Wheat bran supplementation significantly improves the polystyrene consumption capacity of Zophobas atratus larvae. However, the underlying mechanism remains unclear, limiting further advancements in degradation efficiency. This study seeks to clarify the mechanism by analyzing intestinal morphology, gut microbiota structure, gene transcription, and targeted metabolites. Specifically, histopathology results demonstrated that wheat bran supplementation alleviated polystyrene-induced intestinal injury in larvae. From a genetic perspective, genes related to annexins and tight junction proteins were upregulated in intestinal tissues. These genetic changes positively correlated with increased levels of short-chain fatty acids, eicosanoids, and beneficial bacteria (e.g., Latilactobacillus curvatus). Moreover, wheat bran supplementation alleviated gut microbiota dysbiosis, suppressed pathogenic bacteria, reduced over upregulation of NADPH oxidase activity related genes, and up-regulated genes linked to the intestinal immune system process pathway, thereby mitigating the intestinal injury. It also upregulated genes associated with the aromatase activity pathway, promoting the degradation of polystyrene and its intermediates. In summary, wheat bran supplementation enhanced the polystyrene degradation efficiency of Z. atratus larvae by upregulating genes linked to the aromatase activity pathway and mitigating intestinal injury (through modulation of intestinal gene transcription, microbiota structure, and metabolites). Our findings offer new insights into improving the efficiency of insect-mediated plastic biodegradation.

The characteristic of cardiorenal syndrome (CRS) is simultaneous damage to both the heart and kidneys. CRS has caused a heavy burden of mortality and incidence rates worldwide. The regulation of host microbiota metabolism that triggers heart and kidney damage is an emerging research field that promotes a new perspective on cardiovascular risk. We summarize current studies from bench to bedside of gut microbiota-derived metabolites to better understand CRS in the context of gut microbiota-derived metabolites. We focused on the involvement of gut microbiota-derived metabolites in the pathophysiology of CRS, including lipid and cholesterol metabolism disorders, coagulation abnormalities and platelet aggregation, oxidative stress, endothelial dysfunction, inflammation, mitochondrial damage and energy metabolism disorders, vascular calcification and renal fibrosis, as well as emerging therapeutic approaches targeting CRS metabolism in gut microbiota-derived metabolites which provides an innovative treatment approach for CRS to improve patient prognosis and overall quality of life.

Redox (reduction-oxidation) imbalance is a physiological feature regulated by a well-maintained equilibrium between reactive oxygen species (ROS) and oxidative stress (OS), the defense system of the body (antioxidant enzymes). The redox system comprises regulated levels of ROS in the cells, tissues and the overall organ system. The levels of ROS are synchronized by gradients of electrons that are generated due to sequential reduction and oxidation of various biomolecules by various enzymes. Such redox reactions are present in each cell, irrespective of any tissue or organ. Failure in such coordinated regulation of redox reactions leads to the production of excessive ROS and free radicals. Excessively produced free radicals and oxidative stress affect various cellular and molecular processes required for cell survival and growth, leading to pathophysiological conditions and, ultimately, organ failure. Overproduction of free radicals and oxidative stress are the key factors involved in the onset and progression of pathophysiological conditions associated with various cardiovascular and renal diseases. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are glucose-lowering drugs prescribed to diabetic patients. Interestingly, apart from their glucose-lowering effect, these drugs exhibit beneficial effects in non-diabetic patients suffering from various cardiovascular and chronic kidney diseases, perhaps due to their antioxidant properties. Recently, it has been demonstrated that SGLT2is exhibit strong antioxidant properties by reducing ROS and OS. Hence, in this review, we aim to present the novel antioxidant role of SGLT2is and their consequent beneficial effects in various cardiovascular and renal disease states.

Plant-based diets emphasize higher intake of plant foods and are low in animal products. Individuals following plant-based diets have a lower risk of chronic conditions; however, the mechanisms underlying these associations are not completely understood. Omics data have opened opportunities to investigate the mechanistic effect of dietary intake on health outcomes. Here, we review omics analyses of plant-based diets in feeding and observational studies, showing that although metabolomics and proteomics identified candidate biomarkers and distinct pathways modifiable by plant-based diets, current evidence from transcriptomics and methylomics is limited. We also argue that future studies should examine how unhealthful plant-based diets are associated with a higher risk of health outcomes and integrate multiple omics data from feeding studies to provide further mechanistic insights.

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.

Para-cresol (p-cresol), and its primary human metabolite p-cresol sulfate (pCS), are among the most studied gut-derived metabolites relevant to autism spectrum disorder (ASD). P-cresol is produced by bacterial modification of phenylalanine or tyrosine and is one of many potentially deleterious metabolites produced by the gut microbiota. Seventeen studies have observed p-cresol and/or p-cresol sulfate as being higher in the urine of children with autism spectrum disorder (ASD) vs. controls. P-cresol has harmful effects on the body, including within the gut, brain, kidneys, liver, immune system, and mitochondria. Some of these effects may contribute to autism and comorbid symptoms. In the gut, p-cresol acts as an antibiotic, altering the gut microbiome to favor the bacteria that produce it. In the mitochondria, p-cresol disrupts ATP production and increases oxidative stress, which is also common in autism. In the brain, p-cresol impairs neuronal development. P-cresol inactivates dopamine beta-hydroxylase, which converts dopamine to noradrenaline. P-cresol sulfate impairs kidney function and is linked to chronic kidney disease (CKD), which is more common in ASD adults. P-cresol also interferes with immune function. Three animal studies have demonstrated that p-cresol causes autism-related symptoms in mice, and that mice can be recovered by the administration of fecal microbiota transplant from healthy mice. Similarly, it was found that microbiota transplant therapy treatment in children with ASD significantly reduced p-cresol sulfate levels to normal and led to significant improvements in gastrointestinal (GI) and ASD symptoms. In summary, p-cresol and pCS likely contribute to ASD core symptoms in a substantial subset of children with ASD.

Chronic kidney disease (CKD) is recognized as a common disorder worldwide. Protein-binding uremic toxins that cannot be efficiently removed by extracorporeal renal replacement therapies, such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS), are associated with high risks of cardiovascular complications and high mortality in CKD population. This study aimed to explore the therapeutical effects of Huangkuisiwu formula (HKSWF) on CKD rats. Moreover, the underlying mechanisms of HKSWF to inhibit the biosynthesis of IS and PCS were studied. Untargeted metabolomics based on UHPLC-QTOF/MS was conducted to analyze the alterations of endogenous metabolites in plasma. Levels of IS and PCS in plasma and peripheral tissues, as well as levels of amino acids in colonic contents were analyzed by UHPLC-TQ/MS. Levels of indole and p-cresol, the precursors of IS and PCS, in feces and colonic contents were quantified by HPLC-FLD. mRNA and protein expression of sulfotransferase 1 a1 (SULT1A1) were determined by qPCR and Western blotting, respectively. The ability of colonic microbiota to metabolize amino acids into precursors, as well as the activity of sulfotransferase to catalyze precursors into uremic toxins were evaluated by detecting corresponding products from specific substrates. 16S rRNA sequencing were conducted to analyze the profile of gut microbiota. The results showed that HKSWF significantly alleviated the structural and functional impairment of kidney, as well as improved the global metabolic disorders in CKD rats. IS and PCS were identified as the key differential metabolites that contributed to the effects of HKSWF. HKSWF significantly reduced the levels of IS and PCS in plasma, kidney, liver and heart of CKD rats. HKSWF showed no significant effects on the expression of SULT1A1 or the activity of sulfotransferase. HKSWF significantly decreased the levels of indole and p-cresol in the colonic contents and feces of CKD rats, by inhibiting the ability of colonic microbiota to metabolize tryptophan and tyrosine into indole and p-cresol. Alterations in the profile of amino acids and gut microbiota in CKD rats were significantly improved by HKSWF treatment. Conclusively, HKSWF inhibited gut-microbiota mediated biosynthesis of indole and p-cresol, to alleviate the accumulation of IS and PCS in CKD rats.

Cardiovascular-kidney-metabolic (CKM) syndrome is a systemic clinical condition characterized by pathological and physiological interactions among metabolic abnormalities, chronic kidney disease, and cardiovascular diseases, leading to multi-organ dysfunction and a higher incidence of cardiovascular endpoints. Traditional approaches to managing CKM syndrome risk are inadequate in these patients, necessitating strategies targeting specific CKM syndrome risk factors. Increasing evidence suggests that addressing uremic toxins and/or pathways induced by uremic toxins may reduce CKM syndrome risk and treat the disease. This review explores the interactions among heart, kidney, and metabolic pathways in the context of uremic toxins and underscores the significant role of uremic toxins as potential therapeutic targets in the pathophysiology of these diseases. Strategies aimed at regulating these uremic toxins offer potential avenues for reversing and managing CKM syndrome, providing new insights for its clinical diagnosis and treatment.

Metabolites produced as intermediaries or end-products of microbial metabolism provide crucial signals for health and diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD). These metabolites include products of the bacterial metabolism of dietary substrates, modification of host molecules (such as bile acids [BAs], trimethylamine-N-oxide, and short-chain fatty acids), or products directly derived from bacteria. Recent studies have provided new insights into the association between MASLD and the risk of developing chronic kidney disease (CKD). Furthermore, alterations in microbiota composition and metabolite profiles, notably altered BAs, have been described in studies investigating the association between MASLD and the risk of CKD. This narrative review discusses alterations of specific classes of metabolites, BAs, fructose, vitamin D, and microbiota composition that may be implicated in the link between MASLD and CKD.

p-cresol and indole are uremic compounds which undergo sulfonation to generate the highly toxic p-cresol sulfate (pCS) and indoxyl sulfate (IxS). They are also subjected to glucuronidation to produce the less toxic p-cresol glucuronide (pCG) and indoxyl glucuronide (IG). We developed and validated an assay to quantify these metabolites in HepaRG cells. We also tested the effects of mefenamic acid on their in-situ formations in relation to the development of cellular necrosis.

HepaRG cells were exposed to p-cresol or indole (0-1 mM) with mefenamic acid (0-3000 nM) for 24 hours to generate uremic metabolites. Cells were also exposed to 0.5 mM p-cresol or indole with/without 30 nM mefenamic acid to characterize lactate dehydrogenase (LDH) release.

The assay exhibited high sensitivity and wide calibration ranges covering human concentrations. HepaRG cells also generated physiologically-relevant concentrations of each metabolite. Mefenamic acid inhibited pCS formation in a concentration-dependent manner without affecting pCG, IxS, or IG. Mefenamic acid also reduced LDH release from p-cresol (by 50.12±5.86%) or indole (56.26±3.58%).

This novel assay is capable of quantifying these metabolites in HepaRG cells. Our novel findings suggest that mefenamic acid can be potentially utilized therapeutically to attenuate pCS-associated toxicities.

Despite previous studies supporting a close relationship between constipation and chronic kidney disease (CKD), the potential impact of constipation on incident CKD and the role of laxatives remains uncertain. We analyzed longitudinal data from the UK Biobank, which links baseline assessment data with follow-up data from hospital episode statistics and general practice records. Constipation was defined with diagnostic codes or regular use of laxatives at baseline as reported in the questionnaire. Cox proportional hazard models were used to evaluate the association between constipation and incident CKD. After excluding individuals with pre-existing CKD or missing covariates, 118,020 participants with general practice follow-up data were included in the main analysis. Over a median follow-up of 7.4 years, 6,833 (5.8%) patients developed CKD. Constipation was significantly associated with increased risk of CKD development in the multivariable adjusted models (hazard ratio [HR] 1.51, 95% confidence interval [CI] 1.37-1.67) for ICD-defined constipation, HR 1.34, 95% CI 1.23-1.47 for constipation defined by ICD codes or laxative use). Patients with ICD-defined constipation, even when taking laxatives, were found to have a higher risk of incident CKD than those without constipation (HR 1.42, 95% CI 1.08-1.85). We found no moderating effects of laxative use on the association between constipation and incident CKD. Constipation is independently associated with incident CKD in the large population-based longitudinal cohort. These findings highlight constipation as a potential risk factor or predictor of CKD development. Further research is warranted to elucidate the role of laxatives in controlled study designs.

Chronic kidney disease (CKD) is a multifactorial disease affecting more than 13.4% of the world's population and is a growing public health problem. It is silent in its early stages and leads to irreversible kidney damage as the disease progresses. A key factor in this progression is the bidirectional relationship between CKD and gut dysbiosis, which creates an imbalance that promotes the accumulation of uremic toxins (UTs), contributing to renal fibrosis, endothelial dysfunction, and decreased glomerular filtration rate. In addition, CKD itself exacerbates gut dysbiosis by altering the composition of the gut microbiota (GM) and promoting the growth of pathogenic microorganisms. Therefore, it is crucial to explore new therapeutic strategies, and the use of probiotics and synbiotics has shown promise in modulating the GM. Numerous preclinical studies have shown that the use of probiotics in CKD has a beneficial effect on the kidney by reducing UTs, apoptosis, inflammation, and oxidative stress. Probiotic treatment has also been associated with restoration of intestinal integrity, modulation of microbial composition and diversity, and increased production of short-chain fatty acids (SCFAs). These positive results have also been observed in patients at different stages of CKD, where the use of probiotics and/or synbiotics was able to improve creatinine levels and uremic parameters and alleviate abdominal discomfort, in addition to modulating GM and reducing serum endotoxin levels. Although recent studies have explored the benefits of probiotics in the treatment of CKD, further research is needed to determine their long-term efficacy and clinical relevance. This review focuses on the factors driving gut dysbiosis in CKD, its role in disease progression, and the potential of probiotics as a therapeutic strategy.

Gut microbiota is a complex and dynamic system that plays critical roles in human health and various disease. Progressive chronic kidney disease (CKD) suggests that patients irreversibly progress to end-stage kidney disease and need renal replacement treatments, including dialysis and transplantation. Ample evidence indicates that local oxidative stress and inflammation play pivotal roles in the pathogenesis and progression of CKD and dysbiosis of gut microbiota. CKD is always accompanied by intestinal inflammation and oxidative stress, which lead to rapid systemic translocation of bacterial-derived uraemic toxins, including indoxyl sulphate, phenyl sulphate and indole-3-acetic acid, and the consequent development and aggravation of renal fibrosis. Although inflammation and oxidative stress have been extensively discussed, there is a paucity of reports on the effects of gut microbiota on renal fibrosis and gut microbiota mediation of oxidative stress and inflammation. This review provides an overview of gut microbiota on inflammation and oxidative stress in renal fibrosis, briefly discusses regulation of the gut flora using microecological preparations and natural products, such as resveratrol, curcumin and emodin as treatments for CKD, and provides a clear pathophysiological rationale for the design of promising therapeutic strategies.

Our objective was to examine the factors associated with the serum angiopoietin-2/angiopoietin-1 (Angpt-2/Angpt-1) ratio in peritoneal dialysis (PD) patients and to investigate the association between Angpt-2/Angpt-1 ratio and cardiovascular and all-cause mortality.

Patients on PD who were prevalent between January 2014 and April 2015 in the center of Renji Hospital were enrolled. At the time of enrollment, serum and dialysate samples were collected to detect biochemical parameters, serum angiopoietin-2 and angiopoietin-1 levels. Patients were dichotomized into two groups according to a median of Angpt-2/Angpt-1 ratio and followed up prospectively until the end of the study.

A total of 325 patients were enrolled, including 168 males (51.7%) with a mean age of 56.9 ± 14.2 years and a median PD duration of 32.4 (9.8-55.9) months. Multiple linear regression showed pulse pressure (β = 0.206, p < .001) and high-sensitivity C-reactive protein (hs-CRP) (β = 0.149, p = .011) were positively correlated with serum Angpt-2/Angpt-1 ratio, while residual renal function (RRF) (β= -0.219, p < .001) was negatively correlated with serum Angpt-2/Angpt-1 ratio. Multivariate Cox regression analysis showed the high serum Angpt-2/Angpt-1 ratio was an independent predictor of cardiovascular mortality (hazard ratio (HR)=2.467, 95% confidence interval (CI) 1.243-4.895, p = .010) and all-cause mortality (HR = 1.486, 95%CI 1.038-2.127, p = .031). In further subgroup analysis by gender, a significant association was shown in high Angpt-2/Angpt-1 ratio with all-cause mortality in male (p < .05), but not in female patients (p>.05).

High Angpt-2/Angpt-1 ratio is an independent risk factor for cardiovascular and all-cause mortality in PD patients.

Elevated systemic inflammation, common in obesity, increases cardiovascular disease risk. Obesity is linked to a pro-inflammatory gut microbiota that releases uremic toxins like p-cresylsulfate (PCS) and indoxyl sulfate (IS), which are implicated in coronary atherosclerosis, insulin resistance, and chronic kidney disease. This study examines the relationship between total PCS and IS levels and central obesity in patients with stable coronary artery disease (CAD).

A cross-sectional study was conducted on 373 consecutive patients with stable CAD from a single center. Serum levels of total PCS and IS were measured using an Ultra Performance LC System. Central obesity was evaluated using a body shape index (ABSI) and conicity index (CI). Six obesity-related proteins were also analyzed. Structural equation modeling (SEM) assessed direct and indirect effects of total PCS, IS, and the six obesity-related proteins on central obesity.

Significant positive correlations were found between total PCS and IS with waist-to-hip ratio (WHR) (r = 0.174, p = 0.005 for total PCS; r = 0.144, p = 0.021 for IS), CI (r = 0.273, p < 0.0001 for total PCS; r = 0.260, p < 0.0001 for IS), and ABSI (r = 0.297, p < 0.0001 for total PCS; r = 0.285, p < 0.0001 for IS) in male patients, but not in female patients. Multivariate analysis showed higher odds ratios (ORs) for elevated CI (OR = 3.18, 95% CI: 1.54-6.75, p = 0.002) and ABSI (OR = 3.28, 95% CI: 1.54-7.24, p = 0.002) in patients with high PCS levels, and elevated CI (OR = 2.30, 95% CI: 1.15-4.66, p = 0.018) and ABSI (OR = 2.22, 95% CI: 1.07-4.72, p = 0.033) in those with high IS levels, compared to those with low toxin levels. SEM analysis indicated that total PCS and IS directly impacted central obesity indices and indirectly influenced central adiposity measures like WHR through high sensitivity C-reactive protein (hs-CRP) (β = 0.252, p < 0.001).

Circulating total PCS and IS contribute to central obesity in male patients with stable CAD, partially mediated by hs-CRP.

Sarcopenia is a prevalent condition in patients with chronic kidney disease (CKD), intricately linked to adverse prognoses, heightened cardiovascular risks, and increased mortality rates. Extensive studies have found a close and complex association between gut microbiota, kidney and muscle. On one front, patients with CKD manifest disturbances in gut microbiota and alterations in serum metabolites. These abnormal microbiota composition and metabolites in turn participate in the development of CKD. On another front, altered gut microbiota and its metabolites may lead to significant changes in metabolic homeostasis and inflammation, ultimately contributing to the onset of sarcopenia. The disturbance of gut microbial homeostasis, coupled with the accumulation of toxic metabolites, exerts deleterious effects on skeletal muscles in CKD patients with sarcopenia. This review meticulously describes the alterations observed in gut microbiota and its serum metabolites in CKD and sarcopenia patients, providing a comprehensive overview of pertinent studies. By delving into the intricate interplay of gut microbiota and serum metabolites in CKD-associated sarcopenia, we aim to unveil novel treatment strategies for ameliorating their symptoms and prognosis.

Renal fibrosis represents a critical pathological condition in the progression of renal dysfunction, characterized by aberrant accumulation of extracellular matrix (ECM) and structural alterations in renal tissue. Recent research has highlighted the potential significance of gut microbiota and demonstrated their influence on host health and disease mechanisms through the production of bioactive metabolites. This review examines the role of alterations in gut microbial composition and their metabolites in the pathophysiological processes underlying renal fibrosis. It delineates current therapeutic interventions aimed at modulating gut microbiota composition, encompassing dietary modifications, pharmacological approaches, and probiotic supplementation, while evaluating their efficacy in mitigating renal fibrosis. Through a comprehensive analysis of current research findings, this review enhances our understanding of the bidirectional interaction between gut microbiota and renal fibrosis, establishing a theoretical foundation for future research directions and potential clinical applications in this domain.

The rising global incidence of chronic inflammatory diseases calls for innovative and sustainable medical solutions. Brewers' spent grain (BSG), a byproduct of beer production, presents a unique opportunity in this regard. This review explores the multifaceted health benefits of BSG, with a focus on managing chronic kidney disease (CKD). BSG is identified as a potent prebiotic with potential as a therapeutic agent in CKD. We emphasize the role of gut dysbiosis in CKD and discuss how BSG could help mitigate metabolic derangements resulting from dysbiosis and CKD. Fermentation of BSG further enhances its positive impact on gut health. Incorporating fermented BSG as a key component in preventive health care could promote a more sustainable and healthier future. By optimizing the use of this typically discarded byproduct, we can align proactive health-care strategies with responsible resource management, benefiting both people and the environment.

The composition of the gut microbiota varies among end-stage renal disease (ESRD) patients on the basis of their mode of renal replacement therapy (RRT), with notably more pronounced dysbiosis occurring in those undergoing hemodialysis (HD). Interventions such as dialysis catheters, unstable hemodynamics, strict dietary restrictions, and pharmacotherapy significantly alter the intestinal microenvironment, thus disrupting the gut microbiota composition in HD patients. The gut microbiota may influence HD-related complications, including cardiovascular disease (CVD), infections, anemia, and malnutrition, through mechanisms such as bacterial translocation, immune regulation, and the production of gut microbial metabolites, thereby affecting both the quality of life and the prognosis of patients. This review focuses on alterations in the gut microbiota and its metabolites in HD patients. Additionally, understanding the impact of the gut microbiota on the complications of HD could provide insights into the development of novel treatment strategies to prevent or alleviate complications in HD patients.

Renal injury, a prevalent clinical outcome with multifactorial etiology, imposes a substantial burden on society. Currently, there remains a lack of effective management and treatments. Extensive research has emphasized the diverse biological effects of natural polysaccharides, which exhibit promising potential for mitigating renal damage. This review commences with the pathogenesis of four common renal diseases and the shared mechanisms underlying renal injury. The renoprotective roles of polysaccharides in vivo and in vitro are summarized in the following five aspects: anti-oxidative stress effects, anti-apoptotic effects, anti-inflammatory effects, anti-fibrotic effects, and gut modulatory effects. Furthermore, we explore the structure-activity relationship and bioavailability of polysaccharides in relation to renal injury, as well as investigate their utility as biomaterials for alleviating renal injury. The clinical experiments of polysaccharides applied to patients with chronic kidney disease are also reviewed. Broadly, this review provides a comprehensive perspective on the research direction of natural polysaccharides in the context of renal injury, with the primary aim to serve as a reference for the clinical development of polysaccharides as pharmaceuticals and prebiotics for the treatment of kidney diseases.

Diabetic kidney disease (DKD) is one of the main microvascular complications of diabetes mellitus, as well as the leading cause of end-stage renal disease. Intestinal microbiota has emerged as a crucial regulator of its occurrence and development. Dysbiosis of the intestinal microbiota can disrupt the intestinal mucosal barrier, abnormal immunological response, reduction in short-chain fatty acid metabolites, and elevation of uremic toxins, all closely related to the occurrence and development of DKD. However, the underlying mechanisms of how intestinal microbiota and its metabolites influence the onset and progression of DKD has not been fully elucidated. In the current review, we will try to summarize the microecological mechanism of DKD by focusing on three aspects: the intestinal microbiota and its associated metabolites, and the "gut-kidney axis," and try to summarize therapies targeted at managing the intestinal microbiota, expecting to provide theoretical basis for the subsequent study of the relationship between intestinal homeostasis and DKD, and will open an emerging perspective and orientation for DKD treatment.

Monosodium glutamate (MSG) is used as a common food additive in some foods. However, based on our search and knowledge, no comprehensive study discussed the effect of MSG on the human gut microbiome. In this study, the effects of MSG on the gut microbiome, liver, and kidney were performed. Data were collected from databases including PubMed, Scopus, Web of Science, and ScienceDirect using the search strategy and keywords. Finally, 14 eligible studies were selected for systematic review. This study provides a new perspective on the effects of MSG on the gut flora, shedding light on the potential relationship between MSG intake and human health.

Diabetic nephropathy is a common complication of diabetes and a considerable contributor to end-stage renal disease. Evidence indicates that glucose dysregulation and lipid metabolism comprise a pivotal pathogenic mechanism in diabetic nephropathy. However, current treatment outcomes are limited, as they only provide symptomatic relief without preventing disease progression. The gut microbiota is a group of microorganisms that inhabit the human intestinal tract and play a crucial role in maintaining host energy balance, metabolism, and immune activity. Patients with diabetic nephropathy exhibit altered gut microbiota, suggesting its potential involvement in the onset and progression of the disease. However, how a perturbed microbiota induces and promotes diabetic nephropathy remains unelucidated. This article summarizes the evidence of the impact of gut microbiota on the progression of diabetic nephropathy, with a particular focus on the molecular mechanisms involved, aiming to provide new insights into the treatment of diabetic nephropathy.

We previously reported that rosmarinic acid (RA) ameliorated renal fibrosis in a unilateral ureteral obstruction (UUO) murine model of chronic kidney disease. This study aimed to determine whether RA attenuates indoxyl sulfate (IS)-induced renal fibrosis by regulating the activation of the NLRP3 inflammasome/IL-1β/Smad circuit. We discovered the NLRP3 inflammasome was activated in the IS treatment group and downregulated in the RA-treated group in a dose-dependent manner. Additionally, the downstream effectors of the NLRP3 inflammasome, cleaved-caspase-1 and cleaved-IL-1β showed similar trends in different groups. Moreover, RA administration significantly decreased the ROS levels of reactive oxygen species in IS-treated cells. Our data showed that RA treatment significantly inhibited Smad-2/3 phosphorylation. Notably, the effects of RA on NLRP3 inflammasome/IL-1β/Smad and fibrosis signaling were reversed by the siRNA-mediated knockdown of NLRP3 or caspase-1 in NRK-52E cells. In vivo, we demonstrated that expression levels of NLRP3, c-caspase-1, c-IL-1β, collagen I, fibronectin and α-SMA, and TGF- β 1 were downregulated after treatment of UUO mice with RA or RA + MCC950. Our findings suggested RA and MCC950 synergistically inhibited UUO-induced NLRP3 signaling activation, revealing their renoprotective properties and the potential for combinatory treatment of renal fibrosis and chronic kidney inflammation.

Dietary-resistant starch is emerging as a potential therapeutic tool to limit the negative effects of diabetes on the kidneys. However, its metabolic and immunomodulatory effects have not yet been fully elucidated.

Six-week-old db/db mice were fed a diet containing 12.5% resistant starch or a control diet matched for equivalent regular starch for 10 weeks. db/m mice receiving the control diet were utilised as non-diabetic controls. Freshly collected kidneys were digested for flow cytometry analysis of immune cell populations. Kidney injury was determined by measuring albuminuria, histology, and immunohistochemistry. Portal vein plasma was collected for targeted analysis of microbially-derived metabolites. Intestinal histology and tight junction protein expression were assessed.

Resistant starch limited the development of albuminuria in db/db mice. Diabetic db/db mice displayed a decline in portal vein plasma levels of acetate, propionate, and butyrate, which was increased with resistant starch supplementation. Diabetic db/db mice receiving resistant starch had a microbially-derived metabolite profile similar to that of non-diabetic db/m mice. The intestinal permeability markers lipopolysaccharide and lipopolysaccharide binding protein were increased in db/db mice consuming the control diet, which was not seen in db/db mice receiving resistant starch supplementation. Diabetes was associated with an increase in the kidney neutrophil population, neutrophil activation, number of C5aR1+ neutrophils, and urinary complement C5a excretion, all of which were reduced with resistant starch. These pro-inflammatory changes appear independent of fibrotic changes in the kidney.

Resistant starch supplementation in diabetes promotes beneficial circulating microbially-derived metabolites and improves intestinal permeability, accompanied by a modulation in the inflammatory profile of the kidney including neutrophil infiltration, complement activation, and albuminuria. These findings indicate that resistant starch can regulate immune and inflammatory responses in the kidney and support the therapeutic potential of resistant starch supplementation in diabetes on kidney health.

Several studies have reported dietary microorganisms' beneficial effects on human health. We aimed to detect the potential association between dietary live microbe intake and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM) through a cross-sectional analysis of the National Health and Nutrition Examination Survey from 1999 to 2018.

According to the Sanders classification system of dietary live microbes, the study participants were divided into three groups: low, medium, and high live microbe groups. In patients with T2DM, DKD was assessed by glomerular filtration rate (< 60 mL/min/1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration algorithm), proteinuria (urinary albumin to creatinine ratio ≥ 30 mg/g), or both. Weighted univariate and multivariate logistic regression and subgroup analyses were conducted to investigate the independent association between dietary live microbe and DKD.

The study included 3836 participants, of whom 1467 (38.24%) had DKD for the diagnosis. Our study demonstrated that participants in the high dietary live microbe group were more likely to be older, female, non-Hispanic White, have higher education levels, have a lower prevalence of smoking, have a high poverty-income ratio, have higher energy intake, lower haemoglobin (HbA1c) and serum creatinine levels, and lower risk of progression. After adjustment for covariates, patients in the high dietary live microbe group had a low prevalence of DKD, whereas no significant association with DKD was found between the medium and low dietary live microbe groups. No statistically significant interaction was observed in all subgroup analyses except for HbA1c (p for interaction < 0.05).

Our results indicate that high dietary live microbe intake was associated with a low DKD prevalence.

Indoxyl sulfate (IxS) and p-cresyl sulfate (pCS) are toxic uremic compounds with documented pathological outcomes. This review critically and comprehensively analyzes the available liquid chromatography-mass spectrometry methods quantifying IxS and pCS in human matrices and the biological applications of these validated assays. Embase, Medline, PubMed, Scopus, and Web of Science were searched until December 2023 to identify assays with complete analytical and validation data (N = 23). Subsequently, citation analysis with PubMed and Scopus was utilized to identify the biological applications for these assays (N = 45). The extraction methods, mobile phase compositions, chromatography, and ionization methods were evaluated with respect to overall assay performance (e.g., sensitivity, separation, interference). Most of the assays focused on human serum/plasma, utilizing acetonitrile or methanol (with ammonium acetate/formate or formic/acetic acid), liquid-liquid extraction, reverse phase (e.g., C18) chromatography, and gradient elution for analyte separation. Mass spectrometry conditions were also consistent in the identified papers, with negative electrospray ionization, select multiple reaction monitoring transitions and deuterated internal standards being the most common approaches. The validated biological applications indicated IxS and/or pCS were correlated with renal disease progression and cardiovascular outcomes, with limited data on central nervous system disorders. Methods for reducing IxS and/or pCS concentrations were also identified (e.g., drugs, natural products, diet, dialysis, transplantation) where inconsistent findings have been reported. The clinical monitoring of IxS and pCS is gaining significant interest, and this review will serve as a useful compendium for scientists and clinicians.

Chronic hyperglycemia-induced oxidative stress plays a crucial role in the development of diabetic nephropathy (DN). Moreover, adverse extracellular matrix (ECM) accumulation elevates renal resistive index leading to progressive worsening of the pathology in DN. Nimbidiol is an alpha-glucosidase inhibitor, isolated from the medicinal plant, 'neem' (Azadirachta indica) and reported as a promising anti-diabetic compound. Previously, a myriad of studies demonstrated an anti-oxidative property of a broad-spectrum neem-extracts in various diseases including diabetes. Our recent study has shown that Nimbidiol protects diabetic mice from fibrotic renal dysfunction in part by mitigating adverse ECM accumulation. However, the precise mechanism remains poorly understood.

The present study aimed to investigate whether Nimbidiol ameliorates renal injury by reducing oxidative stress in type-1 diabetes. To test the hypothesis, wild-type (C57BL/6J) and diabetic Akita (C57BL/6-Ins2Akita/J) mice aged 10-14 weeks were used to treat with saline or Nimbidiol (400 μg kg-1 day-1) for 8 weeks.

Diabetic mice showed elevated blood pressure, increased renal resistive index, and decreased renal vasculature compared to wild-type control. In diabetic kidney, reactive oxygen species and the expression levels of 4HNE, p22phox, Nox4, and ROMO1 were increased while GSH: GSSG, and the expression levels of SOD-1, SOD-2, and catalase were decreased. Further, eNOS, ACE2, Sirt1 and IL-10 were found to be downregulated while iNOS and IL-17 were upregulated in diabetic kidney. The changes were accompanied by elevated expression of the renal injury markers viz., lipocalin-2 and KIM-1 in diabetic kidney. Moreover, an upregulation of p-NF-κB and a downregulation of IkBα were observed in diabetic kidney compared to the control. Nimbidiol ameliorated these pathological changes in diabetic mice.

Altogether, the data of our study suggest that oxidative stress largely contributes to the diabetic renal injury, and Nimbidiol mitigates redox imbalance and thereby protects kidney in part by inhibiting NF-κB signaling pathway in type-1 diabetes.

In recent years, preclinical research on diabetic kidney disease (DKD) has surged to the forefront of scientific and clinical attention. DKD has become a pervasive complication of type 2 diabetes. Given the complexity of its etiology and pathological mechanisms, current interventions, including drugs, dietary modifications, exercise, hypoglycemic treatments and lipid-lowering methods, often fall short in achieving desired therapeutic outcomes. Iridoids, primarily derived from the potent components of traditional herbs, have been the subject of long-standing research. Preclinical data suggest that iridoids possess notable renal protective properties; however, there has been no summary of the research on their efficacy in the management and treatment of DKD. This article consolidates findings from in vivo and in vitro research on iridoids in the context of DKD and highlights their shared anti-inflammatory activities in treating this condition. Additionally, it explores how certain iridoid components modify their chemical structures through the regulation of intestinal flora, potentially bolstering their therapeutic effects. This review provides a focused examination of the mechanisms through which iridoids may prevent or treat DKD, offering valuable insights for future research endeavors. Please cite this article as: Zhou TY, Tian N, Li L, Yu R. Iridoids modulate inflammation in diabetic kidney disease: A review. J Integr Med. 2024; 22(3): 210-222.

Disruption of gut microbiota underpins some of the metabolic alterations observed in chronic kidney disease (CKD).

In a nonrandomized, open-label, 3-phase pilot trial, with repeated measures within each phase, we examined the efficacy of oligofructose-enriched inulin (p-inulin) in changing the gut microbiome and their metabolic products in 15 patients with CKD. The stability of microbiome and metabolome was studied during the pretreatment phase (8 weeks), a p-inulin treatment phase (12 weeks), and a post treatment phase (8 weeks) of the study.

Study participants completed 373 of the 420 expected study visits (88.8%). Adherence to p-inulin was 83.4%. 16S rRNA sequencing was performed in 368 stool samples. A total of 1085 stool, urine, and plasma samples were subjected to untargeted metabolomic studies. p-inulin administration altered the composition of the gut microbiota significantly, with an increase in abundance of Bifidobacterium and Anaerostipes. Intersubject variations in microbiome and metabolome were larger than intrasubject variation, indicating the stability of the gut microbiome within each phase of the study. Overall metabolite compositions assessed by beta diversity in urine and stool metabolic profiles were significantly different across study phases. Several specific metabolites in stool, urine, and plasma were significant at false discovery rate (FDR) ≤ 0.1 over phase. Specifically, there was significant enrichment in microbial metabolites derived from saccharolysis.

Results from our study highlight the stability of the gut microbiome and the expansive effect of p-inulin on microbiome and host cometabolism in patients with CKD. Findings from this study will enable rigorous design of microbiome-based intervention trials.

Uremic toxins (UTs), particularly protein-bound uremic toxins (PBUTs), accumulate in chronic kidney disease (CKD) patients, causing significant health complications like uremic syndrome, cardiovascular disease, and immune dysfunction. The binding of PBUTs to plasma proteins such as albumin presents a formidable challenge for clearance, as conventional dialysis is often insufficient. With advancements in the classification and understanding of UTs, spearheaded by the European Uremic Toxins (EUTox) working group, over 120 molecules have been identified, prompting the development of alternative therapeutic strategies. Innovations such as online hemodiafiltration aim to enhance the removal process, while novel adsorptive therapies offer a means to address the high affinity of PBUTs to plasma proteins. Furthermore, the exploration of molecular displacers, designed to increase the free fraction of PBUTs, represents a cutting-edge approach to facilitate their dialytic clearance. Despite these advancements, the clinical application of displacers requires more research to confirm their efficacy and safety. The pursuit of such innovative treatments is crucial for improving the management of uremic toxicity and the overall prognosis of CKD patients, emphasizing the need for ongoing research and clinical trials.

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes mellitus (DM) that poses a serious risk as it can lead to end-stage renal disease (ESRD). DKD is linked to changes in the diversity, composition, and functionality of the microbiota present in the gastrointestinal tract. The interplay between the gut microbiota and the host organism is primarily facilitated by metabolites generated by microbial metabolic processes from both dietary substrates and endogenous host compounds. The production of numerous metabolites by the gut microbiota is a crucial factor in the pathogenesis of DKD. However, a comprehensive understanding of the precise mechanisms by which gut microbiota and its metabolites contribute to the onset and progression of DKD remains incomplete. This review will provide a summary of the current scenario of metabolites in DKD and the impact of these metabolites on DKD progression. We will discuss in detail the primary and gut-derived metabolites in DKD, and the mechanisms of the metabolites involved in DKD progression. Further, we will address the importance of metabolomics in helping identify potential DKD markers. Furthermore, the possible therapeutic interventions and research gaps will be highlighted.

Inflammation, metabolic acidosis, renin-angiotensin system activation, insulin resistance, and impaired perfusion to skeletal muscles, among others, are possible causes of uremic sarcopenia. These conditions induce the activation of the nuclear factor-kappa B and mitogen-activated protein kinase pathways, adenosine triphosphate ubiquitin-proteasome system, and reactive oxygen species system, resulting in protein catabolism. Strategies for the prevention and treatment of sarcopenia in chronic kidney disease (CKD) are aerobic and resistance exercises along with nutritional interventions. Anabolic hormones have shown beneficial effects. Megestrol acetate increased weight, protein catabolic rate, and albumin concentration, and it increased intracellular water component and muscle mass. Vitamin D supplementation showed improvement in physical function, muscle strength, and muscle mass. Correction of metabolic acidosis showed an increase in protein intake, serum albumin levels, body weight, and mid-arm circumference. The kidney- gut-muscle axis indicates that dysbiosis and changes in gut-derived uremic toxins and short-chain fatty acids affect muscle mass, composition, strength, and functional capacity. Biotic supplements, AST-120 administration, hemodiafiltration, and preservation of residual renal function are alleged to reduce uremic toxins, including indoxyl sulfate (IS) and p-cresyl sulfate (PCS). Synbiotics reversed the microbiota change in CKD patients and decreased uremic toxins. AST-120 administration changed the overall gut microbiota composition in CKD. AST-120 prevented IS and PCS tissue accumulation, ameliorated muscle atrophy, improved exercise capacity and mitochondrial biogenesis, restored epithelial tight junction proteins, and reduced plasma endotoxin levels and markers of oxidative stress and inflammation. In a human study, the addition of AST-120 to standard treatment had modest beneficial effects on gait speed change and quality of life.

This retrospective cohort study aimed to be the first to evaluate the association between plasma protein-bound uremic toxins (PBUTs) concentrations, echocardiographic parameters of heart failure (HF), and incident HF events in patients with chronic kidney disease (CKD) not on dialysis.

Retrospective, single-centre, cohort study at the Ghent University Hospital, Belgium. Adults with CKD stages G1-G5, not on dialysis, could be included. Exclusion criteria were ongoing pregnancy, age <18 years, active acute infection, active malignancy, history of transplantation, or a cardiovascular event within 3 months prior to inclusion. Free and total concentrations of five PBUTs were quantified at baseline: indoxyl sulfate (IxS), p-cresyl sulfate (pCS), p-cresyl glucuronide (pCG), indole-3 acetic acid (IAA), and hippuric acid (HA). Patients were grouped into three echocardiographic categories: normal left ventricular ejection fraction (LVEF) and normal left ventricular end-diastolic pressure (LVEDP), normal LVEF and increased LVEDP, and reduced LVEF, based on available echocardiographic data in a time interval of ±6 months around the plasma sample collection. A total of 523 patients were included between January 2011 and January 2014. Echocardiographic data within the predefined timeframe were available for 210 patients (40% of patients). Levels of pCG and pCS were significantly higher in patients with reduced (<50%) versus normal LVEF (P < 0.05). After a median follow-up 5.5 years, 43 (8.4%) patients reached the composite endpoint of hospitalization or mortality due to HF. Free fractions of IxS, pCS, and pCG showed the strongest association with clinical outcome: free IxS: HR 1.71 (95% CI 1.11-2.63; P = 0.015), free pCS: HR 1.82 (95% CI 1.11-3.01; P = 0.019), and free pCG: HR 1.67 (95% CI 1.08-2.58; P = 0.020), and these results were independent of age, gender, body mass index, diabetes, and systolic blood pressure. In models that were also adjusted for serum creatinine, the free fractions of these PBUTs remained significant.

Elevated free concentrations of IxS, pCG, and pCS were independently associated with an increased risk of HF events in non-dialysed CKD patients. Further research is necessary to confirm these findings and investigate the potential impact of PBUT-lowering interventions on HF events in this patient group.

Fushen Granule is an improved granule based on the classic formula Fushen Formula, which is used for the treatment of peritoneal dialysis-related intestinal dysfunction in patients with end-stage renal disease. However, the effect and mechanism of this granule on the prevention and treatment of chronic renal failure have not been fully elucidated.

A 5/6 nephrectomy model of CRF was induced and Fushen Granule was administered at low and high doses to observe its effects on renal function, D-lactate, serum endotoxin, and intestinal-derived metabolic toxins. The 16SrRNA sequencing method was used to analyze the abundance and structure of the intestinal flora of CRF rats. A FMT assay was also used to evaluate the effects of transplantation of Fushen Granule fecal bacteria on renal-related functional parameters and metabolic toxins in CRF rats.

Gavage administration of Fushen Granule at low and high doses down-regulated creatinine, urea nitrogen, 24-h urine microalbumin, D-lactate, endotoxin, and the intestinal-derived toxins indophenol sulphateand p-cresol sulphate in CRF rats. Compared with the sham-operated group in the same period, CRF rats had a decreased abundance of the firmicutes phylum and an increased abundance of the bacteroidetes phylum at the phylum level, and a decreasing trend of the lactobacillus genus at the genus level. Fushen Granule intervention increased the abundance of the firmicutes phylum, decreased the abundance of the bacteroidetes phylum, and increased the abundance of the lactobacillus genus. The transplantation of Fushen Granule fecal bacteria significantly reduced creatinine(Cr), blood urea nitrogen(Bun), uric acid(UA), 24-h urinary microalbumin, D-lactate, serum endotoxin, and enterogenic metabolic toxins in CRF rats. Compared with the sham-operated group, the transplantation of Fushen Granule fecal bacteria modulated the Firmicutes and Bacteroidetes phyla and the Lactobacillus genus.

Fushen Granule improved renal function and intestinal barrier function by regulating intestinal flora, inhibiting renal fibrosis, and delaying the progression of chronic renal failure.

Chronic kidney disease (CKD), which is globally on the rise, has become an urgent challenge from the perspective of public health, given its risk factors such as end-stage renal failure, cardiovascular diseases, and infections. The pathophysiology of CKD, including dialysis patients, is deeply associated with enhanced oxidative stress in both the kidneys and the entire body. Therefore, the introduction of a safe and widely applicable antioxidant therapy is expected as a measure against CKD. Electrolyzed hydrogen water (EHW) generated through the electrolysis of water has been confirmed to possess chemical antioxidant capabilities. In Japan, devices producing this water have become popular for household drinking water. In CKD model experiments conducted to date, drinking EHW has been shown to suppress the progression of kidney damage related to hypertension. Furthermore, clinical studies have reported that systemic oxidative stress in patients undergoing dialysis treatment using EHW is suppressed, leading to a reduction in the incidence of cardiovascular complications. In the future, considering EHW as one of the comprehensive measures against CKD holds significant importance. The medical utility of EHW is believed to be substantial, and further investigation is warranted.

Introduction: Huangkui capsule (HKC) is made from the ethanol extract of Abelmoschus manihot (L.) Medik [Malvaceae; abelmoschi corolla] and received approval from the China Food and Drug Administration (Z19990040) in 1999. Currently, HKC is used for treatment of the patients with diabetic nephropathy (DN) in China. The bioactive chemical constituents in HKC are total flavonoids of A. manihot (L.) Medik (TFA). The present study aims to identify the primary flavonoid metabolites in HKC and TFA and their metabolism fates in db/db mice, the animal model for the study of type 2 diabetes and DN. Methods: HKC (0.84 g/kg/d) and TFA (0.076 g/kg/d) or vehicle were respectively administered daily via oral gavage in db/db mice for 4 weeks. The metabolism fate of the main metabolites of HKC in serum, liver, kidney, heart, jejunum, colon, jejunal contents, colonic contents, and urine of db/db mice were analyzed with a comprehensive metabolite identification strategy. Results and Discussion: In db/db mice administered with HKC and TFA, 7 flavonoid prototypes and 38 metabolites were identified. The related metabolic pathways at Phases I and II reactions included dehydroxylation, deglycosylation, hydrogenation, methylation, glucuronidation, sulphation, and corresponding recombined reactions. Quercetin, isorhamnetin, quercetin sulphate, quercetin monoglucuronide, and isorhamnetin monoglucuronide presented a high exposure in the serum and kidney of db/db mice. Thereby, the present study provides a pharmacodynamic substance basis for better understanding the mechanism of A. manihot (L.) Medik for medication of DN.

To determine serum and urine concentrations of the uremic retention solutes (URSs), indoxyl sulfate (IS), p-cresol sulfate (PCS), and trimethylamine N-oxide (TMAO), and gut microbiota composition in individuals with moderate chronic kidney disease (CKD) compared with matched adults without CKD in a 6-day controlled feeding study.

This study was a secondary analysis in which 8 adults with moderate CKD were matched for age, sex, and race with 8 adults without CKD in a parallel-arm, 6-day controlled feeding study. IS, PCS, and TMAO were quantified using liquid chromatography-mass spectrometry in fecal samples, fasting serum, and fasting spot urine samples collected at the end of the feeding period.

Fasting serum URS concentrations were 2.8 to 4.9x higher in CKD compared to controls (all P < .05). No differences were found in the composition of the gut microbiota between patients with and without CKD when analyzing samples for α-diversity, β-diversity, and only minor abundance differences across taxa were apparent. Estimated glomerular filtration rate (eGFR) was inversely related to each serum URS in the whole cohort (all P < .01). However, within groups the relationships between eGFR and serum URS remained strong for CKD patients for IS and TMAO (both P < .05) but weakened for PCS (P = .10). eGFR was only correlated with urine PCS in the whole cohort (P = .03); within groups, no correlation for eGFR with any urine URS was observed. Only urine TMAO was higher in CKD compared to controls (P < .05).

Serum URS concentrations are elevated in adults with CKD compared to matched non-CKD adults without differences in gut microbiota composition after consuming the same controlled study diet for 6 days. Future studies are needed to determine if specific dietary components may differentially alter the microbiota and URS.

In the human gut, there is a metabolically active microbiome whose metabolic products reach various organs and are used in the physiological activities of the body. When dysbiosis of intestinal microbial homeostasis occurs, pathogenic metabolites may increase and one of them is trimethyl amine-N-oxide (TMAO). TMAO is thought to have a role in the pathogenesis of insulin resistance, diabetes, hyperlipidemia, atherosclerotic heart diseases, and cerebrovascular events. TMAO level is also associated with renal inflammation, fibrosis, acute kidney injury, diabetic kidney disease, and chronic kidney disease. In this review, the effect of TMAO on various kidney diseases is discussed.

In today's industrialized society food consumption has changed immensely toward heightened red meat intake and use of artificial sweeteners instead of grains and vegetables or sugar, respectively. These dietary changes affect public health in general through an increased incidence of metabolic diseases like diabetes and obesity, with a further elevated risk for cardiorenal complications. Research shows that high red meat intake and artificial sweeteners ingestion can alter the microbial composition and further intestinal wall barrier permeability allowing increased transmission of uremic toxins like p-cresyl sulfate, indoxyl sulfate, trimethylamine n-oxide and phenylacetylglutamine into the blood stream causing an array of pathophysiological effects especially as a strain on the kidneys, since they are responsible for clearing out the toxins. In this review, we address how the burden of the Western diet affects the gut microbiome in altering the microbial composition and increasing the gut permeability for uremic toxins and the detrimental effects thereof on early vascular aging, the kidney per se and the blood-brain barrier, in addition to the potential implications for dietary changes/interventions to preserve the health issues related to chronic diseases in future.

The gut microbiota-brain axis has been associated with the pathogenesis of numerous disorders, but the mechanism(s) underlying these links are generally poorly understood. Accumulating evidence indicates the involvement of gut microbe-derived metabolites. Circulating levels of the gut microbe/host co-metabolite p-cresol sulfate (pCS) correlate with cerebrovascular event risk in individuals with chronic kidney disease (CKD), but whether this relationship is mechanistic is unclear. We hypothesized that pCS would impair the function of the blood-brain barrier (BBB), the primary brain vasculature interface. We report that pCS exposure impairs BBB integrity in human cells in vitro and both acutely (≤6 hours) and chronically (28 days) in mice, enhancing tracer extravasation, disrupting barrier-regulating tight junction components and ultimately exerting a suppressive effect upon whole-brain transcriptomic activity. In vitro and in vivo mechanistic studies showed that pCS activated epidermal growth factor receptor (EGFR) signaling, sequentially activating the intracellular signaling proteins annexin A1 and STAT3 to induce mobilization of matrix metalloproteinase MMP-2/9 and disruption to the integrity of the BBB. This effect was confirmed as specific to the EGFR through the use of both pharmacological and RNA interference approaches. Confirming the translational relevance of this work, exposure of the cerebromicrovascular endothelia to serum from hemodialysis patients in vitro led to a significant increase in paracellular permeability, with the magnitude of permeabilization closely correlating with serum pCS, but not most other uremic toxin, content. Notably, this damaging effect of hemodialysis patient serum was prevented by pharmacological blockade of the EGFR. Our results define a pathway linking the co-metabolite pCS with BBB damage and suggest that targeting the EGFR may mitigate against cerebrovascular damage in CKD. This work further provides mechanistic evidence indicating the role of gut microbe-derived metabolites in human disease.