Can supplementation of tryptophan in parenteral nutrition increase melatonin and alleviate inflammatory response?

OBJECTIVE: Endogenous melatonin is produced from tryptophan which is an essential amino acid. Besides its role in the regulation of sleep patterns, melatonin has anti-inflammatory effects. In this case-control study, we aimed to compare tryptophan and melatonin levels and their relationship with the inflammatory response, specifically serum interleukin-1, interleukin-6, and c-reactive protein levels following major abdominal surgery in patients with food restriction and who receive parenteral nutritional therapy. METHODS: We enrolled 40 patients between the ages of 18 and 65 years in the study. We collected blood and urine samples 48 h before the operation and on postoperative days 1, 3, and 5. RESULTS AND CONCLUSION: The tryptophan levels in the experimental group were higher than in the control group but failed to reach any statistical difference. Melatonin levels were increased in both groups following the surgery compared with preoperative levels. The increase in the experimental group was statistically different 3 days after the surgery. The difference in the level of interleukin-1 between the control and the experimental groups was greatest on postoperative day 3. On postoperative day 3, the interleukin-6 level in the treatment group was slightly higher than in the control group. We did not find any difference in the levels of c-reactive protein between the groups. As a result, the levels of tryptophan and melatonin were increased in the parenteral nutrition group, irrespective of the postoperative inflammatory response.

Enhanced tryptophan-kynurenine metabolism via indoleamine 2,3-dioxygenase 1 induction in dermatomyositis.

OBJECTIVES: Extrahepatic tryptophan (Trp)-kynurenine (Kyn) metabolism via indoleamine 2,3-dioxygenase 1 (IDO1) induction was found to be associated with intrinsic immune regulation. However, the Trp-Kyn metabolism-associated immune regulation in dermatomyositis (DM) remains unknown. Therefore, we aimed to investigate the clinical relevance of the Trp-Kyn metabolism via IDO1 induction in DM. METHODS: Liquid chromatography-mass spectrometry (HPLC-MS) was used to examine the serum Kyn and Trp concentrations in DM. In addition, we used X-tile software to determine the optimal cutoff value of the Kyn/Trp ratio, a surrogate marker for Trp-Kyn metabolism. Spearman analysis was performed to evaluate the association of Trp-Kyn metabolism with muscle enzymes and inflammatory markers. RESULTS: DM patients had significantly higher serum Kyn/Trp ratio (× 10-3) when compared with the healthy controls. The serum Kyn/Trp ratio was positively correlated with the levels of muscle enzymes and inflammatory markers. In addition, the serum Kyn/Trp ratio significantly decreased (36.89 (26.00-54.00) vs. 25.00 (18.00-37.00), P = 0.0006) after treatment. DM patients with high serum Kyn/Trp ratio had a significantly higher percentage of muscle weakness symptoms (62.5% vs. 20.0%, P = 0.019) and higher levels of LDH (316.0 (236.0-467.0) vs. 198.0 (144.0-256.0), P = 0.004) and AST (56.5 (35.0-92.2) vs. 23.0 (20.0-36.0), P = 0.002)) than those with low serum Kyn/Trp ratio. Multiple Cox regression analyses identified ln(Kyn/Trp) (HR 4.874, 95% CI 1.105-21.499, P = 0.036) as an independent prognostic predictor of mortality in DM. CONCLUSIONS: DM patients with enhanced Trp-Kyn metabolism at disease onset are characterized by more severe disease status and poor prognosis. Intrinsic immune regulation function via enhanced Trp-Kyn metabolism by IDO1 induction may be a potential therapeutic target in DM. Key Points • HPLC-MS identified increased serum Kyn/Trp ratio in DM patients, which positively correlated with levels of muscle enzymes and inflammatory markers and was downregulated upon treatment. • Cox regression analyses identified ln(Kyn/Trp) as an independent prognostic predictor of mortality in DM. • Monitoring intrinsic immune regulation function should be considered a potential therapeutic target in DM patients.

Kynurenine pathway in Coronavirus disease (COVID-19): Potential role in prognosis.

BACKGROUND: It is known that inflammatory responses play an important role in the pathophysiology of COVID-19. AIMS: In this study, we aimed to examine the role of kynurenine (KYN) metabolism on the severity of COVID-19 disease AQ5. MATERIALS & METHODS: Seventy COVID-19 patients of varying severity and 30 controls were included in the study. In addition to the classical laboratory parameters, KYN, tryptophan (TRP), kynurenic acid (KYNA), 3 hydroxykynurenine (3OHKYN), quinolinic acid (QA), and picolinic acid (PA) were measured with mass spectrometry. RESULTS: TRP, KYN, KYN:TRP ratio, KYNA, 3OHKYN, PA, and QA results were found to be significantly different in COVID-19 patients (p < 0.001 for all). The KYN:TRP ratio and PA of severe COVID-19 patients was statistically higher than that of mild-moderate COVID-19 patients (p < 0.001 for all). When results were examined, statistically significant correlations with KYN:TRP ratio, IL-6, ferritin, and procalcitonin were only found in COVID-19 patients. ROC analysis indicated that highest AUC values were obtained by KYN:TRP ratio and PA (0.751 vs 0.742). In determining the severity of COVID-19 disease, the odd ratios (and confidence intervals) of KYN:TRP ratio and PA levels that were adjusted according to age, gender, and comorbidity were determined to be 1.44 (1.1-1.87, p = 0.008) and 1.06 (1.02-1.11, p = 0.006), respectively. DISCUSSION & CONCLUSION: According to the results of this study, KYN metabolites play a role in the pathophysiology of COVID-19, especially KYN:TRP ratio and PA could be markers for identification of severe COVID-19 cases.

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.

The impact of bariatric surgery on serum tryptophan-kynurenine pathway metabolites.

This study aims to explore the immediate effects of bariatric surgery on serum tryptophan-kynurenine pathway metabolites in individuals with type 2 diabetes and BMI > 30. With the goal of providing insight into the link between tryptophan pathway metabolites, type 2 diabetes, and chronic obesity-induced inflammation. This longitudinal study included 20 participants. Half were diagnosed with type 2 diabetes. 11 and 9 underwent RYGB and SG respectively. Blood samples were obtained at pre-operative and 3 months post-operative timepoints. Tryptophan and downstream metabolites of the kynurenine pathway were quantified with an ultrahigh-performance liquid chromatography tandem mass spectrometry with electrospray ionisation method. At 3 months post-operation, RYGB led to significant reductions in tryptophan, kynurenic acid and xanthurenic acid levels when compared to baseline. Significant reductions of the same metabolites after surgery were also observed in individuals with T2D irrespective of surgical procedure. These metabolites were significantly correlated with serum HbA1c levels and BMI. Bariatric surgery, in particular RYGB reduces serum levels of tryptophan and its downstream kynurenine metabolites. These metabolites are associated with T2D and thought to be potentially mechanistic in the systemic processes of obesity induced inflammation leading to insulin resistance. Its reduction after surgery is associated with an improvement in glycaemic control (HbA1c).

Association of plasma tryptophan concentration with periaqueductal gray matter functional connectivity in migraine patients.

Altered periaqueductal gray matter (PAG) functional connectivity contributes to brain hyperexcitability in migraine. Although tryptophan modulates neurotransmission in PAG projections through its metabolic pathways, the effect of plasma tryptophan on PAG functional connectivity (PAG-FC) in migraine has not been investigated yet. In this study, using a matched case-control design PAG-FC was measured during a resting-state functional magnetic resonance imaging session in migraine without aura patients (n = 27) and healthy controls (n = 27), and its relationship with plasma tryptophan concentration (TRP) was assessed. In addition, correlations of PAG-FC with age at migraine onset, migraine frequency, trait-anxiety and depressive symptoms were tested and the effect of TRP on these correlations was explored. Our results demonstrated that migraineurs had higher TRP compared to controls. In addition, altered PAG-FC in regions responsible for fear-cascade and pain modulation correlated with TRP only in migraineurs. There was no significant correlation in controls. It suggests increased sensitivity to TRP in migraine patients compared to controls. Trait-anxiety and depressive symptoms correlated with PAG-FC in migraine patients, and these correlations were modulated by TRP in regions responsible for emotional aspects of pain processing, but TRP did not interfere with processes that contribute to migraine attack generation or attack frequency.

Metabolite trajectories across the perinatal period and mental health: A preliminary study of tryptophan-related metabolites, bile acids and microbial composition.

Depression and anxiety during pregnancy and postpartum are common, but affected women differ in timing, trajectories, and extent of symptoms. The objective of this pilot, feasibility study is to analyze trajectories of serotonin and tryptophan-related metabolites, bile acid metabolites, and microbial composition, in relation to psychiatric history and current symptoms across the perinatal period. Serum and fecal samples were collected from 30 women at three times points in the perinatal period and assayed with LC-MS/MS and 16S sequencing respectively. We defined mean trajectories for each metabolite, clustered individuals by metabolite trajectories, tested associations between metabolites, and examined metabolite levels in relation to microbial composition. Findings of note include: (1) changes in kynurenine and the ratio of kynurenic acid to kynurenine from second trimester to third trimester were strongly associated with baseline primary and secondary bile acids. (2) Secondary bile acid UDCA and its conjugated forms were associated with lower bacterial diversity and levels of Lachnospiraceae, a taxa known to produce Short Chain Fatty Acids. (3) History of anxiety was associated with UDCA levels, but history of major depression was not associated with any of the bile acids. (4) There was a trend towards lower dietary fiber for those with history of anxiety or depression. Overall, our results reveal substantial temporal variation in tryptophan-related metabolites and in bile acid metabolites over the perinatal period, with marked inter-individual variability. Trajectories of TRP -related metabolites, primary and secondary bile acids, and the absence or presence of microbes that produce Short Chain Fatty Acids (SCFAs) considered in concert have the potential to differentiate individuals based on perinatal adaptations that may impact mental and overall health.

Investigation of the Relationship among Cortisol, Pro-inflammatory Cytokines, and the Degradation of Tryptophan into Kynurenine in Patients with Major Depression and Suicidal Behavior.

BACKGROUND: The increased degradation of tryptophan (Trp) along the kynurenine (Kyn) pathway due to inflammation and/or activation of the hypothalamic-pituitary-adrenal (HPA) axis has been reported among the biological factors involved in the pathophysiology of major depressive disorder (MDD) and suicide. However, the interaction among these multiple factors is not yet completely clarified. METHODS: We studied plasma levels of Trp, Kyn, cortisol and proinflammatory cytokines (IL-1, IL- 6, IL-12, IL-20) and calculated the ratio Kyn/Trp as an index of the breakdown of Trp into Kyn in 31 suicidal MDD patients and 67 non-suicidal MDD patients. RESULT: We confirmed that suicidal MDD patients have reduced plasma Trp, higher Kyn and Kyn/Trp ratio, and no difference in cortisol levels than non-suicidal MDD patients. IL-1 and IL-12 levels were significantly higher in suicidal MDD than in non-suicidal MDD (p=0.034 and p=0.023, respectively), whereas Il-6 and IL-20 levels were equal in the two groups. The Kyn/Trp ratio was positively correlated with a pro-inflammatory cytokines index (r=0.309, p=0.002) and cortisol (r=0.368, p=0.001). Notably, the variance in the Kyn/Trp ratio explained by the model including both cortisol and inflammatory parameters as dependent variables, substantially improved compared with the models in which the two parameters were considered separately. CONCLUSION: These findings show that both cortisol and proinflammatory cytokines are involved in the enhanced breakdown of Trp into Kyn occurring in suicidal MDD patients, thus adding new knowledge on the biological mechanisms leading to the activation of the Kyn pathway in MDD and suicide.

Analysis of Serum Metabolomics in Rats with Osteoarthritis by Mass Spectrometry.

Osteoarthritis is a common multifactorial chronic disease that occurs in articular cartilage, subchondral bone, and periarticular tissue. The pathogenesis of OA is still unclear. To investigate the differences in serum metabolites between OA and the control group, liquid chromatography/mass spectrometry (LC/MS)-based metabolomics was used. To reveal the pathogenesis of OA, 12 SD male rats were randomly divided into control and OA groups using collagenase to induce OA for modeling, and serum was collected 7 days after modeling for testing. The OA group was distinguished from the control group by principal component analysis and orthogonal partial least squares-discriminant analysis, and six biomarkers were finally identified. These biomarkers were metabolized through tryptophan metabolism, glutamate metabolism, nitrogen metabolism, spermidine metabolism, and fatty acid metabolism pathways. The study identified metabolites that may be altered in OA, suggesting a role in OA through relevant metabolic pathways. Metabolomics, as an important tool for studying disease mechanisms, provides useful information for studying the metabolic mechanisms of OA.

Kynurenine pathway activation and deviation to anthranilic and kynurenic acid in fibrosing chronic graft-versus-host disease.

Fibrosing chronic graft-versus-host disease (cGVHD) is a debilitating complication of allogeneic stem cell transplantation (alloSCT). A driver of fibrosis is the kynurenine (Kyn) pathway, and Kyn metabolism patterns and cytokines may influence cGVHD severity and manifestation (fibrosing versus gastrointestinal [GI] cGVHD). Using a liquid chromatography-tandem mass spectrometry approach on sera obtained from 425 patients with allografts, we identified high CXCL9, high indoleamine-2,3-dioxygenase (IDO) activity, and an activated Kyn pathway as common characteristics in all cGVHD subtypes. Specific Kyn metabolism patterns could be identified for non-severe cGVHD, severe GI cGVHD, and fibrosing cGVHD, respectively. Specifically, fibrosing cGVHD was associated with a distinct pathway shift toward anthranilic and kynurenic acid, correlating with reduced activity of the vitamin-B2-dependent kynurenine monooxygenase, low vitamin B6, and increased interleukin-18. The Kyn metabolite signature is a candidate biomarker for severe fibrosing cGVHD and provides a rationale for translational trials on prophylactic vitamin B2/B6 supplementation for cGVHD prevention.

L. rhamnosus improves the immune response and tryptophan catabolism in laying hen pullets.

In mammals, early-life probiotic supplementation is a promising tool for preventing unfavourable, gut microbiome-related behavioural, immunological, and aromatic amino acid alterations later in life. In laying hens, feather-pecking behaviour is proposed to be a consequence of gut-brain axis dysregulation. Lactobacillus rhamnosus decreases stress-induced severe feather pecking in adult hens, but whether its effect in pullets is more robust is unknown. Consequently, we investigated whether early-life, oral supplementation with a single Lactobacillus rhamnosus strain can prevent stress-induced feather-pecking behaviour in chickens. To this end, we monitored both the short- and long-term effects of the probiotic supplement on behaviour and related physiological parameters. We hypothesized that L. rhamnosus would reduce pecking behaviour by modulating the biological pathways associated with this detrimental behaviour, namely aromatic amino acid turnover linked to neurotransmitter production and stress-related immune responses. We report that stress decreased the proportion of cytotoxic T cells in the tonsils (P = 0.047). Counteracting this T cell depression, birds receiving the L. rhamnosus supplementation significantly increased all T lymphocyte subset proportions (P < 0.05). Both phenotypic and genotypic feather peckers had lower plasma tryptophan concentrations compared to their non-pecking counterparts. The probiotic supplement caused a short-term increase in plasma tryptophan (P < 0.001) and the TRP:(PHE + TYR) ratio (P < 0.001). The administration of stressors did not significantly increase feather pecking in pullets, an observation consistent with the age-dependent onset of pecking behaviour. Despite minimal changes to behaviour, our data demonstrate the impact of L. rhamnosus supplementation on the immune system and the turnover of the serotonin precursor tryptophan. Our findings indicate that L. rhamnosus exerts a transient, beneficial effect on the immune response and tryptophan catabolism in pullets.

Tryptophan metabolism is inversely regulated in the tumor and blood of patients with glioblastoma.

Tryptophan (Trp)-catabolic enzymes (TCEs) produce metabolites that activate the aryl hydrocarbon receptor (AHR) and promote tumor progression and immunosuppression in glioblastoma. As therapies targeting TCEs or AHR become available, a better understanding of Trp metabolism is required. Methods: The combination of LC-MS/MS with chemical isobaric labeling enabled the simultaneous quantitative comparison of Trp and its amino group-bearing metabolites in multiple samples. We applied this method to the sera of a cohort of 43 recurrent glioblastoma patients and 43 age- and sex-matched healthy controls. Tumor volumes were measured in MRI data using an artificial neural network-based approach. MALDI MSI visualized Trp and its direct metabolite N-formylkynurenine (FK) in glioblastoma tissue. Analysis of scRNA-seq data was used to detect the presence of Trp metabolism and AHR activity in different cell types in glioblastoma. Results: Compared to healthy controls, glioblastoma patients showed decreased serum Trp levels. Surprisingly, the levels of Trp metabolites were also reduced. The decrease became smaller with more enzymatic steps between Trp and its metabolites, suggesting that Trp availability controls the levels of its systemic metabolites. High tumor volume associated with low systemic metabolite levels and low systemic kynurenine levels associated with worse overall survival. MALDI MSI demonstrated heterogeneity of Trp catabolism across glioblastoma tissues. Analysis of scRNA-seq data revealed that genes involved in Trp metabolism were expressed in almost all the cell types in glioblastoma and that most cell types, in particular macrophages and T cells, exhibited AHR activation. Moreover, high AHR activity associated with reduced overall survival in the glioblastoma TCGA dataset. Conclusion: The novel techniques we developed could support the identification of patients that may benefit from therapies targeting TCEs or AHR activation.

δEPCD: the electrophysiologic coefficient of depressiveness.

Despite research advances, recently identified biological markers for depression are either non-specific or impractical in daily clinical practice. Hence, we aim to identify a novel biomarker: δEPCD, the electrophysiologic coefficient of depressiveness. δEPCD must be sensitive and specific to the vulnerability towards depression. It should also detect the presence of a depressive clinical state and be able to quantify its severity. Moreover, it should be easily accessible and cost-effective. Accordingly, combining high-frequency heart rate variability (HF-HRV), which reflects a reduction in vagal tone, and tryptophan metabolism, which influences serotonin synthesis pathway, may have a good diagnostic and prognostic accuracy in depression. δEPCD is the multiplication of the intrinsic difference between state 0 (rest) and state 1 (exposure to stress) of HF-HRV and the plasma concentration ratio between quinolinic acid and kynurenine. δEPCD theoretically fluctuates between -1000 and 0 where being closer to 0 signifies no vulnerability to depression. Individuals with a score between -16.7 and -167 have a high vulnerability to depression. Finally, individuals with a δEPCD closer to -1000 have the most severe forms of depression. δEPCD is theoretically conceived to be easy to assess and monitor which makes it a candidate for further evaluation of reliability and validity.CLINICAL SIGNIFICANCEDepression is currently diagnosed based on emotional and behavioural symptoms; however there is currently a rising interest in the field of neurobiological markers that could improve diagnostic accuracy.Many current biological approaches are primarily based on single neurobiological markers that are either non-specific or impractical in daily clinical practice.Among other neurological effects, depression may modify the parasympathetic nervous system tone and disturb the tryptophan metabolism.The electrophysiological coefficient of depressiveness δEPCD combines heart rate variability (HRV) and tryptophan metabolism to reflect the intrinsic individual vulnerability towards depression and the inherent severity of an index depressive disorder.δEPCD is the intrinsic difference between state 0 (without stress) and state 1 (exposed to a stressful task) of the high-frequency heart rate variability multiplied by the intrinsic difference between both states, e.g. state 0 and 1, of the plasma concentration ratio of quinolinic acid over kynurenine.

Biological and Clinical Factors Contributing to the Metabolic Heterogeneity of Hospitalized Patients with and without COVID-19.

The Corona Virus Disease 2019 (COVID-19) pandemic represents an ongoing worldwide challenge. The present large study sought to understand independent and overlapping metabolic features of samples from acutely ill patients (n = 831) that tested positive (n = 543) or negative (n = 288) for COVID-19. High-throughput metabolomics analyses were complemented with antigen and enzymatic activity assays on plasma from acutely ill patients collected while in the emergency department, at admission, or during hospitalization. Lipidomics analyses were also performed on COVID-19-positive or -negative subjects with the lowest and highest body mass index (n = 60/group). Significant changes in amino acid and fatty acid/acylcarnitine metabolism emerged as highly relevant markers of disease severity, progression, and prognosis as a function of biological and clinical variables in these patients. Further, machine learning models were trained by entering all metabolomics and clinical data from half of the COVID-19 patient cohort and then tested on the other half, yielding ~78% prediction accuracy. Finally, the extensive amount of information accumulated in this large, prospective, observational study provides a foundation for mechanistic follow-up studies and data sharing opportunities, which will advance our understanding of the characteristics of the plasma metabolism in COVID-19 and other acute critical illnesses.

Clinical Relevance of Serum Kyn/Trp Ratio and Basal and IFNγ-Upregulated IDO1 Expression in Peripheral Monocytes in Early Stage Melanoma.

Immune escape is an early phenomenon in cancer development/progression. Indoleamine 2,3-dioxygenase 1 (IDO1) is a normal endogenous mechanism of acquired peripheral immune tolerance and may therefore be tumor-promoting. This study investigated the clinical relevance of IDO1 expression by immune cells in the lymph nodes and blood and of the serum kynurenine/tryptophan (Kyn/Trp) ratio in 65 systemic treatment naïve stage I-III melanoma patients. Blood samples were collected within the first year of diagnosis. Patients had a median follow-up of 61 months. High basal IDO1 expression in peripheral monocytes and low IFNγ-induced IDO1 upregulation correlated with worse outcome independent from disease stage. Interestingly studied factors were not interrelated. During follow-up, the risk of relapse was 9% (2/22) in the subgroup with high IFNγ-induced IDO1 upregulation in monocytes. In contrast, if IDO1 upregulation was low, relapse occurred in 30% (3/10) of patients with low basal IDO1 expression in monocytes and in 61.5% (8/13) in the subgroup with high basal IDO1 expression in monocytes (Log-Rank test, p=0.008). This study reveals some immune features in the blood of early stage melanoma that may be of relevance for disease outcome. These may offer a target for sub-stratification and early intervention.

Hypoxic preconditioning protects against ischemic kidney injury through the IDO1/kynurenine pathway.

Prolonged cellular hypoxia leads to energetic failure and death. However, sublethal hypoxia can trigger an adaptive response called hypoxic preconditioning. While prolyl-hydroxylase (PHD) enzymes and hypoxia-inducible factors (HIFs) have been identified as key elements of oxygen-sensing machinery, the mechanisms by which hypoxic preconditioning protects against insults remain unclear. Here, we perform serum metabolomic profiling to assess alterations induced by two potent cytoprotective approaches, hypoxic preconditioning and pharmacologic PHD inhibition. We discover that both approaches increase serum kynurenine levels and enhance kynurenine biotransformation, leading to preservation of NAD+ in the post-ischemic kidney. Furthermore, we show that indoleamine 2,3-dioxygenase 1 (Ido1) deficiency abolishes the systemic increase of kynurenine and the subsequent renoprotection generated by hypoxic preconditioning and PHD inhibition. Importantly, exogenous administration of kynurenine restores the hypoxic preconditioning in the context of Ido1 deficiency. Collectively, our findings demonstrate a critical role of the IDO1-kynurenine axis in mediating hypoxic preconditioning.

Metabolite Biomarkers of CKD Progression in Children.

BACKGROUND AND OBJECTIVES: Metabolomics facilitates the discovery of biomarkers and potential therapeutic targets for CKD progression. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated an untargeted metabolomics quantification of stored plasma samples from 645 Chronic Kidney Disease in Children (CKiD) participants. Metabolites were standardized and logarithmically transformed. Cox proportional hazards regression examined the association between 825 nondrug metabolites and progression to the composite outcome of KRT or 50% reduction of eGFR, adjusting for age, sex, race, body mass index, hypertension, glomerular versus nonglomerular diagnosis, proteinuria, and baseline eGFR. Stratified analyses were performed within subgroups of glomerular/nonglomerular diagnosis and baseline eGFR. RESULTS: Baseline characteristics were 391 (61%) male; median age 12 years; median eGFR 54 ml/min per 1.73 m2; 448 (69%) nonglomerular diagnosis. Over a median follow-up of 4.8 years, 209 (32%) participants developed the composite outcome. Unique association signals were identified in subgroups of baseline eGFR. Among participants with baseline eGFR ≥60 ml/min per 1.73 m2, two-fold higher levels of seven metabolites were significantly associated with higher hazards of KRT/halving of eGFR events: three involved in purine and pyrimidine metabolism (N6-carbamoylthreonyladenosine, hazard ratio, 16; 95% confidence interval, 4 to 60; 5,6-dihydrouridine, hazard ratio, 17; 95% confidence interval, 5 to 55; pseudouridine, hazard ratio, 39; 95% confidence interval, 8 to 200); two amino acids, C-glycosyltryptophan, hazard ratio, 24; 95% confidence interval 6 to 95 and lanthionine, hazard ratio, 3; 95% confidence interval, 2 to 5; the tricarboxylic acid cycle intermediate 2-methylcitrate/homocitrate, hazard ratio, 4; 95% confidence interval, 2 to 7; and gulonate, hazard ratio, 10; 95% confidence interval, 3 to 29. Among those with baseline eGFR <60 ml/min per 1.73 m2, a higher level of tetrahydrocortisol sulfate was associated with lower risk of progression (hazard ratio, 0.8; 95% confidence interval, 0.7 to 0.9). CONCLUSIONS: Untargeted plasma metabolomic profiling facilitated discovery of novel metabolite associations with CKD progression in children that were independent of established clinical predictors and highlight the role of select biologic pathways.

Immunometabolic signatures predict risk of progression to sepsis in COVID-19.

Viral sepsis has been proposed as an accurate term to describe all multisystemic dysregulations and clinical findings in severe and critically ill COVID-19 patients. The adoption of this term may help the implementation of more accurate strategies of early diagnosis, prognosis, and in-hospital treatment. We accurately quantified 110 metabolites using targeted metabolomics, and 13 cytokines/chemokines in plasma samples of 121 COVID-19 patients with different levels of severity, and 37 non-COVID-19 individuals. Analyses revealed an integrated host-dependent dysregulation of inflammatory cytokines, neutrophil activation chemokines, glycolysis, mitochondrial metabolism, amino acid metabolism, polyamine synthesis, and lipid metabolism typical of sepsis processes distinctive of a mild disease. Dysregulated metabolites and cytokines/chemokines showed differential correlation patterns in mild and critically ill patients, indicating a crosstalk between metabolism and hyperinflammation. Using multivariate analysis, powerful models for diagnosis and prognosis of COVID-19 induced sepsis were generated, as well as for mortality prediction among septic patients. A metabolite panel made of kynurenine/tryptophan ratio, IL-6, LysoPC a C18:2, and phenylalanine discriminated non-COVID-19 from sepsis patients with an area under the curve (AUC (95%CI)) of 0.991 (0.986-0.995), with sensitivity of 0.978 (0.963-0.992) and specificity of 0.920 (0.890-0.949). The panel that included C10:2, IL-6, NLR, and C5 discriminated mild patients from sepsis patients with an AUC (95%CI) of 0.965 (0.952-0.977), with sensitivity of 0.993(0.984-1.000) and specificity of 0.851 (0.815-0.887). The panel with citric acid, LysoPC a C28:1, neutrophil-lymphocyte ratio (NLR) and kynurenine/tryptophan ratio discriminated severe patients from sepsis patients with an AUC (95%CI) of 0.829 (0.800-0.858), with sensitivity of 0.738 (0.695-0.781) and specificity of 0.781 (0.735-0.827). Septic patients who survived were different from those that did not survive with a model consisting of hippuric acid, along with the presence of Type II diabetes, with an AUC (95%CI) of 0.831 (0.788-0.874), with sensitivity of 0.765 (0.697-0.832) and specificity of 0.817 (0.770-0.865).

Altered kynurenine pathway metabolism in patients with ankylosing spondylitis.

BACKGROUND: Various studies reported that increased proinflammatory cytokines in patients with ankylosing spondylitis (AS). Proinflammatory cytokines can affect the expression of various kynurenine pathway enzymes and therefore lead to metabolic changes that can affect the inflammatory response and immunity. Our aim was to measure serum levels of kynurenine pathway metabolites in patients with AS. METHODS: The study included 85 patients with AS and 50 healthy volunteers. Serum tryptophan, kynurenine, kynurenic acid, 3-hydroxyanthranilic acid, 3-hydroxykynurenine, quinolinic acid concentrations were measured with tandem mass spectrometry. In addition, participants were divided into four groups according to the treatment regimen: TNF-α inhibitor group, conventional therapy group, control group and newly diagnosed AS group. These groups were compared in terms of kynurenine pathways metabolites, interleukin 6 (IL-6), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels. RESULTS: Serum tryptophan, kynurenic acid, 3-hydroxykynurenine levels were significantly decreased (p < 0.05) in both AS groups compared to the control group, while the levels of kynurenine, quinolinic acid, CRP, ESR, and IL-6 were higher (p < 0.05). The Kynurenine/Tryptophan ratio and CRP levels of the conventional therapy and anti-TNF therapy group were significantly lower than the newly diagnosed AS patients (p < 0.05). CONCLUSION: As a result of our study, we found that altered kynurenine pathway metabolism in patients with AS. Conventional therapy and anti-TNF-α therapy are effective in reducing the Kynurenine/Tryptophan ratio and CRP levels, although the effect of both treatments on other metabolites appears to be limited.