Persistent organic pollutants (POPs) are known to disrupt gut microbiota composition and host metabolism, primarily through dietary exposure. In this study, we investigate the impact of 2,3,7,8-tetrachlorodibenzofuran (TCDF) on gut microbiota and host metabolic processes. RNA-seq analysis revealed that TCDF exposure significantly affected tryptophan metabolism, lipid metabolic pathways, and immune system function. Metagenomic and metabolomic analyses further showed that TCDF reduced the abundance of Mucispirillum schaedleri and levels of two key tryptophan metabolites, indole-3-carboxaldehyde (3-IAld) and Indole acrylic acid (IA). Supplementation with 3-IAld and IA alleviated TCDF-induced liver toxicity in mouse, as evidenced by reduced Cyp1a1 expression, and mitigated intestinal inflammation, reflected by lower pro-inflammatory cytokines (Ifn-γ and Il-1β) in the colon. Additionally, 3-IAld and IA supplementation enhanced intestinal barrier function, as demonstrated by increased Mucin 2 (MUC2) expression in the gut mucosa of mouse. These findings suggest that TCDF exposure disrupts the gut microbiome and host metabolic balance, and highlight the potential therapeutic role of tryptophan-derived metabolites in mitigating environmental pollutant-induced damage.

Advanced maternal age (AMA) is defined as a pregnancy in a woman older than 35 years of age. AMA increases the risk for both maternal and neonatal complications, including miscarriage and stillbirth. AMA has also been linked to neurodevelopmental and neuropsychiatric disorders in the offspring. Recent studies have found that age-associated compositional shifts in the gut microbiota contribute to altered microbial metabolism and enhanced inflammation in the host. We investigated the specific contribution of the maternal microbiome on pregnancy outcomes and offspring behavior by recolonizing young female mice with aged female microbiome prior to pregnancy. We discovered that pre-pregnancy colonization of young dams with microbiome from aged female donors significantly increased fetal loss. There were significant differences in the composition of the gut microbiome in pups born from dams recolonized with aged female biome that persisted through middle age. Offspring born from dams colonized with aged microbiome also had significant changes in levels of neurotransmitters and metabolites in the blood and the brain. Adult offspring from dams colonized with an aged microbiome displayed persistent depressive- and anxiety-like phenotypes. Collectively, these results demonstrate that age-related changes in the composition of the maternal gut microbiome contribute to chronic alterations in the behavior and physiology of offspring. This work highlights the potential of microbiome-targeted approaches, even prior to birth, may reduce the risk of neuropsychiatric disorders.

Hepatic fibrosis (HF) represents a pivotal stage in the progression and potential reversal of cirrhosis, underscoring the importance of early identification and therapeutic intervention to modulate disease trajectory.

To explore the complex relationship between chronic hepatitis B (CHB)-related HF and gut microbiota to identify microbiota signatures significantly associated with HF progression in CHB patients using advanced machine learning algorithms.

This study included patients diagnosed with CHB and classified them into HF and non-HF groups based on liver stiffness measurements. The HF group was further subdivided into four subgroups: F1, F2, F3, and F4. Data on clinical indicators were collected. Stool samples were collected for 16S rRNA sequencing to assess the gut microbiome. Microbiota diversity, relative abundance, and linear discriminant analysis effect size (LEfSe) were analyzed in different groups. Correlation analysis between clinical indicators and the relative abundance of gut microbiota was performed. The random forest and eXtreme gradient boosting algorithms were used to identify key differential gut microbiota. The Shapley additive explanations were used to evaluate microbiota importance.

Integrating the results from univariate analysis, LEfSe, and machine learning, we identified that the presence of Dorea in gut microbiota may be a key feature associated with CHB-related HF. Dorea possibly serves as a core differential feature of the gut microbiota that distinguishes HF from non-HF patients, and the presence of Dorea shows significant variations across different stages of HF (P < 0.05). The relative abundance of Dorea significantly decreases with increasing HF severity (P = 0.041). Moreover, the gut microbiota composition in patients with different stages of HF was found to correlate with several liver function indicators, such as γ-glutamyl transferase, alkaline phosphatase, total bilirubin, and the aspartate aminotransferase/alanine transaminase ratio (P < 0.05). The associated pathways were predominantly enriched in biosynthesis, degradation/utilization/assimilation, generation of precursors, metabolites, and energy, among other categories.

HF affects the composition of the gut microbiota, indicating that the gut microbiota plays a crucial role in its pathophysiological processes. The abundance of Dorea varies significantly across various stages of HF, making it a potential microbial marker for identifying HF onset and progression.

Background/Objectives: Despite substantial research, the causal relationships between gut microbiota (GM) and age-related macular degeneration (AMD) remain unclear. We aimed to explore these causal associations using Mendelian randomization (MR) and elucidate the potential mechanisms mediated by blood metabolites. Methods: We utilized the 211 GM dataset (n = 18,340) provided by the MiBioGen consortium. AMD outcome data were sourced from the MRC Integrated Epidemiology Unit (IEU) OpenGWAS Project. We performed bidirectional MR, two mediation analyses, and two-step MR to assess the causal links between GM and different stages of AMD (early, dry, and wet). Results: Our findings indicate that the Bacteroidales S24.7 group and genus Dorea are associated with an increased risk of early AMD, while Ruminococcaceae UCG011 and Parasutterella are linked to a higher risk of dry AMD. Conversely, Lachnospiraceae UCG004 and Anaerotruncus are protective against dry AMD. In the case of wet AMD, Intestinimonas and Sellimonas increase risk, whereas Anaerotruncus and Rikenellaceae RC9 reduce it. Additionally, various blood metabolites were implicated: valine, arabinose, creatine, lysine, alanine, and apolipoprotein A1 were associated with early AMD; glutamine and hyodeoxycholate-with a reduced risk of dry AMD; and androsterone sulfate, epiandrosterone sulfate, and lipopolysaccharide-with a reduced risk of wet AMD. Notably, the association between family Oxalobacteraceae and early AMD was mediated by valine, accounting for 19.1% of the association. Conclusions: This study establishes causal links between specific gut microbiota and AMD, mediated by blood metabolites, thereby enhancing our understanding of the gut-retina axis in AMD pathophysiology.

The Healthy Eating Index (HEI)-2015 measures diet quality and is associated with a lower risk of death from chronic disease. Dietary components may affect health via multiple mechanisms, including decreasing inflammation and affecting immune activation.

We hypothesized that the overall HEI-2015 score, or individual component scores, would be associated with altered inflammation and immune activation in healthy adults.

The association of HEI-2015 scores with 88 inflammation and immune activation markers was examined in 346 adults without diagnosed disease using general linear models to adjust for covariates, including visceral fat mass index (VFMI).

The overall HEI-2015 score was inversely associated with plasma C-reactive protein (CRP) and leukocyte concentrations, which are markers of inflammation, but these associations lost statistical significance with adjustment for VFMI. However, even with VFMI adjustment, the total vegetable score was inversely associated with total lymphocyte concentration (β = -0.157 ± 0.052, P = 0.019) and with monocyte and neutrophil activation (e.g., classic monocyte CD11b β = -0.153 ± 0.055, P = 0.030; neutrophil CD11b β = -0.122 ± 0.051, P = 0.049). The refined grain score was inversely associated with percent NK-T cells (β =-0.171 ± 0.058, P = 0.037), IL-10 production by T cells (β = -0.204 ± 0.057, P = 0.0039), and positively associated with plasma soluble CD14 (β = 0.220 ± 0.059, P = 0.0041). The total dairy score was positively associated with production of multiple cytokines by lipopolysaccharide-stimulated peripheral blood mononuclear cells [e.g., interleukin (IL)-1β β = 0.182 ± 0.054, P = 0.0066].

Adjustment for VFMI decreased the association of HEI-2015 with inflammation, consistent with the known role of adiposity in mediating effects of poor diet on inflammation. This study also identified component scores associated with various aspects of immune activation that bear further study to clarify possible health benefits. This trial was registered at clinicaltrials.gov as NCT02367287.

Immune function is affected by vitamin D status, but the optimal serum 25-hydroxy vitamin D [25(OH)D] concentration for immune function is not known.

We hypothesized that 25(OH)D would be associated with markers of inflammation and immune activation.

We identified associations between 25(OH)D and immune markers from 361 healthy adults using polynomial regression. Linear regression was used to define the slope (β) of significant linear associations, and piecewise regression identified inflection points (IPs) for curvilinear associations with P < 0.05. IPs with a slope difference (SD) P < 0.05 before and after were significant.

25(OH)D had linear, negative associations with interleukin (IL)-6 (β: -0.126; P = 0.009) and macrophage-derived chemokine (MDC) (β: -0.108; P = 0.04) and a linear, positive association with matrix metalloproteinase (MMP)-1 (β: 0.108; P = 0.04). Among the significant curvilinear associations, 2 showed negative associations below but positive associations above an IP with nearly significant SD P values, including percentage of effector-memory CD8 T cells (IP: 56.2 nmol/L; SD P = 0.067) and platelet concentration (IP: 38.9 nmol/L; SD P = 0.058). The opposite associations, positive below and negative above an IP, were seen for eotaxin (IP: 49.5 nmol/L; SD P = 0.049); interferon (IFN)-γ-induced protein-10 (IP-10) (IP: 71.8 nmol/L; SD P = 0.02); percentage of CD4 T cells expressing programmed cell death protein (PD)-1 (IP: 71.2 nmol/L; SD P = 0.01); percentage of Tregs expressing human leukocyte antigen, DR isotype (HLA-DR) (IP: 67.5 nmol/L; SD P < 0.0001); percentage of memory Tregs (IP: 68.8 nmol/L; SD P = 0.002); and percentage of memory Tregs expressing HLA-DR (IP: 68.8 nmol/L; SD P = 0.0008).

These findings are consistent with low vitamin D status allowing and higher vitamin D status dampening inflammation and immune activation. IP analysis identified possible thresholds for vitamin D effects on immune function. Two of 3 IPs at ∼50 nmol/L show higher inflammation below this concentration, suggesting 50 nmol/L as a minimum target for dampening inflammation. IPs at ∼70 nmol/L identify a threshold for CD4 T-cell activity, including Treg activation and IFN-γ-driven production of the T-cell chemokine IP-10, suggesting an optimal concentration for regulating adaptive immunity. This study was registered at clinicaltrials.gov as NCT02367287.

Indole-3-propionic acid (IPA), a metabolite produced by gut microbiota through tryptophan metabolism, has recently been identified as playing a pivotal role in bone metabolism. IPA promotes osteoblast differentiation by upregulating mitochondrial transcription factor A (Tfam), contributing to increased bone density and supporting bone repair. Simultaneously, it inhibits the formation and activity of osteoclasts, reducing bone resorption, possibly through modulation of the nuclear factor-κB (NF-κB) pathway and downregulation of osteoclast-associated factors, thereby maintaining bone structural integrity. Additionally, IPA provides indirect protection to bone health by regulating host immune responses and inflammation via activation of receptors such as the Aryl hydrocarbon Receptor (AhR) and the Pregnane X Receptor (PXR). This review summarizes the roles and signaling pathways of IPA in bone metabolism and its impact on various bone metabolic disorders. Furthermore, we discuss the therapeutic potential and limitations of IPA in treating bone metabolic diseases, aiming to offer novel strategies for clinical management.

Myocardial infarction, a type of coronary artery disease, results from various factors such as genetic predisposition, lifestyle choices, and immune system regulation. The exact causal links between immune cells, plasma metabolites, and myocardial infarction are currently unclear. Therefore, our study employed the Mendelian randomization approach to explore these potential causal relationships. To investigate the impact of immune cells on the risk of myocardial infarction mediated by alterations in plasma metabolite levels, we employed the Mendelian randomization (MR) framework. Our analysis utilized 5 distinct MR techniques (inverse variance weighted [IVW], weighted median, MR-Egger, simple mode, and weighted mode) to evaluate causal relationships among 731 immune cell types, 1400 plasma metabolites, and myocardial infarction. Genetic instruments for immune cells and metabolites were identified using data from a meta-analysis of genome-wide association studies. Furthermore, sensitivity analyses were performed to verify the robustness of our results, identify potential heterogeneity, and examine possible pleiotropic effects. IVW results indicated that IgD-CD38br lymphocytes was a risk factor for myocardial infarction, whereas IgD-CD38br lymphocytes also acted as a protective factor against myocardial infarction. Additionally, the glycerol to palmitoylcarnitine (C16) ratio was identified as a protective factor for myocardial infarction. IgD-CD38br lymphocytes could exert a detrimental effect on myocardial infarction by negatively regulating the glycerol to palmitoylcarnitine (C16) ratio, with the mediation effect ratio being 9%. IgD-CD38br lymphocytes potentially increase the risk of myocardial infarction by negatively affecting the glycerol to palmitoylcarnitine (C16) ratio. This finding opens avenues for developing early diagnostic tools and targeted therapies for myocardial infarction.

We aimed to explore changes in plasma and urine indole lactic acid (ILA) levels and the relationship between inflammation and ILA in chronic kidney disease (CKD) patients and healthy people.

Forty-seven CKD patients and 30 healthy individuals were included in this study. One-way ANOVA was used for variables with normal distribution and homogeneous variance. A rank-sum test was performed for non-normally distributed variables. Correlation analyses were performed using Pearson's or Spearman correlation analyses. Independent relationship between patients and CKD was analyzed using ordinal and binary logistic regressions. Receiver operating characteristic (ROC) curve was used.

Plasma and urine ILA levels were positively correlated (r = 0.51, P < 0.01). Plasma ILA was positively correlated with BMI, age, creatinine, BUN, triglycerides, and uric acid and negatively correlated with hemoglobin levels. Urine ILA levels were positively correlated with age, creatinine, BUN, and uric acid and negatively correlated with hemoglobin and albumin levels. Ordered logistic regression analysis showed that CKD was significantly correlated with plasma ILA (OR=4.49, P < 0.01), urinary ILA (OR=2.14,P < 0.01), urea levels (OR=1.43, P < 0.01) and hemoglobin levels (OR=0.95, P < 0.01) were significantly related. ROC curves indicated that plasma and urinary ILA were reliable predictors of CKD. CKD was correlated with plasma, urine ILA (OR=5.92, P < 0.01; OR=2.79, P < 0.01) and Hs-CRP (OR=2.45, P < 0.01).

Plasma and urine ILA can potentially be used as biomarkers of CKD and inflammatory status.

The prevalence of pulmonary tuberculosis (PTB) as an infectious disease continues to contribute significantly to global mortality. According to recent studies, the gut microbiota of PTB patients and healthy controls (HCs) show significant disparities. However, the causal relationship between them has yet to be elucidated.

We conducted a study using Mendelian Randomization (MR) to explore the potential causal link between gut microbiota and pulmonary tuberculosis (PTB). The summary statistics of the gut microbiota were acquired from the MiBioGen consortium, while data on PTB were sourced from pheweb.jp. A range of statistical methodologies were employed to evaluate causality, encompassing inverse variance weighting (IVW), MR-Egger, weighted median (WM), weighted model, and simple model. We utilized instrumental variables (IVs) that have a direct causal relationship with PTB to annotate SNPs, aiming to discover the genes harboring these genetic variants and uncover potential associations between host genes and the microbiome in patients with PTB.

Among the 196 bacterial traits in the gut microbiome, we have identified a total of three microbiomes that exhibit a significant association with PTB. The occurrence of Dorea (P = 0.0458, FDR-adjusted P = 0.0458) and Parasutterella (P = 0.0056, FDR-adjusted P = 0.0168) was linked to an elevated risk of PTB, while the presence of Lachnoclostridium (P = 0.0347, FDR-adjusted P = 0.0520) demonstrated a protective effect against PTB. Our reverse Two-Sample Mendelian Randomization (TSMR) analysis did not yield any evidence supporting the hypothesis of reverse causality from PTB to alterations in the intestinal flora.

We have established a connection between the gut microbiota and PTB through gene prediction analysis, supporting the use of gut microecological therapy in managing PTB and paving the way for further understanding of how gut microbiota contributes to PTB's development.

Previous research has linked serum metabolite levels to iridocyclitis, yet their causal relationship remains unexplored. This study investigated this potential causality by analyzing pooled data from 7824 iridocyclitis patients in a Genome-Wide Association Study (GWAS) using Mendelian randomization (MR) and linkage disequilibrium score regression (LDSC). Employing rigorous quality control and comprehensive statistical methods, including sensitivity analyses, we examined the influence of 486 serum metabolites on iridocyclitis. Our MR analysis identified 23 metabolites with significant causal effects on iridocyclitis, comprising 17 known and 6 unidentified metabolites. Further refinement using Cochran's Q test and MR-PRESSO indicated 16 metabolites significantly associated with iridocyclitis risk. LDSC highlighted the heritability of certain metabolites, underscoring genetic influences on their levels. Notably, tryptophan, proline, theobromine, and 7-methylxanthine emerged as risk factors, while 3,4-dihydroxybutyrate appeared protective. These findings enhance our understanding of the metabolic interactions in iridocyclitis, offering insights for diagnosis, unraveling pathophysiological mechanisms, and informing potential avenues for prevention and personalized treatment.

Neuroinflammation has been postulated to be a key factor in the pathogenesis of major depressive disorder (MDD). With this is mind, there has been a wave of research looking into pro-inflammatory mediators as potential biomarkers for MDD. One such mediator is the acute phase protein, C-reactive protein (CRP). While several studies have investigated the potential of CRP as a biomarker for MDD, the results have been inconsistent. One explanation for the lack of consistent findings may be that the high-sensitivity CRP tests utilized in these studies only measure the pentameric isoform of CRP (pCRP). Recent research, however, has indicated that the monomeric isoform of CRP (mCRP) is responsible for the pro-inflammatory function of CRP, while pCRP is weakly anti-inflammatory. The objective of this minireview is to re-examine the evidence of CRP involvement in MDD with a view of mCRP as a potential biomarker.

Chronic inflammation may develop over time in healthy adults as a result of a variety of factors, such as poor diet directly affecting the composition of the intestinal microbiome, or by causing obesity, which may also affect the intestinal microbiome. These effects may trigger the activation of an immune response that could eventually lead to an inflammation-related disease, such as colon cancer. Before disease develops it may be possible to identify subclinical inflammation or immune activation attributable to specific intestinal bacteria normally found in the gut that could result in future adverse health impacts. In the present study, we examined a group of healthy men and women across a wide age range with and without obesity to determine which bacteria were associated with particular types of immune activation to identify potential preclinical markers of inflammatory disease risk. Several associations were found that may help develop dietary interventions to lower disease risk.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are common kidney diseases in clinics with high morbidity and mortality, but their pathogenesis is intricate. Tryptophan (Trp) is a fundamental amino acid for humans, and its metabolism produces various bioactive substances involved in the pathophysiology of AKI and CKD. Metabolomic studies manifest that Trp metabolites like kynurenine (KYN), 5-hydroxyindoleacetic acid (5-HIAA), and indoxyl sulfate (IS) increase in AKI or CKD and act as biomarkers that facilitate the early identification of diseases. Meanwhile, KYN and IS act as ligands to exacerbate kidney damage by activating aryl hydrocarbon receptor (AhR) signal transduction. The reduction of renal function can cause the accumulation of Trp metabolites which in turn accelerate the progression of AKI or CKD. Besides, gut dysbiosis induces the expansion of Enterobacteriaceae family to produce excessive IS, which cannot be excreted due to the deterioration of renal function. The application of Trp metabolism as a target in AKI and CKD will also be elaborated. Thus, this study aims to elucidate Trp metabolism in the development of AKI and CKD, and explores the relative treatment strategies by targeting Trp from the perspective of metabolomics to provide a reference for their diagnosis and prevention.

Although activation of inflammatory processes is essential to fight infections, its prolonged impact on brain function is well known to contribute to the pathophysiology of many medical conditions, including neuropsychiatric disorders. Therefore, identifying novel strategies to selectively counter the harmful effects of neuroinflammation appears as a major health concern. In that context, this study aimed to test the relevance of a nutritional intervention with saffron, a spice known for centuries for its beneficial effect on health.

For this purpose, the impact of an acute oral administration of a standardized saffron extract, which was previously shown to display neuromodulatory properties and reduce depressive-like behavior, was measured in mice challenged with lipopolysaccharide (LPS, 830 μg/kg, ip).

Pretreatment with saffron extract (6.5 mg/kg, per os) did not reduce LPS-induced sickness behavior, preserving therefore this adaptive behavioral response essential for host defense. However, it interfered with delayed changes of expression of cytokines, chemokines and markers of microglial activation measured 24 h post-LPS treatment in key brain areas for behavior and mood control (frontal cortex, hippocampus, striatum). Importantly, this pretreatment also counteracted by that time the impact of LPS on several neurobiological processes contributing to inflammation-induced emotional alterations, in particular the activation of the kynurenine pathway, assessed through the expression of its main enzymes, as well as concomitant impairment of serotonergic and dopaminergic neurotransmission.

Altogether, this study provides important clues on how saffron extract interferes with brain function in conditions of immune stimulation and supports the relevance of saffron-based nutritional interventions to improve the management of inflammation-related comorbidities.

Progressive age-associated change in frequencies and functional capacities of immune cells is known as immunosenescence. Despite data linking chronic environmental, physiological, and psychosocial stressors with accelerated aging, how stress contributes to immunosenesence is not well characterized.

To help delineate the contribution of cumulative physiological stress on immunosensence we assessed relationships between a composite measurement of cumulative physiological stress, reflecting the functioning of the hypothalamic-pituitary-adrenal axis, sympathetic nervous system, cardiovascular system, and metabolic processes, and lymphocyte changes typically affiliated with aging in a cohort of healthy volunteers ranging from 18 to 66 y.

Physiological stress load positively correlated with subject age in the study cohort and was significantly higher in adults 50-66 y compared to adults 18-33 y and 34-49 y. Using physiological stress load, we identified a significant age-dependent association between stress load and frequencies of circulating regulatory T lymphocytes (Tregs). Frequencies were higher in younger participants, but only in participants exhibiting low physiological stress load. As stress load increased, frequencies of Tregs decreased in young participants but were unchanged with increasing stress load in middle and older age individuals. Follow-up analysis of stress load components indicated lower circulating DHEA-S and higher urinary norepinephrine as the primary contributors to the effects of total stress load on Tregs. In addition, we identified age-independent inverse associations between stress load and frequencies of naïve Tregs and naïve CD4 T cells and positive associations between stress load and frequencies of memory Tregs and memory CD4 T cells. These associations were primarily driven by stress load components waist circumference, systolic and diastolic blood pressure, CRP, and HbA1c. In summary, our study results suggest that, in younger people, physiological stress load may diminish regulatory T cell frequencies to levels seen in older persons. Furthermore, independent of age, stress load may contribute to contraction of the naïve Treg pool and accumulation of memory Treg cells.

Registered on ClincialTrials.gov (Identifier: NCT02367287).

Tryptophan (Trp) is an essential amino acid that can be metabolized via endogenous and exogenous pathways, including the Kynurenine Pathway, the 5-Hydroxyindole Pathway (also the Serotonin pathway), and the Microbial pathway. Of these, the Microbial Trp metabolic pathways in the gut have recently been extensively studied for their production of bioactive molecules. The gut microbiota plays an important role in host metabolism and immunity, and microbial Trp metabolites can influence the development and progression of various diseases, including inflammatory, cardiovascular diseases, neurological diseases, metabolic diseases, and cancer, by mediating the body's immunity. This review briefly outlines the crosstalk between gut microorganisms and Trp metabolism in the body, starting from the three metabolic pathways of Trp. The mechanisms by which microbial Trp metabolites act on organism immunity are summarized, and the potential implications for disease prevention and treatment are highlighted.

Fatigue is a frequent symptom in hemodialysis (HD), and the indolamine-2,3-dioxygenase (IDO) metabolic trap has been hypothesized in the pathogenesis of fatigue. The association between IDO activity according to fatigue and its relationship with muscle mass and function in HD patients was verified. Chronic HD patients were considered, and fatigue was assessed. The plasma kynurenines and tryptophan ratio (Kyn/Trp), as surrogate of IDO activity, and interleukin (IL)-6 were measured. Muscularity was assessed by BIA and muscle strength by hand-grip dynamometer. 50 HD patients were enrolled, and fatigue was present in 24% of the cohort. Patients with fatigue showed higher Kyn/Trp (p = 0.005), were older (p = 0.007), and IL-6 levels resulted higher than in non-fatigue patients (p < 0.001). HD patients with fatigue showed lower intracellular water (surrogate of muscle mass) (p < 0.001), as well as lower hand grip strength (p = 0.02). The Kyn/Trp ratio positively correlated with IL-6 and ECW/ICW (p = 0.004 and p = 0.014). By logistic regression analysis, higher ICW/h² was associated with lower odds of fatigue (OR, 0.10; 95% CI, 0.01 to 0.73). In conclusion, our cohort fatigue was associated with a higher Kyn/Trp ratio, indicating a modulation of IDO activity. The Kyn/Trp ratio correlated with IL-6, suggesting a potential role of IDO and inflammation in inducing fatigue and changes in muscularity.