A scientific review published in Discover Neuroscience proposes a preliminary classification dividing major depressive disorder into three composite subtypes based on abnormal interactions among tryptophan metabolic pathways along the microbiota-gut-brain axis. The authors synthesized recent literature indexed in the PubMed database to examine metabolic crosstalk across the kynurenine, indole, and serotonin pathways.

According to the review, major depressive disorder represents a widespread and disabling psychiatric condition that affects approximately 332 million individuals across the globe. Epidemiological data highlighted in the analysis indicate an adult prevalence rate of 5.7 percent worldwide. While the long-standing monoamine neurotransmitter deficiency hypothesis remains a foundational model in psychiatric medicine, the authors note that it does not provide an adequate biological explanation for treatment-resistant depression.

The clinical challenge of treatment resistance is substantial, with the authors observing that treatment-resistant depression affects up to 30 percent of patients diagnosed with major depressive disorder. To address this clinical heterogeneity, the researchers evaluate the microbiota-gut-brain axis as an integrative framework capable of explaining distinct physiological profiles through tryptophan metabolic disruptions, specifically tracking the kynurenine, indole, and serotonin or 5-hydroxytryptamine pathways.

Within this framework, the authors propose three complex subtypes based on abnormal interactions among these metabolic pathways. The first is an indole-kynurenine-related disorder subtype, characterized by an imbalance in intestinal flora alongside intestinal barrier damage. The second is a serotonin-kynurenine dual-pathway disorder subtype, which the authors identify as arising from inflammatory processes competing directly for available tryptophan supplies.

The review delineates a third subtype described as an overall indole-kynurenine-serotonin disorder, representing the most severe presentation among the proposed classifications. In this composite manifestation, dysregulation spans all three metabolic branches concurrently and is accompanied by the disruption of the blood-brain barrier.

The authors note that each proposed subtype corresponds to specific biomarker profiles and hypothesized variations in treatment susceptibility, providing a theoretical foundation to guide individualized precision therapies for patients exhibiting abnormal microbiota-gut-brain axis metabolism. However, the researchers emphasize that several of these subtypes and therapeutic strategies remain conceptual at present and must be validated through prospective clinical trials.

Subject of Research: Tryptophan metabolism and major depressive disorder subtypes in the microbiota-gut-brain axis

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

Article References: Jiani, W., Yinghe, Y., Jiani, Z., Tan, Z., Yingxi, L., & Bo, J. (2026). Tryptophan metabolic pathway crosstalk and composite subtypes of major depressive disorder through the microbiota-gut-brain axis. Discover Neuroscience, 21(1), Article 86. https://doi.org/10.1186/s13064-026-00322-0

Image Credits: AI Generated

DOI: 10.1186/s13064-026-00322-0

Keywords: major depressive disorder, tryptophan metabolism, microbiota-gut-brain axis, kynurenine pathway, serotonin, indole pathway, treatment-resistant depression, neuroscience, Tryptophan, metabolic, pathway, crosstalk