Review

Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health

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Science  28 Jul 2017:
Vol. 357, Issue 6349, eaaf9794
DOI: 10.1126/science.aaf9794

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From stomach ache to depression

Our gut hurts and we feel miserable. Such disparate phenomena are mechanistically connected, but how? Cervenka et al. review the many pathways taken by dietary tryptophan as it is metabolized into kynurenines. These metabolites distribute into homeostatic networks that integrate diverse aspects of mammalian physiology. Depending on physiological context, kynurenines influence health and disease states ranging from intestinal conditions to inflammation to cancer progression. Further, they can mediate the effects of exercise, mood, and neuronal excitability and, ultimately, communicate with the microbiota.

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Structured Abstract

BACKGROUND

The essential amino acid tryptophan is a substrate for the generation of several bioactive compounds with important physiological roles. Only a small fraction of ingested tryptophan is used in anabolic processes, whereas the large majority is metabolized along the kynurenine pathway of tryptophan degradation. This pathway generates a range of metabolites, collectively known as kynurenines, involved in inflammation, immune response, and excitatory neurotransmission. Kynurenines have been linked to several psychiatric and mental health disorders such as depression and schizophrenia. In addition, due to the close relationship between kynurenine metabolism and inflammatory responses, kynurenines are emerging as recognized players in a variety of diseases such as diabetes and cancer. Because the levels of enzymes of the kynurenine pathway in peripheral tissues tend to be much higher than in the brain, their contribution to the kynurenine pathway can have both local and systemic consequences. Due to their characteristics, kynurenine and its metabolites have the right profile to fill the role of mediators of interorgan communication.

ADVANCES

Understanding how the tryptophan-kynurenine pathway is regulated in different tissues, and the diverse biological activities of its metabolites, has become of interest to many areas of science. The bioavailability of tryptophan can be affected by factors that range from gut microbiome composition to systemic inflammatory signals. Gut-resident bacteria can directly absorb tryptophan and thus limit its availability to the host organism. The resulting metabolites can have local effects on both microbiome and host cells and even mediate interspecies communication. In addition, the biochemical fate of absorbed tryptophan will be affected by cross-talk with other nutrients and even by individual fitness, because skeletal muscle has recently been shown to contribute to kynurenine metabolism. With exercise training, skeletal muscle increases the expression of kynurenine aminotransferase enzymes and shifts peripheral kynurenine metabolism toward the production of kynurenic acid. As a consequence, alleviating the accumulation of kynurenine in the central nervous system can positively affect mental health, such as reducing stress-induced depressive symptoms.

The kynurenine pathway is highly regulated in the immune system, where it promotes immunosuppression in response to inflammation or infection. Kynurenine reduces the activity of natural killer cells, dendritic cells, or proliferating T cells, whereas kynurenic acid promotes monocyte extravasation and controls cytokine release. Perturbations in the kynurenine pathway have been linked to several diseases. High kynurenine levels can increase the proliferation and migratory capacity of cancer cells and help tumors escape immune surveillance. Kynurenine metabolites have been proposed as markers of type 2 diabetes and may interfere at some level with either insulin secretion or its action on target cells. Kynurenines can signal through different tissue-specific extra- and intracellular receptors in a network of events that integrates nutritional and environmental cues with individual health and fitness.

OUTLOOK

The modulation of tryptophan-kynurenine metabolism using lifestyle and pharmacological interventions could help prevent and treat several diseases with underlying inflammatory mechanisms, including metabolic, oncologic, and mental health disorders. In this context, and considering the substantial effect that the gut microbiome can have on preabsorptive tryptophan metabolism, it is tempting to envision the use of probiotic-based therapies. The discovery that aerobic exercise training can reduce kynurenine levels in circulation and in the central nervous system could have important implications for the development of future generations of antidepressant medications. This again stresses the many advantages of remaining physically active throughout life. Understanding the multiple levels of control of the kynurenine pathway could help predict susceptibility to disease linked to environmental and dietary signals.

The kynurenine pathway generates tryptophan metabolites with diverse biological activities throughout the body.

Although mainly studied in relation to the brain and mental health, the action of kynurenine metabolites on peripheral tissues might be even more profound. They serve as important mediators of interorgan and interkingdom cross-talk, connecting seemingly diverse processes such as the effects of exercise training and pathologies such as inflammatory diseases, cancer, and depression.

Abstract

Kynurenine metabolites are generated by tryptophan catabolism and regulate biological processes that include host-microbiome signaling, immune cell response, and neuronal excitability. Enzymes of the kynurenine pathway are expressed in different tissues and cell types throughout the body and are regulated by cues, including nutritional and inflammatory signals. As a consequence of this systemic metabolic integration, peripheral inflammation can contribute to accumulation of kynurenine in the brain, which has been associated with depression and schizophrenia. Conversely, kynurenine accumulation can be suppressed by activating kynurenine clearance in exercised skeletal muscle. The effect of exercise training on depression through modulation of the kynurenine pathway highlights an important mechanism of interorgan cross-talk mediated by these metabolites. Here, we discuss peripheral mechanisms of tryptophan-kynurenine metabolism and their effects on inflammatory, metabolic, oncologic, and psychiatric disorders.

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