Search Results (59)

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

p-Cresyl sulfate (PCS), a gut-derived uremic toxin with proinflammatory and cytotoxic effects, has been implicated in cardiovascular injuries among patients with chronic kidney disease (CKD). Aortic stiffness (AS), assessed by carotid–femoral pulse wave velocity (cfPWV), is a recognized predictor of cardiovascular risk. This study investigated the association between serum PCS levels and AS in patients with nondialysis-dependent CKD. In total, 165 patients with nondialysis-dependent CKD were enrolled. Clinical data and fasting blood samples were collected. Arterial stiffness (AS) was assessed bilaterally by measuring carotid–femoral pulse wave velocity (cfPWV) on both the left and right sides. A value above 10 m/s was considered indicative of increased stiffness. Serum PCS levels were quantified using high-performance liquid chromatography–mass spectrometry. Fifty patients (30.3%) had AS. The AS group was significantly older and had higher diabetes prevalence, systolic blood pressure, fasting glucose, urinary protein-creatinine ratio, and PCS levels than the control group. In the multivariate analysis, both PCS (odds ratio [OR]: 1.097; 95% confidence interval [CI]: 1.024–1.175; p = 0.008) and age (OR: 1.057; 95% CI: 1.025–1.090; p < 0.001) were independently associated with AS. In conclusion, elevated serum PCS and older age were independently associated with AS. Thus, PCS is a potential early marker of vascular damage in CKD. Full article

Chronic kidney disease (CKD) has a high prevalence worldwide, with an increasing incidence. One of the mechanisms of CKD progression involves a disordered inter-organ relationship between the kidneys and the intestine, known as the kidney-gut axis. In CKD, two pathological gut conditions—disturbed gut microbiota composition called uremic dysbiosis and leaky gut—contribute to the progression of CKD. Dysbiosis is associated with the increased production of gut-derived uremic toxins, leaky gut, and chronic systemic inflammation, leading to worsening uremia, which in turn aggravates the gut condition. This vicious cycle should be a target of the therapeutic strategy against CKD. The modulation of uremic dysbiosis, including prebiotics, probiotics, and synbiotics, has been a typical treatment approach, although clinical evidence for their efficacy has been insufficient. Some non-antibiotic drugs have an impact on human gut bacteria that are believed to play a role in their clinical efficacy on kidney function. Nutrition therapies, including a low-protein diet, dietary fiber, a Mediterranean diet, and whole grains, positively influence gut microbiota composition and have been linked to a decreased risk of CKD. Novel strategies are currently being explored, involving the use of postbiotics, microbiome sequencing techniques, and fecal microbiota transplantation, although clinical application remains to be tested. Human trials investigating the above-mentioned interventions remain inconclusive due to several limitations, including dietary variability and genetic factors. Future research should focus on the development of more effective probiotics, prebiotics, and microbial metabolism-modifying drugs, not only for CKD but for other systemic diseases as well. Full article

Gut-derived uremic toxins (UTs) contribute to cardiovascular disorders like atherosclerosis and cardiomyopathy in patients with chronic kidney disease (CKD), causing increased cardiovascular morbidity and mortality. The intermediate steps between higher concentrations of gut-derived UTs and organ damage caused by UTs are still insufficiently understood. Glycosaminoglycans (GAGs) as components of the extracellular matrix are known to interact with various ligands such as growth factors or receptors, thereby influencing (patho)physiological processes. We previously found that the UT inorganic phosphate (Pi) induces the synthesis and sulphation of the GAGs heparan sulphate and chondroitin sulphate in the rat vascular smooth muscle cell (VSMC) line A7r5 and in the human endothelial cell (EC) line EA.Hy926. The aim of this study was to investigate if other organic UTs modulate GAGs in vascular cells as well. We treated ex vivo cultures of rat aortic rings as well as primary rat VSMCs and human ECs with the UTs Pi, indoxylsulphate (IS), p-cresylsulphate (pCS), trimethylamine N-oxide (TMAO), and urea, and analyzed the samples by histological staining, qPCR, western blot, HPLC, and colorimetric assays. The UT treatment of aortic rings and cells increased contents of sulphated GAGs and hyaluronic acid. UT-treated cells contained higher amounts of 4S- and 6S-sulphated GAGs compared to controls. This was accompanied by altered expressions of genes and proteins relevant for GAG metabolism. Mechanistically, the effects of the UTs on GAGs involve the activation of the PI3K/Akt pathway and of the transcription factor NF-κB. In conclusion, the UT-induced remodeling of the cardiovascular matrix by upregulation of sulphated GAGs and hyaluronic acid in aortic tissue and vascular cells might be a missing link between gut-derived UT and pathophysiological alterations in the cardiovascular system in the sense of a gut–matrix axis. Full article

Patients with chronic kidney disease (CKD) are at a significantly increased risk of cardiovascular (CV) mortality, which cannot be fully accounted for by traditional risk factors. Background/Objectives: The aim of this study is to evaluate the impact of adipokines, myokines, gut-microbiota-derived uremic toxins, and nutritional status on the risk of CV mortality in patients undergoing kidney replacement therapy (KRT). Methods: This study includes 84 hemodialysis (HD) patients and 44 peritoneal dialysis (PD) patients. Adipokines and myokines concentrations were measured using enzyme-linked immunosorbent assays (ELISA), while gut-microbiota-derived uremic toxins were quantified using liquid chromatography-tandem mass spectrometry (LC–MS/MS). Nutritional status was assessed using the seven-point Subjective Global Assessment (SGA) and anthropometric measurements. The survival was analyzed using Kaplan–Meier curves with the log-rank test, along with univariate and multivariate Cox proportional hazards regression. Results: The mean follow-up period was 18.2 (8) months for the HD group and 14.3 (8) months for the PD group. During the 2-year follow-up, 15.5% of HD patients and 6.8% of PD patients died due to cardiovascular disease (CVD). In the HD group, age, blood urea nitrogen (BUN), phosphorus, interleukin-6 (IL-6), high-sensitivity C-protein (hsCRP), and neutrophil-to-lymphocyte ratio (NLR) levels were significantly associated with CV mortality. HD patients who died had significantly lower myostatin/IL-6 ratios. CV mortality was significantly associated with age and potassium levels in the PD group. Conclusions: The examined adipokines, myokines, and gut-microbiota-derived uremic toxins exert a less significant direct influence on survival compared to widely recognized indicators, including age, nutritional status, and inflammatory markers. Full article

The gut–kidney axis represents the complex interactions between the gut microbiota and kidney, which significantly impact the progression of chronic kidney disease (CKD) and overall patient health. In CKD patients, imbalances in the gut microbiota promote the production of uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, which impair renal function and contribute to systemic inflammation. Mechanisms like endotoxemia, immune activation and oxidative stress worsen renal damage by activating pro-inflammatory and oxidative pathways. Insights into these mechanisms highlight the impact of gut-derived metabolites, bacterial translocation, and immune response changes on kidney health, suggesting new potential approaches for CKD treatment. Clinical applications, such as dietary interventions, prebiotics, probiotics and fecal microbiota transplantation, are promising in adjusting the gut microbiota to alleviate CKD symptoms and slow disease progression. Current research highlights the clinical relevance of the gut–kidney axis, but further study is essential to clarify these mechanisms’ diagnostic biomarkers and optimize therapeutic interventions. This review emphasizes the importance of an integrated approach to CKD management, focusing on the gut microbiota as a therapeutic target to limit kidney injury. Full article

The gut dysbiosis present in chronic kidney disease (CKD) has been associated with anemia. Factors such as the accumulation of gut-derived uremic toxins, increased gut barrier permeability-induced inflammation, and a reduced intestinal production of short-chain fatty acids (SCFAs), all associated with changes in the intestinal microbiota composition in CKD, may lead to the development or worsening of anemia in renal patients. Understanding and addressing these mechanisms related to gut dysbiosis in CKD patients can help to delay the development of anemia and improve its control in this population. One approach is to avoid or reduce the use of drugs linked to gut dysbiosis in CKD, such as phosphate binders, oral iron supplementation, antibiotics, and others, unless they are indispensable. Another approach involves introducing dietary changes that promote a healthier microbiota and/or using prebiotics, probiotics, or symbiotics to improve gut dysbiosis in this setting. These measures can increase the presence of SCFA-producing saccharolytic bacteria and reduce proteolytic bacteria, thereby lowering the production of gut-derived uremic toxins and inflammation. By ameliorating CKD-related gut dysbiosis, these strategies can also improve the control of renal anemia and enhance the response to erythropoiesis-stimulating agents (ESAs) in ESA-resistant patients. In this review, we have explored the relationship between gut dysbiosis in CKD and renal anemia and propose feasible solutions, both those already known and potential future treatments. Full article

Deranged gut microbiota can release increased levels of uremic toxins leading to exacerbated kidney injury. In diabetic kidney disease (DKD), phenyl sulfate (PS) derived from tyrosine catabolism by gut microbiota has been demonstrated to be both an early diagnostic marker and a therapeutic target. In this perspective article, we summarize PS generation pathways and recent findings on PS and kidney injury in DKD. Increasing evidence has shown that the underlying mechanisms of PS-induced kidney injury mainly involve oxidative stress, redox imbalance, and mitochondrial dysfunction, which all may be targeted to attenuate PS-induced kidney injury. For future research directions, we think that a deeper understanding of the pathogenic role of PS in kidney injury using a variety of diabetic animal models should be investigated. Moreover, we also suggest beneficial approaches that could be used to mitigate the deleterious effect of PS on the kidney. These approaches include caloric restriction, tyrosine restriction, and administration of ketogenic drugs, ketogenic diets or natural products; all of which should be conducted under obese and diabetic conditions. Full article

Serum uremic toxins markedly increase in cats with chronic kidney disease (CKD) and have deleterious consequences. Renaltec is an oral adsorbent that binds uremic toxin precursors in the gut. In this prospective cohort study utilizing 13 purpose-bred cats with remnant kidney model-induced CKD (12 IRIS Stage 2, 1 IRIS Stage 3) eating a standardized renal diet, we aimed to assess the effect of Renaltec administration on serum indoxyl sulfate (IDS) and p-cresol sulfate (pCS) concentrations. Cats were sequentially treated with standard of care for 56 days, 500 mg Renaltec orally once daily for 56 days, and then three months later, 500 mg Renaltec orally twice daily for 56 days. Serum IDS and pCS concentrations were measured 28 and 56 days after the administration of Renaltec. Blood pressure and kidney function were measured before and 56 days after the administration of Renaltec. Significant decreases in serum IDS and pCS concentrations were observed for both once- and twice-daily dosing, particularly during the first 28 days of administration. More cats with BID dosing had clinically significant reductions in serum IDS and pCS concentrations than with SID dosing. Renaltec can reduce the serum concentrations of deleterious gut-derived uremic toxins in cats with CKD. Full article

Gut microbiota-derived uremic toxins (UT) accumulate in patients with chronic kidney disease (CKD). Dietary phosphorus and protein restriction are common in CKD treatment, but the relationship between dietary phosphorus, a key nutrient for the gut microbiota, and protein-derived UT is poorly studied. Thus, we explored the relationship between dietary phosphorus and serum UT in CKD rats. For this exploratory study, we used serum samples from a larger study on the effects of dietary phosphorus on intestinal phosphorus absorption in nephrectomized (Nx, n = 22) or sham-operated (sham, n = 18) male Sprague Dawley rats. Rats were randomized to diet treatment groups of low or high phosphorus (0.1% or 1.2% w/w, respectively) for 1 week, with serum trimethylamine oxide (TMAO), indoxyl sulfate (IS), and p-cresol sulfate (pCS) analyzed by LC-MS. Nx rats had significantly higher levels of serum TMAO, IS, and pCS compared to sham rats (all p < 0.0001). IS showed a significant interaction between diet and CKD status, where serum IS was higher with the high-phosphorus diet in both Nx and sham rats, but to a greater extent in the Nx rats. Serum TMAO (p = 0.24) and pCS (p = 0.34) were not affected by dietary phosphorus levels. High dietary phosphorus intake for 1 week results in higher serum IS in both Nx and sham rats. The results of this exploratory study indicate that reducing dietary phosphorus intake in CKD may have beneficial effects on UT accumulation. Full article

Chronic diseases (CD) may result from a combination of genetic factors, lifestyle and social behaviours, healthcare system influences, community factors, and environmental determinants of health. These risk factors frequently coexist and interact with one another. Ongoing research and a focus on personalized interventions are pivotal strategies for preventing and managing chronic disease outcomes. A wealth of literature suggests the potential involvement of gut microbiota in influencing host metabolism, thereby impacting various risk factors associated with chronic diseases. Dysbiosis, the perturbation of the composition and activity of the gut microbiota, is crucial in the etiopathogenesis of multiple CD. Recent studies indicate that specific microorganism-derived metabolites, including trimethylamine N-oxide, lipopolysaccharide and uremic toxins, contribute to subclinical inflammatory processes implicated in CD. Various factors, including diet, lifestyle, and medications, can alter the taxonomic species or abundance of gut microbiota. Researchers are currently dedicating efforts to understanding how the natural progression of microbiome development in humans affects health outcomes. Simultaneously, there is a focus on enhancing the understanding of microbiome–host molecular interactions. These endeavours ultimately aim to devise practical approaches for rehabilitating dysregulated human microbial ecosystems, intending to restore health and prevent diseases. This review investigates how the gut microbiome contributes to CD and explains ways to modulate it for managing or preventing chronic conditions. Full article

Microbiota-based strategies are a novel auxiliary therapeutic and preventative way of moderating chronic kidney disease (CKD). Lactobacillus mixture (Lm) was previously demonstrated to exert a renal-protective function in the CKD mice model. The efficacy of probiotics in pet foods is a relatively new area of study, and thus verifying the potential health benefits is necessary. This study evaluated the efficacy of Lm treats in feline CKD and elucidated the mechanisms underlying host-microbe interactions. CKD cats (2 and 3 stages) were administrated probiotic pet treats daily (10 g) for 8 weeks. The results demonstrated that during the eight weeks of Lm administration, creatinine was reduced or maintained in all cats with CKD. Similarly, gut-derived uremic toxin (GDUT), indoxyl sulfate (IS), were potential clinical significance in IS after Lm treatment (confidence intervals = 90%). The life quality of the cats also improved. Feline gut microbiome data, metabolic functional pathway, and renal function indicator analyses revealed the possible mechanisms involved in modulating CKD feline microbial composition. Further regulation of the microbial functions in amino acid metabolism after Lm administration contributed to downregulating deleterious GDUTs. The current study provides potential adjuvant therapeutic insights into probiotic pet foods or treats for pets with CKD. Full article

In chronic kidney disease (CKD), metabolic derangements resulting from the interplay between decreasing renal excretory capacity and impaired gut function contribute to accelerating disease progression and enhancing the risk of complications. To protect residual kidney function and improve quality of life in conservatively managed predialysis CKD patients, current guidelines recommend protein-restricted diets supplemented with essential amino acids (EAAs) and their ketoanalogues (KAs). In clinical studies, such an approach improved nitrogen balance and other secondary metabolic disturbances, translating to clinical benefits, mainly the delayed initiation of dialysis. There is also increasing evidence that a protein-restricted diet supplemented with KAs slows down disease progression. In the present review article, recent insights into the role of KA/EAA-supplemented protein-restricted diets in delaying CKD progression are summarized, and possible mechanistic underpinnings, such as protein carbamylation and gut dysbiosis, are elucidated. Emerging evidence suggests that lowering urea levels may reduce protein carbamylation, which might contribute to decreased morbidity and mortality. Protein restriction, alone or in combination with KA/EAA supplementation, modulates gut dysbiosis and decreases the generation of gut-derived uremic toxins associated, e.g., with cardiovascular disease, inflammation, protein energy wasting, and disease progression. Future studies are warranted to assess the effects on the gut microbiome, the generation of uremic toxins, as well as markers of carbamylation. Full article

The purpose of this study was to evaluate the effect of feeding healthy adult cats with foods containing variable protein concentrations on the fecal microbiome and serum concentrations of the gut-derived uremic toxins indoxyl sulfate, p-cresol sulfate (pCS), and trimethylamine-n-oxide. Twenty healthy young adult cats were randomized into two groups and fed either a low-protein diet (LPD; 7.4 g/100 kcal ME) or a high-protein diet (HPD; 11.0 g/100 kcal ME) for a 12-week period. Serum uremic toxin concentrations were measured via liquid chromatography tandem mass spectrometry, and the fecal microbiome was characterized using shallow sequence shotgun metagenomics. Cats that consumed the HPD had higher pCS concentrations at 8 weeks (p = 0.028) when compared to baseline. After 12 weeks, cats fed the HPD had higher fecal alpha diversity indices at both the taxonomic and functional levels and lower fecal Bifidobacterium relative abundance compared to those cats fed the LPD. In conclusion, a change in diet and dietary protein concentration shifted the fecal microbial community and microbial function. Feeding cats a high amount of protein increased serum concentrations of the uremic toxin pCS; however, the effect was short-lived. Full article

The composition of the gut microbiome is altered in patients with chronic kidney disease (CKD). Dysbiosis leads to decreased levels of stool organic acids (OAs) and systemic inflammation, followed by accumulation of uremic toxins (UTs) and the development of end-stage kidney disease (ESKD). We assessed the relationship between the microbiome and UT levels or the development of ESKD by comparing patients undergoing hemodialysis (HD) and those with normal renal function (NRF). This cross-sectional study recruited 41 patients undergoing HD and 38 sex- and age-matched patients with NRF, and gut microbiome, levels of plasma UTs, inflammatory markers, and stool OAs were compared. The indices of beta-diversity differed significantly between patients with NRF and those undergoing HD, and between patients undergoing HD with and without type 2 diabetes. The levels of stool total OA, inflammatory markers, and UTs differed significantly between the patients with NRF and those undergoing HD. The combined main effects of type 2 diabetes and kidney function status were accumulation of indoxyl sulfate and p-cresyl sulfate. The relative abundances of Negativicutes and Megamonas were associated with development of ESKD and with the levels of UTs, even after adjustment for factors associated with the progression of ESKD. The present study indicates that the gut environment differs between patients with NRF and those undergoing HD and between patients undergoing HD with and without type 2 diabetes. Moreover, ESKD patients with diabetes accumulate more UTs derived from the gut microbiome, which might be associated with cardio-renal diseases and poor prognosis. Full article