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      Tryptophan metabolism, its relation to inflammation and stress markers and association with psychological and cognitive functioning: Tasmanian Chronic Kidney Disease pilot study

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          Abstract

          Background

          Adults with chronic kidney disease (CKD) exhibit alterations in tryptophan metabolism, mainly via the kynurenine pathway, due to higher enzymatic activity induced mainly by inflammation. Indoles produced by gut-microflora are another group of tryptophan metabolites related to inflammation and conditions accompanying CKD. Disruptions in tryptophan metabolism have been associated with various neurological and psychological disorders. A high proportion of CKD patients self-report symptoms of depression and/or anxiety and decline in cognitive functioning. This pilot study examines tryptophan metabolism in CKD and explores associations with psychological and cognitive functioning.

          Methods

          Twenty-seven adults with CKD were part of 49 patients recruited to participate in a prospective pilot study, initially with an eGFR of 15–29 mL/min/1.73 m 2. Only participants with viable blood samples and complete psychological/cognitive data at a 2-year follow-up were included in the reported cross-sectional study. Serum samples were analysed by Liquid Chromatography coupled to Mass Spectrometry, for tryptophan, ten of its metabolites, the inflammation marker neopterin and the hypothalamic–pituitary–adrenal (HPA) axis marker cortisol.

          Results

          The tryptophan breakdown index (kynurenine / tryptophan) correlated with neopterin (Pearson R = 0.51 P = 0.006) but not with cortisol. Neopterin levels also correlated with indoxyl sulfate ( R = 0.68, P < 0.0001) and 5 metabolites of tryptophan ( R range 0.5–0.7, all P ≤ 0.01), which were all negatively related to eGFR ( P < 0.05). Higher levels of kynurenic acid were associated with lower cognitive functioning (Spearman R = −0.39, P < 0.05), while indole-3 acetic acid (IAA) was correlated with anxiety and depression ( R = 0.52 and P = 0.005, R = 0.39 and P < 0.05, respectively).

          Conclusions

          The results of this preliminary study suggest the involvement of inflammation in tryptophan breakdown via the kynurenine pathway, yet without sparing tryptophan metabolism through the 5-HT (serotonin) pathway in CKD patients. The multiple moderate associations between indole-3 acetic acid and psychological measures were a novel finding. The presented pilot data necessitate further exploration of these associations within a large prospective cohort to assess the broader significance of these findings.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12882-016-0387-3) contains supplementary material, which is available to authorized users.

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          Most cited references54

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          Inflammation-associated depression: from serotonin to kynurenine.

          In the field of depression, inflammation-associated depression stands up as an exception since its causal factors are obvious and it is easy to mimic in an animal model. In addition, quasi-experimental studies can be carried out in patients who are treated chronically with recombinant cytokines for a medical condition since these patients can be studied longitudinally before, during and after stimulation of the immune system. These clinical studies have revealed that depression is a late phenomenon that develops over a background of early appearing sickness. Incorporation of this feature in animal models of inflammation-associated depression has allowed the demonstration that alterations of brain serotoninergic neurotransmission do not play a major role in the pathogenesis. This is in contrast to the activation of the tryptophan degrading enzyme indoleamine 2,3-dioxygenase that generates potentially neurotoxic kynurenine metabolites such as 3-hydroxy kynurenine and quinolinic acid. Although the relative importance of peripherally versus centrally produced kynurenine and the cellular source of production of this compound remain to be determined, these findings provide new targets for the treatment of inflammation-associated depression that could be extended to other psychiatric conditions mediated by activation of neuroimmune mechanisms. Copyright © 2010 Elsevier Ltd. All rights reserved.
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            When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders.

            Previous theories have emphasized the role of excessive glucocorticoid activity in the pathology of chronic stress. Nevertheless, insufficient glucocorticoid signaling (resulting from decreased hormone bioavailability or reduced hormone sensitivity) may have equally devastating effects on bodily function. Such effects may be related in part to the role of glucocorticoids in restraining activation of the immune system and other components of the stress response, including the sympathetic nervous system (SNS) and corticotropin-releasing hormone (CRH). The literature on neuroendocrine function and glucocorticoid-relevant pathologies in stress-related neuropsychiatric disorders, including posttraumatic stress disorder and major depression, was reviewed. Although not occurring together, both hypocortisolism and reduced responsiveness to glucocorticoids (as determined by dexamethasone challenge tests) were reliably found. Stress-related neuropsychiatric disorders were also associated with immune system activation/inflammation, high SNS tone, and CRH hypersecretion, which are all consistent with insufficient glucocorticoid-mediated regulation of stress hyperresponsiveness. Finally, antidepressants, a mainstay in the treatment of stress-related disorders, were regularly associated with evidence of enhanced glucocorticoid signaling. Neuroendocrine data provide evidence of insufficient glucocorticoid signaling in stress-related neuropsychiatric disorders. Impaired feedback regulation of relevant stress responses, especially immune activation/inflammation, may, in turn, contribute to stress-related pathology, including alterations in behavior, insulin sensitivity, bone metabolism, and acquired immune responses. From an evolutionary perspective, reduced glucocorticoid signaling, whether achieved at the level of the hormone or its receptor, may foster immune readiness and increase arousal. Emphasis on insufficient glucocorticoid signaling in stress-related pathology encourages development of therapeutic strategies to enhance glucocorticoid signaling pathways.
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              The new '5-HT' hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression.

              This paper reviews the body of evidence that not only tryptophan and consequent 5-HT depletion, but also induction of indoleamine 2,3-dioxygenase (IDO) and the detrimental effects of tryptophan catabolites (TRYCATs) play a role in the pathophysiology of depression. IDO is induced by interferon (IFN)γ, interleukin-6 and tumor necrosis factor-α, lipopolysaccharides and oxidative stress, factors that play a role in the pathophysiology of depression. TRYCATs, like kynurenine and quinolinic acid, are depressogenic and anxiogenic; activate oxidative pathways; cause mitochondrial dysfunctions; and have neuroexcitatory and neurotoxic effects that may lead to neurodegeneration. The TRYCAT pathway is also activated following induction of tryptophan 2,3-dioxygenase (TDO) by glucocorticoids, which are elevated in depression. There is evidence that activation of IDO reduces plasma tryptophan and increases TRYCAT synthesis in depressive states and that TDO activation may play a role as well. The development of depressive symptoms during IFNα-based immunotherapy is strongly associated with IDO activation, increased production of detrimental TRYCATs and lowered levels of tryptophan. Women show greater IDO activation and TRYCAT production following immune challenge than men. In the early puerperium, IDO activation and TRYCAT production are associated with the development of affective symptoms. Clinical depression is accompanied by lowered levels of neuroprotective TRYCATs or increased levels or neurotoxic TRYCATs, and lowered plasma tryptophan, which is associated with indices of immune activation and glucocorticoid hypersecretion. Lowered tryptophan and increased TRYCATs induce T cell unresponsiveness and therefore may exert a negative feedback on the primary inflammatory response in depression. It is concluded that activation of the TRYCAT pathway by IDO and TDO may be associated with the development of depressive symptoms through tryptophan depletion and the detrimental effects of TRYCATs. Therefore, the TRYCAT pathway should be a new drug target in depression. Direct inhibitors of IDO are less likely to be useful drugs than agents, such as kynurenine hydroxylase inhibitors; drugs which block the primary immune response; compounds that increase the protective effects of kynurenic acid; and specific antioxidants that target IDO activation, the immune and oxidative pathways, and 5-HT as well. Copyright © 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Naama.Karu@utas.edu.au , karu@ualberta.ca
                Charlotte.McKercher@utas.edu.au
                D.Nichols@utas.edu.au
                Noel.Davies@utas.edu.au
                Robert.Shellie@utas.edu.au , rshellie@trajanscimed.com
                Emily.Hilder@utas.edu.au , emily.hilder@unisa.edu.au
                Matthew.Jose@utas.edu.au
                Journal
                BMC Nephrol
                BMC Nephrol
                BMC Nephrology
                BioMed Central (London )
                1471-2369
                10 November 2016
                10 November 2016
                2016
                : 17
                : 171
                Affiliations
                [1 ]ACROSS, School of Physical Sciences, University of Tasmania, Hobart, Tasmania Australia
                [2 ]Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania Australia
                [3 ]Central Science Laboratory, University of Tasmania, Hobart, Tasmania Australia
                [4 ]School of Medicine, University of Tasmania, Hobart, Tasmania Australia
                [5 ]Renal unit, Royal Hobart Hospital, Hobart, Tasmania Australia
                [6 ]Present address: The Metabolomics Innovation Centre (TMIC), Department of Biological Sciences, University of Alberta, Edmonton, Alberta T6G 2E9 Canada
                [7 ]Present address: Trajan Scientific and Medical, 7 Argent Place, Ringwood, Victoria 3134 Australia
                [8 ]Present address: Future Industries Institute, University of South Australia, Mawson Lakes Campus, GPO Box 2471, Adelaide, South Australia 5001 Australia
                Article
                387
                10.1186/s12882-016-0387-3
                5103367
                27832762
                47ab81a5-b78e-462f-bf3d-43f896df59da
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 8 September 2015
                : 3 November 2016
                Funding
                Funded by: Royal Hobart Hospital Research Foundation
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2016

                Nephrology
                chronic kidney disease,tryptophan,kynurenine,neopterin,cortisol,inflammation,depression,anxiety,cognition

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