The Kynurenine Pathway and multi-System Neuro-Developmental & Psychiatric disorders

"The immune-KYN-neuroendocrine interaction"

​Val's Take/Conjecture

• One of the big paradigm shifts of the 21st Century is recognizing Neuro-Developmental and Psychiatric Disorders as MULTI-SYSTEM DISORDERS, not just BRAIN DISORDERS.

• In 1987,  the Psychoneuroimmunology Research Society (PNIRS) established the Brain, Behavior, and Immunity Journal --- that also now includes the Endocrine System.

• The KYNURENINE PATHWAY has emerged not only as a common molecular pathway for Neuro-Developmental, Psychiatric and Neuro-Degenerative Disorders --- but also much of our chronic disease epidemic of Diabetes, Auto-Immune Disorders, Cancer, etc.

• Maternal Immune Activation is associated with increased risk of Type 1 and Type 2 Diabetes and Cancer and thought to increase the risk of adult on-set Auto-Immune Disease in offspring.
  • Further, those illnesses often come with psychiatric symptoms.  

​Diet and Exercise are important, but if we're not recognizing "NEURO-DEVELOPMENTAL IMPAIRMENT" of MULTIPLE SYSTEMS OF THE BODY through various biological mechanisms such as:

• ​Maternal Immune Activation
• Paternal Immune Activation
• Microglia Dysregulation
• Immune Dysregulation
• Endocrine Dysregulation
• Dysregulation of the KYNURENINE PATHWAY
• ​Microbiota Dysregulation
• Metabolic Dysregulation
• ​Etc.

---- We're going to have an incomplete and highly misleading understanding of what's going on.

​Diverse Physiological Roles of Kynurenine Pathway Metabolites: Updated Implications for Health and Disease (2025)

​Abstract

Tryptophan is an essential amino acid critical for human health. It plays a pivotal role in numerous physiological and biochemical processes through its metabolism.

The kynurenine (KYN) pathway serves as the principal metabolic route for tryptophan, producing bioactive metabolites, including KYN, quinolinic acid, and 3-hydroxykynurenine.

Numerous studies are actively investigating the relationship between tryptophan metabolism and physiological functions.

These studies are highlighting the interactions among metabolites that may exert synergistic or antagonistic effects, such as neuroprotective or neurotoxic, and pro-oxidative or antioxidant activities.

Minor disruptions in the homeostasis of these metabolites can result in immune dysregulation, contributing to a spectrum of diseases.

These diseases include neurological disorders, mental illnesses, cardiovascular conditions, autoimmune diseases, and chronic kidney disease.

[See also Targeting the kynurenine pathway: another therapeutic opportunity in the metabolic crosstalk between cancer and immune cells (2025)]

Therefore, understanding the physiological roles of the KYN pathway metabolites is essential for elucidating the contribution of tryptophan metabolism to health regulation.

The present review emphasizes the physiological roles of KYN pathway metabolites and their mechanisms in disease development, aiming to establish a theoretical basis for leveraging dietary nutrients to enhance human health.

​Implications of Kynurenine Pathway Metabolism for the Immune System, Hypothalamic-Pituitary-Adrenal Axis, and Neurotransmission in Alcohol Use Disorder (2024)

​Abstract
​
In recent years, there has been a marked increase in interest in the role of the kynurenine pathway (KP) in mechanisms associated with addictive behavior.

Numerous reports implicate KP metabolism in influencing the immune system, hypothalamic-pituitary-adrenal (HPA) axis, and neurotransmission, which underlie the behavioral patterns characteristic of addiction.

​An in-depth analysis of the results of these new studies highlights interesting patterns of relationships, and approaching alcohol use disorder (AUD) from a broader neuroendocrine-immune system perspective may be crucial to better understanding this complex phenomenon.

In this review, we provide an up-to-date summary of information indicating the relationship between AUD and the KP, both in terms of changes in the activity of this pathway and modulation of this pathway as a possible pharmacological approach for the treatment of AUD.

​The correlation of inflammation, tryptophan-kynurenine pathway, and suicide risk in adolescent depression (2024)

Accumulating evidence suggests a role for the tryptophan-kynurenine pathway (TKP) in the psychopathology of major depressive disorder (MDD).

Abnormal inflammatory profile and production of TKP neurotoxic metabolites appear more pronounced in MDD with suicidality.  .  .  .

"Our findings indicated that serum inflammatory cytokines were robustly associated with IDO and KMO activity, along with significantly decreased serum level of TRP, increased level of 3-HK, and higher suicide risk in adolescent depression."
Accumulating evidence suggests a role for the tryptophan-kynurenine pathway (TKP) in the psychopathology of major depressive disorder (MDD).

Abnormal inflammatory profile and production of TKP neurotoxic metabolites appear more pronounced in MDD with suicidality.  .  .  .

"Our findings indicated that serum inflammatory cytokines were robustly associated with IDO and KMO activity, along with significantly decreased serum level of TRP, increased level of 3-HK, and higher suicide risk in adolescent depression."

​​Maternal immune activation induces neurodevelopmental impairments of adult offspring through alterations in tryptophane-kynurenine pathway in the placenta (2024)

​The kynurenine pathway: a finger in every pie (2020)

​Abstract

The kynurenine pathway (KP) plays a critical role in generating cellular energy in the form of nicotinamide adenine dinucleotide (NAD+).

Because energy requirements are substantially increased during an immune response, the KP is a key regulator of the immune system.

Perhaps more importantly in the context of psychiatry, many kynurenines are neuroactive, modulating neuroplasticity and/or exerting neurotoxic effects in part through their effects on NMDA receptor signaling and glutamatergic neurotransmission.

​As such, it is not surprising that the kynurenines have been implicated in psychiatric illness in the context of inflammation.

However, because of their neuromodulatory properties, the kynurenines are not just additional members of a list of inflammatory mediators linked with psychiatric illness, but in preclinical studies have been shown to be necessary components of the behavioral analogs of depression and schizophrenia-like cognitive deficits.

Further, as the title suggests, the KP is regulated by, and in turn regulates multiple other physiological systems that are commonly disrupted in psychiatric disorders, including endocrine, metabolic, and hormonal systems.

​This review provides a broad overview of the mechanistic pathways through which the kynurenines interact with these systems, thus impacting emotion, cognition, pain, metabolic function, and aging, and in so doing potentially increasing the risk of developing psychiatric disorders.

Novel therapeutic approaches targeting the KP are discussed.

Moreover, electroconvulsive therapy, ketamine, physical exercise, and certain non-steroidal anti-inflammatories have been shown to alter kynurenine metabolism, raising the possibility that kynurenine metabolites may have utility as treatment response or therapeutic monitoring biomarkers.