INTRODUCTION: Impulsivity and aggression are often interlinked behavioral traits that have major implications for our society. Therefore, the study of this phenomenon and derivative interventions that could lead to better control of impulsive aggression are of interest. METHODS: We analyzed the composition and diversity of the gut bacterial microbiome of 33 impulsively violent female convicts with dissocial personality disorder and 20 non-impulsive age-matched women. Further, levels of assorted neurotransmitters and short-chain fatty acids (SCFAs) were analyzed in serum and stool samples. We also assessed all participants using a battery of psychological questionnaires and tested possible correlations between the collected clinical data and the composition and diversity of their microbiomes and metabolites. RESULTS: We identified four bacterial amplicon sequencing variants that were differentially abundant in non-impulsive versus impulsive women - the genera Bacteroides, Barnesiella, and the order Rhodospirillales were more abundant in impulsive women. In contrast, the genus Catenisphaera was more abundant in non-impulsive women. Fecal tryptophan levels were significantly higher in impulsive women. Association analysis revealed a strong positive intercorrelation between most fecal SCFAs in the entire dataset. CONCLUSIONS: Our study demonstrated possible associations between gut microbiomes and their metabolites and impulsive behavior in a unique cohort of prisoners convicted of violent assaults and a matched group of non-impulsive women from the same prison. Genus Bacteroides, which was differentially abundant in the two groups, encoded enzymes that affect serotonin pathways and could contribute to this maladaptive behavior. Similarly, increased fecal tryptophan levels in impulsive individuals could affect neuronal circuits in the brain. INTRODUCTION: Impulsivity and aggression are often interlinked behavioral traits that have major implications for our society. Therefore, the study of this phenomenon and derivative interventions that could lead to better control of impulsive aggression are of interest. METHODS: We analyzed the composition and diversity of the gut bacterial microbiome of 33 impulsively violent female convicts with dissocial personality disorder and 20 non-impulsive age-matched women. Further, levels of assorted neurotransmitters and short-chain fatty acids (SCFAs) were analyzed in serum and stool samples. We also assessed all participants using a battery of psychological questionnaires and tested possible correlations between the collected clinical data and the composition and diversity of their microbiomes and metabolites. RESULTS: We identified four bacterial amplicon sequencing variants that were differentially abundant in non-impulsive versus impulsive women - the genera Bacteroides, Barnesiella, and the order Rhodospirillales were more abundant in impulsive women. In contrast, the genus Catenisphaera was more abundant in non-impulsive women. Fecal tryptophan levels were significantly higher in impulsive women. Association analysis revealed a strong positive intercorrelation between most fecal SCFAs in the entire dataset. CONCLUSIONS: Our study demonstrated possible associations between gut microbiomes and their metabolites and impulsive behavior in a unique cohort of prisoners convicted of violent assaults and a matched group of non-impulsive women from the same prison. Genus Bacteroides, which was differentially abundant in the two groups, encoded enzymes that affect serotonin pathways and could contribute to this maladaptive behavior. Similarly, increased fecal tryptophan levels in impulsive individuals could affect neuronal circuits in the brain.
- MeSH
- agrese fyziologie MeSH
- dospělí MeSH
- feces * mikrobiologie chemie MeSH
- impulzivní chování * fyziologie MeSH
- kyseliny mastné těkavé analýza metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- střevní mikroflóra * fyziologie MeSH
- tryptofan krev metabolismus MeSH
- zločinci MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
During pregnancy the alterations of kynurenine and tryptophan metabolism play an important role in local signalling and the prevention of fetal rejection. The aim was to investigate urinary levels of kynurenine and tryptophan during physiological pregnancy, and to determine their stability in urine during sample storage at different conditions. Urinary samples were obtained from 73 healthy pregnant women (median age 31 years), during the 1st, 2nd, and 3rd trimesters and from 42 healthy non-pregnant women (median age 30 years). Liquid chromatography methods using selective and sensitive mass spectrometry detection were used for analysis. Urinary neopterin, kynurenine, and tryptophan increased during the pregnancy and in comparison to the non-pregnant women. No correlation of the analytes with gestation age within each trimester and among the different analytes was observed. Kynurenine and tryptophan were stable in urine for 14 days at 4 °C, 6 months at - 22 °C, and 12 months at - 84 °C. Present results demonstrate differences in urinary concentrations of kynurenine, tryptophan, and neopterin between women with physiological pregnancy and healthy women. Simultaneous determination of kynurenine, tryptophan and neopterin may be explored in the disorders of pregnancy in future investigations.
- MeSH
- chromatografie kapalinová MeSH
- dospělí MeSH
- kynurenin * moč MeSH
- lidé MeSH
- mladý dospělý MeSH
- neopterin * moč MeSH
- těhotenství MeSH
- tryptofan * moč MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
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.
- 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
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.
- 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
In the first days of life, the newborns' intestinal microbiota develops simultaneously with the intestinal gut barrier and follows intestinal immunity. The mode of delivery shows significant impact on microbial development and, thus, the initiation of the tryptophan catabolism pathway. Further antibiotics (ATB) treatment of mothers before or during delivery affects the microbial and tryptophan metabolite composition of stool of the caesarean- and vaginal-delivered newborns. The determination of microbiome and levels of tryptophan microbial metabolites in meconium and stool can characterize intestinal colonization of a newborn. From 134 samples from the Central European Longitudinal Studies of Parents and Children: The Next Generation (CELSPAC: TNG) cohort study, 16S rRNA gene sequencing was performed, and microbial tryptophan metabolites were quantified using ultra-high-performance liquid chromatography with triple-quadrupole mass spectrometry. Microbial diversity and concentrations of tryptophan metabolites were significantly higher in stool compared to meconium. Treatment of mothers with ATB before or during delivery affects metabolite composition and microbial diversity in stool of vaginal- and caesarean-delivered newborns. Correlation of microbial and metabolite composition shows significant positive correlations of indol-3-lactic acid, N-acetyl-tryptophan and indol-3-acetic acid with Bifidobacterium, Bacteroides and Peptoclostridium. The positive effect of vaginal delivery on newborns' microbiome development is degraded when mother is treated with ATB before or during delivery. KEY POINTS: • Antibiotic treatment diminishes the positive effects of vaginal delivery. • Antibiotic treatment affects metabolite and microbial composition in newborns. • Bifidobacterium and Peptoclostridium could be the producer of indole-lactic acid.
- MeSH
- antibakteriální látky * MeSH
- Bifidobacterium metabolismus růst a vývoj MeSH
- feces * mikrobiologie chemie MeSH
- indoly metabolismus MeSH
- kyseliny indoloctové metabolismus MeSH
- lidé MeSH
- longitudinální studie MeSH
- mekonium * mikrobiologie chemie MeSH
- novorozenec MeSH
- RNA ribozomální 16S * genetika MeSH
- střevní mikroflóra * účinky léků MeSH
- tryptofan * metabolismus MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Východiská: Endometriálny karcinóm (EC) je najčastejšou rakovinou ženského reprodukčného traktu vo vyspelých krajinách. Prognóza a päťročná miera prežitia úzko súvisia so štádiom pri diagnostikovaní. Súčasné rutinné diagnostické metódy EC sú buď málo špecifické alebo pre pacientku nepríjemné, invazívne a bolestivé. Aktuálne je zlatým diagnostickým štandardom endometriálna biopsia. Včasná a neinvazívnu diagnostika EC vyžaduje identifikáciu nových markerov ochorenia a skríningový test aplikovateľný do rutinnej laboratórnej diagnostiky. Aplikácia necielenej metabolomiky v kombinácii s nástrojmi umelej inteligencie a bioštatistiky má potenciál kvalitatívne a kvantitatívne prezentovať metabolóm, ale jej zavedenie do rutinnej diagnostiky je z dôvodu finančnej, časovej aj interpretačnej náročnosti v súčasnosti nereálne. Fluorescenčná spektrálna analýza telových tekutín využíva autofluorescenciu určitých metabolitov na definovanie zloženia metabolómu za fyziologických podmienok. Cieľ: Tento prehľadový článok poukazuje na potenciál fluorescenčnej spektroskopie pri včasnej detekcii EC. Dáta získané trojrozmernou fluorescenčnou spektroskopiou definujú kvantitatívne aj kvalitatívne zloženie komplexného fluorescenčného metabolómu a sú vhodné na identifikáciu biochemických metabolických zmien spojených s karcinogenézou endometria. Autofluorescencia biologických tekutín má perspektívu poskytnúť nové molekulové markery EC. Integráciou algoritmov strojového učenia a umelej inteligencie pri dátovej analýze fluorescenčného metabolómu má táto technika veľký potenciál byť implementovaná do rutinnej laboratórnej diagnostiky.
Background: Endometrial carcinoma (EC) is the most common cancer of the female reproductive tract in developed countries. The prognosis and 5-year survival rates are closely tied to the stage diagnosis. Current routine diagnostic methods of EC are either lacking specificity or are uncomfortable, invasive and painful for the patient. As of now, the gold diagnostic standard is endometrial biopsy. Early and non-invasive diagnosis of EC requires the identification of new biomarkers of disease and a screening test applicable to routine laboratory diagnostics. The application of untargeted metabolomics combined with artificial intelligence and biostatistics tools has the potential to qualitatively and quantitatively represent the metabolome, but its introduction into routine diagnostics is currently unrealistic due to the financial, time and interpretation challenges. Fluorescence spectral analysis of body fluids utilizes autofluorescence of certain metabolites to define the composition of the metabolome under physiological conditions. Purpose: This review highlights the potential of fluorescence spectroscopy in the early detection of EC. Data obtained by three-dimensional fluorescence spectroscopy define the quantitative and qualitative composition of the complex fluorescent metabolome and are useful for identifying biochemical metabolic changes associated with endometrial carcinogenesis. Autofluorescence of biological fluids has the prospect of providing new molecular markers of EC. By integrating machine learning and artificial intelligence algorithms in the data analysis of the fluorescent metabolome, this technique has great potential to be implemented in routine laboratory diagnostics.
- MeSH
- diagnostické techniky a postupy MeSH
- fluorescenční spektrometrie metody MeSH
- lidé MeSH
- metabolomika metody MeSH
- nádory endometria * diagnostické zobrazování metabolismus MeSH
- optické zobrazování * metody MeSH
- tělesné tekutiny diagnostické zobrazování MeSH
- tryptofan fyziologie metabolismus MeSH
- uterus diagnostické zobrazování MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy 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.
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.
- 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
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.
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.
- 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
