Overview
Quinolinic acid (QA) is a neurotoxic metabolite of the kynurenine pathway — the branch of tryptophan catabolism driven by IFN-γ-induced IDO activation. QA is an NMDA receptor agonist that causes excitotoxic neuronal death at elevated concentrations. It is produced primarily by activated microglia and macrophages, and its accumulation in the CNS is implicated in schizophrenia, depression, Alzheimer's, and MS.
The Kynurenine Branch Point
Tryptophan → kynurenine branches into:
- Astrocyte branch → kynurenic acid (KYNA) — neuroprotective NMDA antagonist.
- Microglia branch → quinolinic acid (QA) — neurotoxic NMDA agonist.
Chronic inflammation (elevated IFN-γ, IL-6, TNF-alpha) activates microglia, shifting the balance toward QA → excitotoxicity [1] [2].
Microbiome Connection
The gut microbiome determines tryptophan partitioning: dysbiosis → inflammation → IDO induction → tryptophan shunting from serotonin synthesis to kynurenine → QA accumulation in the brain. Restoring SCFA-producing commensals reduces inflammation → reduces IDO → restores serotonin production and reduces QA.
Cross-References
- kynurenine pathway — metabolic pathway producing QA
- ifn gamma — drives IDO activation
- microglia — primary QA producer in CNS
- serotonin — QA pathway competes with serotonin for tryptophan
- tryptophan — shared precursor
- neuroinflammation — inflammation drives QA accumulation