO, GRIN2A, STAT3 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 AHR, IDO1, KYNU, HAAO, GRIN2A, STAT3.
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 or antibiotic-induced dysbiosis mice are colonized with SCFA-producing commensals (e.g., Faecalibacterium prausnitzii, Roseburia intestinalis) or receive oral SCFA supplementation (b | Kynurenine/tryptophan ratio in prefrontal cortex will decrease from ~0.15 to <0.10; quinolinic acid levels will drop from ~800 pg/mg to <560 pg/mg; microglial I | — no observation — | pending | 0.72 |
| IF we stratify a cohort of 500 Parkinson's disease patients and 500 age-matched controls by fecal SCFA concentrations (low tertile vs. high tertile) and measure CSF kynurenine/tryptophan ratio and qui | Low-SCBA group will have mean CSF kynurenine/tryptophan ratio of 0.28 ± 0.09 vs. 0.16 ± 0.06 in high-SCBA group; quinolinic acid: 1250 ± 380 pg/mL vs. 595 ± 210 | — no observation — | pending | 0.68 |