Autism spectrum disorder (ASD) has been associated with disruptions in tryptophan (TRP) metabolism, affecting the production of key neuroactive metabolites. Investigating these metabolic pathways could yield valuable biomarkers for ASD severity and progression. We included 44 children with ASD and 44 healthy children, members of the same family. The average age in the ASD group was 10.7 years, while the average age in the control group was 9.4 years. Urinary tryptophan metabolites were quantified via liquid chromatography-mass spectrometry operating multiple reaction monitoring (MRM). Urinary creatinine was analyzed on an Advia 2400 analyzer using the Jaffe reaction. Statistical comparisons were made between ASD subgroups based on CARS scores. Our findings indicate that children with ASD have higher TRP concentrations (19.94 vs. 16.91; p = 0.04) than their siblings. Kynurenine (KYN) was found at higher levels in children with ASD compared to children in the control group (82.34 vs. 71.20; p = 0.86), although this difference was not statistically significant. The ASD group showed trends of higher KYN/TRP ratios and altered TRP/ indole-3-acetic acid (IAA) and TRP/5-hydroxyindoleacetic acid (5-HIAA) ratios, correlating with symptom severity. Although the numbers of the two groups were different, our findings suggest that mild and severe illnesses involve separate mechanisms. However, further comprehensive studies are needed to validate these ratios as diagnostic tools for ASD.
- Klíčová slova
- CARS, autism spectrum disorder, kynurenine, tryptophan,
- MeSH
- biologické markery * moč MeSH
- dítě MeSH
- kynurenin * moč metabolismus MeSH
- kyselina hydroxyindoloctová moč MeSH
- kyseliny indoloctové moč metabolismus MeSH
- lidé MeSH
- metabolom MeSH
- metabolomika * metody MeSH
- mladiství MeSH
- poruchy autistického spektra * moč metabolismus MeSH
- studie případů a kontrol MeSH
- tryptofan * moč metabolismus MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- biologické markery * MeSH
- indoleacetic acid MeSH Prohlížeč
- kynurenin * MeSH
- kyselina hydroxyindoloctová MeSH
- kyseliny indoloctové MeSH
- tryptofan * MeSH
Kidney dysfunction often leads to neurological impairment, yet the complex kidney-brain relationship remains elusive. We employed spatial and bulk metabolomics to investigate a mouse model of rapid kidney failure induced by mouse double minute 2 (Mdm2) conditional deletion in the kidney tubules to interrogate kidney and brain metabolism. Pathway enrichment analysis of a focused plasma metabolomics panel pinpointed tryptophan metabolism as the most altered pathway with kidney failure. Spatial metabolomics showed toxic tryptophan metabolites in the kidneys and brains, revealing a connection between advanced kidney disease and accelerated kynurenine degradation. In particular, the excitotoxic metabolite quinolinic acid was localized in ependymal cells in the setting of kidney failure. These findings were associated with brain inflammation and cell death. Separate mouse models of ischemia-induced acute kidney injury and adenine-induced chronic kidney disease also exhibited systemic inflammation and accumulating toxic tryptophan metabolites. Patients with advanced chronic kidney disease (stage 3b-4 and stage 5) similarly demonstrated elevated plasma kynurenine metabolites, and quinolinic acid was uniquely correlated with fatigue and reduced quality of life. Overall, our study identifies the kynurenine pathway as a bridge between kidney decline, systemic inflammation, and brain toxicity, offering potential avenues for diagnosis and treatment of neurological issues in kidney disease.
- Klíčová slova
- Amino acid metabolism, Chronic kidney disease, Nephrology, Neurological disorders, Neuroscience,
- MeSH
- akutní poškození ledvin metabolismus chemicky indukované patologie MeSH
- chronická renální insuficience metabolismus patologie komplikace MeSH
- kynurenin * metabolismus MeSH
- kyselina chinolinová * toxicita metabolismus krev MeSH
- ledviny metabolismus patologie MeSH
- lidé MeSH
- metabolomika MeSH
- modely nemocí na zvířatech MeSH
- mozek * metabolismus patologie MeSH
- myši MeSH
- tryptofan * metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- kynurenin * MeSH
- kyselina chinolinová * MeSH
- tryptofan * MeSH
The increasing use of cannabis during pregnancy raises concerns about its impact on fetal development. While cannabidiol (CBD) shows therapeutic promise, its effects during pregnancy remain uncertain. We investigated CBD's influence on tryptophan (TRP) metabolism in the human placenta. TRP is an essential amino acid that is metabolized via the serotonin and kynurenine (KYN) pathways, which are critical for fetal neurodevelopment. We used human term villous placental explants, an advanced ex vivo model, to study CBD's impact on key TRP metabolic enzymes. In addition, vesicles isolated from the microvillous membrane (MVM) of the human placenta were used to assess CBD's effect on placental serotonin uptake. Explants were exposed to CBD at therapeutic (0.1, 1, 2.5 μg/ml) and non-therapeutic (20 and 40 μg/ml) concentrations to determine its effects on the gene and protein expression of key enzymes in TRP metabolism and metabolite release. CBD upregulated TRP hydroxylase (TPH) and downregulated monoamine oxidase (MAO-A), resulting in reduced levels of 5-hydroxyindoleacetic acid (HIAA). It also downregulated serotonin transporter expression and inhibited serotonin transport across the MVM by up to 60% while simultaneously enhancing TRP metabolism via the kynurenine pathway by upregulating indoleamine-pyrrole 2,3-dioxygenase (IDO-1). Among kynurenine pathway enzymes, kynurenine 3 monooxygenase (KMO) was upregulated while kynurenine aminotransferase 1 (KAT-1) was downregulated; the former is associated with neurotoxic metabolite production, while the latter is linked to reduced neuroprotective metabolite levels. Overall, these results indicate that CBD modulates TRP catabolism in the human placenta, potentially disrupting the tightly regulated homeostasis of the serotonin and KYN pathways.
- Klíčová slova
- Cannabidiol, Kynurenine, Pregnancy, Serotonin, Tryptophan,
- MeSH
- kanabidiol * farmakologie MeSH
- kynurenin metabolismus MeSH
- lidé MeSH
- placenta * metabolismus účinky léků MeSH
- serotonin * metabolismus MeSH
- těhotenství MeSH
- tryptofan * metabolismus MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- kanabidiol * MeSH
- kynurenin MeSH
- serotonin * MeSH
- tryptofan * MeSH
OBJECTIVES: Concentrations of neopterin, kynurenine and kynurenine/tryptophan ratios predict prognosis and the need for oxygen therapy in patients hospitalized for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The aims of the present study were to evaluate the changes of these biomarkers early in the course of infection, the association with the prior coronavirus disease (COVID-19) vaccination and therapeutic administration of Anti-SARS-CoV-2 monoclonal antibodies, investigation of other potential biomarkers including neuropilin, 8-hydroxy-2-deoxyguanosine and 8-hydroxyguanosine in patients hospitalized with SARS-CoV-2 infection and an assessment of these biomarkers and vitamins A, E and D in patients with post-COVID syndrome. METHODS: Urine and blood samples were obtained on the 1st to the 4th day and 4th to 7th day from 108 patients hospitalized with COVID-19. Chromatography tandem mass spectrometry methods were used to analyse neopterin, kynurenine, tryptophan, liposoluble vitamins, and DNA damage biomarkers. RESULTS: A statistically significant decrease of neopterin, kynurenine and kynurenine/tryptophan ratios was observed on after 4th to 7th day of hospitalization, and concentrations of these biomarkers were increased in patients with poor prognosis and subsequent post-COVID syndrome. The concentrations of remaining biomarker and vitamins were not associated with outcomes, although markedly decreased concentrations of vitamin A, E and D were noted. CONCLUSIONS: The concentrations of neopterin, kynurenine and kynurenine/tryptophan ratios decrease during the course of infection SARS-CoV-2 and are associated with the post-COVID syndrome. No other prognostic biomarkers were identified.
- Klíčová slova
- COVID-19, kynurenine, neopterin, post-COVID, tryptophan, vitamins,
- MeSH
- biologické markery * krev MeSH
- COVID-19 * krev MeSH
- dospělí MeSH
- hospitalizace MeSH
- kynurenin * krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- neopterin * krev moč MeSH
- postakutní syndrom COVID-19 MeSH
- SARS-CoV-2 * izolace a purifikace MeSH
- senioři MeSH
- tryptofan * krev MeSH
- vitamin A krev MeSH
- vitamin D krev MeSH
- vitamin E krev MeSH
- vitaminy krev MeSH
- zánět krev MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- biologické markery * MeSH
- kynurenin * MeSH
- neopterin * MeSH
- tryptofan * MeSH
- vitamin A MeSH
- vitamin D MeSH
- vitamin E MeSH
- vitaminy MeSH
Maternal immune activation during pregnancy is a risk factor for offspring neuropsychiatric disorders. Among the mechanistic pathways by which maternal inflammation can affect fetal brain development and programming, those involving tryptophan (TRP) metabolism have drawn attention because various TRP metabolites have neuroactive properties. This study evaluates the effect of bacterial (lipopolysaccharides/LPS) and viral (polyinosinic:polycytidylic acid/poly I:C) placental infection on TRP metabolism using an ex vivo model. Human placenta explants were exposed to LPS or poly I:C, and the release of TRP metabolites was analyzed together with the expression of related genes and proteins and the functional activity of key enzymes in TRP metabolism. The rate-limiting enzyme in the serotonin pathway, tryptophan hydroxylase, showed reduced expression and functional activity in explants exposed to LPS or poly I:C. Conversely, the rate-limiting enzyme in the kynurenine pathway, indoleamine dioxygenase, exhibited increased activity, gene, and protein expression, suggesting that placental infection mainly promotes TRP metabolism via the kynurenine (KYN) pathway. Furthermore, we observed that treatment with LPS or poly I:C increased activity in the kynurenine monooxygenase branch of the KYN pathway. We conclude that placental infection impairs TRP homeostasis, resulting in decreased production of serotonin and an imbalance in the ratio between quinolinic acid and kynurenic acid. This disrupted homeostasis may eventually expose the fetus to suboptimal/toxic levels of neuroactive molecules and impair fetal brain development.
- Klíčová slova
- fetal brain development, intrauterine infections, placenta, programming, tryptophan metabolism,
- MeSH
- indolamin-2,3,-dioxygenasa metabolismus MeSH
- kynurenin * metabolismus MeSH
- lidé MeSH
- lipopolysacharidy toxicita MeSH
- placenta * metabolismus MeSH
- poly I metabolismus MeSH
- serotonin metabolismus MeSH
- těhotenství MeSH
- tryptofan metabolismus MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- indolamin-2,3,-dioxygenasa MeSH
- kynurenin * MeSH
- lipopolysacharidy MeSH
- poly I MeSH
- serotonin MeSH
- tryptofan MeSH
Multiple sclerosis is a debilitating autoimmune disease, characterized by chronic inflammation of the central nervous system. While the significance of the gut microbiome on multiple sclerosis pathogenesis is established, the underlining mechanisms are unknown. We found that serum levels of the microbial postbiotic tryptophan metabolite indole-3-carboxaldehyde (3-IAld) inversely correlated with disease duration in multiple sclerosis patients. Much like the host-derived tryptophan derivative L-Kynurenine, 3-IAld would bind and activate the Aryl hydrocarbon Receptor (AhR), which, in turn, controls endogenous tryptophan catabolic pathways. As a result, in peripheral lymph nodes, microbial 3-IAld, affected mast-cell tryptophan metabolism, forcing mast cells to produce serotonin via Tph1. We thus propose a protective role for AhR-mast-cell activation driven by the microbiome, whereby natural metabolites or postbiotics will have a physiological role in immune homeostasis and may act as therapeutic targets in autoimmune diseases.
- Klíčová slova
- 3-IAld, Aryl hydrocarbon receptor, Mast cells, Multiple sclerosis, Serotonin,
- MeSH
- kynurenin metabolismus MeSH
- lidé MeSH
- ligandy MeSH
- receptory aromatických uhlovodíků metabolismus MeSH
- roztroušená skleróza * MeSH
- tryptofan * metabolismus MeSH
- tryptofanhydroxylasa metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- AHR protein, human MeSH Prohlížeč
- kynurenin MeSH
- ligandy MeSH
- receptory aromatických uhlovodíků MeSH
- TPH1 protein, human MeSH Prohlížeč
- tryptofan * MeSH
- tryptofanhydroxylasa MeSH
Some pathological conditions affecting the human body can also disrupt metabolic pathways and thus alter the overall metabolic profile. Knowledge of metabolic disturbances in specific diseases could thus enable the differential diagnosis of otherwise similar conditions. This work therefore aimed to comprehensively characterize changes in tryptophan metabolism in selected neurodegenerative diseases. Levels of 18 tryptophan-related neuroactive substances were determined by high throughput and sensitive ultrahigh-performance liquid chromatography-tandem mass spectrometry in time-linked blood serum and cerebrospinal fluid samples from 100 age-matched participants belonging to five cohorts: healthy volunteers (n = 21) and patients with Lewy body disease (Parkinson's disease and dementia with Lewy bodies; n = 31), four-repeat tauopathy (progressive supranuclear palsy and corticobasal syndrome; n = 10), multiple system atrophy (n = 13), and Alzheimer's disease (n = 25). Although these conditions have different pathologies and clinical symptoms, the discovery of new biomarkers is still important. The most statistically significant differences (with p-values of ≤0.05 to ≤0.0001) between the study cohorts were observed for three tryptophan metabolites: l-kynurenine in cerebrospinal fluid and 3-hydroxy-l-kynurenine and 5-hydroxy-l-tryptophan in blood serum. This led to the discovery of distinctive correlation patterns between the profiled cerebrospinal fluid and serum metabolites that could provide a basis for the differential diagnosis of neurodegenerative tauopathies and synucleinopathies. However, further large-scale studies are needed to determine the direct involvement of these metabolites in the studied neuropathologies, their response to medication, and their potential therapeutic relevance.
- Klíčová slova
- Alzheimer’s disease, Parkinson’s disease, Tryptophan metabolic pathway, cerebrospinal fluid, neurodegenerative disease, serum,
- MeSH
- Alzheimerova nemoc * diagnóza MeSH
- biologické markery MeSH
- kynurenin MeSH
- lidé MeSH
- poruchy proteostázy * MeSH
- sérum MeSH
- tauopatie * MeSH
- tryptofan MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- biologické markery MeSH
- kynurenin MeSH
- tryptofan MeSH
OBJECTIVES: Currently, no biomarker or scoring system could clearly identify patients at risk of progression to a severe coronavirus disease (COVID)-19. Even in patients with known risk factors, the fulminant course cannot be predicted with certainty. Analysis of commonly determined clinical parameters (frailty score, age, or body mass index) together with routine biomarkers of host response (C-reactive protein and viral nucleocapsid protein) in combination with new biomarkers neopterin, kynurenine, and tryptophan, could aid in predicting the patient outcome. METHODS: In 2021 and 2022, urine and serum samples were prospectively collected on 1st to 4th day after hospital admission in 108 consecutive COVID-19 patients hospitalized at the University Hospital Hradec Králové, Czech Republic. Delta and omicron virus variants were studied. Neopterin, kynurenine and tryptophan were determined by liquid chromatography. RESULTS: A significant correlation was observed between urinary and serum biomarker concentrations. Urinary and serum neopterin, kynurenine and kynurenine/tryptophan ratio were significantly (p≤0.05) higher in patients who subsequently needed oxygen therapy vs. patients without oxygen therapy. These parameters were also significantly increased in patients who died during the hospitalization compared to survivors. Complex equations have been derived using the investigated biomarkers and other clinical or laboratory parameters to predict the risk of subsequent oxygen therapy or death during hospitalization. CONCLUSIONS: Present data demonstrate that neopterin, kynurenine and kynurenine/tryptophan ratio in the serum or in the urine represent promising biomarkers in the management of COVID-19 that may help to guide important therapeutic decisions.
- Klíčová slova
- COVID-19, HPLC, kynurenine, neopterin, prognosis, urine,
- MeSH
- biologické markery MeSH
- COVID-19 * diagnóza MeSH
- kynurenin * MeSH
- kyslík MeSH
- lidé MeSH
- neopterin MeSH
- prognóza MeSH
- SARS-CoV-2 MeSH
- tryptofan MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- biologické markery MeSH
- kynurenin * MeSH
- kyslík MeSH
- neopterin MeSH
- tryptofan MeSH
Kynurenine, the first product of tryptophan degradation via the kynurenine pathway, has become one of the most frequently mentioned biomarkers in recent years. Its levels in the body indicate the state of the human physiology. Human serum and plasma are the main matrixes used to evaluate kynurenine levels and liquid chromatography is the dominant technique for its determination. However, their concentrations in blood do not always correspond to the levels in other matrixes obtained from the affected individuals. It is therefore important to decide when it is appropriate to analyse kynurenine in alternative matrices. However, liquid chromatography may not be the best option for the analysis. This review presents alternatives that can be used and summarizes the features that need to be considered prior to kynurenine determination. Possible approaches to kynurenine analysis in a variety of human matrixes, their challenges, and limitations are critically discussed.
- Klíčová slova
- Bioanalysis, Diagnostics, Human matrices, Kynurenine,
- MeSH
- biologické markery MeSH
- chromatografie kapalinová MeSH
- krevní plazma chemie MeSH
- kynurenin * analýza metabolismus MeSH
- lidé MeSH
- tryptofan * metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- biologické markery MeSH
- kynurenin * MeSH
- tryptofan * MeSH
In humans, most free tryptophan is degraded via kynurenine pathways into kynurenines. Kynurenines modulate the immune system, central nervous system, and skeletal muscle bioenergetics. Consequently, kynurenine pathway metabolites (KPMs) have been studied in the context of exercise. However, the effect of vitamin D supplementation on exercise-induced changes in KPMs has not been investigated. Here, we analyzed the effect of a single high-dose vitamin D supplementation on KPMs and tryptophan levels in runners after an ultramarathon. In the study, 35 amateur runners were assigned into two groups: vitamin D supplementation group, administered 150,000 IU vitamin D in vegetable oil 24 h before the run (n = 16); and control (placebo) group (n = 19). Blood was collected for analysis 24 h before, immediately after, and 24 h after the run. Kynurenic, xanthurenic, quinolinic, and picolinic acids levels were significantly increased after the run in the control group, but the effect was blunted by vitamin D supplementation. Conversely, the decrease in serum tryptophan, tyrosine, and phenylalanine levels immediately after the run was more pronounced in the supplemented group than in the control. The 3-hydroxy-l-kynurenine levels were significantly increased in both groups after the run. We conclude that vitamin D supplementation affects ultramarathon-induced changes in tryptophan metabolism.
- Klíčová slova
- kynurenine, skeletal muscle damage, ultramarathon, vitamin D,
- MeSH
- centrální nervový systém metabolismus MeSH
- kynurenin * metabolismus MeSH
- lidé MeSH
- potravní doplňky MeSH
- tryptofan * metabolismus MeSH
- vitamin D MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
- Názvy látek
- kynurenin * MeSH
- tryptofan * MeSH
- vitamin D MeSH
