Beneficial gut bacteria convert dietary tryptophan into neuroprotective metabolites like indole-3-propionic acid, which activate aryl hydrocarbon receptors in microglia, shifting them from pro-inflammatory to anti-inflammatory phenotypes. Precision probiotic therapy could restore this protective pathway.
Curated pathway from expert analysis
graph TD
A["Tryptophan Dietary Intake"] -->|"substrate"| B["Gut Microbiome Metabolism"]
B -->|"produces"| C["Indole-3-Propionic Acid"]
C -->|"crosses BBB via MCT1/MCT2"| D["CNS Entry"]
D -->|"ligand binding"| E["AHR Activation"]
E -->|"transcriptional regulation"| F["IL10 Gene Expression"]
E -->|"transcriptional regulation"| G["TGFB1 Gene Expression"]
F -->|"anti-inflammatory"| H["Microglial M2 Polarization"]
G -->|"immunosuppressive"| H
H -->|"reduces"| I["Neuroinflammation"]
I -->|"prevents"| J["Synaptic Loss"]
I -->|"prevents"| K["Neuronal Death"]
L["Dysbiosis"] -->|"reduces"| B
M["Probiotic Therapy"] -->|"restores"| B
N["AHR Agonists"] -->|"activates"| E
O["Neuroprotection"]
J -->|"maintains"| O
K -->|"maintains"| O
classDef mechanism fill:#4fc3f7,color:#0d0d1a
classDef pathology fill:#ef5350,color:#0d0d1a
classDef therapy fill:#81c784,color:#0d0d1a
classDef outcome fill:#ffd54f,color:#0d0d1a
classDef genetics fill:#ce93d8,color:#0d0d1a
class A,C,D,E mechanism
class L,I,J,K pathology
class M,N therapy
class O outcome
class B,F,G,H genetics

No curated PDB or AlphaFold mapping for AHR yet. Search RCSB →
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, IL10, TGFB1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| If hypothesis is true, intervention identify patients most likely to benefit from intervention | identify patients most likely to benefit from intervention | — no observation — | pending | 0.30 |
| If hypothesis is true, intervention enroll 40-60 participants across dose-escalation cohorts, with primary endpoints focusing on tolerability, microbiome engraftment efficiency, and pharmacokinetic pa | enroll 40-60 participants across dose-escalation cohorts, with primary endpoints focusing on tolerability, microbiome engraftment efficiency, and pharmacokineti | — no observation — | pending | 0.30 |
| If hypothesis is true, intervention incorporate biosafety switches, enhanced colonization factors, and inducible metabolite production systems responsive to disease biomarkers or external signals | incorporate biosafety switches, enhanced colonization factors, and inducible metabolite production systems responsive to disease biomarkers or external signals | — no observation — | pending | 0.30 |