The human gut microbiome (GM) influences host physiology through the production of bioactive metabolites. Increasing evidence links GM dysbiosis to neuropsychiatric disorders (NPDs), including anxiety disorders, major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ), via bidirectional signaling along the gut-brain axis (GBA). Among the pathways connecting gut and brain, the tryptophan-kynurenine pathway (TKP) has emerged as a central inflammatory and neuromodulatory mechanism. During immune activation and dysbiosis, tryptophan metabolism shifts toward kynurenine production, generating metabolites with distinct biological effects. Kynurenic acid (KYNA) exerts neuroprotective actions through NMDA receptor antagonism and reduced oxidative stress, whereas quinolinic acid (QUIN) and 3-hydroxykynurenine (3-HK) promote excitotoxicity, mitochondrial dysfunction, and neurodegeneration. Altered KYNA/QUIN balance appears to represent a transdiagnostic feature across NPDs, with preferential QUIN accumulation in mood disorders and pathological KYNA elevation in SCZ, suggesting potential therapeutic relevance. In parallel, the aryl hydrocarbon receptor (AhR), activated by tryptophan-derived microbial metabolites, regulates intestinal barrier integrity, immune responses, and neuroimmunometabolic signaling, functioning as a molecular link between the GM, immune system, and brain. This review explores the interactions among GM dysbiosis, TKP alterations, mitochondrial dysfunction, and AhR signaling in anxiety disorders, MDD, BD, and SCZ, highlighting their potential as biomarkers and targets for personalized therapies.
Gut-Brain Axis