Tryptophan metabolic pathway crosstalk and composite subtypes of major depressive disorder through the microbiota-gut-brain axis

Major depressive disorder (MDD) is a common and disabling mental illness affecting approximately 332 million people worldwide, with an adult prevalence rate of 5.7%. Although the hypothesis of monoamine neurotransmitter deficiency plays a fundamental role, it cannot fully explain treatment-resistant depression (TRD), which can affect up to 30% of patients. The microbiota-gut-brain axis (MGBA) now provides a systematic framework for understanding the heterogeneity of MDD. This article reviews the recent literature evidence on tryptophan metabolism within the MGBA in the PubMed database, focusing on kynurenine (Kyn), indole, and the serotonin/5-hydroxytryptamine (5-HT) pathways. A preliminary classification is proposed: three complex MDD subtypes based on abnormal interactions among these metabolic pathways: the indole-Kyn-related disorder subtype characterized by intestinal flora imbalance and barrier damage; the serotonin-Kyn dual-pathway disorder subtype caused by the competition of inflammation for tryptophan; and the overall indole-Kyn-serotonin disorder subtype representing the most severe form, accompanied by the disruption of the blood-brain barrier. Each subtype is associated with specific biomarker profiles and hypothesized treatment susceptibility. This framework may help implement individualized precision interventions for patients with depression characterized by abnormal MGBA-related tryptophan metabolism, but some subtypes and treatment strategies are currently conceptual and need to be verified in prospective clinical trials. Clinical trial registration: Not applicable