Tryptophan metabolism within the gut–brain axis in depression: mechanisms, association with heterogeneity, and therapeutic opportunities

Depression is a highly heterogeneous psychiatric disorder, characterized by substantial variability in clinical manifestations, treatment responses, and disease progression, thereby posing significant challenges to precision diagnosis and therapeutic intervention. Accumulating evidence indicates that dysregulated tryptophan metabolism, mediated through dynamic crosstalk with the gut microbiota and the gut-brain axis (GBA), plays a pivotal role in both the pathophysiology and biological heterogeneity of depression. In this review, we delineate the contributions of the three principal tryptophan metabolic pathways—the kynurenine, serotonin, and microbial indole pathways—in modulating neuroimmune signaling, neurotransmitter function, and gut-brain communication. Moreover, we synthesize current evidence demonstrating that microbiota-dependent tryptophan metabolism exhibits distinct profiles across clinical, demographic, immunometabolic, trauma-related, and genetically defined depressive phenotypes, thereby establishing its role as a unifying biological framework underlying depressive heterogeneity. We further provide a critical appraisal of emerging therapeutic strategies targeting microbiota-associated tryptophan metabolism, including pharmacological, nutritional, microbial, and traditional Chinese medicine-based interventions. Future investigations should integrate multi-omics approaches, longitudinal study designs, and mechanistic validation with artificial intelligence to elucidate causal relationships between microbiota-associated tryptophan metabolism and depressive heterogeneity, ultimately facilitating biomarker discovery and the development of precision therapeutics.