Dietary Tryptophan Allocation in Depression: Serotonin–Kynurenine Balance, Microbial Indole Pathways, and Inflammatory Phenotypes

Depression is defined by clinical symptoms, but its biology varies considerably among patients. In this review, dietary tryptophan allocation describes the routes taken by tryptophan after intestinal absorption. Some is incorporated into proteins. Some enters serotonin and melatonin synthesis or the kynurenine pathway, while gut bacteria convert another fraction into indole compounds. Brain availability also depends on the circulating free pool and competition with other large neutral amino acids. This term does not imply a new biochemical pathway. It allows these known processes to be considered in relation to inflammation, metabolism, the gut microbiota, medication use, and current disease state. Recent meta-analyses indicate that peripheral tryptophan is lower in depression. They do not show a consistent increase in the kynurenine-to-tryptophan ratio, and findings from cerebrospinal fluid vary between studies. Human multiomics studies have associated microbial and metabolite profiles with cognition and response to treatment, although the evidence remains largely correlational. Changes in kynurenine, 3-hydroxykynurenine, and quinolinic acid are more apparent in inflammatory subgroups than in unselected samples. Modern evidence for L-tryptophan monotherapy is sparse. Trials of 5-hydroxytryptophan and interventions directed at the gut microbiota have also produced mixed results. Studies should characterize participants and sampling conditions more carefully. Diet and competition among amino acids need to be recorded. Albumin concentration, medication exposure, and disease state also affect interpretation. Considering these variables together may improve biomarker analyses and support trials in more biologically homogeneous groups. Dietary tryptophan allocation is proposed for these research purposes, not for clinical diagnosis or routine supplementation.