Tryptophan metabolism: a critical bridge linking gut microbiota to depression

Abstract

Depression is a major global public health challenge with limitations in current therapies. Emerging evidence highlights that gut microbiota (GM) critically regulates the gut-brain axis via tryptophan (Trp) metabolism. Trp is metabolized through host-directed serotonin (5-HT) and kynurenine (KYN) pathways, as well as microbiota-specific indole derivative pathways. In depression, gut dysbiosis shifts Trp metabolism toward the KYN pathway, leading to accumulation of neurotoxic metabolites such as quinolinic acid and reduced 5-HT synthesis. Microbiota-derived indoles, functioning as key aryl hydrocarbon receptor (AhR) ligands, regulate blood-brain barrier integrity, neuroinflammation, and hypothalamic-pituitary-adrenal (HPA) axis function through AhR activation, thereby exerting neuroprotective or pro-inflammatory effects depending on the specific ligand and context. Interventions targeting the Trp-microbiota axis include dietary modifications, probiotics, antibiotics, traditional Chinese medicine, fecal microbiota transplantation, and metabolite supplementation. However, clinical translation is hindered by population heterogeneity, strain specificity, and insufficient dynamic monitoring. Future research should integrate multi-omics and neuroimaging approaches to improve patient stratification and advance Trp metabolism-based precision psychiatry, while emerging computational tools may further support biomarker integration and treatment prediction.