Production, Mechanisms, and Therapeutic Strategies of Tryptophan Metabolites in CNS Diseases

Dec 1, 2025Molecular neurobiology

How Tryptophan Breakdown Products Affect Brain Diseases and Possible Treatments

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Abstract

metabolites are involved in several central nervous system diseases, including Alzheimer's disease and depression.

Tryptophan metabolites are produced through three main pathways: kynurenine, 5-hydroxytryptamine, and indole.
These metabolites can have both protective and harmful effects on the nervous system, depending on their concentration and metabolic context.
Factors such as enzyme regulation, gut microbiota composition, hormones, and the disease environment influence the production of these metabolites.
Modulating the production of neuroprotective versus neurotoxic metabolites may be crucial for developing effective therapeutic strategies for CNS disorders.
Potential treatment approaches include targeting enzymes involved in tryptophan metabolism and altering gut microbiota composition.

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(TRP) metabolites, which are produced from TRP via three pathways-kynurenine, 5-hydroxytryptamine, and indole-are key signaling molecules of the gut-brain axis and are involved in a variety of central nervous system (CNS) disease processes, such as Alzheimer's disease, depression, and schizophrenia by orchestrating inflammatory responses, redox imbalances, neurotransmitter dynamics, mitochondrial dysfunction, and apoptotic/autophagic pathways. However, TRP metabolites exhibit bidirectional modulatory effects, combining different neuroprotective and neurotoxic substances, depending on their metabolic environment and concentration thresholds, posing significant challenges for therapeutic strategies. Therefore, it is important to modulate TRP metabolite production factors, including the regulation of key enzymes in metabolic pathways, the gut microbiota, hormones, and the disease pathology microenvironment, to promote the production of neuroprotective metabolites and inhibit neurotoxic metabolite production. In this review, we detail the influencing factors affecting TRP metabolite production, the regulatory role of TRP metabolites in CNS disorders, and therapeutic strategies related to TRP metabolites for CNS disorders. Targeting TRP metabolizing enzymes or remodeling the ecology of the gut microbiota could be a new strategy for the treatment of CNS diseases, providing a theoretical basis for future precision intervention in CNS diseases.