International Journal of Tryptophan Research最新文献

The kynurenine pathway is the primary route for tryptophan catabolism and has received increasing attention as its association with inflammation and the immune system has become more apparent. This review provides a broad overview of the kynurenine pathway in respiratory diseases, from the initial observations to the characterization of the different cell types involved in the synthesis of kynurenine metabolites and the underlying immunoregulatory mechanisms. With a focus on respiratory infections, the various attempts to characterize the kynurenine/tryptophan (K/T) ratio as an inflammatory marker are reviewed. Its implication in chronic lung inflammation and its exacerbation by respiratory pathogens is also discussed. The emergence of preclinical interventional studies targeting the kynurenine pathway opens the way for the future development of new therapies.

Background: Around 10% of people who had COVID-9 infection suffer from persistent symptoms such as fatigue, dyspnoea, chest pain, arthralgia/myalgia, sleep disturbances, cognitive dysfunction and impairment of mental health. Different underlying pathomechanisms appear to be involved, in particular inflammation, alterations in amino acid metabolism, autonomic dysfunction and gut dysbiosis.

Aim: As routine tests are often inconspicuous in patients with Long COVID (LC), similarly to patients suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), accessible biomarkers indicating dysregulation of specific pathways are urgently needed to identify underlying pathomechanisms and enable personalized medicine treatment. Within this pilot study we aimed to proof traceability of altered metabolism by urine analysis.

Patients and methods: Urine metabolome analyses were performed to investigate the metabolic signature of patients with LC (n = 25; 20 women, 5 men) in comparison to healthy controls (Ctrl, n = 8; 7 women, 1 man) and individuals with ME/CFS (n = 8; 2 women, 6 men). Concentrations of neurotransmitter precursors tryptophan, phenylalanine and their downstream metabolites, as well as their association with symptoms (fatigue, anxiety and depression) in the patients were examined.

Results and conclusion: Phenylalanine levels were significantly lower in both the LC and ME/CFS patient groups when compared to the Ctrl group. In many LC patients, the concentrations of downstream metabolites of tryptophan and tyrosine, such as serotonin, dopamine and catecholamines, deviated from the reference ranges. Several symptoms (sleep disturbance, pain or autonomic dysfunction) were associated with certain metabolites. Patients experiencing fatigue had lower levels of kynurenine, phenylalanine and a reduced kynurenine to tryptophan ratio (Kyn/Trp). Lower concentrations of gamma-aminobutyric acid (GABA) and higher activity of kynurenine 3-monooxygenase (KMO) were observed in patients with anxiety. Conclusively, our results suggest that amino acid metabolism and neurotransmitter synthesis is disturbed in patients with LC and ME/CFS. The identified metabolites and their associated dysregulations could serve as potential biomarkers for elucidating underlying pathomechanisms thus enabling personalized treatment strategies for these patient populations.

The kynurenine pathway (KP) is the main pathway of tryptophan (TRP) metabolism that generates energy for multiple cellular processes. The activity of this pathway has been shown to be dysregulated in multiple human diseases. The resultant modulation of metabolites has been suggested to comprise biomarkers to track disease progression or could identify new therapeutic targets. While metabolite changes can be measured readily in blood, there is limited knowledge on the effect of blood matrices and sample processing time may have on the stability of KP metabolites. Understanding the stability of KP metabolites in blood is integral to obtaining accurate KP data to correlate with clinical pathology. Hence, the aim of this study was to assess the concentration of KP metabolites in matched whole blood, plasma and serum. The impact of pre-analytical sample processing time in the various blood matrices was also analysed. Serum and plasma had the higher concentration of KP metabolites compared to whole blood. Furthermore, concentrations of KP metabolites declined when the collected blood was processed after 24 hours storage at 4°C. Our study shows that that type of blood matrix and the time to processing have an impact on the stability of the KP metabolites. Serum or plasma are the preferred choice of matrix and the isolation of these matrices from whole blood is best performed immediately after collection for optimal analytical KP data.

In this systematic review and meta-analysis, a normative dataset is generated from the published literature on the kynurenine pathway in control participants extracted from case-control and methodological validation studies. Study characteristics were mapped, and studies were evaluated in terms of analytical rigour and methodological validation. Meta-analyses of variance between types of instruments, sample matrices and metabolites were conducted. Regression analyses were applied to determine the relationship between metabolite, sample matrix, biological sex, participant age and study age. The grand mean concentrations of tryptophan in the serum and plasma were 60.52 ± 15.38 μM and 51.45 ± 10.47 μM, respectively. The grand mean concentrations of kynurenine in the serum and plasma were 1.96 ± 0.51 μM and 1.82 ± 0.54 μM, respectively. Regional differences in metabolite concentrations were observed across America, Asia, Australia, Europe and the Middle East. Of the total variance within the data, mode of detection (MOD) accounted for up to 2.96%, sample matrix up to 3.23%, and their interaction explained up to 1.53%; the latter of which was determined to be negligible. This review was intended to inform future empirical research and method development studies and successfully synthesised pilot data. The pilot data reported in this study will inform future precision medicine initiatives aimed at targeting the kynurenine pathway by improving the availability and quality of normative data.

The Aryl hydrocarbon receptor (AhR) is a xenobiotic and endobiotic receptor, which regulates many cellular processes from contaminant metabolism to immunomodulation. Consequently, it is also involved in pathophysiological pathways and now represents a potential therapeutical target. In this review, we will highlight the ancestral function of the protein together with an illustration of its ligand's battery, emphasizing the different responses triggered by these high diverse molecules. Among them, several members of the kynurenine pathway (one key process of tryptophan catabolism) are AhR agonists and are subsequently involved in regulatory functions. We will finally display the interplay between Tryptophan (Trp) catabolism and dysregulation in metabolic pathways drawing hypothesis on the involvement of the AhR pathway in these cancer-related processes.

The aryl hydrocarbon receptor (AHR) exerts major roles in xenobiotic metabolism, and in immune and barrier tissue homeostasis. How AHR activity is regulated by the availability of endogenous ligands is poorly understood. Potent AHR ligands have been shown to exhibit a negative feedback loop through induction of CYP1A1, leading to metabolism of the ligand. Our recent study identified and quantified 6 tryptophan metabolites (eg, indole-3-propionic acid, and indole-3-acetic acid) in mouse and human serum, generated by the host and gut microbiome, that are present in sufficient concentrations to individually activate the AHR. Here, these metabolites are not significantly metabolized by CYP1A1/1B1 in an in vitro metabolism assay. In contrast, CYP1A1/1B metabolizes the potent endogenous AHR ligand 6-formylindolo[3,2b]carbazole. Furthermore, molecular modeling of these 6 AHR activating tryptophan metabolites within the active site of CYP1A1/1B1 reveal metabolically unfavorable docking profiles with regard to orientation with the catalytic heme center. In contrast, docking studies confirmed that 6-formylindolo[3,2b]carbazole would be a potent substrate. The lack of CYP1A1 expression in mice fails to influence serum levels of the tryptophan metabolites examined. In addition, marked induction of CYP1A1 by PCB126 exposure in mice failed to alter the serum concentrations of these tryptophan metabolites. These results suggest that certain circulating tryptophan metabolites are not susceptible to an AHR negative feedback loop and are likely important factors that mediate constitutive but low level systemic human AHR activity.

For the fluorometric determination of picolinic acid in human serum, HPLC-postcolumn UV irradiation using zinc acetate has been developed. Picolinic acid in serum sample was separated on a Capcell Pak C18. The mobile phase consisted of 0.1 mol/L sodium phosphate solution (adjusted to pH 3.0) containing 3.0 mmol/L zinc acetate and 3.5 mmol/L trimethylamine, and delivered at a flow rate of 0.8 mL/minutes. In order to stabilize the retention time (6.5 minutes), a back pressure tube (0.4 m × 0.13 mm i.d.) was attached after the photoreaction tube. Column effluent was irradiated with ultraviolet light to produce fluorescence, excitation wavelength of 336 nm and emission wavelength of 448 nm. The calibration graph for picolinic acid showed linearity when the amount was in the range of 0.89 to 455 pmol, and the detection limit (S/N = 3) was determined to be 0.30 pmol. The pretreatment of serum sample consisted of deproteinized by perchloric acid, potassium hydroxide, and mobile phase. The mean recovery of picolinic acid from serum was 99.0%. Using this procedure, the concentration of picolinic acid in serum of a healthy subject was determined.

Background: Fatigue, sleep disturbance, and neurological symptoms during and after COVID-19 are common and might be associated with inflammation-induced changes in tryptophan (Trp) and phenylalanine (Phe) metabolism.

Aim: This pilot study investigated interferon gamma inducible biochemical pathways (namely Trp catabolism, neopterin, tyrosine [Tyr], and nitrite formation) during acute COVID-19 and reconvalescence.

Patients and methods: Thirty one patients with moderate to severe COVID-19 admitted to the University Hospital of Innsbruck in early 2020 (March-May) were followed up. Neurotransmitter precursors Trp, Phe, Tyr as well as kynurenine (Kyn), neopterin, nitrite, and routine laboratory parameters were analyzed during acute infection and at a follow-up (FU) 60 days thereafter. Clinical symptoms of patients (neurological symptoms, fatigue, sleep disturbance) were recorded and associations with concentrations of laboratory parameters investigated.

Results and conclusion: Almost half of the patients suffered from neurological symptoms (48.4%), the majority of patients experienced sleep difficulties (56.7%) during acute COVID-19. Fatigue was present in nearly all patients. C-reactive protein (CRP), interleukin-6 (IL-6), neopterin, Kyn, Phe concentrations were significantly increased, and Trp levels depleted during acute COVID-19. Patients with sleep impairment and neurological symptoms during acute illness presented with increased CRP and IL-6 concentrations, Trp levels were lower in patients with sleep disturbance. In general, inflammatory markers declined during reconvalescence. A high percentage of patients suffered from persistent symptoms at FU (neurological symptoms: 17.2%, fatigue: 51.7%, sleeping disturbance: 34.5%) and had higher CRP concentrations. Nitrite and Phe levels were lower in patients with sleeping difficulties at FU and Kyn/Trp ratio, as indicator of IDO activity, was significantly lower in patients with neurological symptoms compared to patients without them at FU. In summary, inflammation induced alterations of amino acid metabolism might be related to acute and persisting symptoms of COVID-19.

Background and aims: Indoleamine 2,3 dioxygenase-1 (IDO1), a key enzyme in tryptophan metabolism, is strongly up-regulated both in human inflammatory bowel disease (IBD) and animal models of colitis, however its role in the pathogenesis is still controversial. In this study, we investigated IDO1 expression and activity in a mouse model of DSS-induced chronic colitis as well as in colon biopsies and sera from IBD patients.

Methods: Chronic colitis was induced in mice through the oral administration of dextran sodium sulfate (DSS), and IDO1 activity was induced by i.p. treatment with N-acetyl serotonin (NAS). IDO1 expression and catalytic activity (measured as Kyn/Trp ratio) was evaluated in sera and tissue samples collected from mice and 93 IBD patients under immunotherapy with Vedolizumab (VDZ) or Ustekinumab (UST).

Results: Strong up-regulation of IDO1 was found in colons of mice with acute colitis, which follows disease activity. Enhanced IDO1 activity by NAS treatment protects the intestinal mucosa during the recovery phase of chronic colitis. In IBD patients, IDO1 expression and activity correlate with the severity of mucosal inflammation with inflamed regions showing higher IDO1 expression compared to non-inflamed regions within the same patient. Endoscopic response to VDZ/UST treatment is associated with decreased expression of IDO1.

Conclusions: This is the first study demonstrating immunomodulatory activity of IDO1 in a chronic mouse model of DSS-induced colitis. As its expression and catalytic activity correlate with the grade of mucosal inflammation and treatment response, IDO1 could represent a promising biomarker for disease severity and treatment monitoring in IBD.

The vascular niche of malignant gliomas is a key compartment that shapes the immunosuppressive brain tumor microenvironment (TME). The blood-brain-barrier (BBB) consisting of specialized endothelial cells (ECs) and perivascular cells forms a tight anatomical and functional barrier critically controlling transmigration and effector function of immune cells. During neuroinflammation and tumor progression, the metabolism of the essential amino acid tryptophan (Trp) to metabolites such as kynurenine has long been identified as an important metabolic pathway suppressing immune responses. Previous studies have demonstrated that indoleamine-2,3-dioxygenase-1 (IDO1), a key rate-limiting enzyme in tryptophan catabolism, is expressed within the TME of high-grade gliomas. Here, we investigate the role of endothelial IDO1 (eIDO1) expression for brain tumor immunity. Single-cell RNA sequencing data revealed that in human glioma tissue, IDO1 is predominantly expressed by activated ECs showing a JAK/STAT signaling pathway-related CXCL11⁺ gene expression signature. In a syngeneic experimental glioma model, eIDO1 is induced by low-dose tumor irradiation. However, cell type-specific ablation of eIDO1 in experimental gliomas did not alter frequency and phenotype of tumor-infiltrating T cells nor tumor growth. Taken together these data argue against a dominant role of eIDO1 for brain tumor immunity.