Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health
TL;DR: 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.
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.
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TL;DR: Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.
Abstract: The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within ...
1,775 citations
TL;DR: This review gathers the most recent advances concerning the central role of Trp metabolism in microbiota-host crosstalk in health and disease and aims to facilitate a better understanding of the pathogenesis of human diseases and open therapeutic opportunities.
1,172 citations
TL;DR: This Review aims to define the key classes of microbial-derived metabolites that are altered in IBD, describe the pathophysiological basis of these associations and identify future targets for precision therapeutic modulation.
Abstract: A key role of the gut microbiota in the establishment and maintenance of health, as well as in the pathogenesis of disease, has been identified over the past two decades. One of the primary modes by which the gut microbiota interacts with the host is by means of metabolites, which are small molecules that are produced as intermediate or end products of microbial metabolism. These metabolites can derive from bacterial metabolism of dietary substrates, modification of host molecules, such as bile acids, or directly from bacteria. Signals from microbial metabolites influence immune maturation, immune homeostasis, host energy metabolism and maintenance of mucosal integrity. Alterations in the composition and function of the microbiota have been described in many studies on IBD. Alterations have also been described in the metabolite profiles of patients with IBD. Furthermore, specific classes of metabolites, notably bile acids, short-chain fatty acids and tryptophan metabolites, have been implicated in the pathogenesis of IBD. This Review aims to define the key classes of microbial-derived metabolites that are altered in IBD, describe the pathophysiological basis of these associations and identify future targets for precision therapeutic modulation. Alterations in the gut microbiota and metabolite profiles of patients with IBD have been described. In this Review, Lavelle and Sokol discuss these alterations and their pathophysiological basis, and identify future targets for precision therapeutic modulation.
700 citations
TL;DR: An overview of the physiological and pathophysiological roles of tryptophan metabolism is provided, focusing on the clinical potential and challenges associated with targeting this pathway.
Abstract: L-Tryptophan (Trp) metabolism through the kynurenine pathway (KP) is involved in the regulation of immunity, neuronal function and intestinal homeostasis. Imbalances in Trp metabolism in disorders ranging from cancer to neurodegenerative disease have stimulated interest in therapeutically targeting the KP, particularly the main rate-limiting enzymes indoleamine-2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan-2,3-dioxygenase (TDO) as well as kynurenine monooxygenase (KMO). However, although small-molecule IDO1 inhibitors showed promise in early-stage cancer immunotherapy clinical trials, a phase III trial was negative. This Review summarizes the physiological and pathophysiological roles of Trp metabolism, highlighting the vast opportunities and challenges for drug development in multiple diseases.
664 citations
TL;DR: Current understanding of the immunomodulatory mechanisms of MSCs and issues related to their therapeutic application are discussed, which suggest the plasticity of immunoregulation by M SCs is controlled by the intensity and complexity of inflammatory stimuli.
Abstract: Mesenchymal stem cells (MSCs; also referred to as mesenchymal stromal cells) have attracted much attention for their ability to regulate inflammatory processes. Their therapeutic potential is currently being investigated in various degenerative and inflammatory disorders such as Crohn’s disease, graft-versus-host disease, diabetic nephropathy and organ fibrosis. The mechanisms by which MSCs exert their therapeutic effects are multifaceted, but in general, these cells are thought to enable damaged tissues to form a balanced inflammatory and regenerative microenvironment in the presence of vigorous inflammation. Studies over the past few years have demonstrated that when exposed to an inflammatory environment, MSCs can orchestrate local and systemic innate and adaptive immune responses through the release of various mediators, including immunosuppressive molecules, growth factors, exosomes, chemokines, complement components and various metabolites. Interestingly, even nonviable MSCs can exert beneficial effects, with apoptotic MSCs showing immunosuppressive functions in vivo. Because the immunomodulatory capabilities of MSCs are not constitutive but rather are licensed by inflammatory cytokines, the net outcomes of MSC activation might vary depending on the levels and the types of inflammation within the residing tissues. Here, we review current understanding of the immunomodulatory mechanisms of MSCs and the issues related to their therapeutic applications.
628 citations
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TL;DR: Using metabolic function analyses of identified genes, the human genome is compared with the average content of previously sequenced microbial genomes and humans are superorganisms whose metabolism represents an amalgamation of microbial and human attributes.
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4,111 citations
"Kynurenines: Tryptophan’s metabolit..." refers background in this paper
...The gut microbiota numbers are estimated to outnumber cells in our body by a factor of 10 and tend to increase distally along the intestine (31)....
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TL;DR: A metabolic pathway whereby Trp metabolites from the microbiota balance mucosal reactivity in mice is described, whereby highly adaptive lactobacilli are expanded and produce an aryl hydrocarbon receptor (AhR) ligand-indole-3-aldehyde-that contributes to AhR-dependent Il22 transcription.
1,540 citations
TL;DR: Evidence is provided for a previously unidentified pathophysiological function of the AHR that is constitutively generated by human tumours via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology.
Abstract: Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.
1,462 citations
"Kynurenines: Tryptophan’s metabolit..." refers background in this paper
...The expression of IDO and KATs allow Trp to be metabolized to Kyna, a GPR35 agonist (13) and a ligand for the transcription factor aryl hydrocarbon receptor (AhR) (similar activity has been shown for Kyn) (14, 15)....
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...3) (15, 71), a ligand-activated transcription factor involved inxenobiotic response to foreign substances....
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...Interestingly, the Kyn-AhR axis has been postulated to constitute one of the links between chronic inflammation and tumor progression (15)....
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