Search Results (477)

Objectives: This study aimed to develop a prognostic model for isolated moderate-to-severe traumatic brain injury (TBI) (Glasgow Coma Scale [GCS] ≤ 12) using readily available variables and to explore paired blood–cerebrospinal fluid (CSF) metabolomic signatures. Methods: Consecutive TBI patients admitted between January 2019 and June 2025 were retrospectively analyzed. Multivariate logistic regression with bootstrap internal validation identified predictors of 6-month unfavorable outcome and in-hospital mortality. Untargeted metabolomics was performed on paired blood and CSF samples from 30 matched male patients. Results: Among 405 patients, 266 (65.7%) had unfavorable outcomes and 54 (13.3%) died in hospital. Rotterdam CT Score (odds ratio [OR] 10.59, 95% confidence interval [CI] 6.19–18.14), initial lactate (OR 1.81, 95% CI 1.38–2.36), and blood glucose (OR 1.40, 95% CI 1.21–1.64) predicted unfavorable outcome (area under the receiver operating characteristic curve [AUC] 0.97). GCS motor score (OR 0.50, 95% CI 0.37–0.66), initial lactate (OR 1.57, 95% CI 1.31–1.91), and follow-up lactate (OR 1.57, 95% CI 1.34–1.88) predicted mortality (AUC 0.96). Blood metabolomics revealed enrichment in energy and lipid metabolism pathways. CSF metabolomics highlighted neurotransmitter pathway dysregulation and neuroinflammatory markers, with depleted kynurenic acid in both biofluids. Conclusions: Readily available admission variables enable early bedside risk stratification in TBI. Metabolomic profiling links unfavorable outcomes to systemic energy–lipid dysregulation and central neuroinflammatory–neurotransmitter disturbances, with the tryptophan–kynurenine axis as a potential therapeutic target for neuroprotective strategies. Full article

Major depressive disorder (MDD) is a complex and heterogeneous psychiatric disorder with a high prevalence. Neuroinflammation may define biologically distinct patient subgroups with different mechanisms, clinical phenotypes, and treatment responses. This narrative review integrates current evidence around three linked questions: how neuroinflammatory processes contribute to depression, how biomarkers can identify clinically relevant inflammatory phenotypes, and how these findings can inform anti-inflammatory treatment strategies. The major mechanisms discussed include microglial activation and neuroimmune signaling, hypothalamic–pituitary–adrenal axis dysregulation and glucocorticoid receptor resistance, kynurenine pathway alterations, and cytokine-driven impairment of neurogenesis and synaptic plasticity. These pathways interact with stress responses, neurotransmitter systems, and neuronal function, while their expression may vary according to sex, age, hormonal status, disease stage, and treatment exposure. These interconnected pathways may contribute to depressive symptoms by disrupting neurotransmitter systems and impairing neural plasticity. In addition, this review discusses several candidate biomarkers, including C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF) and transforming growth factor-β1 (TGF-β), which may support patient stratification, treatment prediction, and assessment of target engagement. Clinical trials of anti-inflammatory agents have shown inconsistent and generally modest effects in unselected MDD populations. By integrating mechanistic evidence with biomarker-guided therapeutic implications, this review aims to clarify how neuroinflammatory research may inform more precise and individualized treatment strategies for depression. Full article

Background/Objectives: Vitamin D is a nutrient-related secosteroid system with endocrine, paracrine, immunological, and neurodevelopmental actions relevant to nutritional psychiatry. Psychiatric research has often treated vitamin D either as a cross-sectional correlate of depression or as a non-specific supplement expected to act across heterogeneous diagnostic categories. This narrative review aimed to develop a more discriminating framework in which vitamin D is considered a lifespan neuroimmune and immunometabolic signal whose psychiatric relevance depends on developmental timing, biological context, and phenotype. Methods: Evidence was integrated from developmental epidemiology, neonatal dried-blood-spot studies, randomized trials, meta-analyses, Mendelian randomization studies, clinical guidelines, and mechanistic neuroscience. The review focuses on prenatal and neonatal 25-hydroxyvitamin D, vitamin D-binding protein, free and bioavailable vitamin D, vitamin D receptor signaling, immune and microglial pathways, neurotransmitter systems, neurotrophic signaling, mitochondrial function, oxidative stress, hypothalamic–pituitary–adrenal-axis regulation, and the gut–microbiota–immune–brain axis. Results: The available evidence does not support vitamin D as a universal treatment for psychiatric disorders. Instead, vitamin D deficiency and altered vitamin D biology appear most relevant in biologically and clinically defined risk states, including neurodevelopmental vulnerability, inflammatory depression, psychosis liability, severe mental illness with nutritional deprivation, metabolic comorbidity, and cognitive frailty. Mechanistic data support plausible links with cytokine biology, the tryptophan–kynurenine pathway, dopaminergic and serotonergic systems, stress regulation, and neuroimmune homeostasis. Conclusions: Vitamin D should be conceptualized in psychiatry as a context-dependent neuroimmune and immunometabolic signal rather than a generic psychotropic intervention. Future studies should prioritize biomarker-enriched, developmentally timed, nutrition-centered models of precision prevention and adjunctive care. Full article

Tryptophan (TRP) metabolism has emerged as a critical interface linking inflammation, immune regulation, oxidative stress, and cellular energetics. The kynurenine pathway, the predominant route of TRP degradation, is highly responsive to inflammatory stimuli and generates a spectrum of bioactive metabolites with divergent and context-dependent biological effects. Indoleamine 2,3-dioxygenase 1 (IDO1)-mediated TRP catabolism integrates immune activation with downstream metabolic signaling, influencing redox homeostasis, endothelial function, and mitochondrial energetics, in part by regulating nicotinamide adenine dinucleotide (NAD⁺) synthesis. Alterations in TRP metabolism are consistently observed across cardiometabolic diseases, including obesity, type 2 diabetes (T2D), atherosclerosis, myocardial infarction (MI), and heart failure with preserved ejection fraction (HFpEF), where they are associated with disease severity and adverse outcomes. Importantly, emerging data suggest that cardiometabolic phenotypes are determined not by pathway activation alone, but by the relative distribution of flux across downstream metabolic branches. Depending on the tissue compartment and stage of the disease, different biological effects may be contributed by redox-active kynurenine 3-monooxygenase (KMO)/3-hydroxykynurenine (3-HK)/quinolinic acid (QA) pathways, 3-hydroxyanthranilic acid (3-HAA)-mediated lipid and inflammasome regulation, microbiome-derived indoles, and NAD⁺-generating pathways. This review synthesizes current evidence using a branch-specific and context-dependent framework. We discuss the utility and limitations of the kynurenine-to-tryptophan ratio (KTR) as an upstream biomarker, the need for downstream metabolite panels, and therapeutic opportunities aimed at pathway modulation rather than broad inhibition. Future studies integrating temporal profiling, spatial and cell-specific approaches, large-animal models, and pathway-informed clinical trials will be essential to define causal mechanisms and enable precision therapeutic translation. Full article

Depression is increasingly linked to microbiota–gut–brain axis dysfunction, yet current monoaminergic antidepressants show limited efficacy. This study investigated the therapeutic potential and underlying mechanisms of GV-971, a marine-derived oligosaccharide, in a chronic restraint stress (CRS) mouse model. We first established that 8 h of daily restraint for 4–8 weeks induces a stable depression-like phenotype characterized by behavioral despair and significant reduction in peripheral monoamine neurotransmitters (5-HT and norepinephrine). GV-971 treatment robustly attenuated CRS-induced depression- and anxiety-like behaviors, restored hippocampal serotonin levels, reduced elevated plasma corticosterone concentrations, and ameliorated CRS-induced adrenal cortical hyperplasia. Mechanistically, GV-971 significantly suppressed neuroinflammation by inhibiting microglial hyperactivation in the prefrontal cortex and hippocampus. Concurrently, it repaired intestinal barrier dysfunction, evidenced by reduced permeability, restored mucosal integrity, and recovered goblet cell numbers. Crucially, integrated shot-gun metagenomics and plasma metabolomics revealed that GV-971 not only reshaped microbial taxonomy but also functionally recalibrated the gut ecosystem. It enriched beneficial taxa (e.g., Bifidobacterium pseudolongum, Bacteroides uniformis) and specific metabolic pathways, leading to increased short-chain fatty acids (valeric and caproic acids) and a significant reduction in plasma levels of tryptophan–kynurenine pathway metabolites, specifically the neurotoxic compounds kynurenine and quinolinic acid. Fecal microbiota transplantation (FMT) from GV-971-treated donors partially recapitulated the antidepressant and gut-protective effects in CRS recipients, confirming a causal role for the remodeled microbiota. Collectively, GV-971 exerts antidepressant effects by coordinately remodeling the gut microbiota, normalizing tryptophan and SCFA metabolism, restoring gut barrier integrity, and dampening central neuroinflammation, supporting its potential as a novel gut–brain axis-targeted therapy for depression. Full article

Major depressive disorder (MDD) and anxiety disorders are increasingly understood as conditions involving complex metabolic dysregulation across multiple biological domains. This review aimed to synthesize current clinical and translational evidence on amino acid metabolism, lipid metabolism and short-chain fatty acids (SCFAs) as potential biomarkers, and components of integrative metabolic profiling in these disorders. A structured narrative approach was applied, focusing on studies assessing metabolomic alterations, their clinical correlates and their potential role in patient stratification, and treatment response. The available evidence indicates that amino acid disturbances, particularly within the tryptophan–kynurenine pathway, represent the most consistent and clinically interpretable findings. Lipid-related alterations, especially involving long-chain polyunsaturated fatty acids, provide complementary insights into membrane function, inflammation and neuroplasticity. In contrast, SCFAs appear to function as context-dependent markers rather than robust standalone biomarkers, with their clinical relevance depending on biological matrix, metabolic context and host–microbiota interactions. Importantly, most studies assess individual metabolites rather than integrated metabolic profiles, limiting their interpretability within a metabolomic framework. Overall, current evidence supports a shift toward integrative biomarker models that combine metabolic data with selected molecular and clinical parameters. Future research should focus on standardized, reproducible profiling approaches to enable biologically informed stratification and personalized treatment strategies. Full article

Introduction: Glioblastoma (GBM) is the most aggressive primary tumor of the central nervous system and is highly resistant to temozolomide (TMZ). Rutin is a potent antioxidant with immunomodulatory and anti-glioma effects in vitro, although its mechanisms of action remain incompletely understood. This study investigated the effects of rutin on morphology, viability, redox balance, and pro-tumoral signaling in GBM 2D cultures and 3D spheroids, as well as its association with TMZ sensitivity. Methods: GL15 and U343 human GBM cell lines and primary astrocytes were treated with rutin (5–30 μM) and/or TMZ (125–4000 μM). Cell metabolic activity and viability were assessed by MTT, PI/DiOC18(3) or PI/Hoechst. Cell migration was assessed from spheroid-derived cells, and extracellular matrix (ECM) components (fibronectin and laminin) were evaluated by immunofluorescence. Intracellular reactive oxygen species (ROS) were measured by DCFH-DA fluorescence. IL-6, STAT3, NOS2, and IDO1 gene expression were determined by RT-qPCR, and protein expression of MMP2, fibronectin, STAT3, PI3K, and AKT by Western blotting. Nitric oxide (NO) and L-kynurenine levels were quantified in the supernatant by colorimetric assays. Results: Rutin reduced cell viability and enhanced TMZ cytotoxicity in both 2D and 3D cultures, while exerting selective effects by increasing metabolic activity and attenuating TMZ-induced effects in non-tumoral primary astrocytes. In 3D spheroids, rutin affected structural organization and reduced spheroid-derived cell migration, accompanied by changes in ECM components, including MMP2, fibronectin, and laminin. Rutin decreased intracellular ROS levels and suppressed the TMZ-induced increase in ROS and NOS signaling. These effects were accompanied by modulation of IL-6/STAT3 signaling, along with reduced STAT3, PI3K, and AKT protein levels. Rutin also modulated immunometabolic parameters, including extracellular L-kynurenine and nitric oxide levels, and enhanced TMZ responsiveness following pre-sensitization. Conclusions: Rutin enhances TMZ responsiveness by modulating interconnected pro-tumoral mechanisms, including redox balance, pro-survival signaling, ECM remodeling and migratory behavior, and immunometabolic pathways linked to chemoresistance, supporting its potential as an adjuvant therapeutic strategy. Full article

To investigate the effects of Wuwei Jianpi San (WJPS), a Chinese herbal compound feed additive, on rumen microecology, host metabolism, and immune function in healthy yaks (Bos grunniens), and to determine the optimal supplementation level, 32 yaks with similar initial body weight were randomly assigned to four groups: a control group and three groups receiving 0.5%, 1.0%, or 2.0% WJPS for 90 days. Growth performance, hematological indices, serum antioxidant and immune parameters, tryptophan metabolites, ruminal short-chain fatty acids (SCFAs), and rumen microbiota were analyzed. WJPS supplementation improved growth performance, as shown by a reduced feed-to-gain ratio in all treated groups and tended to increase average daily gain in the 2.0% group. It also enhanced hematological, antioxidant, and immune status, evidenced by increased white blood cell (WBC) and lymphocyte (Lym) counts and elevated interleukin-2 (IL-2), immunoglobulin G (IgG), and superoxide dismutase (SOD) levels. Moreover, 2.0% WJPS increased total SCFAs, acetate, and n-butyrate, while WJPS reduced kynurenine pathway metabolites, including kynurenine, 3-hydroxykynurenine, and quinolinic acid. Metagenomic analysis showed that WJPS tended to shape rumen microbial composition by increasing Bacillota and decreasing Bacteroidota, and these microbial changes were associated with host immune indices and tryptophan metabolism. Overall, 2.0% WJPS showed the best comprehensive effect. Full article

Phyllobilins are chlorophyll metabolites that belong to bilin-type linear tetrapyrroles. Chlorophyll, the omnipresent green pigment from algae to higher plants, is essential for life on Earth, underscoring the significance of its metabolites among phytochemicals. Once largely overlooked, phyllobilins are now gaining recognition for their widespread presence in the human diet through the consumption of fruits and vegetables. This, together with their favorable bioavailability, has heightened the importance of elucidating their bioactive properties. Numerous studies have demonstrated their antioxidant and anticancer activities in vitro, as well as their ability to target actin. The anti-inflammatory effects of phyllobilins have also been demonstrated by evaluating their ability to inhibit the COX-2 pathway or attenuate the activation of the tryptophan–kynurenine pathway. The objective of this review is to highlight the value of phyllobilins by compiling current knowledge, with a particular emphasis on their bioactivity and potential impact on human health. Full article

Polygonum capitatum (PC) is an ethnomedicine with reported antibacterial and anti-inflammatory activities and has been clinically used in urinary tract infection (UTI)-related disorders. However, its in vivo exposure characteristics and metabolically associated therapeutic mechanisms in acute pyelonephritis (AP) remain insufficiently understood. To address this issue, this study aimed to evaluate the therapeutic effects of PC in an Escherichia coli (E. coli)-induced rat model of AP and to explore constituents and metabolic pathways associated with its activity. Different PC extracts were screened for antibacterial and anti-inflammatory activities, and the 70% ethanol extract was selected for further study. Seven major compounds were quantified by HPLC. In AP rats, the pharmacokinetic profiles of these compounds in plasma and the renal cortex were analyzed by microdialysis-coupled HPLC-MS/MS. Pharmacodynamic evaluation included urinary bacterial load, urinalysis, renal function, inflammatory cytokines, and renal histopathology. Exploratory PK–PD analysis, untargeted renal metabolomics, and targeted metabolomics of the tryptophan–kynurenine (Trp–Kyn) pathway were also performed. The 70% ethanol extract of PC exhibited the strongest antibacterial and anti-inflammatory activities. The total content of seven active compounds was 3.85%, with gallic acid being the predominant compound (3.42%). Pharmacokinetic analysis revealed that gallic acid, protocatechuic acid, methyl gallate, and quercitrin achieved relatively high systemic exposure and renal distribution. In AP rats, the pharmacokinetic profiles of several compounds were altered, with increased plasma exposure of protocatechuic acid, vanillic acid, ethyl gallate, and syringic acid, while protocatechuic acid also showed higher exposure in the renal cortex. PC treatment reduced urinary bacterial load, improved renal function and urinalysis parameters, alleviated histopathological injury, and decreased inflammatory mediator levels, particularly in renal tissue. Exploratory PK–PD correlations were observed between several compounds and selected pharmacodynamic indicators. Metabolomic analysis suggested disturbances in glycerophospholipid metabolism and the Trp–Kyn pathway in AP rats, some of which were partially reversed after PC treatment. PC showed antibacterial and anti-inflammatory effects in AP rats. Gallic acid, protocatechuic acid, methyl gallate, and quercitrin may be candidate constituents associated with the therapeutic effects of PC, while modulation of glycerophospholipid metabolism and the Trp–Kyn pathway may be involved in its action against AP. These findings provide preclinical pharmacological evidence supporting the therapeutic potential of PC in AP. Full article

Background: Certain metabolites of the tryptophan-kynurenine (Trp-KYN) pathway, which are primarily cleared via tubular transport, have been linked to end-stage kidney disease (ESKD). Uromodulin—a protein expressed exclusively in the kidneys—is a key regulator of renal structure and function, as well as a direct marker of tubular health. This preliminary study explores the hypothesis that serum uromodulin correlates with Trp-KYN metabolites, potentially revealing new pathophysiological pathways in patients undergoing kidney replacement therapy (KRT). Given the link between serum uromodulin, Trp-KYN metabolites, and tubular function, we examined their correlation in KRT patients. Furthermore, we assessed how various clinical and dialysis parameters influence serum uromodulin levels. Methods: A total of 64 stable patients from a single dialysis center receiving hemodialysis (HD) or hemodiafiltration (HDF) were enrolled. Pre- and post-dialysis concentrations of uromodulin, Trp, KYN, kynurenic acid (KYNA), 3-hydroxykynurenine (3-OHKYN), and their reduction ratios (RRs) were established. High-performance liquid chromatography (HPLC) was used to estimate the KYN pathway metabolite levels, whereas uromodulin concentration was measured using an immunoenzymatic assay. Results: Detectable serum uromodulin was found in only 30 patients. This group was predominantly male (p < 0.001) and characterized by shorter dialysis vintage (p < 0.001), a higher prevalence of residual kidney function (RKF) (p = 0.001) and diabetes mellitus (p = 0.028), higher pre-dialysis serum phosphorus levels (p = 0.015), and more frequent use of loop diuretics (p = 0.004). Furthermore, univariate analysis revealed significantly higher pre-dialysis (p = 0.004) and post-dialysis (p = 0.025) serum Trp concentrations in the uromodulin-positive group. Pre-dialysis serum uromodulin concentration correlated positively with pre-dialysis Trp level (p < 0.001) and negatively with the pre-dialysis KYN/Trp ratio (p = 0.008), but not with other metabolites that are also subject to tubular transport mechanisms. Post-dialysis uromodulin levels correlated positively only with post-dialysis Trp level (p = 0.005). Patients treated with HDF had significantly higher RR for uromodulin than those treated with HD (p = 0.01). Conclusions: The presented data indicate that serum uromodulin levels are correlated with RKF. Additionally, the presence of detectable serum uromodulin may indicate reduced immunological activation, leading to diminished activity within the Trp-KYN pathway. Full article

Background: Nitrous oxide (N₂O) is increasingly used as a recreational drug, leading to neurological and systemic toxicities. However, due to the rapid elimination and minimal alteration of nitrogen oxides, the short direct detection window complicates the assessment of N₂O exposure. Method: In this study, we investigated the effects of chronic N₂O exposure on plasma metabolites using an untargeted metabolomics approach in a mouse model. C57BL/6 mice were exposed to 90,000 ppm N₂O (1 h, twice daily for 28 days) or room air. Plasma samples were analyzed via UHPLC -Triple TOF -MS. Orthogonal partial least squares discriminant analysis (OPLS-DA) and receiver operating characteristic (ROC) curves were used to identify differential metabolites. Result: A total of 35 differential metabolites were identified. Eight metabolites with an area under the curve (AUC) > 0.90 were selected as candidate biomarkers, including up-regulated SOPC and PC(16:0/16:0) (suggesting disrupted phospholipid remodeling and membrane integrity), and down-regulated DL-tryptophan, creatine, ectoine, indole, His-Ser, and Ile-Pro. Pathway enrichment analysis revealed significant alterations in glycine, serine and threonine metabolism; phenylalanine, tyrosine and tryptophan biosynthesis; protein digestion and absorption; and tryptophan metabolism. Conclusions: Our data indicate that chronic N₂O exposure disrupts multiple amino acid-related metabolic pathways (e.g., tryptophan-kynurenine pathway) and phospholipid homeostasis. The identified metabolite changes, along with vitamin B₁₂, homocysteine, and methylmalonic acid, may constitute a specific metabolic fingerprint for N₂O exposure. These findings help reveal the intrinsic mechanistic links underlying metabolic disorders induced by N₂O exposure. Full article

Background/Objectives: This study explores the roles of kynurenine and 5-hydroxytryptophan (5-HTP) in modulating gut microbiota and their potential implications for exudative age-related macular degeneration (AMD). By examining the interplay between these metabolites and the microbiome, we aim to uncover novel pathways that may influence the pathogenesis of AMD. Understanding these associations could lead to innovative therapeutic approaches for managing this leading cause of vision loss in the elderly. To investigate the roles of kynurenine and 5-HTP, alongside the composition of the nasopharyngeal microbiota, in patients with exudative AMD. Methods: Blood metabolite profiling was performed using LC–MS–based metabolomics. Metabolites were extracted with cold methanol/water containing internal standards, filtered through a 10 kDa cutoff filter, separated on a ZIC-HILIC HPLC column, and detected using an Orbitrap mass spectrometer. Metabolites were identified using MZmine 2 software. Results: Patients with exudative AMD exhibited a profound systemic shift in tryptophan metabolism, characterized by significantly lower plasma levels of 5-HTP and higher levels of kynurenine compared to control subjects (p < 0.001 for both). Logistic regression analysis confirmed that both metabolites were independent predictors of AMD status; higher kynurenine levels were associated with increased disease probability, while higher 5-HTP levels demonstrated a protective effect. The kynurenine/5-HTP ratio emerged as a robust biomarker, achieving an area under the curve (AUC) of 0.85 with an optimal threshold of 3.43 (74.1% sensitivity, 84.4% specificity). When integrated with age and gender, the diagnostic performance of the model reached an excellent AUC of 0.92. After adjusting for demographic factors, the kynurenine/5-HTP ratio remained a potent independent risk factor, with each unit increase associated with a 6.30-fold increase in the odds of exudative AMD. Conclusions: Exudative AMD is characterized by a shift in tryptophan metabolism toward the kynurenine pathway, with decreased 5-HTP, increased kynurenine, and an elevated kynurenine/5-HTP ratio. This ratio showed a strong independent association with AMD and excellent diagnostic performance, highlighting its potential as a biomarker and its role in disease pathogenesis. Full article

Glaucoma remains a primary cause of blindness, yet its pathogenesis often extends beyond intraocular pressure (IOP). This review integrates four converging lines of metabolic evidence—aqueous humor (AH) metabolomics, kynurenine pathway (KP) activity, tetrahydrobiopterin (H4BIP) biology, and NAD/one-carbon dysfunction—into a testable framework for retinal ganglion cell vulnerability. By utilizing a systematic AH metabolomics atlas covering glaucoma, pseudoexfoliation, and diabetes on a standardized HILIC-LC-HRMS platform, we demonstrate that, while aromatic amino acid elevations are non-specific markers, kynurenine monooxygenase (KMO) upregulation is a condition-specific glaucoma signature. These local findings are corroborated by systemic evidence: POAG patients exhibit significant folic acid deficiency (p = 0.007) and elevated alpha-1-antitrypsin (AAT). Critically, AAT correlates inversely with both serum folate (r_s = −0.485, p < 0.001) and retinal nerve fiber layer thickness (r_s = −0.386, p = 0.017), providing the first in-patient evidence linking systemic inflammation to structural optic nerve damage. We conclude that KMO serves as a critical enzymatic node linking tryptophan metabolism, H4BIP availability, and NAD synthesis. These results characterize glaucoma as a disease of progressive cofactor failure and define a research agenda for multimodal metabolic neuroprotection. Full article

Tryptophan (Trp) metabolism sits at the intersection of nutrition, the microbiome, mucosal immunity, and tumor adaptation. The broad observation that microbial indoles can support barrier function, whereas tumors exploit kynurenine-pathway metabolism to suppress immunity, is already established in publications. The specific contribution of this review is to organize that literature into a context- and network-based translational framework. Rather than treating indoleamine 2,3-dioxygenase 1 (IDO1) as a single bottleneck, we frame tumor Trp metabolism as a compensatory system linking IDO1, tryptophan 2,3-dioxygenase (TDO2), interleukin-4-induced gene 1 (IL4I1), amino-acid transport, amino-acid stress sensing, and downstream aryl hydrocarbon receptor (AHR) signaling. In healthy tissue, especially the gut, dietary Trp and microbiota-derived indoles can promote epithelial integrity, interleukin-22 (IL-22)-associated programs, and mucosal restraint. In tumors, the same substrate pool is redirected toward Kynurenine, kynurenic acid, indole-3-pyruvate, and related catabolites that impair cytotoxic lymphocytes, expand regulatory T-cell (Treg) and suppressive myeloid compartments, and reinforce invasion and treatment resistance. We also argue that the potential metabolite biomarker interpretation should be context-dependent. Finally, we propose a clinical-context–specific framework for intervention. Dietary and microbiome-based strategies may be most effective in prevention, premalignant states, or supportive care, whereas established cancers are more likely to require biomarker-guided targeting of tumor-associated catabolic pathways and convergent signaling mechanisms. The “paradox” is therefore not that Trp changes chemistry across settings, but that the same nutrient is routed through different cellular contexts, enzymes, ligands, and cell states. Full article