Background:Inflammation and immune activation contribute to the development and progression of heart failure (HF). The kynurenine pathway, linking tryptophan metabolism to inflammation, oxidative stress, and cell death by way of its metabolites (kynurenines), has not been studied as a pathway associated with risk for incident HF. Aims:To investigate whether kynurenine metabolites are associated with incident HF in patients with predominantly stable coronary artery disease. Methods:Serum kynurenine metabolites were quantified in 3841 patients who underwent elective coronary angiography for evaluation of chest pain. Fasting was not routine. Patients with established HF at baseline were excluded. The hazard for incident HF was estimated using Cox regression, adjusted for age, gender, current smoking, diabetes, hypertension, previous myocardial infarction, body mass index, glomerular filtration rate, troponin T, left ventricular ejection fraction, and resting heart rate. Results:During follow-up, 221 participants developed HF. Higher serum concentrations of 3-hydroxykynurenine (HK) were associated with increased HF risk (adjusted HR 1.31, 95% CI 1.07-1.46, P < .001). Conclusion:Higher plasma HK was independently associated with incident HF in patients with predominantly stable coronary artery disease. These findings support a possible link between kynurenine pathway activity and future HF risk, but the underlying mechanisms and clinical implications remain to be established.
Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with metabolic and environmental factors. We investigated associations between urinary tryptophan-pathway metabolites and essential/toxic trace elements in children with ASD and healthy controls. In a cross-sectional cohort of 216 children (149 ASD, 67 controls), urinary tryptophan metabolites were quantified by LC-MS/MS and normalized to creatinine. Trace elements were assessed by ICP-MS. Matching yielded 1:1 (n = 57/57) and 1:2 (n = 30/60) age- and sex-matched subsets. Correlations (Pearson or Spearman, FDR-adjusted) and group comparisons were performed; autism severity (CARS) was analyzed within ASD. Creatinine-normalized tryptamine, 5-hydroxyindoleacetic acid, and N-acetyltryptophan showed moderate, positive correlations with essential elements (Mg, Zn, Se; r ≈ 0.5-0.7; N-acetyltryptophan and IAA correlated modestly with toxic elements (Tl, Cs; r ≈ 0.3-0.4). Group differences in individual metabolites and elements were modest; however, the composite toxic element index was significantly lower in ASD (P = .002). CARS scores did not show robust, FDR-corrected associations. Essential trace elements are closely linked to tryptophan metabolism, suggesting cofactor-dependent modulation in ASD. N-acetyltryptophan may serve as a sensor for specific toxic elements. Intervention studies are warranted to clarify causality.
Inhibition of indoleamine 2,3-dioxygenase (IDO) is a promising therapeutic strategy for cognitive impairment in Alzheimer’s disease (AD). The pro-cognitive effect is often attributed to restoring glycolysis by preventing tryptophan (Trp) conversion to kynurenine (Kyn). However, this overlooks the metabolic fate of Trp when IDO is blocked. Since IDO and tryptophan 2,3-dioxygenase (TDO) compete for the same substrate, inhibiting IDO may shunt Trp toward TDO, potentially increasing Kyn and its downstream catabolites. This commentary explores the hypothesis that the upregulation of anthranilic acid (AA), a Kyn catabolite, contributes to the cognitive benefits of IDO inhibition. Recent evidence shows elevated AA in animal models of AD and individuals with mild cognitive impairment and preclinical AD, where it may serve as an early biomarker. Notably, these elevations and the pro-cognitive effects of AA-modulating compounds like sodium benzoate exhibit sex-specificity, being more prominent in females. The mechanism may involve AA’s dual action on G-protein coupled receptors: antagonism of GPR17 promotes myelination, while agonism of GPR109A may protect myelin from degradation. Preserving myelin integrity is critical, as demyelination is an early event in AD pathogenesis. We propose that AA upregulation is not merely a biomarker but part of a compensatory defense mechanism. Therefore, the pro-cognitive effect of IDO inhibition may be partly mediated by the subsequent shunting of Trp toward TDO and production of the myelin-preserving metabolite, AA. This reframes the therapeutic goal from reducing neurotoxic kynurenines to leveraging the protective potential of the entire pathway.
Cardiovascular diseases (CVDs) represent a significant and escalating health challenge in patients with chronic kidney disease (CKD). In this population, the cardiovascular incidents are markedly elevated, and CVD represents the leading cause of mortality. The pathogenesis of CVD in the course of CKD is multifactorial, and some evidence indicates that disturbances in the kynurenine pathway (KP), the major route of tryptophan metabolism, can also play a significant role in this process. The enhanced activation of the KP and reduced clearance of its metabolites contribute to their accumulation during CKD progression, potentially exacerbating cardiovascular risk. Few data suggest that certain downstream KP metabolites, including 3-hydroxykynurenine (3-HKYN), quinolinic acid (QUIN), and anthranilic acid (AA), are associated with established CVD risk factors, while others, such as 3-hydroxyanthranilic acid (3-HAA) and kynurenic acid (KYNA), exhibit more complex and ambiguous effects, with potential protective actions on the cardiovascular system. The aim of this review is to summarize current knowledge of the roles of individual downstream kynurenine (KYN) metabolites in the development of CVD in the CKD population. Since for some kynurenines there are only isolated or ambiguous reports in this field, the review has been completed with data on the contribution of downstream KYN metabolites in the development of CVD in the general population and in experimental models.
The kynurenine pathway (KP), the primary route of tryptophan (TRP) metabolism, is influenced by inflammation and hypoxia and has been linked to immune dysregulation and oxidative stress. This study investigated the relationship between KP activity and hypoxia in periodontal inflammation, as well as their association with clinical periodontal parameters. A total of 23 systemically healthy patients with stage III, grade B periodontitis and 22 periodontally healthy individuals were included. Salivary and serum levels of tumor necrosis factor-alpha (TNF-α), hypoxia-inducible factor-1 alpha (HIF-1α), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured using ELISA. KP metabolites were analyzed via liquid chromatography-mass spectrometry. Results showed that salivary TNF-α, HIF-1α, and 8-OHdG levels were significantly higher in the periodontitis group (P < .05). Both salivary and serum kynurenine/tryptophan (KYN/TRP) ratios and picolinic acid (PA), along with salivary 3-hydroxykynurenine (3OHKYN) and serum kynurenine (KYN), were elevated in periodontitis (P < .05). In contrast, TRP levels in both saliva and serum were significantly reduced (P < .001). Correlation analyses revealed that TRP levels were negatively associated with periodontal disease severity, whereas the salivary KYN/TRP ratio, 3OHKYN, HIF-1α, 8-OHdG, and TNF-α were positively associated (P < .05). Strong correlations were observed between the saliva and serum compartments, with a strong positive relationship between salivary and serum TRP and a moderate correlation for the KYN/TRP ratios. Multivariate logistic regression identified salivary KYN/TRP ratio and HIF-1α as independent predictors of periodontitis after adjusting for age and gender, with male gender also emerging as a significant factor (P < .05). Overall, the findings suggest that KP alterations, hypoxia, and oxidative stress are closely interconnected in periodontal inflammation. However, due to the cross-sectional design, these associations should not be interpreted as causal. The KP and hypoxia pathways may serve as potential non-invasive biomarkers for periodontitis.
Fatigability in attention deficit hyperactivity disorder (ADHD) is associated with the characteristic inattention behavior. Evidence has indicated that the administration of branched-chain amino acids (BCAAs) to Nagase analbuminemic rats (NARs), a fatigue-prone animal model of ADHD, diminishes central fatigue. This effect is accompanied by competitive inhibition at the L-system amino acid transporter (LAT), which takes tryptophan into the brain. We investigated whether dietary supplementation with BCAAs plus phenylalanine and methionine (BPM) or BCAAs plus 2-amino-2-norbornanecarboxylic acid (BCAAs + BCH) has the effect of synergistically improving central fatigue in rats and humans compared with BCAAs alone. NAR performed exercise duration for 420 minutes (5 out of 5 rats; n = 5/5) using BPM and 542 minutes (n = 5/5) using BCAA + BCH. These were significantly longer than when saline or BCAA alone were administered to rats. When administering BPM supplements to human subjects, they found an efficacy rate of 50% in reducing fatigue compared to a placebo, compared to 38% for BCAA alone. Central fatigue in rats and humans was caused by a common mechanism involving tryptophan as an inducing trigger, and BPM supplementation contributed to the strong amplification effect of competitive inhibition at the LAT, the addition of phenylalanine and methionine. These powerful nutritional strategies improved exercise performance and mood beyond the physiological limits of fatigue. BPM, the natural nutrients, can promote the improvement of ADHD symptoms in humans. Prior to treatment with conventional monoamine reuptake inhibitors, it is necessary to eliminate fatigue by BPM treatment, which is the causative basis of ADHD.
Sleep is crucial for physiological regulation in humans and essential for sustaining life. Although melatonin, an intermediate in the tryptophan (TRP)-serotonin pathway, is widely explored as a modulator of the sleep-wake cycle, the association of TRP-kynurenine (KYN) pathway with sleep or circadian timing remains poorly understood. This work employed Mendelian randomization (MR) to examine possible causal links between sleep-associated phenotypes and metabolites in the TRP-KYN pathway. We applied data derived from genome-wide association research of TRP, KYN, and kynurenate (KYNA), the key metabolites in this pathway, and investigated sleep-related phenotypes extensively, including both self-reported phenotypes and those objectively estimated with an accelerometer. We evaluated the associations between 11 sleep-related phenotypes and plasma and cerebrospinal fluid (CSF) metabolites via two-sample bidirectional MR analysis. The forward MR analysis revealed a positive association between genetically predicted plasma KYN levels and L5 timing, with an OR of 1.194 (95% CI: 1.025-1.389; P = .022) utilizing the inverse variance weighted (IVW) approach. This effect direction was consistent across all MR methods, without evident horizontal pleiotropy or heterogeneity. However, this association was no longer significant after false discovery rate (FDR) correction and should therefore be interpreted as suggestive. In reverse MR analysis, sleep-related phenotypes showed no significant causal effects on CSF and plasma metabolites. To complement the population-level MR analyses, we performed an exploratory, hypothesis-generating in vitro experiment in Rat-1 fibroblasts and found that 200 μM L-kynurenine continuously upregulated Bmal1 mRNA at several circadian time points. Overall, our findings provide suggestive evidence that genetically predicted higher plasma kynurenine are associated with delayed L5 timing, which requires confirmation through replication and mechanistic studies.
Introduction: L-tryptophan supplementation has been studied in endurance sports with controversial results, and its influence on maximal strength sports remains largely unexplored. This study investigated whether L-tryptophan supplementation improves dynamic strength indicators in Paralympic powerlifting athletes. Methodology: A randomized, double-blind, crossover clinical trial was conducted with 13 paralympic powerlifting athletes. The athletes were supplemented with L-tryptophan or placebo for 72 hours before training. Strength was assessed using an encoder, measuring mean propulsive velocity (MPV), maximal velocity (V-max), and power (PO) at different time points (pre, post, 24, and 48 hours) and loads (45% and 80% of 1 RM). Results: L-tryptophan supplementation resulted in higher MPV, V-max, and PO values at the pre-exercise time point compared to placebo. However, after exercise, this difference diminished, and the benefits of supplementation were not sustained after 48 hours. Conclusion: L-tryptophan supplementation appears to temporarily improve pre-exercise strength performance in Paralympic powerlifting athletes, possibly by influencing neuromuscular relaxation.
UVA-1 phototherapy, used in the management of psoriasis, atopic dermatitis and fibrosing skin disorders has been reported to mediate part of its therapeutic benefit via aryl hydrocarbon receptor (AHR) signalling. Accessibility to therapy remains limited and a cost-effective topical preparation permissive of UVA-1 transmission at therapeutic doses whilst offering photoprotection in the UVB and UVA-2 spectra and activity at the AHR would represent a notable therapeutic advance. The amino acid L-tryptophan absorbs maximally at 280 nm with absorbance falling rapidly to 310 nm potentially providing photoprotection in the UVB spectrum. In addition, this amino acid is photo-oxidized to 6-formylindolo[3,2-b] carbazole (FICZ), a potent endogenous ligand of the AHR and is thus a potential candidate for inclusion. Lecithin absorbs UV light in a broad band from 200 to 380 nm with peak absorbance at 235, 271 and 355 nm and has potential as a biodegradable and ecofriendly sunscreen with an efficacy equivalent to traditional sunscreens. A proof-of-concept study was performed to assess whether a topical solution of L-tryptophan formulated to favour the generation of FICZ on photoactivation demonstrated activity at the aryl hydrocarbon receptor (AHR) as assessed by the intensity of cytochrome P450 1A2 staining. Ten participants applied a trial agent consisting of 2% L-tryptophan, 30% sunflower lecithin, 3% polyvinyl alcohol, 20% ethanol, pH 5.8 followed by 36 sessions of progressively graduated sun exposure increasing to a total of 20 J/cm2 as determined by UV integrator over a period 12 weeks. At the end of the trial, biopsies were taken from treated sites and assessed by the intensity of cytochrome P450 1A2 staining. Photo protected skin from the buttock was used as a control. An average baseline value of 53 488 923 units was obtained at the control site and 972 214 294 at the treatment site supporting the concept that this preparation displays activity at the AHR.
Influenza viruses cause a highly contagious, acute pulmonary disease that results in significant mortality each year. These infections trigger the production of interferons, known to induce the expression of the rate-limiting enzyme in the kynurenine degradation pathway in the lungs. As some kynurenine pathway metabolites are biologically active, we aimed to gain a better understanding of their role in influenza A virus infection. The expression of kynurenine pathway enzymes and the levels of their metabolites were quantified in the lungs of C57BL/6 mice 7 days after infection with an H3N2 influenza A virus (IAV). Furthermore, the impact of quinolinic acid supplementation was evaluated on IAV-infected mice and in vitro, in human monocyte-derived macrophages. The expression of key enzymes (IDO1, KMO, and KYNU) increased in mice in the airways of IAV infected mice. High levels of quinolinic acid were produced in the lungs, as revealed by immunohistochemistry in both epithelial cells and immune cells. Oral quinolinic acid supplementation resulted in higher levels of viral mRNA in the lungs and modulated cytokine production, leading to an increased number of neutrophils and interstitial macrophages in lung tissue. In IAV-infected macrophages, the addition of quinolinic acid was associated with higher levels of viral RNA and protein and in increased antiviral and proinflammatory responses (IFN-β, CXCL-1, and TNF-α). These increases were further reduced by memantine, an NMDA receptor antagonist, suggesting that quinolinic acid may modulate the macrophage immune response via NMDA receptors. A deeper understanding of these mechanisms could lead to new therapeutic strategies for influenza infections.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multisystem disorder characterized by hepatic lipid accumulation, low-grade inflammation, and metabolic dysregulation. Although the kynurenine pathway has been implicated in the pathogenesis of metabolic and inflammatory diseases, its contribution to MASLD remains unclear. This study aimed to evaluate tryptophan (TRP) metabolism and its relationship with inflammatory biomarkers and lipid parameters across different grades of steatosis. A total of 88 adults (62 MASLD, 26 healthy controls; aged 20-69 years) were enrolled in this study. Serum concentrations of inflammatory markers (CRP, IL-6, and TNF-α) were determined using immunoassay-based methods, and TRP metabolites (TRP, KYN, KYNA, 3-HK, 3-HAA, QA, PIC) were quantified using validated LC-MS/MS. Steatosis grades (0-3) were assessed via ultrasonography. Statistical analyses included the Mann-Whitney U test, the Kruskal-Wallis test, and the Spearman correlation test. MASLD subjects showed significantly higher BMI, triglycerides, AST, ALT, GGT, CRP, TNF-α, and KYNA levels compared with controls (all P < .05), while HDL-C levels were lower (P = .014). Across steatosis grades, BMI, TG, and CRP increased progressively (P < .001), and IL-6 showed a positive correlation with steatosis severity (r = .280, P < .05). KYNA levels were elevated in early steatosis (Grade 1, P = .008) and inversely correlated with TC and LDL-C (r = -.393 and r = -.384, respectively). The elevation of KYNA may reflect an early compensatory mechanism imitigating hepatic and metabolic stress. Integrating inflammatory and kynurenine pathway biomarkers could improve disease stratification and therapeutic targeting in MASLD.
As a first line of defence for the central nervous system (CNS), microglia play a critical role in maintaining homeostasis within the brain. Upon detection of damage or threats, activated cells release factors to communicate and potentiate immune responses. This activation also increases activity of the kynurenine pathway (KP) and alters expression of key KP enzymes such as indoleamine 2,3-dioxygenase (IDO-1) and kynurenine 3-monooxygenase (KMO), both major contributors in the pathology of several neurodegenerative and psychiatric disorders. This study investigated the impact of pro-inflammatory stimuli on the C20 human microglial cell line, focussing on the regulation of KMO and IDO-1 expression, and the production of cytokines. Additionally, we explored whether the anti-inflammatory effects of dexamethasone (DEXA) influenced these outcomes. This additional characterisation of a physiologically relevant human microglial cell line offers a novel and reliable platform for investigating human-specific microglial biology and function. C20 were challenged for 24 hours with cytokines or lipopolysaccharide (LPS). Gene expression was measured by RT-qPCR and excreted cytokines were quantified using a multiplex array. Our results showed up-regulation of IDO-1 and KMO transcripts, and increased release of pro- and anti-inflammatory cytokines. Notably, these effects were significantly dampened by pre-incubation with DEXA. Furthermore, transcriptomic analyses supported these data by highlighting TNF-α-activated enriched pathways, as well as those down-regulated in samples co-treated with DEXA. This study contributes to the understanding of key mechanisms regulated in human microglia by immune challenges and supports the crucial role of synthetic glucocorticoids (GCs) in moderating the microglial immune response induced by pro-inflammatory signals. These data support the use of GCs as possible therapeutic interventions for diseases associated with neuroinflammation, particularly those with altered KP metabolism.
Background:Altered tryptophan (Trp) metabolism and disrupted nicotinamide adenine dinucleotide (NAD+) synthesis are hallmarks of IBD, yet how intestinal microbiota contribute to these metabolic shifts during intestinal inflammation remains poorly understood. Methods:We used targeted metabolomics to systematically profile Trp- and NAD+-related metabolites across multiple biological compartments - including tissues, luminal contents, stool and serum - in mice treated with dextran sulfate sodium (DSS) alone or in combination with a broad-spectrum antibiotic (ABX) cocktail. Results:Microbial depletion significantly attenuated colitis and increased host Trp bioavailability, implicating the gut microbiota as a competitive Trp consumer. In DSS colitis, Trp degradation along the kynurenine pathway (KP) was exaggerated but blocked at the key KP enzyme quinolinate phosphoribosyltransferase (QPRT), resulting in mucosal NAD(H) depletion. ABX co-treatment normalized metabolite conversion along the KP and restored mucosal NAD(H) levels, revealing a dual role of the gut microbiota during colitis: while they compete with the host for Trp utilization, they simultaneously shape host KP regulation and NAD+ de novo synthesis, supporting host energy homeostasis. Conclusion:Our findings demonstrate that mucosal NAD+ de novo synthesis is a microbially regulated metabolic process that alleviates intestinal inflammation and may represent a novel therapeutic target in IBD through modulation of the gut microbiota or their metabolites.
Tryptophan metabolism, with its breakdown along the kynurenine pathway, is linked to the diminishing quality of life (QoL) of cancer patients. Rice bran arabinoxylan compound (RBAC) is a plant-based immunomodulator shown to improve the global QoL and functioning beyond the placebo during systemic cancer treatment in a randomised-controlled trial (RBAC-QoL study). However, whether RBAC improved QoL through the tryptophan pathway and the role of tryptophan and its kynurenine metabolite in these QoL outcomes was not investigated. In this study, serum tryptophan and kynurenine were analysed using samples collected from the RBAC-QoL study with a validated liquid chromatography method and monitored via fluorescence detection. This secondary analysis was conducted using repeated-measures ANOVA, Spearman’s correlation, and linear mixed models.The results show that RBAC supplementation had no significant effect on tryptophan metabolism compared to the placebo. Tryptophan significantly (p ≤ 0.05) correlated positively with global QoL, physical and social functioning and negatively with fatigue, dyspnoea, appetite loss and diarrhoea. Kynurenine also demonstrated significant (p ≤ 0.05), but weaker correlations with physical and social functioning (positively), as well as fatigue and dyspnoea (negatively), albeit weaker than tryptophan. The kynurenine-to-tryptophan ratio exhibited no significant correlations with QoL. Stepwise reduction of a linear mixed model of haematological, renal, liver, and immune markers revealed that tryptophan and gamma-glutamyl transferase are prominent predictors (p < 0.001) of QoL. RBAC and serum tryptophan appeared to have an additive effect on QoL. Future research should investigate the combined impact of RBAC and tryptophan to assess any potential synergistic effects. Trial registration: The RBAC-QoL study was prospectively registered on the Australian New Zealand Clinical Trials Registry (ANZCTR Reg No: ACTRN12619000562178p, 10/04/2019).
Parkinson’s disease (PD) is identified as the most common neurodegenerative disorder of the central nervous system. Around 8.5 million individuals suffer from PD globally. Neuroinflammation triggers the activation of microglia, resulting in the release of numerous proinflammatory mediators. A major modulator of immune response in Parkinsonism is the kynurenine pathway (KP), probably linked to neurotoxic and inflammatory processes. Two types of compounds are produced by this pathway that act as neurotoxic and neuroprotective. Among these, kynurenic acid released by astrocytes acts as neuroprotective, and quinolinic acid released by microglia acts as neurotoxic by various mechanisms. Previous studies have shown that modulation of enzymes in this pathway can be a therapeutic approach for treating PD. Studies were performed to determine the effect of various drug treatments in inhibiting the enzymes of KP and preventing neurodegeneration. Pharmacological modulators of the KP enzymes will likely be a novel therapeutic approach for PD, and some of the KP metabolites may serve as predictive biomarkers.
Background:The accumulation of quinolinic acid (QUIN) in cerebrospinal fluid and serum may be used as a biomarker for various neuropsychiatric and inflammatory diseases. In this study, we developed a highly sensitive method to measure QUIN. Methods:A reverse-phase high-performance liquid chromatography (HPLC) with fluorescence detection was established based on the enzymatic conversion of QUIN to nicotinic acid mononucleotide by recombinant quinolinic acid phosphoribosyltransferase, followed by the formation of fluorescent (BODIPY)-labeled deamido-NAD by recombinant nicotinic acid mononucleotide adenyltransferase. Results:BODIPY-deamido-NAD was isocratically eluted within 6 minutes using reverse-phase chromatography and its chromatographic peak was resolved. The calibration range, precision, and analytical recovery of the QUIN assay are suitable for the analysis of biological fluids. Compared with published quantitation limits for QUIN measurement by HPLC, this method is at least 30-fold more sensitive and has a lower limit of detection of 5.0 nmol/L. The sensitivity was comparable to that previously reported for gas chromatography/mass spectrometry (GC/MS) and the quantitation results of QUIN from samples of cerebrospinal fluid correlated well with that of the GC/MS method. Conclusions:We established a novel method to quantify QUIN in biological samples. Due to its high sensitivity and the fact that it does not rely on MS instrumentation, this method has the potential for widespread adoption in research laboratories.
Background:The effect of prolonged hyperglycemia on the sensory pathway of the nervous system has been the focus of numerous diabetes studies that aim at understanding the pathophysiology of the underlying inflammatory condition and neuropathy. In this study, we investigate the effects of prolonged hyperglycemia on the motoneurons of the ventral horn of the spinal cord, a lesser-studied area of the nervous system, with a focus on alterations in the Kynurenine Pathway (KP) as potential factors contributing to the induction, progression, and/or chronicity of diabetic neuropathy. Methods:KP metabolites were identified and assessed by immunohistochemistry in cross-sections of the lumbar spinal cord of type 2 diabetes (T2D) streptozotocin-induced (STZ) adult Sprague-Dawley rats. Results:Neuropathy, hyperglycemia, and gait alterations were associated to myelin loss in the spinal cord. KP metabolites were identified in glia, motoneuron, and non-motoneuron. The KP induction, as evidenced by enhanced L-kynurenine (L-KYN) fluorescence, appears to be associated with increased levels of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Notable differences in fluorescence merging of L-KYN with IFN-γ and TNF-α, of Quinolinic acid (QUIN) with 3-Hydroxykynurenine (3-HK), and of QUIN with advanced glycation end products (AGEs) were observed in the T2D group, contrasting with the control (P < .05). Additionally, in ventral horn cells, AGEs emerged as an added pro-inflammatory factor. Conclusions:The KP is activated during diabetic neuropathy, and it displays divergent metabolic profiles in glia, motoneuron, and non-motoneuron, which differ from the controls. Their presence also evolves with time, indicating the dynamic nature of the process.
Feedback and other negative controls are important determinants of metabolic pathway activities. Other than inhibition of indoleamine 2,3-dioxygenase (IDO) by tryptophan (Trp) and nitric oxide (NO) and feedback inhibition of Trp 2,3-dioxygenase (TDO) by NAD(P)H, little is known of potential effects of Trp and kynurenine metabolites on the kynurenine (Kyn) pathway (KP). Whereas previous studies suggested that some Trp metabolites inhibit TDO activity in vitro, when administered in vivo to rats, inhibition is not always demonstrable, suggesting involvement of mitigating factors. To resolve this difference and provide indicators of likely interaction of Trp metabolites with TDO and IDO1, we performed molecular docking in silico of Trp and a range of its metabolites to these 2 KP enzymes. We found that Trp and many of its Kyn and 5-hydroxyindole metabolites docked to the active site of the TDO2 crystal structure, whereas no docking was observed with Kyn or kynurenic acid. Docking of NAD+(P+)H occurred at a different site, provisionally identified as the TDO allosteric site. By contrast, docking to IDO1 was limited to Trp, N'-formylkynurenine, 3-hydroxyanthranilic acid and picolinic acid. We conclude that bioinformatics can resolve controversial issues and identify amino acid residues at unexplored sites. The IDO1 effector nitric oxide (NO) docked to TDO as well as to IDO1. NO controls TDO2 and IDO1 activities in a dual fashion, through provision and limitation of the heme cofactor. We propose NO as a new TDO effector and discuss its role in control of TDO during acute inflammation. We propose TDO as an important player in the acute inflammatory responses in parallel with IDO1.
Background:Irritable Bowel Syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by abdominal pain and altered bowel habits. Tryptophan, an essential amino acid derived from dietary proteins, can be metabolized into various compounds by the gut microbiome. Emerging evidence suggests that tryptophan metabolites play a role in functional gastrointestinal disorders. However, the causal relationship between tryptophan metabolites and IBS remains to be fully elucidated. Objective:This study aims to evaluate the potential causal relationship between tryptophan metabolites and IBS using Mendelian randomization (MR). Methods:Instrumental variables (IVs) were selected from summary data of genome-wide association studies (GWAS) for tryptophan and IBS. SNPs potentially influencing MR results were excluded through outlier detection using MR-PRESSO. Bidirectional two-sample MR analyses were conducted using the inverse-variance weighted (IVW), MR-Egger regression, weighted median, weighted mode, and simple mode methods. The MR-Egger intercept test was employed to assess pleiotropy and heterogeneity among IVs, with visualization of the MR results through scatter plots, funnel plots, and forest plots. Results:Genetically predicted tryptophan metabolites were not associated with the risk of IBS. In the reverse direction, genetically predicted IBS was associated with increased levels of tryptophan, serotonin, and kynurenine in the IVW analysis. Sensitivity and replication analyses confirmed these findings. Conclusion:The findings of this Mendelian randomization study suggest that IBS may lead to elevated levels of tryptophan, serotonin, and kynurenine. These results have important implications for understanding the interplay between tryptophan metabolism and IBS in clinical settings. Further research is warranted to explore the underlying mechanisms.
Dengue, a widespread mosquito-borne disease, annually afflicts millions globally, posing substantial mortality risks. Preceding disease defervescence, a marked and transient surge in antibody-secreting cell (ASC) frequency correlates with disease severity, paralleled by heightened tryptophan degradation. Investigating details of this process through single-cell transcriptomics from public repositories, our data pinpoint CD14+ monocytes as principal IDO1 and IDO2 expressors, implicating them, rather than B cells, in initiating tryptophan metabolism. Interestingly, naive B cells exhibit altered gene expression indicative of early impact by tryptophan deficiency before defervescence with a potential impact on the B cell fate. Dengue-induced ASCs upregulated GCN2, PERK, eIF2a, ATF4 genes as well as BIM and CASP-3. However, the high expression of anti-apoptotic genes (FKBP8 [a CHOP-regulated gene], BCL-XL, BCL-2, MCL-1) allows enhanced ASC survival. Proliferation and differentiation-related genes (eIF4EBP1, RRM2, and HIF1a) were also upregulated in ASCs. These findings untangle how Dengue modulates the host metabolism and B-cell responses, although further research is needed to fully understand their implications on disease progression.
