Search Results (262)

Background/Objectives: Gut-derived tryptophan (Trp) metabolites play important roles in metabolic and cardiovascular regulation. Although animal studies suggest their protective effects against metabolic dysfunction, data in adolescents, particularly those with obesity, remain limited. The objective of this study was to evaluate associations between circulating gut-derived Trp metabolites and markers of cardiometabolic, vascular, and platelet health in adolescents with obesity. Methods: Data were analyzed from 28 adolescents (ages 13–18; mean BMI = 36 ± 6.4 kg/m²). Fasting blood was collected to assess lipid profiles using a clinical analyzer and insulin resistance using the homeostatic model assessment for insulin resistance (HOMA-IR). Gut-derived Trp metabolites were measured by UPLC–mass spectrometry, peak oxygen uptake (VO_{2 peak}) by gas exchange during an incremental cycle ergometer test, and body composition by dual-energy X-ray absorptiometry. Platelet spare respiratory capacity (SRC), endothelial function, and liver fat were measured using high-resolution respirometry, flow-mediated dilation (FMD) of the brachial artery, and magnetic resonance imaging respectively. Results: Indole-3-propionic acid was inversely associated with diastolic blood pressure (rho = −0.39, p = 0.047), total cholesterol (rho = −0.55, p = 0.002), and LDL-C (rho = −0.57, p = 0.0014), independent of sex and obesity severity. Indoxyl sulfate was positively correlated with fasting glucose (rho = 0.47, p = 0.012), and adolescents with impaired fasting glucose had 1.6-fold higher IS levels. Indole-3-acetaldehyde declined with age (rho = −0.50, p = 0.007), and Indole-3-acetic acid and indole were higher in Hispanics vs. non-Hispanics. No significant associations were observed between Trp metabolites and FMD, VO₂ peak, or SRC. Conclusions: Gut-derived Trp metabolites, particularly indole-3-propionic and indoxyl sulfate, are associated with markers of cardiometabolic risk in adolescents with obesity. These findings support their potential relevance in early-onset cardiovascular disease risk. Full article

Autism spectrum disorder (ASD) is increasingly associated with microbial and metabolic disturbances, including the altered production of gut-derived uremic toxins. We investigated urinary concentrations of five representative uremic toxins—indoxyl sulfate (IS), p-cresyl sulfate (PCS), trimethylamine N-oxide (TMAO), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA)—in 161 children with ASD and 71 healthy controls. Toxins were measured using LC-MS/MS and were normalized to creatinine. Subgroup analyses were performed by sex, age group (2–5.9 vs. 6–17 years), and autism severity based on the Childhood Autism Rating Scale (CARS). In addition to individual concentrations, we calculated the total toxin burden, proportional contributions, and functional ratios (IS/PCS, PCS/TMAO, and IS/ADMA). While individual toxin levels did not differ significantly between groups, stratified analyses revealed that PCS was higher in girls and in severe cases of ASD, whereas IS and TMAO were reduced in younger and more severely affected children. The functional ratios shifted consistently with severity—IS/PCS declined from 1.69 in controls to 0.99 in severe cases of ASD, while PCS/TMAO increased from 12.2 to 20.5. These patterns suggest a phenolic-dominant microbial signature and an altered host–microbial metabolic balance in ASD. Functional toxin profiling may offer a more sensitive approach to characterizing metabolic disturbances in ASD than concentration analysis alone. Full article

This study employs a machine learning approach to identify a small-molecule-based signature capable of predicting Alzheimer’s disease (AD). Utilizing metabolomics data from the plasma of a well-characterized cohort of 94 AD patients and 62 healthy controls; metabolite levels were assessed using the Biocrates MxP^® Quant 500 platform. Data preprocessing involved removing low-quality samples, selecting relevant biochemical groups, and normalizing metabolite data based on demographic variables such as age, sex, and fasting time. Linear regression models were used to identify concomitant parameters that consisted of the data for a given metabolite within each of the biochemical families that were considered. Detection of these “concomitant” metabolites facilitates normalization and allows sample comparison. Residual analysis revealed distinct metabolite profiles between AD patients and controls across groups, such as amino acid-related compounds, bile acids, biogenic amines, indoles, carboxylic acids, and fatty acids. Correlation heatmaps illustrated significant interdependencies, highlighting specific molecules like carnosine, 5-aminovaleric acid (5-AVA), cholic acid (CA), and indoxyl sulfate (Ind-SO₄) as promising indicators. Linear Discriminant Analysis (LDA), validated using Leave-One-Out Cross-Validation, demonstrated that combinations of four or five molecules could classify AD with accuracy exceeding 75%, sensitivity up to 80%, and specificity around 79%. Notably, optimal combinations integrated metabolites with both a tendency to increase and a tendency to decrease in AD. A multivariate strategy consistently identified included 5-AVA, carnosine, CA, and hypoxanthine as having predictive potential. Overall, this study supports the utility of combining data of plasma small molecules as predictors for AD, offering a novel diagnostic tool and paving the way for advancements in personalized medicine. Full article

Background: The gut microbiome is a key modulator of the gut–brain axis and may contribute to the pathophysiology of both gastrointestinal and systemic disorders. This study aimed to evaluate gut microbiota composition and tryptophan/phenylalanine metabolism in women with unclassified irritable bowel syndrome (IBS-U), with or without coexisting chronic fatigue syndrome (CFS). Methods: Eighty women were enrolled and divided into two groups: IBS-U without CFS (Group I, n = 40) and IBS-U with coexisting CFS (Group II, n = 40). Microbial composition and diversity were assessed using the GA-map™ Dysbiosis Test, including the dysbiosis index (DI) and Shannon Diversity Index (SDI). Hydrogen and methane levels were measured in breath samples. Urinary concentrations of selected microbial and neuroactive metabolites—homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA), xanthurenic acid (XA), quinolinic acid (QA), hydroxyphenylacetic acid (HPA), and 3-indoxyl sulfate (3-IS)—were quantified using LC-MS/MS. Fatigue severity was assessed using the Chalder Fatigue Questionnaire (CFQ-11) and the fatigue severity scale (FSS). Results: Compared to Group I, patients with IBS-CFS showed significantly greater microbial diversity, higher breath methane levels, and elevated urinary concentrations of QA, XA, 3-IS, and HVA, alongside lower concentrations of 5-HIAA and KYN. Fatigue severity was positively correlated with urinary XA and QA levels. Conclusions: Women with IBS and coexisting CFS exhibit distinct gut microbiota and tryptophan metabolite profiles compared to those without fatigue. The observed metabolite–symptom associations, particularly involving neuroactive kynurenine derivatives, warrant further investigation. These preliminary findings should be interpreted as hypothesis-generating and require validation through high-resolution microbiome analyses, functional pathway profiling, and longitudinal or interventional studies to clarify causality and clinical significance. Full article

Declining kidney function contributes to the accumulation of uraemic toxins produced by gut microbiota, leading to the uraemic syndrome. This study aimed to identify associations between uraemic toxins, diet quality, symptoms and the gut microbiota in individuals initiating peritoneal dialysis. A cross-sectional analysis of baseline data from participants in a longitudinal study was conducted. Symptom scores using the Integrated Palliative Care Outcomes Scale-Renal were recorded. Plasma p-Cresyl sulfate, indoxyl sulfate and trimethylamine N-oxide were measured using liquid chromatography-mass spectrometry. Gut microbiota was determined using 16S rRNA sequencing. Multivariate linear models examined associations across the cohort. Data from 43 participants (mean age 61 ± 13 years; 70% male; median eGFR 7 mL/min/1.73 m²) were analysed. Diabetes was the primary cause of kidney disease (51.2%). Patients were classified into ‘high’ (n = 18) and ‘low’ (n = 26) uraemic toxin groups using K-means clustering. The ‘high’ group had a lower eGFR (p < 0.05) but no differences in diet quality or symptom scores. Significant differences in alpha and beta diversity were observed between the groups (p = 0.01). The ‘high’ group had increased Catenibacterium, Prevotella, Clostridia, and decreased Ruminococcus gnavus abundances. Multivariate models identified 32 genera associated with uraemic toxins, including positive associations of Oscillospiraceae UCG-002 and UCG-005 with p-cresyl sulfate, and negative associations with Actinomyces and Enterococcus. Patients with kidney failure initiating peritoneal dialysis have distinct uraemic toxin profiles, associated with differences in microbial diversity. This phenotype was also associated with differences in residual kidney function but not with diet or symptom severity. Longitudinal studies are required to determine causality and guide therapeutic interventions. Full article

Background: Chronic non-communicable diseases (NCDs) are a major global health challenge, with unhealthy diets contributing significantly to their burden. Metabolomics data offer new possibilities for identifying nutritional biomarkers, as demonstrated in short-term intervention studies. This study investigated associations between habitual dietary intake and urinary metabolites, a not well-studied area. Methods: Data were available from 496 participants of the population-based MEIA study. Linear and median regression models examined associations between habitual dietary intake and metabolites, adjusted for possible confounders. K-means clustering identified urinary metabolite clusters, and multinomial regression models were applied to analyze associations between food intake and metabolite clusters. Results: Using linear regression models, previously reported associations could be replicated, including citrus intake with proline betaine, protein intake with urea, and fiber intake with hippurate. Novel findings include positive associations of poultry intake with taurine, indoxyl sulfate, 1-methylnicotinamide, and trimethylamine-N-oxide. Milk substitutes were positively associated with urinary uracil, pseudouridine, 4-hydroxyhippurate, and 3-hydroxyhippurate, and inversely associated with quinic acid. Dietary fiber intake showed a positive association with 3-(3-hydroxyphenyl)-3-hydroxypropionic acid and a negative association with indoxyl sulfate. We identified sucrose and taurine as key metabolites differentiating metabolite clusters. Multinomial regression analysis confirmed significantly different dietary associations across clusters, particularly for fruits, processed meat, poultry, and alcoholic beverages. Conclusions: This study highlights established and novel food–metabolite associations, demonstrating the potential of urinary metabolomics for use as nutritional biomarkers in individuals from the general population. Full article

Background and Objectives: The worldwide prevalence of chronic kidney disease (CKD) continues to increase, representing a major concern for public health systems. CKD is associated with gut microbiota dysbiosis, which may exacerbate disease progression by increasing the levels of uremic toxins, systemic inflammation, and oxidative stress. Modulation of the gut microbiota through biotic supplementation has been proposed as a potential therapeutic strategy to slow CKD progression and mitigate its complications. This study aimed to evaluate the effect of 10-month synbiotic supplementation on estimated glomerular filtration rate (eGFR), circulating concentrations of indoxyl sulfate (IS), p-cresyl sulfate (p-CS), interleukin-6 (IL-6), and malondialdehyde (MDA) in patients with stage IV–V CKD not receiving dialysis, in comparison to placebo. Materials and Methods: Fifty non-dialysis CKD IV–V patients were assigned (n = 25 each) via matched, non-randomized allocation (age, sex, and primary disease) to synbiotic or placebo. This single-blind, placebo-controlled trial blinded participants and laboratory personnel. The synbiotic group received daily capsules containing Lactobacillus acidophilus La-14 (2 × 10¹¹ CFU/g) + fructooligosaccharides; controls received identical placebo. Adherence was monitored monthly (pill counts, diaries), with < 80% over two visits resulting in withdrawal. The eGFR, IS, p-CS, IL-6, and MDA were measured at baseline and month 10. Results: Forty-two patients (21/arm) completed the study; eight withdrew (4 per arm). At 10 months, the change in eGFR was −1.2 ± 2.5 mL/min/1.73 m² (synbiotic) vs. −3.5 ± 3.0 mL/min/1.73 m² (placebo); between-group difference in change was 2.3 mL/min/1.73 m² (95% CI: 0.5–4.1; p = 0.014; adjusted p = 0.07). IS decreased by −15.4 ± 8.2 ng/L vs. −3.1 ± 6.5 ng/L; between-group difference in change was −12.3 ng/L (95% CI: −17.8 to −6.8; p < 0.001; adjusted p = 0.005). No significant differences were observed for p-CS, IL-6, or MDA after correction. Conclusions: Synbiotic supplementation over a 10-month period resulted in a trend toward decreased serum IS levels in patients with advanced CKD, suggesting potential benefits of microbiota-targeted therapies. However, no significant effects were observed on renal function, inflammatory, or oxidative stress markers. Further large-scale studies are warranted to confirm these findings and explore the long-term impact of synbiotics in CKD management. Full article

Chronic kidney disease (CKD) is associated with the systemic accumulation of uremic toxins (UTs) due to impaired renal elimination. Among these, indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are particularly challenging because of their high protein binding and limited removal by dialysis. In addition to renal excretion, the transport of IS and PCS, and their microbiota-derived precursors, indole and p-cresol, across key physiological barriers—the intestinal barrier, blood–brain barrier, and renal proximal tubule—critically influences their distribution and elimination. This review provides an overview of transporter-mediated mechanisms involved in the disposition of IS, PCS, and their microbial precursors, indole and p-cresol. It also examines how these UTs may interact with commonly prescribed drugs in CKD, particularly those that share transporter pathways as substrates or inhibitors. These drug–toxin interactions may influence the pharmacokinetics and toxicity of IS and PCS, but remain poorly characterized and largely overlooked in clinical settings. A better understanding of these processes may guide future efforts to optimize pharmacotherapy and support more informed management of CKD patients, particularly in the context of polypharmacy. Full article

Indoxyl sulfate (IS), which is a protein-bound uremic toxin, is involved in vascular dysfunction and cardiovascular risk in subjects with chronic kidney disease (CKD). However, its role in peripheral arterial stiffness (PAS) remains unclear. This cross-sectional study evaluated the relationship between IS and PAS in patients diagnosed with CKD stages 3 through 5 who are not undergoing dialysis. Patients with CKD from a single center were enrolled. High-performance liquid chromatography analyzed the serum IS levels. PAS was evaluated using brachial–ankle pulse wave velocity (baPWV). IS was independently associated with PAS (odds ratio [OR]: 1.389 for 1 μg/mL increase in IS, 95% confidence interval [CI]: 1.086–1.775, p = 0.009) in a multivariable analysis after adjustment for age, hypertension, diabetes mellitus, blood pressure, lipid profiles, renal function, albumin, and proteinuria. Moreover, the mean baPWV (p = 0.010), left baPWV (p = 0.009), and right baPWV (p = 0.015) levels significantly correlated with the log-transformed IS (log-IS) levels. The area under the receiver operating characteristic curve for serum IS as a predictor of PAS was determined to be 0.667 (95% CI: 0.580−0.754; p = 0.0002). IS was associated with PAS in non-dialysis CKD stages 3–5, suggesting that IS may be a possible vascular risk marker. Future studies should address the nature of the relationship between IS and vascular dysfunction and assess therapeutic strategies to reduce IS. Full article

Background/Objectives: Chronic kidney disease is associated with increased intestinal barrier permeability, leading to heightened inflammation and oxidative stress. These changes contribute to complications such as cardiovascular disease, anemia, altered mineral metabolism, and CKD progression. Interventions using prebiotics, probiotics, and synbiotics may mitigate dysbiosis and improve intestinal barrier function, Under this premise, the objective of this network meta-analysis was to evaluate the effect of probiotics, prebiotics, and synbiotics in reducing uremic toxins produced by the gut microbiota in CKD patients. Methods: A systematic review and network meta-analysis of randomized clinical trials (RCTs) was performed in the following databases: Web of Science, Scopus, the Cochrane Register of Controlled Trials, and PubMed published between 2019 and 2023. The analysis focused on the use of prebiotics, probiotics, and synbiotics in CKD patients at stages 3 to 5, as per KDIGO guidelines, and their association with reductions in uremic toxins such as Indoxyl Sulfate, p-Cresyl Sulfate, urea, and creatinine. The risk of bias was assessed using the Cochrane risk of bias tool (RoB 2), with evaluations conducted independently by two reviewers, and a third consulted for disagreements. The study follows the PRISMA statement. Results: The studies included 331 patients, primarily male, across CKD stages 3a to 5. The interventions positively impacted the gut microbiota composition, leading to reductions in free and total p-Cresyl Sulfate (SUCRA: 72.6% and 66.2, respectively) and indoxyl sulfate (SUCRA: 88.5% and 83.1%). Conclusions: The findings suggest that modulating the gut microbiota through these interventions can effectively reduce specific uremic toxins. However, further trials are necessary to better understand microbiota modulation and its impact on intestinal bacterial composition (PROSPERO number: CRD42023438901). Full article

Hemodialysis patients exhibit endothelial dysfunction, contributing to elevated cardiovascular risk and complications of the arteriovenous access. These patients have elevated serum levels of myostatin, a member of the transforming growth factor-β (TGFβ) superfamily, and of the uremic toxin indoxyl sulfate, both of which are pro-inflammatory towards endothelial cells. We hypothesized that myostatin and indoxyl sulfate may synergistically induce endothelial dysfunction by impairing endothelial proliferation and promoting a pro-inflammatory phenotype. We first investigated the effect of myostatin on cultured endothelial cells in the presence of indoxyl sulfate. We then examined the association between serum myostatin concentrations and the occurrence of cardiovascular and arteriovenous access complications in hemodialysis patients. In vitro, myostatin exhibited endotheliotoxic effects in the presence of a uremic concentration of indoxyl sulfate, enhanced its antiproliferative effect, and amplified MCP-1 and IL-8 chemokine upregulation. In patients, high myostatin concentrations correlated with indoxyl sulfate concentrations and were associated with an increased risk of arteriovenous access complications. These findings suggest that myostatin amplifies endothelial injury mediated by indolic uremic toxins and might contribute to AV access complications. Full article

Chronic kidney disease (CKD) has become one of the most rapidly advancing diseases of the century, contributing significantly to increased mortality and morbidity. Metabolomics presents a promising approach to understanding CKD pathogenesis and identifying novel biomarkers for early diagnosis. This study evaluated serum and urine metabolomic profiles in CKD patients with declining glomerular filtration rates (eGFR). Using targeted metabolomics, we quantified seven potential metabolites in blood and urine samples from 20 healthy individuals and 99 CKD patients staged by eGFR according to the KDIGO guidelines. The analysis was conducted using ultra-high performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight mass spectrometry. The metabolites investigated included L-phenylalanine, L-methionine, arginine, indoxyl sulfate, kynurenic acid, and L-acetylcarnitine. Quantitative assessments were performed using pure standards and validated through methods such as the limit of detection (LOD) and limit of quantification (LOQ). The findings identified potential biomarkers for early CKD diagnosis: in serum, L-phenylalanine, L-methionine, arginine, kynurenic acid, and indoxyl sulfate, while L-acetylcarnitine was significant in urine. These biomarkers could provide valuable insights into CKD progression and support in developing more effective diagnostic tools for early intervention. Full article

Background: The mixed type of irritable bowel syndrome (IBS-M) is characterized by recurrent constipation and diarrhea. The cause of the variability of these symptoms is not sufficiently understood. The aim of this study was to perform metagenomic and metabolic assessment of the gut microbiome in constipation and diarrheal period of IBS-M. Methods: This study included 30 women, aged 28–47 years old, with the symptoms which aligned with those of IBS-M, according to the Rome IV Criteria. Results: In both periods of the disease, the dysbiosis index (DI), the Shannon diversity index (SDI), the hydrogen–methane and ammonia breath tests, as well as the selected bacterial metabolites (-p-hydroxyphenyl acetic acid (HPA), 3-indoxyl sulfate (Indican, 3-IS)), and hippuric acid (A) in urine, were determined. The dysbiosis index (DI) in the period of constipation was 3.73 ± 0.90 points, and in the diarrheal period it did not change significantly 3.93 ± 0.75 points (p > 0.05). During the diarrheal period, the diversity of bacteria increases from 2.16 ± 0.59 to 2.74 ± 0.50 points on the Shannon dietary index (p < 0.001). The gut microbiome profile also changed, especially during the diarrheal period where an abundance of Bifidobacterium spp. and Lactobacillus spp. decreased significantly. In addition, during this period, the levels of hydrogen and ammonia in breath air increased, while the methane level decreased. The differences also concern the results of urinary metabolites, especially related to hippuric acid and indican. During the diarrheal period, the levels of hydrogen and ammonia ions increased, while the methane level decreased. The differences also concern the results of urinary metabolites, especially related to hippuric acid and indican. Conclusions: In patients with IBS-M, periodic changes in the profile and metabolism of the gut microbiome occur, which coexist with recurrent symptoms such as constipation and diarrhea. Full article

Chronic kidney disease is a global health burden with a rising incidence and prevalence in developed and developing nations. Once established, it results in a progressive accumulation of a myriad of uraemic toxins. Peritoneal dialysis (PD) uses the body’s peritoneal membrane to remove these toxins across a semipermeable membrane to restore and maintain homeostasis. Traditionally, dialysis adequacy has been measured through clearance of urea and creatinine. However, numerous studies have shown marginal links comparing the clearance of urea and creatinine with clinical outcomes reflected in the recent changes to the ISPD guidelines on dialysis adequacy. Instead, attention has focused on protein-bound uraemic toxins (PBTs). Produced by gut bacteria, these molecules are highly protein-bound and poorly removed by either dialysis or absorptive agents. Elevated concentrations of molecules such as p-cresyl sulfate and indoxyl sulfate have been associated with abnormal cellular function and poor patient outcomes. However, widespread use of these measures to determine dialysis adequacy has been limited by the need for specialized techniques required for measurement. Altering the gut microbiome to reduce generation of PBTs through increased dietary fiber might be an alternate approach to better patient outcomes, with some initial positive reports. This report explores advantages and limitations of measuring uraemic toxins in PD, now and in the foreseeable future. Full article

Chronic kidney disease (CKD) is a significant public health concern. Osteoarthritis (OA), a common form of arthritis, has been shown to have a dramatically increased prevalence, particularly among individuals aged 40–50 and older, in the presence of CKD. Furthermore, CKD may exacerbate the progression and impact of OA. A survey study revealed that 53.9% of CKD patients undergoing long-term hemodialysis were diagnosed with OA. These findings underscore the potential association between CKD and OA. Uremic toxins, such as indoxyl sulfate, p-cresyl sulfate, transforming growth factor-β, and advanced glycation end-products, are regarded as potential risk factors in various CKD-related conditions, affecting bone and joint metabolism. However, whether these factors serve as a bridging mechanism between CKD and OA comorbidities, as well as their detailed roles in this context, remains unclear. Addressing the progression of OA in CKD patients and identifying effective treatment and prevention strategies is an urgent challenge that warrants immediate attention. This review focuses on describing and discussing the molecular pathological mechanisms underlying CKD-associated OA and the possible therapeutic strategies. Full article