Tryptophan Ratio Research Articles

Plasma Kynurenine to Tryptophan Ratio Is Negatively Associated with Linear Growth of Children Living in a Slum of Bangladesh: Results from a Community-Based Intervention Study.

.Chronic exposure to infectious agents results in environmental enteric dysfunction—a significant contributor to childhood stunting. Low plasma tryptophan (TRP), increased kynurenine (KYN), and KYN–TRP (KT) ratio are associated with infections and chronic immune activation. We postulated that both these conditions are interlinked, and therefore aimed to identify the association between KT ratio and the linear growth of Bangladeshi children. A total of 480 stunted and at risk of being stunted children aged 12–18 months were enrolled and provided nutrition intervention for 90 days. Plasma samples were assessed using liquid chromatography tandem mass spectrometry to measure TRP and KYN concentrations. Multivariable linear regression with generalized estimating equations was applied to analyze association between the KT ratio and linear growth. Tryptophan, KYN, and KT ratio were significantly higher in stunted children than in children at risk of being stunted both at baseline and at the end of nutrition intervention. Following intervention, the median (interquartile range [IQR]) KYN concentration was significantly reduced from 4.6 (3.6, 5.4) µmol/L to 3.9 (0.3, 7.6) µmol/L, and median (IQR) KT ratio decreased from 104 (80.9, 131) to 92.8 (6.6, 247) in stunted children. We also found KT ratio to be negatively associated (coefficient = −0.7; 95% CI = −1.13, −0.26; P-value = 0.002) with linear growth. In addition, KYN and KT ratio were positively correlated with fecal neopterin and plasma C-reactive protein, whereas TRP was negatively correlated with both of these biomarkers and alpha-1-acid glycoprotein. Our findings imply that KT ratio is associated in the pathophysiology of stunting as well as with biomarkers of inflammation in Bangladeshi children.

The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies.

The importance of tryptophan as a precursor for neuroactive compounds has long been acknowledged. The metabolism of tryptophan along the kynurenine pathway and its involvement in mental disorders is an emerging area in psychiatry. We performed a meta-analysis to examine the differences in kynurenine metabolites in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ). Electronic databases were searched for studies that assessed metabolites involved in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, quinolinic acid, 3-hydroxykynurenine, and their associate ratios) in people with MDD, SZ, or BD, compared to controls. We computed the difference in metabolite concentrations between people with MDD, BD, or SZ, and controls, presented as Hedges' g with 95% confidence intervals. A total of 101 studies with 10,912 participants were included. Tryptophan and kynurenine are decreased across MDD, BD, and SZ; kynurenic acid and the kynurenic acid to quinolinic acid ratio are decreased in mood disorders (i.e., MDD and BD), whereas kynurenic acid is not altered in SZ; kynurenic acid to 3-hydroxykynurenine ratio is decreased in MDD but not SZ. Kynurenic acid to kynurenine ratio is decreased in MDD and SZ, and the kynurenine to tryptophan ratio is increased in MDD and SZ. Our results suggest that there is a shift in the tryptophan metabolism from serotonin to the kynurenine pathway, across these psychiatric disorders. In addition, a differential pattern exists between mood disorders and SZ, with a preferential metabolism of kynurenine to the potentially neurotoxic quinolinic acid instead of the neuroprotective kynurenic acid in mood disorders but not in SZ.

Toxoplasma gondii Effects on the Relationship of Kynurenine Pathway Metabolites to Acoustic Startle Latency in Schizophrenia vs. Control Subjects.

Background: Chronic infection with Toxoplasma gondii (TOXO) results in microcysts in the brain that are controlled by inflammatory activation and subsequent changes in the kynurenine pathway. TOXO seropositivity is associated with a heightened risk of schizophrenia (SCZ) and with cognitive impairments. Latency of the acoustic startle response, a putative index of neural processing speed, is slower in SCZ. SCZ subjects who are TOXO seropositive have slower latency than SCZ subjects who are TOXO seronegative. We assessed the relationship between kynurenine pathway metabolites and startle latency as a potential route by which chronic TOXO infection can lead to cognitive slowing in SCZ.Methods: Fourty-seven SCZ subjects and 30 controls (CON) were tested on a standard acoustic startle paradigm. Kynurenine pathway metabolites were measured using liquid chromatography-tandem mass spectrometry were kynurenine (KYN), tryptophan (TRYP), 3-hydroxyanthranilic acid (3-OHAA), anthranilic acid (AA), and kynurenic acid (KYNA). TOXO status was determined by IgG ELISA.Results: In univariate ANCOVAs on onset and peak latency with age and log transformed startle magnitude as covariates, both onset latency [F(1,61) = 5.76; p = 0.019] and peak latency [F(1,61) = 4.34; p = 0.041] were slower in SCZ than CON subjects. In stepwise backward linear regressions after stratification by Diagnosis, slower onset latency in SCZ subjects was predicted by higher TRYP (B = 0.42; p = 0.008) and 3-OHAA:AA (B = 3.68; p = 0.007), and lower KYN:TRYP (B = −185.42; p = 0.034). In regressions with peak latency as the dependent variable, slower peak latency was predicted by higher TRYP (B = 0.47; p = 0.013) and 3-OHAA:AA ratio (B = 4.35; p = 0.010), and by lower KYNA (B = −6.67; p = 0.036). In CON subjects neither onset nor peak latency was predicted by any KYN metabolites. In regressions stratified by TOXO status, in TOXO positive subjects, slower peak latency was predicted by lower concentrations of KYN (B = −8.08; p = 0.008), KYNA (B = −10.64; p = 0.003), and lower KYN:TRYP ratios (B = −347.01; p = 0.03). In TOXO negative subjects neither onset nor peak latency was predicted by any KYN metabolites.Conclusions: KYN pathway markers predict slowing of startle latency in SCZ subjects and in those with chronic TOXO infection, but this is not seen in CON subjects nor TOXO seronegative subjects. These findings coupled with prior work indicating a relationship of slower latency with SCZ and TOXO infection suggest that alterations in KYN pathway markers may be a mechanism by which neural processing speed, as indexed by startle latency, is affected in these subjects.

Analysis of the interaction between tryptophan-related compounds and ATP-binding cassette transporter G2 (ABCG2) using targeted metabolomics

ATP-binding cassette transporter G2 (ABCG2) is involved in the secretion of several compounds in milk. The in vitro and in vivo interactions between tryptophan-related compounds and ABCG2 were investigated. The tryptophan metabolome was determined by liquid chromatography-tandem mass spectrometry in milk and plasma from wild-type and Abcg2−/− mice as well as dairy cows carrying the ABCG2 Y581S polymorphism (Y/S) and noncarrier animals (Y/Y). The milk-to-plasma ratios of tryptophan, kynurenic acid, kynurenine, anthranilic acid, and xanthurenic acid were higher in wild-type mice than in Abcg2−/− mice. The ratio was 2-fold higher in Y/S than in Y/Y cows for kynurenine. In vitro transport assays confirmed that some of these compounds were in vitro substrates of the transporter and validated the differences observed between the two variants of the bovine protein. These findings show that the secretion of metabolites belonging to the kynurenine pathway into milk is mediated by ABCG2.

Tryptophan-kynurenine ratio as a biomarker of bladder cancer.

To investigate plasma and urinary kynurenine (KYN)-tryptophan (TRP) ratios in bladder cancer, expression of indoleamine 2,3-dioxygenase 1 (IDO1) in relation to tryptophan 2,3-dioxygenase (TDO2) in bladder tumour, and the correlation of KYN-TRP ratio with bladder tumour burden. Metabotyping of the TRP-KYN metabolic axis was performed via a clinical case-control study. Expression of IDO1 and TDO2 was measured in human biopsied tissues. Correlational experiments between KYN-TRP ratio and bladder tumour were performed using a murine orthotopic prostate-specific antigen (PSA)-secreting MB49 bladder cancer model. We established for the first time that plasma TRP level was significantly decreased, while both plasma and urinary KYN-TRP ratios were significantly higher in bladder cancer patients, and expression level of IDO1 but not TDO2 was increased in human bladder tumour. We reported the positive correlation between IDO1 expression, KYN-TRP ratio, normalized PSA to creatinine, and bladder tumour burden in the murine model. Kynurenine-tryptophan ratio is a promising surveillance biomarker for bladder cancer, but would require further validation before clinical translation.

Preclinical investigations and a first-in-human phase I trial of M4112, the first dual inhibitor of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2, in patients with advanced solid tumors

BackgroundM4112 is an oral, potent, and selective indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) dual inhibitor. Here, we report preclinical data and first-in-human phase I data, including safety,...

Amino Acid Metabolites Associated with Chronic Kidney Disease: An Eight-Year Follow-Up Korean Epidemiology Study.

The discovery of metabolomics-based biomarkers has been a focus of recent kidney dysfunction research. In the present study, we aimed to identify metabolites associated with chronic kidney disease (CKD) in the general population using a cross-sectional study design. At baseline, 6.5% of subjects had CKD. Pearson correlation analysis showed that 28 metabolites were significantly associated with estimated glomerular filtration rate (eGFR) after Bonferroni correction. Among these metabolites, 4 acylcarnitines, 12 amino acids, 4 biogenic amines, 1 phosphatidylcholine, and 1 sphingolipid were associated with CKD (p < 0.05). After eight years, 13.5% of subjects had CKD. Three amino acid metabolites were positively associated with new-onset CKD: citrulline [odds ratio (OR): 2.41, 95% confidence interval (CI): 1.26–4.59], kynurenine (OR: 1.98, 95% CI: 1.05–3.73), and phenylalanine (OR: 2.68, 95% CI: 1.00–7.16). The kynurenine:tryptophan ratio was also associated with CKD (OR: 3.20; 95% CI: 1.57–6.51). The addition of multiple metabolites significantly improved the CKD prediction by C statistics (0.756–0.85, p < 0.0001), and the net reclassification improvement was 0.84 (95% CI: 0.72–0.96). Elevated hs-C reactive protein (CRP) was associated with new-onset CKD (OR: 1.045, 95% CI: 1.005–1.086); however, this association disappeared following adjustment with the kynurenine:tryptophan ratio. The levels of citrulline and kynurenine and their ratio to tryptophan in CKD patients with proteinuria were worse than those with one or neither characteristic. Together, the results of this study demonstrate that amino acid metabolites are associated with CKD eight years after initial metabolite assessment. These results could improve the identification of subjects at high risk of CKD who have modified amino acid metabolism.

Impaired cognitive function in Crohn’s disease: Relationship to disease activity

Background & aimsImpaired attention and response inhibition have been reported in patients with Crohn’s disease (CD) in clinical remission. Prospective studies are needed to determine whether this is a stable feature of CD and whether a similar impairment is evident in ulcerative colitis (UC). Thus, our aims were to examine whether patients with CD and UC exhibited a persistent impairment in attentional performance, and if this impairment was related to key biological indices of relevance to cognition. MethodsA prospective observational study was conducted on fifteen patients with CD and 7 with UC in clinical remission recruited from a specialty clinic and 30 healthy matched control participants. A neuropsychological assessment was carried out at baseline (visit 1) and at a 6 month follow-up (visit 2). Plasma proinflammatory cytokines, the plasma kynurenine:tryptophan (Kyn:Trp) ratio and the salivary cortisol awakening response (CAR) were also determined at each visit. ResultsAcross visits, patients with CD exhibited impaired attentional performance (p ​= 0.023). Plasma IL-6 (P ​= ​0.001) and the Kyn:Trp ratio (P ​= ​0.03) were consistently elevated and the CAR significantly blunted (P ​< ​0.05) in patients with CD. No significant relationships were identified between any biochemical parameter and altered cognitive performance. ConclusionsImpaired cognitive function is a stable feature of patients with CD. These data suggest that even where remission has been achieved, the functional impact of an organic gastrointestinal disorder on cognition is still evident. However, it is unclear at present if physiological changes due to disease activity play a role in cognitive impairment in CD.

Tryptophan Depletion through a Low Protein Diet Alters Renal Structure and Function in Young Male Mice

Low protein diets have been used in patients with chronic kidney disease to decrease uremic burden, but its use is controversial due to concerns about malnutrition. Long term use of a low‐protein diet may also impact bone health through reduction of the essential amino acid, tryptophan. We have previously shown that feeding a low‐protein diet with increased levels of its metabolite, kynurenine (a change that also occurs in aging) to adult mice leads to bone loss. The kidney regulates many important factors for bone health such as Vitamin D, and in conjunction with parathyroid hormone, phosphate and calcium. Since aging is known to also impact the kidney, we hypothesized that alterations in the normal ratio of tryptophan to kynurenine would impact kidney structure and function. We fed 3‐mo‐old male mice one of four diets [normal 18% protein (NP) or low 8% protein (LP) with or without kynurenine added] for 8 weeks. Mice were housed in metabolic cages for baseline measurements and again at the end of the feeding for 24‐hr urine collection. At sacrifice, kidneys were weighed to detect changes in renal mass, frozen for Western blotting or formalin‐fixed for histological analysis. As expected, we found decreased albuminuria with LP; however, there was a further reduction with KYN treatment in LP mice. There was significant diuresis (2.2±0.31 vs. 0.8±0.1 ml/day) in LP compared to NP mice that was attenuated in KYN mice (1.0±0.2ml/day); this effect may be due in part to a reduction in AQP2 levels. Natriuresis followed a similar trend but did not reach significance (0.12±0.01 vs. 0.08±0.01 mmol/day). Renal mass alone (0.17±0.00 vs. 0.20±0.01 g) and kidney weight/body weight (0.0055±0.0001 vs. 0.0059±0.0001) was decreased in LP mice with no further impact of KYN. Thus, while changes in the tryptophan to kynurenine ratio seem to impact the kidney, the changes vary with the renal parameter investigated.Support or Funding InformationAG036675

A First Plasmodium vivax Natural Infection Induces Increased Activity of the Interferon Gamma-Driven Tryptophan Catabolism Pathway.

The human immune response that controls Plasmodium infection in the liver and blood stages of the parasite life cycle is composed by both pro- and anti-inflammatory programs. Pro-inflammatory responses primarily mediated by IFN-γ controls the infection, but also induce tolerogenic mechanisms to limit host damage, including the tryptophan (TRP) catabolism pathway mediated by the enzyme Indoleamine 2,3-Dioxygenase (IDO1), an enzyme that catalyzes the degradation of TRP to kynurenines (KYN). Here we assessed total serum kynurenines and cytokine dynamics in a cohort of natural Plasmodium vivax human infection and compared them to those of endemic healthy controls and other febrile diseases. In acute malaria, the absolute free kynurenine (KYN) serum levels and the KYN to TRP (KYN/TRP) ratio were significantly elevated in patients compared to healthy controls. Individuals with a diagnosis of a first malaria episode had higher serum KYN levels than individuals with a previous malaria episode. We observed an inverse relationship between the serum levels of IFN-γ and IL-10 in patients with a first malaria episode compared to those of subjects with previous history of malaria. Kynurenine elevation was positively correlated with serum IFN-γ levels in acute infection, whereas, it was negatively correlated with parasite load and P. vivax LDH levels. Overall, the differences observed between infected individuals depended on the number of Plasmodium infections. The decrease in the KYN/TRP ratio in malaria-experienced subjects coincided with the onset of anti-P. vivax IgG. These results suggest that P. vivax infection induces a strong anti-inflammatory program in individuals with first time malaria, which fades with ensuing protective immunity after subsequent episodes. Understanding the tolerance mechanisms involved in the initial exposure would help in defining the balance between protective and pathogenic immune responses necessary to control infection and to improve vaccination strategies.

Digestible trypthophan and digestilbe lysine ratios in diets for growing japanese quails

The objective of this study was to evaluate the effects of different tryptophan and digestible lysine ratios for growing Japanese quails (1 to 40 days of age) with repercussions on the early stage of production (41 to 110 days of age). A total of 1000 one day old Japanese quails were distributed at random, with five tryptophan and digestible lysine ratios, 10 replicates and 20 birds per experimental unit. A tryptophan- deficient basal diet was formulated with 1.48 g of digestible tryptophan /kg, corresponding to a ratio of tryptophan and lysine of 0.14. This basal diet was supplemented with five levels of L-tryptophan (98%), replacing glutamic acid corresponding to the tryptophan and lysine ratio of 0.14 (no supplementation); ratios of 0.16; 0.18; 0.20 and 0.22, being the diets isocaloric and isonitrogenous. The performance of the birds in the growing and egg laying phases was evaluated. Although body weight and weight gain until 40 days of age had increased (P&lt;0,001) and feed intake in the egg laying phase had decreased (P=0,037) in a linear fashion, LRP was the one with the best adjustment for those parameters. The effect was quadratic for feed intake (P=0,0069), feed conversion (P=0,0032) and viability (P&lt;0,001) of the birds in the growing phase. A quadratic effect was found for egg production per bird housed at one day of age (P&lt;0,001), weight gain at 110 days of age (P=0,039) and feed conversion per egg mass (P=0,046) in the laying phase. Intake of tryptophan increased (P&lt;0,001) and egg production per housed bird in the laying phase linearly decreased (P&lt;0,001) with the increase in the ratios between tryptophan and lysine. The digestible tryptophan and digestible lysine ratio is 0.18 (1.88 g of tryptophan/kg and 10.5 g of lysine/kg of diet), corresponding to an intake of 20.63 mg of tryptophan per bird per day, in the diet for growing, provides greater viability of birds in the growing phase and a satisfactory performance of Japanese quails in the laying phase.

IDO Targeting in Sarcoma: Biological and Clinical Implications.

Sarcomas are heterogeneous malignant mesenchymal neoplasms with limited sensitivity to immunotherapy. We recently demonstrated an increase in Kynurenine Pathway (KP) activity in the plasma of sarcoma patients treated with pembrolizumab. While the KP has already been described to favor immune escape through the degradation of L-Tryptophan and production of metabolites including L-Kynurenine, Indoleamine 2,3 dioxygenase (IDO1), a first rate-limiting enzyme of the KP, still represents an attractive therapeutic target, and its blockade had not yet been investigated in sarcomas. Using immunohistochemistry, IDO1 and CD8, expression profiles were addressed within 203 cases of human sarcomas. At a preclinical level, we investigated the modulation of the KP upon PDL1 blockade in a syngeneic model of sarcoma through mRNA quantification of key KP enzymes within the tumor. Furthermore, in order to evaluate the possible anti-tumor effect of IDO blockade in combination with PDL1 blockade, an innovative IDO inhibitor (GDC-0919) was used. Its effect was first assessed on Kynurenine to Tryptophan ratio at plasmatic level and also within the tumor. Following GDC-0919 treatment, alone or in combination with anti-PDL1 antibody, tumor growth, immune cell infiltration, and gene expression profiling were measured. IDO1 expression was observed in 39.1% of human sarcoma cases and was significantly higher in tumors with high CD8 infiltration. In the pre-clinical setting, blockade of PDL1 led to a strong anti-tumor effect and was associated with an intratumoral inflammatory cytokines signature driven by Ifng but also with a modulation of the KP enzymes including Ido1 and Ido2. IDO1 inhibition using GDC-0919 resulted in (i) a significant decrease of plasmatic Kynurenine to Tryptophan ratio and in (ii) a decrease of tumoral Kynurenine. However, GDC-0919 used alone or combined with anti-PDL1, did not show anti-tumoral activity and did not affect the tumor immune cell infiltrate. In order to elucidate the mechanism(s) underlying the lack of effect of GDC-0919, we analyzed the gene expression profile of intratumoral biopsies. Interestingly, we have found that GDC-0919 induced a downregulation of the expression of pvr and granzymes, and an upregulation of inhba and Dtx4 suggesting a potential role of the IDO pathway in the control of NK function.

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer.

Many patients with cancer suffer from anemia, depression, and an impaired quality of life (QoL). These patients often also show decreased plasma tryptophan levels and increased kynurenine concentrations in parallel with elevated concentrations of Th1 type immune activation marker neopterin. In the course of anti-tumor immune response, the pro-inflammatory cytokine interferon gamma (IFN-γ) induces both, the enzyme indoleamine 2,3-dioxygenase (IDO) to degrade tryptophan and the enzyme GTP-cyclohydrolase I to form neopterin. High neopterin concentrations as well as an increased kynurenine to tryptophan ratio (Kyn/Trp) in the blood of cancer patients are predictive for a worse outcome. Inflammation-mediated tryptophan catabolism along the kynurenine pathway is related to fatigue and anemia as well as to depression and a decreased QoL in patients with solid tumors. In fact, enhanced tryptophan breakdown might greatly contribute to the development of anemia, fatigue, and depression in cancer patients. IDO activation and stimulation of the kynurenine pathway exert immune regulatory mechanisms, which may impair anti-tumor immune responses. In addition, tumor cells can degrade tryptophan to weaken immune responses directed against them. High IDO expression in the tumor tissue is associated with a poor prognosis of patients. The efficiency of IDO-inhibitors to inhibit cancer progression is currently tested in combination with established chemotherapies and with immune checkpoint inhibitors. Inflammation-mediated tryptophan catabolism and its possible influence on the development and persistence of anemia, fatigue, and depression in cancer patients are discussed.

The relationship between plasma serotonin and kynurenine pathway metabolite levels and the treatment response to escitalopram and desvenlafaxine

IntroductionThe response of patients with major depressive disorders (MDD) to antidepressant treatments have been shown to be affected by multiple factors, including disease severity and inflammation. Increasing evidence indicates that the kynurenine metabolic pathway is activated by inflammation in MDD patients and plays a role in the pathophysiology of depression. Antidepressant treatments have been reported to affect kynurenine pathway metabolite levels as well. This study investigates differential associations between the antidepressant treatment outcome to escitalopram versus desvenlafaxine with the pre-treatment and post-treatment-changes in serotonin and kynurenine pathway metabolite levels. MethodsThe levels of serotonin and of kynurenine pathway metabolites were measured in plasma using liquid chromatography-mass spectrometry (LC-MS) in 161 currently depressed patients with MDD at baseline and after 8 weeks of treatment with either escitalopram or desvenlafaxine. Treatment response was defined conventionally by a reduction of at least 50% in the Hamilton Depression Rating Scale 21 item (HAMD-21) total score from baseline; remission was defined by reaching a post-treatment HAMD-21 score ≤7. ResultsResponse to escitalopram treatment was associated with higher baseline serotonin levels (p = 0.022), lower baseline kynurenine (Kyn)/tryptophan (Trp) ratio (p = 0.008) and lower baseline quinolinic acid (QuinA)/tryptophan (Trp) ratio (p = 0.047), suggesting a lower inflammation state. Greater improvement in depression symptoms as measured by percent change of HAMD-21 score from baseline was also associated with higher baseline serotonin levels (p = 0.033) in escitalopram treatment arm. Furthermore, remitters to escitalopram treatment showed significant increases in the kynurenic acid (KynA)/3-hydroxykynurenine (3HK) ratio after treatment (p = 0.015). In contrast, response to desvenlafaxine treatment was not associated with any metabolite analyzed. We also confirmed a previous report that plasma serotonin levels are lower in MDD patients compared to healthy controls (p = 0.004) and that the kynurenine plasma level is negatively associated with depression symptom severity (p = 0.047). ConclusionsIn MDD patients the antidepressant response to escitalopram was positively associated with baseline serotonin levels and inversely associated with activation of the kynurenine pathway. These results appear consistent with previous literature showing that biomarker evidence of inflammation is associated with lower response to antidepressants from the selective serotonin reuptake inhibitor class. Moreover, increases in the kynurenic acid (KynA)/3-hydroxykynurenine (3HK) ratio, which previously has been characterized as a neuroprotective index, were associated with full remission under escitalopram treatment.

A Validation Study on IDO Immune Biomarkers for Survival Prediction in Non-Small Cell Lung Cancer: Radiation Dose Fractionation Effect in Early-Stage Disease.

We recently reported that indoleamine 2, 3-dioxygenase (IDO) activity is significantly correlated with more distant metastasis and worse survival. The present study examined whether radiotherapy (RT) dose fractionation correlates with IDO-mediated immune activity in patients with early-stage NSCLC.Methods: Patients with newly diagnosed stage I-II NSCLC treated with either conventionally fractionated 3-dimensional conformal radiotherapy (3DCRT) or stereotactic body radiotherapy (SBRT) were analyzed. Levels of two key molecules associated with the IDO immune checkpoint, serum kynurenine and the kynurenine:tryptophan ratio (K:T ratio), were measured at pre-RT, during-RT, and 3-month post-RT. The relationship between disease control outcomes [overall survival (OS), progression free survival, and local/regional/distant failure rates] and absolute levels of these markers, as well as dynamic changes in their levels during RT, was studied. Fifty-six patients (SBRT = 28, 3DCRT = 28) with early-stage NSCLC were studied. In all patients, higher kynurenine post-RT was significantly associated with worse OS ([HR, 1.25; 95% confidence interval (CI), 1.01-1.55; P = 0.044). No statistically significant differences in absolute kynurenine levels or the K:T ratio were observed in patients treated with 3DCRT or SBRT at any of the three time points. However, the absolute kynurenine levels rose significantly more post-RT in the 3DCRT patients with a median increase 0.721 ng/mL, compared to that of SBRT patients (0.115 ng/mL); P = 0.022. This study validated that elevated IDO activity correlated with worse survival outcomes in patients with early-stage NSCLC treated with definitive RT. Hypofractionated SBRT may have less immunosuppressive effect than 3DCRT, as measured by IDO.

Saturated Fatty Acid Intake Is Associated With Increased Inflammation, Conversion of Kynurenine to Tryptophan, and Delta-9 Desaturase Activity in Healthy Humans.

Saturated fat ingestion has previously been linked to increases in inflammation. However the relationship between saturated fatty acid (SFA) intake and the kynureine:tryptophan ratio ([Kyn]:[Trp]), a marker of inflammation, has not been previously investigated. This study evaluated in healthy, middle aged, individuals (men = 48, women = 52), potential relationships between SFA intake, red blood cell (RBC) membrane SFAs and monounsaturated fatty acids (MUFA), the [Kyn]:[Trp] ratio, C-reactive protein (CRP), TNF-α and Δ9 desaturase activity. [Kyn]:[Trp] was positively associated with increases in Total fat (P = .034) intake, including Total SFA (P = .029) and Total MUFA (P = .042) intakes. Unexpectedly the [Kyn]:[Trp] ratio was inversely associated with the percentage of Total SFA (P = .004) and positively associated with percentage of Total MUFA (P = .012) present in the RBC membrane. We found a positive association between Δ9 desaturase activity, responsible for the desaturation of a various SFAs to MUFAs, and [Kyn]:[Trp] (P = .008). [Kyn]:[Trp] was also positively associated with CRP (P = .044), however no significant relationship between [Kyn]:[Trp] and TNF-α was found. This study shows for the first time that SFA consumption increases inflammatory pathways linked to increased tryptophan to kynurenine conversion, even in healthy humans. Our data also suggests that SFA linked increases in inflammation occur concomitantly with an upregulation of Δ9 desaturase activity resulting in increased desaturation of SFA substrates to their MUFA derivatives.

Serum Neopterin Levels and IDO Activity as Possible Markers for Presence and Progression of Hepatitis B

AbstractChronic Hepatitis B virus (HBV) is still one of the major reasons for liver related mortality and morbidity all around the world. This study aimed to investigate the possible relationship between the immune system activation and presence, as well as progression, of hepatitis B infection by monitoring the tryptophan degradation and serum neopterin levels in patients with HBV. 110 patients with HBV and 23 healthy subjects were included in the study. The patients had significantly higher neopterin levels and increased kynurenine to tryptophan ratios, which were most probably due to enhanced indoleamine 2,3-dioxygenase (IDO) activity compared to healthy control. A strong positive correlation was found between neopterin levels and IDO activity in patient group. Neopterin levels and IDO activity were markedly increased in patients with histological activity index (HAI) ≥4 compared to HAI&lt;4, and a significant correlation was found between neopterin and HAI. Moreover, there was a significant correlation between albumin levels and IDO activity in HBV patients. These findings suggest that tryptophan degradation results from IFN-γ-induced IDO activation, likewise depletion of albumin synthesis in HBV patients may result from diminished tryptophan availability. In conclusion, based on the study results, serum neopterin levels and IDO activity could provide additional immunological information for monitoring liver histological activity and can be used as prognostic markers in HBV disease.

Effects of IDO1 and TDO2 inhibition on cognitive deficits and anxiety following LPS-induced neuroinflammation.

Sustained immune activation leads to cognitive dysfunctions, depression-, and anxiety-like behaviours in humans and rodents. It is modelled by administration of lipopolysaccharides (LPS) to induce expression of pro-inflammatory cytokines that then activate indoleamine 2,3 dioxygenase (IDO1), the rate-limiting enzyme in the kynurenine pathway of tryptophan metabolism. Here, we ask whether chronic IDO1 inhibition by 1-methyl-tryptophan (1-MT, added at 2 g/l in the drinking water) or chronic inhibition of tryptophan 2,3 dioxygenase (TDO2), another enzyme capable of converting tryptophan to kynurenine, by 680C91 (15 mg/kg per os), can rescue LPS-induced (0.83-mg/kg intraperitoneally) anxiety and cognitive deficits. We also investigate the acute effects of 680C91 on serotonergic, dopaminergic, and kynurenine pathway metabolites. We examined LPS-induced deficits in trace fear conditioning and anxiety in the light-dark box and elevated plus maze (EPM) in group-housed C57Bl6/N mice. Kynurenine pathway metabolites and monoamine levels were measured via high-performance liquid chromatography. Chronic blockade of IDO1 with 1-MT did not rescue cognitive deficits or abrogate the anxiogenic behaviour caused by LPS despite a decrease in the brain kynurenine:tryptophan ratio. However, 1-MT by itself demonstrated anxiolytic properties in the EPM. Acute and chronic inhibition of TDO2 elevated brain levels of tryptophan, while chronic inhibition of TDO2 was unsuccessful in rescuing cognitive deficits and abrogating the anxiety caused by LPS. In line with previous studies, we show that LPS administration induces anxiety and cognitive dysfunctions in mice that however were not reversed by chronic blockade of IDO1 or TDO2 at the doses used.

Kynurenine suppresses osteoblastic cell energetics in vitro and osteoblast numbers in vivo.

Aging is a progressive process associated with declining tissue function over time. Kynurenine, an oxidized metabolite of the essential amino acid tryptophan that increases in abundance with age, drives cellular processes of aging and dysfunction in many tissues, and recent work has focused on understanding the pathways involved in the harmful effects of kynurenine on bone. In this study, we sought to investigate the effects of controlled kynurenine administration on osteoblast bioenergetics, in vivo osteoblast abundance, and marrow fat accumulation. Additionally, as an extension of earlier studies with dietary administration of kynurenine, we investigated the effects of kynurenine on Hdac3 and NCoR1 expression and enzymatic deacetylase activity as potential mechanistic contributors to the effects of kynurenine on osteoblasts. Kynurenine administration suppressed cellular metabolism in osteoblasts at least in part through impaired mitochondrial respiration, and suppressed osteoblastic numbers in vivo with no concurrent effects on marrow adiposity. Deleterious effects of kynurenine treatment on osteoblasts were more pronounced in female models as compared to males. However, kynurenine treatment did not inhibit Hdac3's enzymatic deacetylase activity nor its repression of downstream glucocorticoid signaling. As such, future work will be necessary to determine the mechanisms by which increased kynurenine contributes to aging bone bioenergetics. The current study provides novel further support for the idea that kynurenine contributes to impaired osteoblastic function, and suggests that impaired matrix production by kynurenine-affected osteoblasts is attributed in part to impaired osteoblastic bioenergetics. As circulating kynurenine levels in increase with age, and human bone density inversely correlates with the serum kynurenine to tryptophan ratio, these mechanisms may have important relevance in the etiology and pathogenesis of osteoporosis in humans.

Neopterin levels and Kyn/Trp ratios were significantly increased in dengue virus patients and subsequently decreased after recovery

ObjectivesDuring dengue fever, a pronounced gamma-interferon immune response produces neopterin and promotes tryptophan degradation by the enzyme indoleamine-2,3-dioxygenase 1 (IDO-1). Activated IDO-1 is indicated by an increased kynurenine to tryptophan ratio (Kyn/Trp) in patients. MethodsPlasma levels of neopterin, kynurenine, and tryptophan were measured in 72 hospitalized dengue virus (DENV) patients and 100 healthy individuals. Plasma levels of neopterin, kynurenine, and tryptophan were also measured prospectively in a second cohort of 13 DENV patients; on the day of hospitalization, on day 2–3 at discharge, and 7–10 days after discharge. DENV RNA positivity was determined by qualitative and quantitative methodologies. ResultsDENV RNA-positive patients presented significantly higher levels of neopterin (mean 36.5nmol/l) and Kyn/Trp ratios (mean 102μmol/mmol) compared to DENV RNA-negative individuals. A significant correlation between neopterin levels and Kyn/Trp ratios was observed in both DENV RNA-positive (Spearman’s rho=0.37, p< 0.01) and DENV RNA-negative (Spearman’s rho=0.89, p<0.001) patients. Kyn/Trp ratios were negatively correlated with platelet counts (Spearman’s rho=−0.43, p<0.01) and positively correlated with liver enzymes: AST (Spearman’s rho=0.68, p<0.01) and ALT (Spearman’s rho=0.51, p<0.05). In addition, the follow-up data presented a significant decrease in neopterin levels and Kyn/Trp ratios within 10 days after hospital entry. ConclusionsNeopterin levels and Kyn/Trp ratios were significantly increased in DENV patients and subsequently decreased after recovery.