Elevated Levels Of Kynurenine Research Articles

The Difference in Serum Metabolomic Profiles between the Good and Poor Outcome Groups at 3 Months in the Early and Late Phases of Aneurysmal Subarachnoid Hemorrhage.

We aimed to investigate the characteristics of serum metabolomics in aneurysmal subarachnoid hemorrhage patients (aSAH) with different 3-month outcomes (good = modified Rankin score: 0-3 vs. poor = mRS 4-6). We collected serum samples from 46 aSAH patients at 24 (D1) and 168 (D7) hours after injury for analysis by liquid chromatography-mass spectrometry. Ninety-six different metabolites were identified. Groups were compared using multivariate (orthogonal partial least squares discriminant analysis), univariate, and receiving operator characteristic (ROC) methods. We observed a marked decrease in serum homocysteine levels at the late phase (D7) compared to the early phase (D1). At both D1 and D7, mannose and sorbose levels were notably higher, alongside elevated levels of kynurenine (D1) and increased 2-hydroxybutyrate, methyl-galactoside, creatine, xanthosine, p-hydroxyphenylacetate, N-acetylalanine, and N-acetylmethionine (all D7) in the poor outcome group. Conversely, levels of guanidinoacetate (D7) and several amino acids (both D1 and D7) were significantly lower in patients with poor outcomes. Our results indicate significant changes in energy metabolism, shifting towards ketosis and alternative energy sources, both in the early and late phases, even with adequate enteral nutrition, particularly in patients with poor outcomes. The early activation of the kynurenine pathway may also play a role in this process.

Abstract PR-010: Dual targeting of IDO1/TDO2 inhibits tumor progression and attenuates the immune suppressive tumor microenvironment

Abstract Introduction: High-grade serous carcinoma (HGSC) tumors of the ovary, fallopian tube, or peritoneum are predicted to be immunogenic since the presence of tumor-infiltrating lymphocytes conveys a better prognosis. However, the efficacy of immunotherapies has been limited due to the immune-suppressed tumor immune microenvironment (TIME), which is established through tumor metabolism and immune-suppressive metabolites that directly affect immune cell function by depleting nutrients and activating immune-suppressive transcriptional programs. The tryptophan (TRP) catabolism pathway is a critical regulator of immune-suppressed TIME; however, clinical trials targeting the pathway to date have demonstrated limited response. Note there are two structurally distinct rate-limiting TRP catabolizing enzymes, Indoleamine 2,3-Dioxygenase (IDO1) and Tryptophan 2,3-Dioxygenase (TDO2), that evolved separately to catabolize tryptophan into Kynurenine (KYN). Most TRP catabolism inhibitors (e.g., Epacadostat) have primarily targeted IDO1, which may explain the mild anti-tumor effects of Epacadostat. Thus, we hypothesize that targeting both enzymes involved in TRP catabolism will alleviate the immune-suppressed TIME. Methods: We assessed primary human ascites fluid (IRB #07-0395) with global untargeted metabolomics. Using a panel of HGSC cell lines, we assessed genetic (small hairpin-mediated knockdown and overexpression) and pharmacologic (Epacadostat [IDO1 inhibitor], AT-0174 [IDO1/TDO2 inhibitor], 66cl4 [TDO2 inhibitor], StemRegenin 1 [AhR inhibitor]) modulation of IDO1, TDO2, and aryl hydrocarbon receptor (AhR, signal transducer of KYN). Proliferation assays in 2D and 3D. We examined the response of IDO1/TDO2 inhibition in two syngeneic murine models (ID8 Tp53-/- and BR-Luc Tp53-/-, Brca1-/-, myr-AKT, MYC). Multispectral immunohistochemistry (mIHC) and flow cytometry defined the TIME. Results: Elevated KYN levels are correlated to an inflamed TIME. The depletion of TRP and increased KYN negatively affect the anti-tumor immune response. HGSC cell lines and clinical outcomes depend more on TDO2 than IDO1. In contrast to knocking down IDO1 and AhR, TDO2 knockdown inhibited HGSC cell growth, and overexpression of TDO2 induced cancer cell proliferation. Targeting both IDO1 and TDO2 significantly inhibited TRP catabolism. Notably, only the combined IDO1/TDO2 inhibition resulted in the downregulation of PD-L1. In a syngeneic HGSC murine model, a first-in-class orally available dual IDO1/TDO2 inhibitor (AT-0174) significantly inhibited tumor progression, reduced tumor-associated macrophages, and reduced expression of immune-suppressive proteins, including PD-L1, on immune and tumor cells. Conclusions: These studies demonstrate the importance of TDO2 and the potential of AT-0174 to overcome an immune-suppressed TIME. The findings represent a novel approach to targeting TRP catabolism that may improve tumor response rates to immune therapy. Citation Format: Lyndsey Crump, Jessica Floyd, Elizabeth Woodruff, Mike Bickerdike, Li-Wei Kuo, Miriam Post, Silviu Itescu, Jennifer Richer, Benjamin G. Bitler. Dual targeting of IDO1/TDO2 inhibits tumor progression and attenuates the immune suppressive tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr PR-010.

Causal association between kynurenine and depression investigated using two-sample mendelian randomization.

As research progresses, the intricate metabolic connections between depression and tryptophan, as well as kynurenine (KYN), have become increasingly evident. In studies investigating the relationship between KYN and depression, the conclusions reached thus far have been inconsistent. Therefore, we propose employing a two-sample mendelian randomization (MR) approach to further elucidate the relationship between KYN and depression. We utilized extensive data from large-scale genome-wide association studies to identify single nucleotide polymorphisms that act as instrumental variables for kynurenine and depression in European ancestry populations, ensuring compliance with MR assumptions. We employed five MR algorithms, namely, weighted median, MR-Egger, inverse variance weighted (IVW), simple mode, and weighted mode, with IVW as the primary analysis method. Sensitivity tests were conducted using Cochran's Q test, MR-Egger intercept test, MR Pleiotropy Residual Sum and Outlier, and Leave-one-out analysis.The IVW analysis revealed that each standard deviation increase in kynurenine corresponded to a 1.4-fold increase in the risk of depression (OR = 1.351, 95% CI 1.110-1.645, P = 0.003). The direction of the effect size (positive or negative) was consistent with the findings from the other four algorithms. Sensitivity tests indicated no heterogeneity or horizontal pleiotropy among the instrumental variables. Elevated levels of kynurenine have a causal relationship with an increased risk of developing depression.

Alterations in the Kynurenine-Tryptophan Pathway and Lipid Dysregulation Are Preserved Features of COVID-19 in Hemodialysis.

Coronavirus disease 2019 (COVID-19)-induced metabolic alterations have been proposed as a source for prognostic biomarkers and may harbor potential for therapeutic exploitation. However, the metabolic impact of COVID-19 in hemodialysis (HD), a setting of profound a priori alterations, remains unstudied. To evaluate potential COVID-19 biomarkers in end-stage kidney disease (CKD G5), we analyzed the plasma metabolites in different COVID-19 stages in patients with or without HD. We recruited 18 and 9 asymptomatic and mild, 11 and 11 moderate, 2 and 13 severely affected, and 10 and 6 uninfected HD and non-HD patients, respectively. Plasma samples were taken at the time of diagnosis and/or upon admission to the hospital and analyzed by targeted metabolomics and cytokine/chemokine profiling. Targeted metabolomics confirmed stage-dependent alterations of the metabolome in non-HD patients with COVID-19, which were less pronounced in HD patients. Elevated kynurenine levels and lipid dysregulation, shown by an increase in circulating free fatty acids and a decrease in lysophospholipids, could distinguish patients with moderate COVID-19 from non-infected individuals in both groups. Kynurenine and lipid alterations were also associated with ICAM-1 and IL-15 levels in HD and non-HD patients. Our findings support the kynurenine pathway and plasma lipids as universal biomarkers of moderate and severe COVID-19 independent of kidney function.

Elevated Kynurenine Levels in Patients with Primary Sjögren's Syndrome.

We aimed to investigate the plasma levels of tryptophan (Trp) and its metabolites in patients with primary Sjögren's syndrome (pSS). The study included 34 pSS patients and 42 healthy individuals, and serum Trp and kynurenine (Kyn) concentrations were measured by liquid chromatography with tandem mass spectrometry. Trp degradation was predicted using the ratio of Kyn and Trp concentrations (Kyn/Trp). In our study, the mean serum Trp concentration was found to be considerably lower in the pSS group than in the control group (P = .001). The levels of Kyn (P = .019) and the Kyn/Trp ratio (P < .001) were significantly higher in the pSS group than in the control group. The Kyn/Trp ratio was negatively correlated with C-reactive protein (r = -0.369, P = .032). We found that Kyn pathway metabolism was altered in patients with pSS. This suggests that Trp metabolism may be closely linked to the disease pathogenesis of pSS.

System analysis based on the cancer–immunity cycle identifies ZNF207 as a novel immunotherapy target for hepatocellular carcinoma

BackgroundImmune checkpoint inhibitors as monotherapies for advanced hepatocellular carcinoma (HCC) fail to achieve satisfying results, while combination therapies show greater efficacy. Therefore, identifying new combined targets for immune checkpoint inhibitors...

Tryptophan Metabolism Is Associated with BMI and Adipose Tissue Mass and Linked to Metabolic Disease in Pediatric Obesity.

The obesity epidemic has contributed to an escalating prevalence of metabolic diseases in children. Overnutrition leads to increased tryptophan uptake and availability. An association between the induction of the tryptophan catabolic pathway via indoleamine 2,3-dioxygenase (IDO) activity and obesity-related inflammation has been observed. This study aimed to investigate the impact of pediatric obesity on tryptophan metabolism and the potential relationship with metabolic disease. In this prospective cohort study, plasma kynurenine, tryptophan, and serotonin levels were measured by ELISA, and IDO activity was estimated by calculating the kynurenine/tryptophan ratio in a clinically characterized population with severe obesity (BMI ≥ 97th percentile) aged 9 to 19 (n = 125). IDO activity and its product kynurenine correlated with BMI z-score and body fat mass, whereas concentrations of serotonin, the alternative tryptophan metabolite, negatively correlated with these measures of adiposity. Kynurenine and tryptophan, but not serotonin levels, were associated with disturbed glucose metabolism. Tryptophan concentrations negatively correlated with adiponectin and were significantly higher in prediabetes and metabolically unhealthy obesity. In conclusion, BMI and body fat mass were associated with increased tryptophan catabolism via the kynurenine pathway and decreased serotonin production in children and adolescents with severe obesity. The resulting elevated kynurenine levels may contribute to metabolic disease in obesity.

Utilization of Metabolomics to Identify Biomarkers in Hematological Malignancies: Role of IDO and the Tryptophan Pathway

Drug resistance is a major problem in the treatment of cancer, particularly in hematological malignancies where many patients relapse and become refractory to current standard of care chemotherapy (SOC). In Acute Myeloid Leukemia (AML) and Diffuse Large B-cell Lymphoma (DLBCL), relapse post-SOC occurs in about 10-40% and 40% of patients respectively (Shi, Das et al. 2013, Thol, Schlenk et al. 2015). This highlights the critical need for the identification of drug resistance mechanisms to help physicians make better clinical decisions and improve patient outcomes. Given the emerging role of the tumor microenvironment in mediating drug resistance, we employed a targeted, quantitative metabolomics approach, utilizing Mass Spectrometry and the AbsoluteIDQ p180 Kit from Biocrates Life Sciences to identify predictive and prognostic biomarkers. We hypothesize one such mechanism of resistance involves catabolism of the essential amino acid Tryptophan (Trp). The catabolism of tryptophan is a central pathway maintaining an immunosuppressive microenvironment in many cancer types by regulating both innate and adaptive immunity. Trp can be catabolized by tryptophan hydroxylase into serotonin. Alternatively, it can be catabolized by Indoleamine-2,3-dioxygenase (IDO) and Tryptophan-2,3-dioxygenase (TDO) into kynurenine (kyn). IDO/TDO driven production of kynurenine promotes the development, stabilization, and activation of Tregs, while suppressing effector T cells (pro-inflammatory Th1 and Th17 pathways) all of which contribute to immune system impairment in cancer bearing individuals.A pilot study aimed at evaluating changes in the tryptophan pathway in human serum samples from commercially available AML and DLBCL patients who had undergone standard of care treatments was performed. This was accomplished through mass spectrometry analysis of tryptophan, kynurenine, and serotonin, along with 185 additional metabolites, using the Absolute IDQ p180 kit by Biocrates. Analysis was performed using MetaboAnalyst 3.0 and Graphpad prism software. As seen in Figure 1A, we found significant increases in kynurenine in the serum from the commercially available Newly Diagnosed (Newly Dx) (n=20, p<0.001) and Relapsed/Refractory (R/R) AML patients (n=19, p<0.001) compared to normal donors (n=20). We also observed additional defects in the tryptophan pathway with significantly lower serotonin production (p<0.0001) in the malignant population. Similarly, in Figure 1B, we showed that Newly Dx DLBCL patients had significantly elevated levels of kynurenine (n=18, p<0.01) compared to normal donors (n=20), and the R/R population was elevated even further (n=12, p<0.001), with a trend towards decreased kynurenine levels in remission patients (n=9, p=0.0595). Interestingly, the ratio of Kyn/Trp (indicative of IDO activity) is significantly decreased in the remission population (p<0.05) when compared to the R/R DLBCL population, suggesting this might serve as a prognostic biomarker. Unlike in AML, no significant changes in serotonin were observed. Given these results, a retrospective study is underway to establish which will serve as the best biomarkers (predictive and prognostic) for patients treated with Amgen therapies. [Display omitted] DisclosuresFinger:Amgen, Inc.: Employment, Equity Ownership. Wong:Amgen, Inc.: Employment, Equity Ownership. Gray:Amgen, Inc.: Employment, Equity Ownership. Rock:Amgen, Inc.: Employment, Equity Ownership. Loberg:Amgen Inc.: Employment, Equity Ownership. Fitzpatrick:Amgen Inc.: Employment, Equity Ownership. Smith:Amgen, Inc.: Employment, Equity Ownership. Wang:Amgen, Inc.: Employment, Equity Ownership. Dos Santos:Amgen Inc.: Employment.

Caffeine protects against stress-induced murine depression through activation of PPAR\u03b3C1\u03b1-mediated restoration of the kynurenine pathway in the skeletal muscle

Exercise prevents depression through peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α)-mediated activation of a particular branch of the kynurenine pathway. From kynurenine (KYN), two independent metabolic pathways produce neurofunctionally different metabolites, mainly in somatic organs: neurotoxic intermediate metabolites via main pathway and neuroprotective end product, kynurenic acid (KYNA) via the branch. Elevated levels of KYN have been found in patients with depression. Herein, we investigated whether and how caffeine prevents depression, focusing on the kynurenine pathway. Mice exposed to chronic mild stress (CMS) exhibited depressive-like behaviours with an increase and decrease in plasma levels of pro-neurotoxic KYN and neuroprotective KYNA, respectively. However, caffeine rescued CMS-exposed mice from depressive-like behaviours and restored the plasma levels of KYN and KYNA. Concomitantly, caffeine induced a key enzyme converting KYN into KYNA, namely kynurenine aminotransferase-1 (KAT1), in murine skeletal muscle. Upon caffeine stimulation murine myotubes exhibited KAT1 induction and its upstream PGC-1α sustainment. Furthermore, a proteasome inhibitor, but not translational inhibitor, impeded caffeine sustainment of PGC-1α, suggesting that caffeine induced KAT1 by inhibiting proteasomal degradation of PGC-1α. Thus, caffeine protection against CMS-induced depression may be associated with sustainment of PGC-1α levels and the resultant KAT1 induction in skeletal muscle, and thereby consumption of pro-neurotoxic KYN.

Early and late behavioral consequences of ethanol withdrawal: focus on brain indoleamine 2,3 dioxygenase activity.

Anxiety and depression are symptoms associated with ethanol withdrawal that lead individuals to relapse. In the kynurenine pathway, the enzyme indoleamine 2,3 dioxygenase (IDO) is responsible for the conversion of tryptophan to kynurenine, and dysregulation of this pathway has been associated with psychiatric disorders, such as anxiety and depression. The present study evaluated the early and late behavioral and biochemical effects of ethanol withdrawal in rats. Male Wistar rats were submitted to increasing concentrations of ethanol in drinking water during 21 days. In experiment 1, both control and withdrawal groups were submitted to a battery of behavioral tests 3, 5, 10, 19, and 21 days following ethanol removal. In experiment 2, animals were euthanized 3 days (short-term) or 21 days (long-term) after withdrawal, and the brains were dissected altogether, following kynurenine concentration analysis in prefrontal cortex, hippocampus, and striatum. Short-term ethanol withdrawal decreased the exploration of the open arms in the elevated plus-maze. In the forced swimming test, long-term ethanol-withdrawn rats displayed higher immobility time than control animals. Ethanol withdrawal altered neither locomotion nor motor coordination of rats. In experiment 2, kynurenine concentrations were increased in the prefrontal cortex after a long-term period of withdrawal. In conclusion, short-term ethanol withdrawal produced anxiety-like behaviors, while long-term withdrawal favored depressive-like behaviors. Long-term ethanol withdrawal elevated kynurenine levels, specifically in the prefrontal cortex, suggesting that the depressive-like responses observed after long-term withdrawal might be related to the increased IDO activity.

Free-amino acid metabolic profiling of visceral adipose tissue from obese subjects.

Interest in adipose tissue pathophysiology and biochemistry have expanded considerably in the past two decades due to the ever increasing and alarming rates of global obesity and its critical outcome defined as metabolic syndrome (MS). This obesity-linked systemic dysfunction generates high risk factors of developing perilous diseases like type 2 diabetes, cardiovascular disease or cancer. Amino acids could play a crucial role in the pathophysiology of the MS onset. Focus of this study was to fully characterize amino acids metabolome modulations in visceral adipose tissues (VAT) from three adult cohorts: (i) obese patients (BMI 43-48) with metabolic syndrome (PO), (ii) obese subjects metabolically well (O), and (iii) non obese individuals (H). 128 metabolites identified as 20 protein amino acids, 85 related compounds and 13 dipeptides were measured by ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) and gas chromatography-/mass spectrometry GC/MS, in visceral fat samples from a total of 53 patients. Our analysis indicates a probable enhanced BCAA (leucine, isoleucine, valine) degradation in both VAT from O and PO subjects, while levels of their oxidation products are increased. Also PO and O VAT samples were characterized by: elevated levels of kynurenine, a catabolic product of tryptophan and precursor of diabetogenic substances, a significant increase of cysteine sulfinic acid levels, a decrease of 1-methylhistidine, and an up regulating trend of 3-methylhistidine levels. We hope this profiling can aid in novel clinical strategies development against the progression from obesity to metabolic syndrome.

Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors

Trisomy 21 (T21) causes Down syndrome (DS), affecting immune and neurological function by ill-defined mechanisms. Here we report a large metabolomics study of plasma and cerebrospinal fluid, showing in independent cohorts that people with DS produce elevated levels of kynurenine and quinolinic acid, two tryptophan catabolites with potent immunosuppressive and neurotoxic properties, respectively. Immune cells of people with DS overexpress IDO1, the rate-limiting enzyme in the kynurenine pathway (KP) and a known interferon (IFN)-stimulated gene. Furthermore, the levels of IFN-inducible cytokines positively correlate with KP dysregulation. Using metabolic tracing assays, we show that overexpression of IFN receptors encoded on chromosome 21 contribute to enhanced IFN stimulation, thereby causing IDO1 overexpression and kynurenine overproduction in cells with T21. Finally, a mouse model of DS carrying triplication of IFN receptors exhibits KP dysregulation. Together, our results reveal a mechanism by which T21 could drive immunosuppression and neurotoxicity in DS.

Elevated kynurenine levels in diffuse cutaneous and anti-RNA polymerase III positive systemic sclerosis

Systemic sclerosis (SSc) is a systemic disease characterized by vasculopathy, progressive fibrosis and autoimmune activation. Tryptophan (Trp) metabolism has been linked to altered immune cell function and to malignancy. We have investigated the role of Trp metabolic pathway in SSc measuring serum Trp, Kynurenine (Kyn) and Trp/Kyn ratio in a cohort of 97 SSc patients and 10 healthy controls. Association with disease characteristics was evaluated. We found that Trp levels in SSc patients were significantly lower compared to HCs. We also found that patients with diffuse cutaneous (dcSSc) had lower levels of Trp compared to limited cutaneous (lcSSc). These results were paralleled by higher levels of Kyn found in SSc patients compared to HCs and significantly lower levels in dcSSc compared to lcSSc. The autoantibody profile was also found to be significantly associated with Kyn and Trp levels as anti-RNA-polymerase III (ARA) positive patients were shown to have lower Trp levels and higher Kyn levels compared with anti-centromere and anti-topoisomerase I positive patients. Moreover, the highest Trp/Kyn was found in ARA+ patients with dcSSc, suggesting that an activation of the Kyn pathway, is more specifically associated with this subset of SSc patients. Stability over time makes these markers of Trp metabolism feasible for SSc stratification.

Dysbiosis of the Vaginal Microbiota and Higher Vaginal Kynurenine/Tryptophan Ratio Reveals an Association with Chlamydia trachomatis Genital Infections.

The natural course of Chlamydia trachomatis urogenital tract infections varies between individuals. While protective immunity can occur, some women can become reinfected, contributing to the development of severe pathology. While the reasons for these differences are unknown, an individual's response to induced interferon-γ (IFN-γ) is suggested to be critical. IFN-γ induction of the enzyme indoleamine 2,3-dioxygenase, which depletes tryptophan, may be the key. One hypothesis suggests that indole-producing bacteria in the vaginal microbiota can provide a substrate for the Chlamydia to synthesize tryptophan, rescuing the Chlamydia from host IFN-γ attack. We studied a cohort of 25 women who were either, Chlamydia negative, Chlamydia positive with a single infection, or Chlamydia positive with repeated infection, to test our hypothesis. We characterized their vaginal microbiota, cytokine response, as well as their tryptophan, kynurenine and indole concentrations directly in vaginal secretions. We found that C. trachomatis urogenital tract infections either initial or repeat infections, were associated with elevated vaginal kynurenine/tryptophan ratios, primarily as a result of elevated kynurenine levels. In addition, vaginal microbiota of community state type (CST) IV showed significantly lower vaginal tryptophan levels compared to CST I and III, which might be related to a higher abundance of indole producers found within this group. Furthermore, we found a higher abundance of indole producers in women who cleared their Chlamydia infection post antibiotic treatment. This study demonstrates for the first time in vivo, the association between high vaginal kynurenine/tryptophan ratios and C. trachomatis infections. In addition, tryptophan depletion was associated with vaginal microbiota of CST IV.

Microbiota alteration is associated with the development of stress-induced despair behavior

Depressive disorders often run in families, which, in addition to the genetic component, may point to the microbiome as a causative agent. Here, we employed a combination of behavioral, molecular and computational techniques to test the role of the microbiota in mediating despair behavior. In chronically stressed mice displaying despair behavior, we found that the microbiota composition and the metabolic signature dramatically change. Specifically, we observed reduced Lactobacillus and increased circulating kynurenine levels as the most prominent changes in stressed mice. Restoring intestinal Lactobacillus levels was sufficient to improve the metabolic alterations and behavioral abnormalities. Mechanistically, we identified that Lactobacillus-derived reactive oxygen species may suppress host kynurenine metabolism, by inhibiting the expression of the metabolizing enzyme, IDO1, in the intestine. Moreover, maintaining elevated kynurenine levels during Lactobacillus supplementation diminished the treatment benefits. Collectively, our data provide a mechanistic scenario for how a microbiota player (Lactobacillus) may contribute to regulating metabolism and resilience during stress.

Influence of Hepatitis C Virus Sustained Virological Response on Immunosuppressive Tryptophan Catabolism in ART-Treated HIV/HCV Coinfected Patients.

Background:We previously reported an association between tryptophan (Trp) catabolism and immune dysfunction in HIV monoinfection. Coinfection with HIV is associated with more rapid evolution of hepatitis C virus (HCV)–associated liver disease despite antiretroviral therapy (ART), possibly due to immune dysregulation. We hypothesized that liver fibrosis in HIV/HCV coinfection would be associated with immune dysfunction and alterations in Trp metabolism.Methods:Trp catabolism and inflammatory soluble markers were assessed in plasma samples from ART-treated HIV/HCV-coinfected patients (n = 90) compared with ART-treated HIV-monoinfected patients and noninfected subjects. Furthermore, 17 additional coinfected patients with sustained virological response (SVR) were assessed longitudinally 6 months after completion of interferon-α/ribavirin treatment.Results:HIV/HCV patients had higher Trp catabolism compared with HIV-monoinfected and healthy individuals. Elevated kynurenine levels in HIV/HCV patients with liver fibrosis correlated with the prognostic aspartate aminotransaminase to platelet ratio (APRI scores) and insulin levels. Furthermore, HIV/HCV patients had elevated levels of disease progression markers interleukin-6 and induced protein 10 and shared similar levels of markers of microbial translocation (intestinal fatty acid-binding protein, soluble CD14 and lipopolysaccharide-binding protein) compared with HIV-monoinfected and healthy individuals. Successful HCV treatment improved APRI score and markers of disease progression and microbial translocation although elevated Trp catabolism remained unchanged 6 months after SVR.Conclusion:ART-treated HIV/HCV-coinfected patients had elevated immunosuppressive Trp catabolism when compared with monoinfected HIV-treated patients, which did not normalize after SVR. These findings suggest that a necroinflammatory liver syndrome persists through inflammation by Trp catabolism after 6 month of SVR.

The kynurenine pathway is involved in bacterial meningitis.

BackgroundBacterial meningitis (BM) is characterized by an intense host inflammatory reaction, which contributes to the development of brain damage and neuronal sequelae. Activation of the kynurenine (KYN) pathway (KP) has been reported in various neurological diseases as a consequence of inflammation. Previously, the KP was shown to be activated in animal models of BM, and the association of the SNP AADAT + 401C/T (kynurenine aminotransferase II - KAT II) with the host immune response to BM has been described. The aim of this study was to investigate the involvement of the KP during BM in humans by assessing the concentrations of KYN metabolites in the cerebrospinal fluid (CSF) of BM patients and their relationship with the inflammatory response compared to aseptic meningitis (AM) and non-meningitis (NM) groups.MethodsThe concentrations of tryptophan (TRP), KYN, kynurenic acid (KYNA) and anthranilic acid (AA) were assessed by HPLC from CSF samples of patients hospitalized in the Giselda Trigueiro Hospital in Natal (Rio Grande do Norte, Brazil). The KYN/TRP ratio was used as an index of indoleamine 2,3-dioxygenase (IDO) activity, and cytokines were measured using a multiplex cytokine assay. The KYNA level was also analyzed in relation to AADAT + 401C/T genotypes.ResultsIn CSF from patients with BM, elevated levels of KYN, KYNA, AA, IDO activity and cytokines were observed. The cytokines INF-γ and IL-1Ra showed a positive correlation with IDO activity, and TNF-α and IL-10 were positively correlated with KYN and KYNA, respectively. Furthermore, the highest levels of KYNA were associated with the AADAT + 401 C/T variant allele.ConclusionThis study suggests a downward modulatory effect of the KP on CSF inflammation during BM.

Muscle Over Mind

Depression is associated with elevated kynurenine levels, a tryptophan metabolite generated under stress and inflammatory conditions. Agudelo et al. (2014) now reveal how PGC-1α1 overexpression in muscle mimics anti-depressant effects of exercise by promoting kynurenine aminotransferase expression, likely preventing kynurenine from crossing the blood brain barrier to disrupt neural plasticity.

Evaluation of kynurenine pathway metabolism in Toxoplasma gondii-infected mice: Implications for schizophrenia

Toxoplasma gondii, an intracellular protozoan parasite, is a major cause of opportunistic infectious disease affecting the brain and has been linked to an increased incidence of schizophrenia. In murine hosts, infection with T. gondii stimulates tryptophan degradation along the kynurenine pathway (KP), which contains several neuroactive metabolites, including 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN) and kynurenic acid (KYNA). As these endogenous compounds may provide a mechanistic connection between T. gondii and the pathophysiology of schizophrenia, we measured KP metabolites in both the brain and periphery of T. gondii-treated C57BL/6 mice 8 and 28days post-infection. Infected mice showed early decreases in the levels of tryptophan in the brain and serum, but not in the liver. These reductions were associated with elevated levels of kynurenine, KYNA, 3-HK and QUIN in the brain. In quantitative terms, the most significant increases in these KP metabolites were observed in the brain at 28days post-infection. Notably, the anti-parasitic drugs pyrimethamine and sulfadiazine, a standard treatment of toxoplasmosis, significantly reduced 3-HK and KYNA levels in the brain of infected mice when applied between 28 and 56days post-infection. In summary, T. gondii infection, probably by activating microglia and astrocytes, enhances the production of KP metabolites in the brain. However, during the first two months after infection, the KP changes in these mice do not reliably duplicate abnormalities seen in the brain of individuals with schizophrenia.

Tryptophan degradation in women with breast cancer: a pilot study

BackgroundAltered tryptophan metabolism and indoleamine 2,3-dioxygenase activity are linked to cancer development and progression. In addition, these biological factors have been associated with the development and severity of neuropsychiatric syndromes, including major depressive disorder. However, this biological mechanism associated with both poor disease outcomes and adverse neuropsychiatric symptoms has received little attention in women with breast cancer. Therefore, a pilot study was undertaken to compare levels of tryptophan and other proteins involved in tryptophan degradation in women with breast cancer to women without cancer, and secondarily, to examine levels in women with breast caner over the course of chemotherapy.FindingsBlood samples were collected from women with a recent diagnosis of breast cancer (n = 33) before their first cycle of chemotherapy and after their last cycle of chemotherapy. The comparison group (n = 24) provided a blood sample prior to breast biopsy. Plasma concentrations of tryptophan, kynurenine, and tyrosine were determined. The kynurenine to tryptophan ratio (KYN/TRP) was used to estimate indoleamine 2,3-dioxygenase activity. On average, the women with breast cancer had lower levels of tryptophan, elevated levels of kynurenine and tyrosine and an increased KYN/TRP ratio compared to women without breast cancer. There was a statistically significant difference between the two groups in the KYN/TRP ratio (p = 0.036), which remained elevated in women with breast cancer throughout the treatment trajectory.ConclusionsThe findings of this pilot study suggest that increased tryptophan degradation may occur in women with early-stage breast cancer. Given the multifactorial consequences of increased tryptophan degradation in cancer outcomes and neuropsychiatric symptom manifestation, this biological mechanism deserves broader attention in women with breast cancer.