The Tryptophan-Kynurenine Pathway as a Key Mediator of the Gut-Brain Axis in Depression and Alzheimer's Disease.

Depression and Alzheimer's disease are among the most prevalent and disabling disorders worldwide, imposing a substantial social, economic, and healthcare burden. Increasing evidence suggests that these conditions share several pathophysiological mechanisms, including chronic inflammation, oxidative stress, mitochondrial dysfunction, altered neurotransmission, and gut microbiota dysbiosis. In recent years, the microbiota-gut-brain axis has emerged as a key regulatory system linking gastrointestinal, immune, metabolic, and neural functions. Within this complex network, the tryptophan-kynurenine pathway has gained considerable attention as a critical mediator connecting gut microbial activity, immune responses, and central nervous system function. This review examines the role of the microbiota-gut-brain axis and the tryptophan-kynurenine pathway in the development and progression of depression and Alzheimer's disease. Particular emphasis is placed on the regulation of tryptophan metabolism by gut microbiota, the inflammatory activation of indoleamine 2,3-dioxygenase, and the generation of neuroactive kynurenine metabolites. Dysregulation of these processes may reduce serotonin synthesis while promoting the accumulation of neurotoxic compounds such as quinolinic acid and 3-hydroxykynurenine, thereby contributing to neuroinflammation, excitotoxicity, cognitive decline, and depressive symptoms. Current evidence also highlights the therapeutic potential of interventions targeting gut microbiota composition and kynurenine pathway activity. A better understanding of these interconnected mechanisms may facilitate the identification of novel biomarkers and the development of personalized strategies for the prevention and treatment of both psychiatric and neurodegenerative disorders.