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Antioxidants
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Tryptophan Metabolism in Health and Disease
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Tryptophan Metabolism in Health and Disease

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 22845

Special Issue Editors

Prof. Dr. Johanna M. Gostner

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Guest Editor
Institute of Medical Biochemistry, Medical University of Innsbruck, 6020 Innsbruck, Austria
Interests: immunometabolism; biochemical toxicology; redox biochemistry; aromatic amino acids; neopterin
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Blanca Laffon

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Guest Editor
Grupo DICOMOSA, Centro de Investigacións Científicas Avanzadas (CICA), Departmento de Psicología, Universidade da Coruña, A Coruña, Spain
Interests: psychobiology; nanotoxicology; occupational and environmental health; biomarkers; genetic toxicology; ageing; cognitive and physical frailty
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Immune-mediated breakdown of the essential amino acid tryptophan along the kynurenine pathway is a key concept in immunity to defend against invading pathogens and malignant cell growth and also, in the long term, to establish tolerance and immunosuppression. Thereby, both the deprivation of the amino acid per se and the formation of bioactive metabolites play an essential role. Increased oxidative stress, as it is present in disorders associated with chronic inflammation, is a trigger of the tryptophan kynurenine axis and shifts tryptophan catabolism away from other routes, such as serotonin formation or protein synthesis. In such situations, plasma antioxidant levels usually decrease. Moreover, tryptophan breakdown metabolite formation can be applied as a surrogate marker of vitamin B-6 status. Changes in the cellular redox milieu are critical for the induction of the catabolic enzyme indoleamine 2,3-dioxygenase (IDO) in immune cells. A number of antioxidants have been shown to attenuate IDO activity in vitro. A reductive milieu particularly suppresses those cytokines that promote cellular immune activation and, thus, IDO activity. Nutritional interventions and vitamin supplementation studies have suggested that the underlying regulatory networks are complex and that microbial-derived indole derivatives that interfere and compete with endogenous kynurenine metabolites have to be considered as well.

Authors are invited to contribute original articles and/or reviews on the cross-talk between tryptophan metabolism and redox sensitive pathways or redox active molecules in vitro or in vivo and also on the involvement of tryptophan metabolism or this cross-talk in disease development or progression. 

Dr. Johanna M. Gostner
Prof. Blanca Laffon
Guest Editors

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Keywords

  • Tryptophan
  • Kynurenine
  • Indoleamine 2,3-dioxygenase
  • Tryptophan 2,3-dioxygenase
  • Tryptophan metabolites
  • Aryl hydrocarbon receptor
  • Transport
  • Immune system
  • Metabolism
  • Psychoneuroimmunology
  • Nutrition
  • Aging
  • Microbiome

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Published Papers (6 papers)

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Research

16 pages, 3678 KiB  
Article
Dietary Supplementation with Cysteine during Pregnancy Rescues Maternal Chronic Kidney Disease-Induced Hypertension in Male Rat Offspring: The Impact of Hydrogen Sulfide and Microbiota-Derived Tryptophan Metabolites
by Chien-Ning Hsu, Chih-Yao Hou, Guo-Ping Chang-Chien, Sufan Lin and You-Lin Tain
Antioxidants 2022, 11(3), 483; https://doi.org/10.3390/antiox11030483 - 28 Feb 2022
Cited by 19 | Viewed by 3503
Abstract
Maternal chronic kidney disease (CKD) is linked to offspring hypertension. The gut microbiome and its tryptophan metabolites, nitric oxide (NO), and renin–angiotensin system (RAS) are closely related to the development of hypertension. Hydrogen sulfide (H2S) has shown an anti-hypertensive effect. Our [...] Read more.
Maternal chronic kidney disease (CKD) is linked to offspring hypertension. The gut microbiome and its tryptophan metabolites, nitric oxide (NO), and renin–angiotensin system (RAS) are closely related to the development of hypertension. Hydrogen sulfide (H2S) has shown an anti-hypertensive effect. Our objective was to test whether l- or d-cysteine supplementation in pregnancy can prevent hypertension programmed by maternal CKD in adult offspring and to explore the protective mechanisms. CKD was induced in pregnant Sprague Dawley rats by a 0.5% adenine diet for 3 weeks. l- or d-cysteine was supplemented at 8 mmol/kg body weight/day during pregnancy. Male offspring were sacrificed at the age of 12 weeks (n = 8 per group). Maternal CKD-induced hypertension was similarly prevented by l- or d-cysteine supplementation. The protective effects of l- and d-cysteine are related to reducing oxidative stress, rebalancing the RAS, and reshaping the gut microbiome. l-cysteine therapy protected adult offspring against hypertension and was associated with enhanced H2S production, restoration of NO bioavailability, enhancement of beneficial genera Oscillibacter and Butyricicoccus, depletion of indole-producing genera Alistipes and Akkermansia, and the reduction of several indole metabolites. d-cysteine treatment increased kynurenic acid, 3-hydroxykynurenine, and xanthurenic acid in the kynurenine pathway, decreased 5-hydroxytryptophan and serotonin in the serotonin pathway, and enriched genera Bacteroides and Odoribacter abundance. In summary, these results suggest that l- and d-cysteine protect against maternal CKD-induced offspring hypertension, likely by enhancing H2S production, modulating gut microbiota and its derived metabolites, and the restoration of NO and RAS. Full article
(This article belongs to the Special Issue Tryptophan Metabolism in Health and Disease)
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19 pages, 2736 KiB  
Article
Cellular Localization of Kynurenine 3-Monooxygenase in the Brain: Challenging the Dogma
by Korrapati V. Sathyasaikumar, Verónica Pérez de la Cruz, Benjamín Pineda, Gustavo Ignacio Vázquez Cervantes, Daniela Ramírez Ortega, David W. Donley, Paul L. Severson, Brian L. West, Flaviano Giorgini, Jonathan H. Fox and Robert Schwarcz
Antioxidants 2022, 11(2), 315; https://doi.org/10.3390/antiox11020315 - 4 Feb 2022
Cited by 13 | Viewed by 3447
Abstract
Kynurenine 3-monooxygenase (KMO), a key player in the kynurenine pathway (KP) of tryptophan degradation, regulates the synthesis of the neuroactive metabolites 3-hydroxykynurenine (3-HK) and kynurenic acid (KYNA). KMO activity has been implicated in several major brain diseases including Huntington’s disease (HD) and schizophrenia. [...] Read more.
Kynurenine 3-monooxygenase (KMO), a key player in the kynurenine pathway (KP) of tryptophan degradation, regulates the synthesis of the neuroactive metabolites 3-hydroxykynurenine (3-HK) and kynurenic acid (KYNA). KMO activity has been implicated in several major brain diseases including Huntington’s disease (HD) and schizophrenia. In the brain, KMO is widely believed to be predominantly localized in microglial cells, but verification in vivo has not been provided so far. Here, we examined KP metabolism in the brain after depleting microglial cells pharmacologically with the colony stimulating factor 1 receptor inhibitor PLX5622. Young adult mice were fed PLX5622 for 21 days and were euthanized either on the next day or after receiving normal chow for an additional 21 days. Expression of microglial marker genes was dramatically reduced on day 22 but had fully recovered by day 43. In both groups, PLX5622 treatment failed to affect Kmo expression, KMO activity or tissue levels of 3-HK and KYNA in the brain. In a parallel experiment, PLX5622 treatment also did not reduce KMO activity, 3-HK and KYNA in the brain of R6/2 mice (a model of HD with activated microglia). Finally, using freshly isolated mouse cells ex vivo, we found KMO only in microglia and neurons but not in astrocytes. Taken together, these data unexpectedly revealed that neurons contain a large proportion of functional KMO in the adult mouse brain under both physiological and pathological conditions. Full article
(This article belongs to the Special Issue Tryptophan Metabolism in Health and Disease)
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21 pages, 1606 KiB  
Article
Exploring Early Detection of Frailty Syndrome in Older Adults: Evaluation of Oxi-Immune Markers, Clinical Parameters and Modifiable Risk Factors
by Armanda Teixeira-Gomes, Blanca Laffon, Vanessa Valdiglesias, Johanna M. Gostner, Thomas Felder, Carla Costa, Joana Madureira, Dietmar Fuchs, João Paulo Teixeira and Solange Costa
Antioxidants 2021, 10(12), 1975; https://doi.org/10.3390/antiox10121975 - 10 Dec 2021
Cited by 10 | Viewed by 3576
Abstract
Ageing is accompanied with a decline in several physiological systems. Frailty is an age-related syndrome correlated to the loss of homeostasis and increased vulnerability to stressors, which is associated with increase in the risk of disability, comorbidity, hospitalisation, and death in older adults. [...] Read more.
Ageing is accompanied with a decline in several physiological systems. Frailty is an age-related syndrome correlated to the loss of homeostasis and increased vulnerability to stressors, which is associated with increase in the risk of disability, comorbidity, hospitalisation, and death in older adults. The aim of this study was to understand the relationship between frailty syndrome, immune activation, and oxidative stress. Serum concentrations of vitamins A and E were also evaluated, as well as inflammatory biomarkers (CRP and IL-6) and oxidative DNA levels. A group of Portuguese older adults (≥65 years old) was engaged in this study and classified according to Fried’s frailty phenotype. Significant increases in the inflammatory mediators (CRP and IL-6), neopterin levels, kynurenine to tryptophan ratio (Kyn/Trp), and phenylalanine to tyrosine ratio (Phe/Tyr), and significant decreases in Trp and Tyr concentrations were observed in the presence of frailty. IL-6, neopterin, and Kyn/Trp showed potential as predictable biomarkers of frailty syndrome. Several clinical parameters such as nutrition, dependency scales, and polypharmacy were related to frailty and, consequently, may influence the associations observed. Results obtained show a progressive immune activation and production of pro-inflammatory molecules in the presence of frailty, agreeing with the inflammageing model. Future research should include different dimensions of frailty, including psychological, social, biological, and environmental factors. Full article
(This article belongs to the Special Issue Tryptophan Metabolism in Health and Disease)
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11 pages, 1727 KiB  
Article
Increased Kynurenine Indicates a Fatal Course of COVID-19
by Harald Mangge, Markus Herrmann, Andreas Meinitzer, Sabine Pailer, Pero Curcic, Zdenka Sloup, Magdalena Holter and Florian Prüller
Antioxidants 2021, 10(12), 1960; https://doi.org/10.3390/antiox10121960 - 7 Dec 2021
Cited by 25 | Viewed by 4772
Abstract
(1) Background: An inefficient immune response accompanied by an overwhelming inflammatory reaction is involved in severe courses of COVID-19. Kynurenine (KYN) has important immune-modulatory functions and may contribute to a failure in controlling SARS-CoV-2. The present study aims to explore biomarkers that [...] Read more.
(1) Background: An inefficient immune response accompanied by an overwhelming inflammatory reaction is involved in severe courses of COVID-19. Kynurenine (KYN) has important immune-modulatory functions and may contribute to a failure in controlling SARS-CoV-2. The present study aims to explore biomarkers that hint at a fatal outcome of COVID-19 early on. (2) Methods: We established a cohort of 148 hospitalized COVID-19 patients for this study. Thirty-one patients died due to a severe COVID-19 course, and 117 recovered within 90 days. We built a biobank by collecting left-over material from these patients whenever blood arrived at the central laboratory of our University hospital for analysis of routine markers. The scientific laboratory analysis comprised KYN, Tryptophan (TRP), KYN/TRP ratio, ferritin, interleukin-6 (IL-6), C-reactive protein (CRP), creatinine, N-terminal pro-natriuretic peptide (NTproBNP), troponin T (TnT), fibrinogen, D-Dimer, prothrombin time (PT), activated partial thromboplastin time (aPTT), antithrombin (AT), protein C, protein S, factor XIII, lupus aPTT, angiotensin-2, vitamin D metabolites, and telomeres in all COVID-19 patients. Basic clinical characteristics and anteceding diseases including cardiovascular, oncologic, renal, hypertension, pulmonary, metabolic (diabetes, obesity) were recorded in a database together with the laboratory data. (3) Results: At the time of diagnosis of SARS-CoV-2 infection those patients who deceased within 90 days afterwards due to COVID-19, had a significantly higher age, higher KYN, KYN/TRP ratio, ferritin, creatinine, and NTproBNP values than SARS-CoV-2 patients who survived COVID-19 along the same time span. In a Kaplan-Meier analysis the variables age, KYN, ferritin, D-Dimer, TnT, NTproBNP, and creatinine showed a significant influence on survival time. Gender, however, showed no influence. In a combined Cox regression analysis KYN had the highest hazard ratio (1.188, 95% CI: 1.071–1.319) followed by age (1.041, 95% CI: 1.011–1.073). In a ROC analysis, KYN values above the cut off limit of 4.82 nmol/l (as specified by Youden index) had a sensitivity of 82% (95% CI: 66–95%) and a specificity of 72% (95% CI: 65–82%) to predict COVID-19 related death within 90 days observation time. (4) Conclusions: Kynurenine is a promising blood biomarker to predict an increased risk of mortality in SARS-CoV-2 infected people already at the time of the first positive SARS-CoV-2 verification detected in these persons. Full article
(This article belongs to the Special Issue Tryptophan Metabolism in Health and Disease)
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13 pages, 591 KiB  
Article
Tryptophan Metabolism in Bipolar Disorder in a Longitudinal Setting
by Frederike T. Fellendorf, Johanna M. Gostner, Melanie Lenger, Martina Platzer, Armin Birner, Alexander Maget, Robert Queissner, Adelina Tmava-Berisha, Cornelia A. Pater, Michaela Ratzenhofer, Jolana Wagner-Skacel, Susanne A. Bengesser, Nina Dalkner, Dietmar Fuchs and Eva Z. Reininghaus
Antioxidants 2021, 10(11), 1795; https://doi.org/10.3390/antiox10111795 - 10 Nov 2021
Cited by 14 | Viewed by 2905
Abstract
Immune-mediated inflammatory processes and oxidative stress are involved in the aetiopathogenesis of bipolar disorder (BD) and weight-associated comorbidities. Tryptophan breakdown via indoleamine 2,3-dioxygenase-1 (IDO-1) along the kynurenine axis concomitant with a pro-inflammatory state was found to be more active in BD, and associated [...] Read more.
Immune-mediated inflammatory processes and oxidative stress are involved in the aetiopathogenesis of bipolar disorder (BD) and weight-associated comorbidities. Tryptophan breakdown via indoleamine 2,3-dioxygenase-1 (IDO-1) along the kynurenine axis concomitant with a pro-inflammatory state was found to be more active in BD, and associated with overweight/obesity. This study aimed to investigate tryptophan metabolism in BD compared to controls (C), stratified by weight classes, in a longitudinal setting, dependent on the incidence of BD episodes. Peripheral tryptophan, kynurenine, and neopterin were assessed in the serum of 226 BD individuals and 142 C. Three samples in a longitudinal assessment were used for 75 BD individuals. Results showed a higher kynurenine/tryptophan in both BD compared to C and overweight compared to normal weight persons. Levels remained stable over time. In the longitudinal course, no differences were found between individuals who were constantly euthymic or not, or who had an illness episode or had none. Findings indicate that tryptophan, kynurenine, and IDO-1 activity may play a role in pathophysiology in BD but are not necessarily associated with clinical manifestations. Accelerated tryptophan breakdown along the kynurenine axis may be facilitated by being overweight. This may increase the risk of accumulation of neurotoxic metabolites, impacting BD symptomatology, cognition, and somatic comorbidities. Full article
(This article belongs to the Special Issue Tryptophan Metabolism in Health and Disease)
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15 pages, 303 KiB  
Article
The Impact of Cardiovascular Rehabilitation on Psychophysiological Stress, Personality and Tryptophan Metabolism: A Randomized Pilot Feasibility Study
by Jolana Wagner-Skacel, Sabrina Mörkl, Nina Dalkner, Frederike Fellendorf, Werner Fitz, Bianca Brix, Ruslan Neshev, Sarah Wedenig, Petra Mächler, Andreas Dorr, Rainer Picha, Maximilian E. Rudlof, Till O. Bartel, Josef M. Tatschl, Johanna M. Gostner, Susanne A. Bengesser, Eva Z. Reininghaus, Josef Jenewein and Nandu Goswami
Antioxidants 2021, 10(9), 1425; https://doi.org/10.3390/antiox10091425 - 7 Sep 2021
Cited by 5 | Viewed by 2700
Abstract
Multicomponent cardiac rehabilitation (CR) is a secondary prevention strategy for cardiac patients to tackle stress and psychosocial wellbeing. However, there is a lack of data on its psychoneuroimmunological effects and of biomarkers to determine individual risk and to develop treatment strategies. We conducted [...] Read more.
Multicomponent cardiac rehabilitation (CR) is a secondary prevention strategy for cardiac patients to tackle stress and psychosocial wellbeing. However, there is a lack of data on its psychoneuroimmunological effects and of biomarkers to determine individual risk and to develop treatment strategies. We conducted a pilot randomized controlled trial (RCT) to investigate the feasibility of deriving psychophysiological stress markers in patients with cardiovascular diseases. Thirty individuals with cardiovascular disease (mean age 58.8 years; 23.3% female) were enrolled and randomized into three treatment groups: standard rehabilitation, yoga, or transcendental meditation (TM). Depression, anxiety, sleep, stress perception, personality functioning, hair cortisol, serum tryptophan, kynurenine and neopterin concentrations were estimated at baseline and after a four-week intervention. Hair cortisol levels decreased significantly after rehabilitation in all groups (F = 15.98, p < 0.001). In addition, personality functioning improved in all patients over time. Participants with impairments in personality functioning showed a positive correlation with baseline neopterin that did not remain significant after Bonferroni correction. Concentrations of serum tryptophan and its metabolite kynurenine did not change significantly. This pilot RCT provides preliminary evidence of multicomponent CR leading to stabilization of hair cortisol levels and improved psychophysiological wellbeing and personality functioning. Impairments in personality functioning were correlated with neopterin levels, which may impact the symptomatology and outcome. Full article
(This article belongs to the Special Issue Tryptophan Metabolism in Health and Disease)
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