Depression is one of the most disabling mental disorders worldwide and characterized by symptoms including worthlessness, anhedonia, sleep, and appetite disturbances. Recently, studies have suggested that tryptophan (Trp) metabolism plays a key role in depressed mood through serotonin and kynurenine pathway involving enzyme tryptophan 5-monooxygenase (TPH) and indoleamine-2,3-dioxygenase (IDO) respectively. Moreover, during neuroinflammation, IDO is activated by proinflammatory cytokines and affects neurogenesis, cognition, disturbed hypothalamic-pituitary-adrenal (HPA) axis, and gut homeostasis by altering the gut bacteria and its metabolites like Trp derivatives. Furthermore, over the decades, researchers have focused on understanding communication between the human microbiome, especially gut microbiota, and mental health, called gut-brain-axis (GBA), particularly through Trp metabolism. Supplementation of probiotics in depression has gained attention from researchers and clinicians. However, there is limited information about probiotics supplementation on depression involving enzyme IDO and kynurenine pathway metabolites. This review discussed the potential role of probiotics in depression through the tryptophan/kynurenine pathway.

This study investigates the impact of a high-fat-rich diet (HFRD) on behavioral, biochemical, neurochemical, and histopathological studies using the hypothalamus of rats following niacin (NCN) administration. The rats were divided into HFRD and normal diet (ND)-fed groups and administered selected doses of NCN, i.e., 25 mg/mL/kg (low dose) and 50 mg/mL/kg (high dose), for 8 weeks. The grouping of male rats (n = 8) was as follows: (i) Vehicle (Veh) + ND; (ii) ND + NCN (low dose); (iii) ND + NCN (high dose); (iv) Veh + HFRD; (v) HFRD + NCN (low dose); and (vi) HFRD + NCN (high dose). Behavioral tests assessed depression-like symptoms and spatial memory; after that, the hypothalamus was isolated for various analyses of sacrificed animals. NCN at both doses decreased food intake and growth rate in both diet groups and demonstrated antidepressant and memory-enhancing effects. HFRD-induced oxido-neuroinflammation decreased with both doses of NCN. HFRD-induced decreases in serotonergic neurotransmission, 5-HT1A receptor expression, and morphological alterations in the rat's hypothalamus were normalized by both doses of NCN. In conclusion, NCN, as a potential antioxidant and neuromodulator, can normalize feeding behavior and produce antidepressant and memory-improving effects in a rat model of obesity following HFRD intake.

HIV-1 disrupts the metabolic profile of people living with HIV (PLWH), including the Tryptophan-Kynurenine (Trp-Kyn) pathway, linked to disease outcomes and comorbidities. Despite numerous studies, consensus on key dysregulated metabolites in antiretroviral therapy (ART)-treated PLWH is lacking. This systematic review compiles data to identify and highlight the most noteworthy Trp-Kyn metabolites.

PubMed, Scopus, and Web of Science databases were searched using a search protocol specifically designed for this study. Studies that investigated the levels of metabolites in the Trp-Kyn pathway in the peripheral blood of PLWH on ART, as well as in healthy control groups were included.

Thirteen metabolomic studies that investigated this pathway met our inclusion criteria. The findings revealed that Trp, Kyn, and the Kyn/Trp ratio (indicative of indoleamine 2,3-dioxygenase IDO activity) were the most investigated metabolites in this metabolic pathway. Evidence consistently demonstrated that Trp levels were lower in PLWH, while predicted IDO activity was consistently higher. Despite the widespread investigation of Kyn, there was no clear consensus on its levels in PLWH, with some studies reporting higher levels and others finding no significant differences compared to HIV-negative controls.

In the modern ART era, Trp metabolism and IDO activity may play key regulatory roles in HIV-1 pathogenesis, as evidenced by the consistent patterns observed across various studies. These metabolites and related pathways warrant further investigation as potential targets for improved diagnostics, prognostics, and therapeutics in the context of HIV-1.

Cataract is a prevalent, progressive lens disorder characterized by gradual opacity, often related to aging. Oxidative stress, ultraviolet radiation, and inflammation contribute to lens damage and protein modifications. Indoleamine 2,3-dioxygenase plays a critical role in tryptophan metabolism, with kynurenines implicated in various diseases. This study aimed to assess IDO activity in cataract patients by analyzing IDO activity in aqueous humor.

The study included 170 cataract surgery patients (60 males, 110 females; mean age 73.9 ± 9.43 years). Cataract severity was categorized using the SPONCS system: SPONCS 1 (1.8%), SPONCS 2 (30.6%), SPONCS 3 (35.3%), SPONCS 4 (11.8%), and SPONCS 5 (20.6%). Aqueous humor samples (50-120 µL) were collected via paracentesis and analyzed using HILIC liquid chromatography with mass spectrometry. Target metabolite quantification was performed using internal standards and calibration curves.

Significant differences in IDO activity were observed across SPONCS groups (X2(4) = 12.0, p = .018, Ɛ2= 0.0707), particularly between SPONCS 2 and SPONCS 5 (p = .013). Age differences across SPONCS groups were also significant (p < .001). Males had lower tryptophan levels than females (p = .027). Correlations were found between SPONCS and IDO activity (rs = -0.255, p < .001), SPONCS and kynurenine (rs = 0.196, p = .011), and kynurenic acid with kynurenine (rs = 0.355, p < .001).

Patients with SPONCS 2 cataract exhibit increased susceptibility to elevated IDO activity and heightened kynurenine production. IDO serves as a more reliable prognostic marker for cataract progression than chronological age. Furthermore, IDO activity may be associated with reduced glutathione levels in human lens epithelial cells, suggesting a potential link between the enzyme and oxidative stress within the lens.

The rising need for sustainable protein sources has made aquaculture vital for securing food supply. A balanced protein-rich diet is essential to support the optimal growth, health, and productivity of farmed aquatic species. Tryptophan, an essential amino acid, plays a crucial role in protein synthesis and serves as a precursor for neurotransmitters such as serotonin (5-hydroxytryptamine) and melatonin, which regulate reproduction, appetite, stress, and aggression in fish. The shift toward sustainable feed solutions emphasizes the need for tryptophan supplementation to address the deficiencies in alternative protein sources. Tryptophan supplementation promotes growth by enhancing protein synthesis, muscle development, and nutrient absorption while mitigating stress and inflammation through serotonin and melatonin synthesis. Its antioxidant properties help regulate oxidative stress, protect against environmental damage, and improve fish resilience. Tryptophan also modulates immune functions and reproductive processes, highlighting its multifaceted significance in aquaculture. Tryptophan interacts synergistically with other nutrients to enhance growth and immune responses. However, imbalanced tryptophan levels can impair growth, immune function, and productivity, thus requiring precise dietary formulations. The optimal tryptophan requirement varies among species and target functions. This review aims to highlight the pivotal role of tryptophan in fish health, growth, stress regulation, immune responses, oxidative damage, reproduction, cannibalism and its interaction with other nutrients, demonstrating its potential to further enhance immune function and support metabolic regulation.

Enteric pathogens exacerbate intestinal inflammation by disrupting microbiota-host metabolic interactions. While T helper 17 (Th17) cells are critical for maintaining intestinal homeostasis, the mechanisms through which enteric pathogens manipulate the function of Th17 cells to drive inflammation remain poorly understood. In this study, we established an immersion infection model using Edwardsiella piscicida in turbot (Scophthalmus maximus) to investigate the mechanism about enteric pathogen-induced intestinal inflammation, and found that E. piscicida infection significantly impairs the function of intestinal Th17 cells. By analyzing changes in the intestinal microbiota and metabolites, we observed a marked increase in the abundance of Proteobacteria phylum, which positively correlated with elevated levels of tryptophan-kynurenine (Trp-Kyn) pathway metabolites. Further investigation revealed that the enhanced Trp-Kyn pathway inhibits the function of intestinal Th17 cells. Importantly, pharmacological inhibition of the Trp-Kyn pathway could restore the function of Th17 cells and alleviate the infection-induced intestinal inflammation. Taken together, these findings uncover a critical link between microbiota-mediated tryptophan metabolism and Th17 cell's dysregulation during enteric pathogen infection in teleost, which provide novel insights into the metabolic reprogramming of host immunity and to identify potential therapeutic targets for mitigating intestinal inflammation.

The kynurenine pathway is a significant metabolic route involved in the catabolism of tryptophan, producing various bioactive metabolites with crucial roles as antioxidants in immune regulation and neurobiology. This study investigates the acid-base properties of picolinic acid, kynurenic acid, kynurenine, and 3-hydroxykynurenine, utilizing computational simulations and experimental techniques, including potentiometric and nuclear magnetic resonance titrations. The results reveal distinct pKa values, with kynurenic acid exhibiting a single dissociation step around 2.4, while kynurenine displays three dissociation steps governed by interactions between its functional groups. Additionally, 3-hydroxykynurenine shows overlapping dissociations in two separate pH regions, suggesting nuanced behavior influenced by its molecular structure. The analysis of intramolecular hydrogen bonding in protonation microspecies across varying pH highlights the relevance of the charge state and hydrogen transfer potential of these metabolites in the context of their radical scavenging ability. At physiological pH, most kynurenine and 3-hydroxykynurenine entities exist in zwitterionic form, with hydrogen bonding stabilizing the aromatic amino group, which may significantly influence their interactions with proteins and reactive oxygen species. This study provides critical insights into the acid-base equilibria of kynurenine pathway metabolites.

In European seabass (Dicentrarchus labrax), dietary tryptophan (TRP) surplus has a notable modulatory effect on the hypothalamic-pituitary-interrenal axis under chronic stress and acute inflammation, affecting cortisol levels and neuroendocrine- and immune-related gene expression. A transcriptomic approach (RNA-seq) was applied to head-kidney samples of fish submitted to confinement stress and/or acute inflammation to uncover the biological mechanisms behind these effects. Undisturbed seabass fed dietary TRP supplementation showed an up-regulation of various innate immune functions, contrasting previous studies which indicated mainly a TRP regulatory role. Upon bacterial injection, TRP-fed fish showed a transcriptomic profile similar to their counterparts fed on control diet, indicating TRP's inability to modulate immune mechanisms under bacterial challenge. Under confinement stress, TRP-fed fish exhibited a molecular profile similar to unstressed control fish, highlighting TRP's role in mitigating stress. However, combining dietary TRP supplementation with confinement stress and immune stimulation by bacterial inoculation resulted in a unique molecular profile. Stressed fish fed TRP did not show the restorative effect of immune stimulation on carbohydrate metabolism and showed downregulated genes related to glycolysis and glycogenolysis. Additionally, transcription upregulation in these fish after bacterial injection included terms related to serine and steroid metabolism (carboxyl ester lipase 2), indicating tryptophan-induced changes in lipid mobilization in the head-kidney, potentially affecting cortisol synthesis and other hormones.

Organ-on-chips (OOCs) technique has transferred real animal models to the in vitro models, especially for the exploration of the gut-brain-axis. In this work, we proposed a novel hydrogel-based microchip system to simulate two of the most indispensable physiological barriers in the gut-brain-axis, providing a feasible tool for studying the bacteria-induced regulations of tryptophan metabolism on cells. Using UV-light-induced hydrogel of alginate-gelatin mixture filled within the microchip as the cell scaffold, different cell layers were successfully inoculated and formed an intestinal barrier (IB) and a blood-brain barrier (BBB) with specific morphology and fundamental functions. Tryptophan-kynurenine pathway, a significant metabolic process in the gut-brain-axis, has been analyzed using this model by liquid chromatography-mass spectrometry and presented a possible explanation of this metabolic mechanism. Under bacterial conditions, the tryptophan in IB was about 1.46 times higher than that in BBB, while this value was about 3.14 times higher for kynurenine, indicating that the BBB has selective permeability to tryptophan and hinders the diffusion of kynurenine. This alginate-gelatin hydrogel scaffold based OOCs system has successfully simulated the dual barriers without moral dilemmas of animal models and analyzed tryptophan metabolism among different physiological barriers, providing an important tool for simulating physiological models with multi-barrier structures.

The kynurenine pathway (KP) might be involved in pathophysiological processes associated with dementia, but clinical studies reported contradictory results. This systematic review and meta-analysis summarized the available evidence for (i) differences in KP metabolites in patients with cognitive impairment compared to cognitively healthy individuals and (ii) associations between KP metabolites and cognitive functioning. English, full-length articles with prospective, cross-sectional, or case-control study designs, published in Pubmed, Embase, PsychINFO, or the Cochrane Database of Systematic Reviews up to October 2023, were included. Random-effects meta-analyses of standardized mean differences (SMD) were performed. Heterogeneity, meta-regression, small study bias, and study quality assessments were carried out. Of 8797 retrieved studies, 98 were eligible for the systematic review. Meta-analyses comparing Alzheimer's disease (AD) dementia patients to controls (n = 27 studies) indicated lower CSF levels of tryptophan (SMD = - 0.26 [95% CI - 0.41, - 0.12]), 3-hydroxykynurenine (- 0.21 [- 0.39, - 0.04]), anthranilic acid (- 0.28 [- 0.48, - 0.08]), and quinolinic acid (- 0.38 [- 0.56, - 0.21]) in AD dementia, while CSF levels of kynurenic acid were higher (0.18 [0.01, 0.35]). Blood levels of tryptophan (- 0.39 [- 0.51, - 0.28]), kynurenic acid (- 0.31 [- 0.47, - 0.15]), xanthurenic acid (- 0.34 [- 0.54, - 0.15]), and 3-hydroxyanthranilic acid (- 0.42 [- 0.61, - 0.22]) were lower in AD dementia. For some of these metabolites, similar directions were observed in meta-analyses comparing individuals with mild cognitive impairment with controls, although the number of included studies in these analyses was relatively small (n = 11). Associations with cognitive test scores were inconclusive and generally non-significant. These results suggest that AD dementia is associated with lower blood levels of several KP metabolites. Findings challenge current assumptions of neurotoxic quinolinic acid levels being associated with dementia.

The kynurenine pathway, the main metabolic pathway of tryptophan degradation, has been mostly studied in neurodegenerative disorders, while its role in cerebrovascular pathology is less clear. We investigated whether kynurenines are associated with markers of neurodegeneration and cerebrovascular pathology in the general population.

Cross-sectional data was used from 1589 individuals (60.0 ± 8.0 years, 54.3 % men) who participated in The Maastricht Study, an observational population-based cohort study. Plasma concentrations of tryptophan, kynurenines, and neopterin were quantified. Neurodegeneration was measured by volumes of intracranial cerebrospinal fluid (CSF), while cerebrovascular pathology was measured by white matter hyperintensity (WMH) volume and presence of cerebral small vessel disease (cSVD), defined as the presence of lacunar infarcts, cerebral microbleeds or a Fazekas score ≥ 2, all derived from 3 T MRI. Associations of kynurenines with these markers were investigated using linear, logistic, and restricted cubic spline regression models adjusted for confounders.

Fully adjusted analyses indicated that higher levels of 3-hydroxyanthranilic acid, kynurenine, kynurenic acid, quinolinic acid, and neopterin were associated with lower CSF volume. For the latter four, associations were non-linear and restricted to participants with already below average concentrations. Higher levels of tryptophan and anthranilic acid were associated with higher CSF volumes in participants with above-average levels. Higher levels of the kynurenine-tryptophan ratio were associated with a lower WMH volume. No evidence was found for associations between individual kynurenines and WMH volume or cSVD presence.

These findings suggest that several kynurenines are associated with neurodegeneration in community-dwelling older adults, but not with cerebrovascular damage.

Background: The kynurenine (KYN) pathway of tryptophan metabolism has been linked to inflammation and cardiovascular risk, but its long-term prognostic value remains unclear. Methods: We analyzed 492 patients from the KORONEF registry who underwent coronary and renal angiography and were followed for a median of 10.2 years. Plasma levels of tryptophan (TRP), KYN, and downstream metabolites were measured. The primary endpoint was all-cause mortality. Results: The mean age was 64.4 ± 9.9 years, and 37.2% of patients were female. Common comorbidities included hypertension (74.8%), dyslipidemia (46.0%), and diabetes (25.8%). Overall mortality reached 29.5% and increased across KYN tertiles: 17.6% (T1), 28.2% (T2), and 42.9% (T3) (p < 0.001). In a multivariable Cox analysis, KYN independently predicted mortality (HR: 1.79; 95% CI: 1.15-2.44; p < 0.001), alongside age, diabetes, prior myocardial infarction, chronic kidney disease, and left ventricular ejection fraction. Other kynurenine pathway metabolites were not independently associated with outcomes. Conclusions: Elevated kynurenine levels independently predict 10-year all-cause mortality in patients undergoing coronary angiography. KYN may represent a useful prognostic biomarker beyond traditional clinical and angiographic variables.

A healthy diet may help to reduce cancer-related fatigue, but evidence is limited and mechanisms remain unclear. Both diet and fatigue following colorectal cancer (CRC) have been linked to metabolites (kynurenines) of the kynurenine pathway (KP). We investigated longitudinal associations between dietary intake and fatigue, and the potential mediating role of the KP, in CRC survivors up to 1 year post-treatment.

Measurements at 6 weeks, 6 months, and 1 year post-treatment were performed in 209 stage I-III CRC survivors. Diet was assessed by 7-day food records. Plasma kynurenines were analyzed using LC-MS/MS. Fatigue, including subjective fatigue, was assessed using validated questionnaires. To analyse longitudinal associations between diet and fatigue and to explore potential mediation by the KP, we used confounder-adjusted multilevel parallel-multiple mediator models with all kynurenines included simultaneously, and simple mediator models with established KP ratios to estimate total (c: diet-fatigue), direct (c': diet-fatigue, while controlling for mediators), metabolite-specific indirect (ab: diet-metabolite-fatigue), and total indirect (ab: diet-metabolites-fatigue) effects.

Higher intake of total carbohydrates and mono- and disaccharides was longitudinally associated with more subjective fatigue, while higher intake of plant protein, total fat, and unsaturated fats was associated with less subjective fatigue (c). Most associations remained statistically significant after controlling for KP metabolites, except for mono- and disaccharides (c'). All kynurenines simultaneously did not mediate longitudinal associations between diet and subjective fatigue (ab). The kynurenic acid-to-quinolinic acid (KA/QA) ratio significantly mediated associations of intakes of carbohydrate, mono- and disaccharides, alcohol, magnesium, and zinc with subjective fatigue, whereas the HKr significantly mediated the association between polysaccharide intake and subjective fatigue (ab).

Our findings suggest that carbohydrate intake is associated with greater fatigue, while protein and fat intake are associated with lower fatigue in CRC survivors up to 1 year post-treatment. While all KP metabolites simultaneously did not significantly mediate associations between diet and fatigue in our population, the KA/QA ratio and HKr were significant mediators in several diet-fatigue associations. These results should be repeated in larger observational studies.

Glioblastoma (GBM) is the most aggressive primary brain tumor exhibiting extensive immune evasion mechanisms that hinder effective therapeutic interventions. This narrative review explores the immunomodulatory pathways contributing to tumor escape in GBM, specifically focusing on the role of Tryptophan (TRP) metabolism and its downstream mediators Tryptophan metabolism through the kynurenine pathway (KP) is initiated by indoleamine 2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO2) enzymes and serves as a crucial mechanism for promoting an immunosuppressive microenvironments and systemic immunotolerance. Emerging evidence also indicates a non-enzymatic role for IDO1 signaling in these processes. The downstream effectors interact with immune cells, inducing local immunosuppression within the tumor microenvironment and altering peripheral immune responses.

We systematically reviewed databases (MEDLINE via PubMed, Science Direct, and Embase) through October 2024 to highlight the interplay between local immune escape mechanisms and circulating immunotolerance, emphasizing the role of TRP metabolic enzymes in supporting GBM progression.

The literature review identified 99 records. TRP-related mechanisms play a central role in fostering immunotolerance in GBM. These phenomena involve intricate interactions between the infiltrating and circulating myeloid and lymphoid compartments, ultimately shaping a tolerant, pro-tumoral environment and the peripheral immunophenotype.

The biological activity of IDO1 and TRP metabolites positions these compounds as potential markers of disease activity and promising molecular targets for future therapeutic approaches.

Tryptophan (T), an essential amino acid, is primarily metabolized (∼90%) to kynurenine (K) by indoleamine 2,3-dioxygenase 1 (IDO1) mainly in intestinal cells. In inflammatory bowel disease (IBD), there is an increase in IDO1 activity which would increase Kynurenine levels and Kynurenine/Tryptophan (K/T) ratio. We hypothesize that alteration in K/T may be an indicator of disease severity in IBD.

55 healthy controls (HC), 55 Ulcerative colitis (UC) (35 active and 20 remission) and 30 Crohn's disease (CD) (20 active and 10 remission) were enrolled from November 2020 to March 2023. Plasma Kyn & Trp were simultaneously estimated using ultra-high-pressure liquid chromatography (UPLC). K/T ratio was correlated with disease activity and fecal calprotectin. In 25 patients follow-up samples were also collected with change in disease activity.

Median K/T ratio was significantly higher in patients with active disease as compared to those in remission and HC (p < .0001). A cut-off of ≤41 distinguished remission/healthy controls with a sensitivity of 92.73%, specificity of 76.36%, and an AUC of 0.9 (95% CI: 0.83-0.95, p < .001). The K/T ratio correlated with FC levels at a diagnostic cut-off of 250 µg/g. A significant reduction in K/T ratio with disease activity was noted in 80% of follow-up patients.

The K/T ratio with a cut-off of 41, correlated with the disease activity in 82% of patients, suggesting that the K/T ratio alters remarkably with disease activity in IBD patients. These findings can be further assessed for disease marker in a larger cohort of IBD patients.

Intrauterine inflammation disrupts tryptophan metabolism in both the placenta and the fetal brain, leading to a shift toward neurotoxic metabolites. These findings highlight the critical role of placental function in neurodevelopment and suggest that inflammation-induced metabolic changes may contribute to neurodevelopmental disorders.

The placenta plays a crucial role beyond nutrient transfer, acting as a dynamic endocrine organ that significantly influences maternal physiology and fetal development. It responds rapidly to even slight changes in the in utero environment to promote fetal survival. Disruptions in placental function are increasingly recognized as key contributors to the origins of neurodevelopmental disorders. In this study, we employed advanced technology to induce intrauterine inflammation through ultrasound-guided administration of LPS into gestational sacs. We then evaluated its effects on the gene expression of enzymes involved in TRP metabolism and conducted a comprehensive LC/MS analysis of the metabolome in the placenta and fetal brain of Wistar rats. Our results show that intraamniotic injection of LPS induces a robust inflammatory response leading to significant alterations in TRP metabolism, including downregulation of tryptophan hydroxylase (TPH) in the placenta, resulting in a decrease in serotonin (5-HT) levels. Similarly, in the fetal brain, exposure to LPS led to reduced Tph expression and increased monoamine oxidase expression, suggesting a decrease in 5-HT synthesis and an increase in its degradation. Furthermore, an upregulation of the kynurenine pathway was observed in both the placenta and fetal brain. Moreover, we detected a shift toward neurotoxicity, evidenced by an imbalance between neuroprotective and neurotoxic metabolites, including decreased levels of kynurenic acid and upregulation of kynurenine monooxygenase in the fetal brain. In conclusion, our findings reveal significant alterations in TRP metabolism following intrauterine inflammation, potentially contributing to neurodevelopmental disorders.

Down syndrome (DS) is a genetic disorder that leads to intellectual disability and accelerated aging, increasing the risk of Alzheimer's disease (AD). The pathophysiology of AD and DS is multifactorial, involving amyloid precursor protein overexpression, neuroinflammation, and oxidative stress. This study investigates kynurenine pathway metabolites in elderly individuals with DS (with/without cognitive decline), AD, and cognitively healthy controls to clarify their roles in these pathogeneses.

A cross-sectional study was conducted involving DS, AD, and healthy participants. Plasma levels of tryptophan, kynurenine, 3-hydroxykynurenine, anthranilic acid, 3-hydroxyanthranilic acid, and quinolinic acid were analyzed by Liquid Chromatography coupled with Tandem Mass spectrometry (LC-MS/MS) methodology.

Elevated kynurenine and other neuroprotective metabolites were found in DS individuals without cognitive decline, while significant differences in neurotoxic metabolites were observed between groups.

Our findings suggest a link between kynurenine pathway dysregulation and cognitive decline, indicating alterations in DS and AD.

There are altered kynurenine pathway metabolites in Down syndrome and Alzheimer's disease. Elevated neuroprotective metabolites are found in Down syndrome without cognitive decline. Significant differences in neurotoxic metabolites among study groups were analyzed. There is a potential link between kynurenine pathway dysregulation and cognitive decline. The study provides insights into metabolic changes in aging and neurodegeneration.

Tryptophan (Trp) is an essential amino acid obtained from human diet. It is involved not only in de novo biosynthesis of proteins but also in complex metabolic pathways. Redox transformation of tryptophan is under-explored in comparison with kynurenine, serotonin and indole pyruvate pathways. We described herein a mass spectrometric approach that can not only detect electron transfer-associated changes in masses and charges, but also identify electron-directed bond cleavages and radical-radical cross-coupling reactions in redox transformation of tryptophan. Photoactive TiO2 that is widely applied in cosmetic products is used as electron donor and receptor because of the capability to generate photoelectrons and holes. It was demonstrated tryptophan undergoes redox transformation through the removal of an electron from amino nitrogen atom by hole oxidization along with an electron capture in the indole ring. The back and forth electron-shuttle converts electric energy into chemical energy that enforces bond cleavages. Sodium-coupled electron transfer (SCET) was found in complementary with proton-coupled electron transfer in tryptophan. The movement of sodium ions avoids electric charge buildup caused by electron transfer. Various redox products were detected on both light irradiated TiO2 and skins, among which β-carboline shows extensive radical scavenging ability for diverse cross-coupling with indole derivatives. Light-independent redox products have been detected in vivo such as in mouse brain, indicating the presence of in vivo electron transfer-directed redox transformation. It has also been revealed that tryptophan can be arylated on Cα and Cβ atoms in response to the exposure of halogenated aromatics.

Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcriptional factor that is activated by a plethora of exogenous and endogenous compounds, including environmental pollutants, drugs, and microbial metabolites. The AhR plays an important role in modulating immunity. Current findings suggest that AhR activation serves as a mechanism for evasion of host antiviral immune response and promotes viral replication. This review will focus on AhR's role in RNA virus infection because they show high mutation rates compared with DNA viruses, and therefo pose one of the greatest threats to humans in terms of potential pandemic risk. Indeed, they include human immunodeficiency virus (HIV), influenza A virus (IAV), coronaviruses (CoVs), Zika virus, and others. Understanding the mechanisms by which AhR influences the immune response to these viruses is critical for developing effective therapeutic strategies. By focusing on the interplay between AhR signaling and RNA virus infections, this review aims to contribute to the growing body of knowledge regarding host-pathogen interactions and the implications for antiviral immunity.

Insulin overdose may cause hypoglycemic encephalopathy. In this study, Mendelian randomization was employed to analyze changes in the serum metabolites of patients with hypoglycemic encephalopathy, and metabolomics analysis was conducted to detect differential metabolites in the serum of a rat model of hypoglycemic encephalopathy induced by insulin overdose. The results indicated an overall upward trend in the tryptophan metabolism pathway in patients with hypoglycemic encephalopathy and rats with hypoglycemic encephalopathy caused by insulin overdose, while serum glutamate levels declined. The metabolic changes in the tryptophan pathway provide new insights into the impact of hypoglycemia on brain function. The related products of the tryptophan metabolism pathway have a certain diagnostic value for hypoglycemic encephalopathy and forensic identification of insulin overdose-induced hypoglycemic encephalopathy death.

Patients resuscitated after out-of-hospital cardiac arrest (OHCA) face high morbidity and mortality rates, primarily due to ischemia-reperfusion injury, a complex metabolic disorder that triggers a significant systemic inflammatory response. Glucocorticoids mitigate inflammation but also impact the cells beyond the immune response. This study aims to identify glucocorticoid effects on plasma metabolites.

This explorative sub-study is part of a two-center, blinded, randomized controlled trial (NCT04624776) examining the effects of high-dose glucocorticoid on comatose patients resuscitated from OHCA of presumed cardiac origin. Following resuscitation, patients received 250 mg of methylprednisolone or a placebo in the prehospital setting. Blood samples were collected upon hospital admission and 48 h later. Sixty metabolites were quantified in the plasma using mass spectrometry and compared between groups.

In the modified intention-to-treat population, 68 patients received methylprednisolone, and 69 received placebo [median age was 66 years (IQR: 56-74) and 83% were men]. Blood samples were available for 130 patients, 121 (88%) at admission and 117 patients (94% of patients alive) after 48 h. Although a nominal difference was observed at admission, no significant metabolic effects were found after correcting for multiple testing. After 48 h, the placebo group had 83.4% (95% CI 16.9-187.6%) higher prostaglandin E2 and higher levels of linolenic acid and arachidonic acid. The methylprednisolone group had higher levels of tryptophan (47.6%; 95% CI 27.9-70.2%), arginine, and propionylcarnitine (C3).

In this exploratory study, early administration of 250 mg of methylprednisolone after resuscitation appeared to drive sustained metabolic effects over 48 h. Specifically, methylprednisolone led to reductions in ω-6 fatty acids and increases in several amino acids, with a notable rise in tryptophan.

The role of inflammation in shaping death risk in diabetes is still unclear.

To study whether inflammation is associated with and helps predict mortality risk in patients with type 2 diabetes. To explore the intertwined link between inflammation and tryptophan metabolism on death risk.

There were 2 prospective cohorts: the aggregate Gargano Mortality Study (1731 individuals; 872 all-cause deaths) as the discovery sample, and the Foggia Mortality Study (490 individuals; 256 deaths) as validation sample. Twenty-seven inflammatory markers were measured. Causal mediation analysis and in vitro studies were carried out to explore the link between inflammatory markers and the kynurenine to tryptophan ratio (KTR) in shaping mortality risk.

Using multivariable stepwise Cox regression analysis, interleukin (IL)-4, IL-6, IL-8, IL-13, RANTES, and interferon gamma-induced protein-10 (IP-10) were independently associated with death. An inflammation score (I score) comprising these 6 molecules is strongly associated with death in both the discovery and the validation cohorts HR (95% CI) 2.13 (1.91-2.37) and 2.20 (1.79-2.72), respectively. The I score improved discrimination and reclassification measures (all P < .01) of 2 mortality prediction models based on clinical variables. The causal mediation analysis showed that 28% of the KTR effect on mortality was mediated by IP-10. Studies in cultured endothelial cells showed that 5-methoxy-tryptophan, an anti-inflammatory metabolite derived from tryptophan, reduces the expression of IP-10, thus providing a functional basis for the observed causal mediation.

Adding the I score to clinical prediction models may help identify individuals who are at greater risk of death. Deeply addressing the intertwined relationship between low-grade inflammation and imbalanced tryptophan metabolism in shaping mortality risk may help discover new therapies targeting patients characterized by these abnormalities.

It is well accepted that attention deficit hyperactivity disorder (ADHD) is in part driven by dysfunction in the monoaminergic neurotransmitter system, but both the extent of dysfunction and possible therapeutic avenues presented by serotonergic neurotransmission is frequently overlooked. As such, we present key evidence for dysfunction in serotonergic transmission, as seen from biochemical, genetic and pharmacological perspectives. An overall deficit in serotonin availability is a common theme throughout the literature, thus this review aims to explore possible dysfunctions in the serotonin synthesis pathway which result in this reduced bioavailability, and investigate whether such dysfunctions could be loci of change in ADHD. We have identified several steps in transmission, namely the conversion of tryptophan to 5-hydroxytryptophan and its use of cofactor tetrahydrobiopterin, which could present promising avenues for development of novel clinical interventions for ADHD.

Elevated brain levels of the essential metals manganese (Mn), copper, or iron induce motor disease. However, mechanisms of metal-induced motor disease are unclear and treatments are lacking. Elucidating the mechanisms of Mn-induced motor disease is particularly important because occupational and environmental Mn overexposure is a global public health problem. To address this, here we combined unbiased transcriptomics and metabolomics with functional studies in a mouse model of human environmental Mn exposure. Transcriptomics unexpectedly revealed that Mn exposure up-regulated expression of metabolic pathways in the brain and liver. Notably, genes in the kynurenine pathway of tryptophan metabolism, which produces neuroactive metabolites that impact neurological function, were up-regulated by Mn. Subsequent unbiased metabolomics revealed that Mn treatment altered kynurenine pathway metabolites in the brain and liver. Functional experiments then demonstrated that pharmacological inhibition of the first and rate-limiting step of the kynurenine pathway fully rescued Mn-induced motor deficits. Finally, elevated Mn directly activates hypoxia-inducible factor (HIF) transcription factors, and additional mechanistic assays identified a role for HIF1, but not HIF2, in regulating expression of hepatic kynurenine pathway genes under physiological or Mn exposure conditions, suggesting that Mn-induced HIF1 activation may contribute to the dysregulation of the kynurenine pathway in Mn toxicity. These findings (1) identify the upregulation of the kynurenine pathway by elevated Mn as a fundamental mechanism of Mn-induced motor deficits; (2) provide a pharmacological approach to treat Mn-induced motor disease; and (3) should broadly advance understanding of the general principles underlying neuromotor deficits caused by metal toxicity.

Quinoline-derived metabolites exhibit notable chemical complexity. What causes minor structural alterations to induce significant changes in disease outcomes? Historically, eclipsed by more straightforward scaffolds, these chemicals serve as a dynamic hub in tryptophan metabolism, linking immunomodulation, excitotoxicity, and cancer. However, many of these compounds struggle to cross the blood-brain barrier, and we still do not fully understand how certain structural changes affect their bioavailability or off-target effects. Thus, contemporary research highlights halogenation, esterification, and computational modeling to enhance structure-activity relationships.

This narrative review emphasizes the integration of rational drug design, multi-target ligands, and prodrug methods in enhancing quinoline scaffolds. We explore each molecule's therapeutic promise, refine each scaffold's design, and develop each derivative to maximize clinical utility. Translating these laboratory findings into clinical practice, however, remains a formidable challenge.

Through the synthesis of findings regarding NMDA receptor antagonism, improved oral bioavailability, and reduced metabolic instability, we demonstrate how single-site changes might modulate excitotoxicity and immunological signaling. Advancing quinoline-based medicines will yield significant advancements in neurology, psychiatry, and oncology. This enlarged framework fosters collaborative discovery, engages various audiences, and advances the field towards next-generation disease-modifying therapies. Robust preclinical validation, patient classification, and comprehensive toxicity evaluations are crucial stages for achieving these extensive endeavors and fostering future therapeutic discoveries globally.

Cumulative evidence indicates that compared to HIV negative individuals, people living with HIV (PLWH) have a higher likelihood of developing depression, anxiety, and cognitive disorders. Depression, which is known to be a persistent and overwhelming feeling of sadness accompanied by a loss of interest in usual activities, is one of the most common mental illnesses encountered during HIV infection. Experts believe that several factors such as neuroinflammation, life stressors, lack of sleep, poor nutritional state, opportunistic infections and comorbidities, and HIV medications are contributing factors favoring the development of depression in PLWH. However, the fundamental mechanisms which underlie the involvement of these factors in the emergence of depression in the context of HIV remain poorly explored. Past researches describing the role of one or two of the preceding factors do exist; however, very few articles tackle this important topic while considering the several different putative causative factors comprehensively in the particular context of HIV infection. Herein, we elaborate on the factors currently understood to be responsible for the development of depression, and discuss the particular fundamental mechanisms whereby each factor may result in the outcome of depression. We believe that the understanding of these factors and of their underlying mechanisms is essential for the development of future therapeutic interventions to alleviate the burden of depression commonly seen in PLWH, and therefore facilitate the development of strategies to improve their overall quality of life.

In this study, we employed a reductionist (yet not simplistic) approach utilizing the established invertebrate model system of the pond snail, Lymnaea stagnalis, to investigate the behavioral and molecular effects of systemic administration of lipopolysaccharide (LPS)-a bacterial endotoxin-on the snails' central ring ganglia. Snails received injections of either a low dose (2.5 μg) or a high dose (25 μg) of LPS, and their behavioral and molecular responses were assessed at 2, 6, and 24 h post-injection. With the high dose, snails exhibited a significant increase in homeostatic aerial respiration lasting for at least 24 h, consistent with a sickness-like state induced by the immune challenge. Additionally, we found that when administered 2, 6, or 24 h before operant conditioning training, the high dose of LPS, impaired memory formation. To further explore the underlying molecular mechanisms, we examined the transcriptional effects of the two doses of LPS in the snails' central ring ganglia. Our analysis showed a dose- and time-dependent upregulation of immune and stress-related genes, including key enzymes involved in the kynurenine pathway (KP), toll-like receptor 4 (TLR4), and heat shock protein 70 (HSP70). Metabolomic analysis suggested that the high LPS dose shifted KP metabolism toward the production of neurotoxic metabolites within the ganglia, indicating a LPS-induced neuroinflammatory state. Together, our findings provide valuable insight into the conserved mechanisms of neuroinflammation in this invertebrate model, offering a simplified yet effective tool to further explore the molecular interactions between the immune and central nervous systems.

Kynurenic acid (KYNA) is one of the metabolites of tryptophan (Trp), which can be supplied by endogenous synthesis or diet and involves various aspects of nutrition and metabolism. KYNA has been proven to be an antagonist of α7-nicotinic acetylcholine and NMDA receptors, which can regulate the neurotransmission of cholinergic and glutaminergic acid, so KYNA is mainly associated with neurodegenerative diseases. Other metabolites in the Trp and kynurenine metabolic pathways, such as 3-hydroxy-l-kynurenine (3-HK), 5-hydroxytryptophan (5-HT), and quinolinic acid (QA), are also involved in immune regulation and have pro-stimulatory or anti-excitatory toxicity. KYNA is present in both the human body and the daily diet, so it has the potential as a new dietary supplement. It may be of great significance in treating psychiatric disorders.

This study aimed to investigate the role of kynurenine in Colorectal Cancer (CRC) and the underlying mechanism.

Enzyme-linked immunosorbent assay was employed to assess the kynurenine concentration. Flow cytometry was utilized to analyze the percentages of CD3+CD4+ and CD3+CD8+ T-cells. Immunofluorescence was used to measure the expression of Programmed Death-Ligand 1 (PD-L1). RNA modification levels in CRC cells were analyzed using a dot blot assay. The interaction between NAT10 and PD-L1 was assessed via RNA immunoprecipitation, dual-luciferase reporter, and immunofluorescence assays. A xenograft tumor rat model was established.

Results indicated that kynurenine suppressed T-cell activation and promoted immune escape. Besides, kynurenine promoted N-Acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) modification. Moreover, NAT10 inhibition improved T-cell activation and suppressed immune escape. Mechanically, NAT10 is bound with the mRNA of PD-L1. Rescue experiments showed that PD-L1 inhibitor treatment reversed the suppressed T-cell activation and the promoted immune escape induced by NAT10 overexpression. In vivo, studies indicated that NAT10 deficiency reversed the promoted tumor growth induced by kynurenine treatment.

In conclusion, kynurenine promoted the immune escape of CRC cells via NAT10-mediated ac4C acetylation of PD-L1.

Cognitive impairment is a core symptom of multiple sclerosis (MS), resulting from inflammation-related brain damage and brain network dysfunction. Inflammation also causes dysregulation of the kynurenine pathway, which is the primary route of tryptophan metabolism. Kynurenine pathway dysregulation is characterised by a shift in concentrations of tryptophan catabolites, also referred to as kynurenines. Some kynurenines have neurotoxic effects that partly resemble the molecular mechanisms of MS pathophysiology underpinning brain damage and brain network dysfunction. The kynurenine pathway may therefore qualify as a mechanistic link between systemic inflammation, brain damage, and cognitive impairment in MS. This perspective article (1) provides an overview of inflammation-related kynurenine pathway dysregulation and MS-relevant neuroimmune properties of kynurenines and (2) summarises the current evidence on associations between systemic kynurenines, imaging metrics of brain structure or related markers, and cognitive performance in populations that present with kynurenine pathway dysregulation and are prone to cognitive impairment. These findings are used to (3) set a research agenda for future studies aimed at clarifying the role of the kynurenine pathway in brain damage and cognitive impairment in MS.

Currently, gastric cancer treatment remains an enormous challenge and requires a multidisciplinary approach. Globally, the incidence and prevalence of gastric cancer vary, with the highest rates found in East Asia, Central Europe, and Eastern Europe. Early diagnosis is critical for successful surgical removal of gastric cancer, but the disease often develops asymptomatically. Therefore, many cases are diagnosed at an advanced stage, resulting in poor survival. Metastatic gastric cancer also has a poor prognosis. Therefore, it is urgent to identify reliable molecular disease markers and develop an effective medical treatment for advanced stages of the disease. This review summarizes potential prognostic or predictive markers of gastric cancer. Furthermore, the role of tryptophan metabolites from the kynurenine pathway as prognostic, predictive, and diagnostic factors of gastric cancer is discussed, as this metabolic pathway is associated with tumor immune resistance.

Aging is associated with immune senescence and gut dysbiosis, both of which are heavily influenced by the diet. In this review, we summarize current knowledge regarding the impact of diets high in fiber, protein, or fat, as well as different dietary components (tryptophan, omega-3 fatty acids, and galacto-oligosaccharides) on the immune system and the gut microbiome in aging. Additionally, this review discusses how aging alters tryptophan metabolism, contributing to changes in immune function and the gut microbiome. Understanding the relationship between diet, the gut microbiome, and immune function in the context of aging is critical to formulate sound dietary recommendations for older individuals, and these personalized nutritional practices will ultimately improve the health and longevity of the elderly.

Alterations in tryptophan-kynurenine (TRP-KYN) pathway are implicated in major depressive disorder (MDD). α7 nicotinic acetylcholine (α7nACh) receptor regulates the hypothalamic-pituitary-adrenal (HPA) axis. We have shown that deficiency of kynurenine 3-monooxygenase (KMO) induces depression-like behaviour via kynurenic acid (KYNA; α7nACh antagonist). In this study, we investigated the involvement of the TRP-KYN pathway in stress-induced behavioural changes and the regulation of the HPA axis.

Mice were exposed to chronic unpredictable mild stress (CUMS) and subjected to behavioural tests. We measured TRP-KYN metabolites and the expression of their enzymes in the hippocampus. KMO heterozygous mice were used to investigate stress vulnerability. We also evaluated the effect of nicotine (s.c.) on CUMS-induced behavioural changes and an increase in serum corticosterone (CORT) concentration.

CUMS decreased social interaction time but increased immobility time under tail suspension associated with increased serum corticosterone concentration. CUMS increased KYNA levels via KMO suppression with microglial decline in the hippocampus. Kmo+/- mice were vulnerable to stress: they exhibited social impairment and increased serum corticosterone concentration even after short-term CUMS. Nicotine attenuated CUMS-induced behavioural changes and increased serum corticosterone concentration by inhibiting the increase in corticotropin-releasing hormone. Methyllycaconitine (α7nACh antagonist) inhibited the attenuating effect of nicotine.

CUMS-induced behavioural changes and the HPA axis dysregulation could be induced by the increased levels of KYNA via KMO suppression. KYNA plays an important role in the pathophysiology of MDD as an α7nACh antagonist. Therefore, α7nACh receptor is an attractive therapeutic target for MDD.

No established blood markers can preoperatively predict postoperative delirium. Blood concentrations of amino acid catabolites and dipeptides, including those secreted extracellularly during T-lymphocyte activation, were investigated as predictors of postoperative delirium using metabolomic analyses to ascertain whether preoperative blood metabolites could predict postoperative delirium. Eighteen and 24 participants were included in the delirium and non-delirium groups, respectively. Higher preoperative levels of amino acid (tryptophan) catabolites, via the indoleamine 2,3-dioxygenase pathway, were observed in the delirium group and identified as potential predictors of postoperative delirium in this study. The delirium group had preoperatively elevated levels of tryptophan catabolites and only a limited increase postoperatively, suggesting that the tryptophan catabolic pathway may be activated preoperatively in patients at high risk of delirium. Non-targeted metabolomic analysis found a set of preoperatively elevated γ-glutamyl dipeptides as potential predictors of postoperative delirium. In vitro experiments showed that T-cell-receptor stimulation increases tryptophan metabolism and specific γ-glutamyl dipeptide secretion, offering a possible explanation for the increased levels of metabolites in postoperative delirium. This study showed that levels of amino acid metabolites associated with blood immune activity may have the potential to predict postoperative delirium.

Epilepsy is a chronic noncommunicable neurological disorder characterized by recurrent seizures and ranks as the seventh most prevalent neurological disease globally. According to the Global Burden of Disease report, 3.40 billion people were affected by epilepsy in 2021. The pathophysiology of epilepsy states that a disturbed balance between excitatory and inhibitory signaling at the synaptic level, which can cause seizure activity, is similar across epilepsies and includes mitochondrial dysfunction, neuroinflammation, and kynurenine metabolites such as kynurenic acid and quinolinic acid. The kynurenine pathway (KP) is the major metabolic pathway in which tryptophan (TRP) is the key precursor which is further converted into a variety of neuroactive substances that can have both neurotoxic metabolites (Quinolinic acid) and neuroprotective metabolites such as kynurenic acid, and picolinic acid. KP plays a significant role in the brain such as the metabolism of TRP, the production of metabolites, and its impact on aging. However, higher concentrations of kynurenine and its metabolites, such as quinolinic acid may increase the frequency and intensity of seizures, and dysregulation of the KP has been linked to the pathophysiology of epilepsy. Concurrently, glutamate and GABA signaling is altered by neuroinflammatory processes linked to epilepsy, which results in excitotoxic neuronal damage. This review aims to provide novel therapeutic strategies that might improve the prognosis of individuals with epilepsy and related disorders by elucidating the mechanisms underlying KP dysregulation in these circumstances. To develop targeted therapies for CNS disorders characterized by inflammation and seizures, it is essential to understand how kynurenine metabolites both promote and prevent excitotoxicity.

Premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) are prevalent emotional disorders in females, characterized by cyclic variations in physiological stress responses and emotional symptoms that correspond with the menstrual cycle. Despite extensive research, the underlying causes of these disorders remain elusive. This review delves into the neurobiological mechanisms connecting stress-induced neuroinflammation with PMS/PMDD. Additionally, it traces the conceptual development and historical context of PMS/PMDD. The review further evaluates clinical evidence on the association between PMS/PMDD and stress, along with findings from both clinical and animal studies that link these disorders to inflammatory processes. Additionally, the neurobiological pathways by which inflammatory responses may play a role in the pathogenesis of PMS/PMDD were elucidated, including their interactions with the hypothalamic-pituitary-ovary (HPO) axis, serotonin-kynurenine (5-HT-KYN) system, GABAergic system, brain-derived neurotrophic factor (BDNF), hypothalamic-pituitary-adrena(HPA)axis and. Future research is encouraged to further investigate the pathogenesis of PMS/PMDD through the perspective of neuroinflammatory responses.

Although MK801-induced NMDA receptor (NMDAR) hypofunction mimics schizophrenia symptoms, the exact factors causing NMDAR inhibition are unknown. Unexpectedly, external stress elicits formaldehyde (FA) generation; FA can induce depression and cognitive impairments by blocking NMDARs. This study explores using FA injection to establish a schizophrenia-like model in mice. Here, we reported that external stress-derived FA induces schizophrenia-like behaviors. Four experimental methods were used to induce schizophrenia-like symptoms in wild-type mice: double electrode stimulation of the ventral tegmental area (VTA), microinjection of FA or tetrahydroisoquinoline (TIQ) into the VTA, and intraperitoneal injection of MK801. Then the metabolic levels of FA and dopamine (DA) in the prefrontal cortex (PFC) and VTA were quantified using ELISA kits. We found that external stress-electrical stimulation via VTA caused schizophrenia-like behaviors, including despairing behavior as measured by the tail suspension test, anhedonia as evaluated by the sucrose preference test, stereotypical behavior as assessed by the marble burying test (MBT), anxiety-like behavior as measured by the open-field test and memory deficit as detected by the Y-maze. These behaviors correlated with increased DA and TIQ levels in the VTA and decreased DA levels in the PFC. High-resolution mass spectrometry (HRMS) and high-performance liquid chromatography (HPLC) confirmed TIQ formation from FA and DA. Furthermore, injecting TIQ into the VTA induced schizophrenia-like symptoms in mice, marked by higher FA and lower DA levels in the PFC than control mice. Strikingly, injecting FA into the VTA as well as administering MK-801 induced schizophrenia-like behaviors associated with reduced DA levels and low activity of tyrosine hydroxylase (TH) and monoamine oxidase (MAO) in the PFC. Hence, microinfusion of FA into the VTA can be used to prepare schizophrenia-like changes mouse model, suggesting that stress-derived FA may act as an endogenous trigger of schizophrenia-like changes.