scholarly journals Synbiotics Alleviate the Gut Indole Load and Dysbiosis in Chronic Kidney Disease

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 114
Author(s):  
Chih-Yu Yang ◽  
Ting-Wen Chen ◽  
Wan-Lun Lu ◽  
Shih-Shin Liang ◽  
Hsien-Da Huang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Gut Microbiota ◽  
Statistical Significance ◽  
Additional Treatment ◽  
Indoxyl Sulfate ◽  
Uremic Toxin ◽  
Healthy Controls ◽  
Gut Dysbiosis ◽  
Novel Concept

Chronic kidney disease (CKD) has long been known to cause significant digestive tract pathology. Of note, indoxyl sulfate is a gut microbe-derived uremic toxin that accumulates in CKD patients. Nevertheless, the relationship between gut microbiota, fecal indole content, and blood indoxyl sulfate level remains unknown. In our study, we established an adenine-induced CKD rat model, which recapitulates human CKD-related gut dysbiosis. Synbiotic treatment in CKD rats showed a significant reduction in both the indole-producing bacterium Clostridium and fecal indole amount. Furthermore, gut microbiota diversity was reduced in CKD rats but was restored after synbiotic treatment. Intriguingly, in our end-stage kidney disease (ESKD) patients, the abundance of indole-producing bacteria, Bacteroides, Prevotella, and Clostridium, is similar to that of healthy controls. Consistently, the fecal indole tends to be higher in the ESKD patients, but the difference did not achieve statistical significance. However, the blood level of indoxyl sulfate was significantly higher than that of healthy controls, implicating that under an equivalent indole production rate, the impaired renal excretion contributes to the accumulation of this notorious uremic toxin. On the other hand, we did identify two short-chain fatty acid-producing bacteria, Faecalibacterium and Roseburia, were reduced in ESKD patients as compared to the healthy controls. This may contribute to gut dysbiosis. We also identified that three genera Fusobacterium, Shewanella, and Erwinia, in the ESKD patients but not in the healthy controls. Building up gut symbiosis to treat CKD is a novel concept, but once proved effective, it will provide an additional treatment strategy for CKD patients.

scholarly journals Gut-Derived Protein-Bound Uremic Toxins

Toxins ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 590 ◽  
Author(s):  
Amanda L. Graboski ◽  
Matthew R. Redinbo
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Gut Microbiota ◽  
Filtration Rate ◽  
Therapeutic Strategies ◽  
Uremic Toxins ◽  
Uremic Toxin ◽  
Risk Of Death ◽  
Gut Dysbiosis ◽  
Causes Of Mortality

Chronic kidney disease (CKD) afflicts more than 500 million people worldwide and is one of the fastest growing global causes of mortality. When glomerular filtration rate begins to fall, uremic toxins accumulate in the serum and significantly increase the risk of death from cardiovascular disease and other causes. Several of the most harmful uremic toxins are produced by the gut microbiota. Furthermore, many such toxins are protein-bound and are therefore recalcitrant to removal by dialysis. We review the derivation and pathological mechanisms of gut-derived, protein-bound uremic toxins (PBUTs). We further outline the emerging relationship between kidney disease and gut dysbiosis, including the bacterial taxa altered, the regulation of microbial uremic toxin-producing genes, and their downstream physiological and neurological consequences. Finally, we discuss gut-targeted therapeutic strategies employed to reduce PBUTs. We conclude that targeting the gut microbiota is a promising approach for the treatment of CKD by blocking the serum accumulation of PBUTs that cannot be eliminated by dialysis.

scholarly journals Uremic toxin indoxyl sulfate promotes proinflammatory macrophage activation by regulation of β-catenin and YAP pathways

2021 ◽  
Author(s):  
Ying Li ◽  
Jing Yan ◽  
Minjia Wang ◽  
Jing Lv ◽  
Fei Yan ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Inflammatory Response ◽  
Macrophage Polarization ◽  
Indoxyl Sulfate ◽  
Uremic Toxin ◽  
Lps Challenge ◽  
Hla Dr ◽  
M1 Macrophage

AbstractEvidence has been shown that indoxyl sulfate (IS) could impair kidney and cardiac functions. Moreover, macrophage polarization played important roles in chronic kidney disease and cardiovascular disease. IS acts as a nephron-vascular toxin, whereas its effect on macrophage polarization during inflammation is still not fully elucidated. In this study, we aimed to investigate the effect of IS on macrophage polarization during lipopolysaccharide (LPS) challenge. THP-1 monocytes were incubated with phorbol 12-myristate-13-acetate (PMA) to differentiate into macrophages, and then incubated with LPS and IS for 24 h. ELISA was used to detect the levels of TNFα, IL-6, IL-1β in THP-1-derived macrophages. Western blot assay was used to detect the levels of arginase1 and iNOS in THP-1-derived macrophages. Percentages of HLA-DR-positive cells (M1 macrophages) and CD206-positive cells (M2 macrophages) were detected by flow cytometry. IS markedly increased the production of the pro-inflammatory factors TNFα, IL-6, IL-1β in LPS-stimulated THP-1-derived macrophages. In addition, IS induced M1 macrophage polarization in response to LPS, as evidenced by the increased expression of iNOS and the increased proportion of HLA-DR+ macrophages. Moreover, IS downregulated the level of β-catenin, and upregulated the level of YAP in LPS-stimulated macrophages. Activating β-catenin signaling or inhibiting YAP signaling suppressed the IS-induced inflammatory response in LPS-stimulated macrophages by inhibiting M1 polarization. IS induced M1 macrophage polarization in LPS-stimulated macrophages via inhibiting β-catenin and activating YAP signaling. In addition, this study provided evidences that activation of β-catenin or inhibition of YAP could alleviate IS-induced inflammatory response in LPS-stimulated macrophages. This finding may contribute to the understanding of immune dysfunction observed in chronic kidney disease and cardiovascular disease.

scholarly journals Indoxyl-Sulfate-Induced Redox Imbalance in Chronic Kidney Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 936
Author(s):  
Chien-Lin Lu ◽  
Cai-Mei Zheng ◽  
Kuo-Cheng Lu ◽  
Min-Tser Liao ◽  
Kun-Lin Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Muscle Wasting ◽  
Mesangial Cells ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Indoxyl Sulfate ◽  
Uremic Toxin ◽  
Tubulointerstitial Injury

The accumulation of the uremic toxin indoxyl sulfate (IS) induces target organ damage in chronic kidney disease (CKD) patients, and causes complications including cardiovascular diseases, renal osteodystrophy, muscle wasting, and anemia. IS stimulates reactive oxygen species (ROS) production in CKD, which impairs glomerular filtration by a direct cytotoxic effect on the mesangial cells. IS further reduces antioxidant capacity in renal proximal tubular cells and contributes to tubulointerstitial injury. IS-induced ROS formation triggers the switching of vascular smooth muscular cells to the osteoblastic phenotype, which induces cardiovascular risk. Low-turnover bone disease seen in early CKD relies on the inhibitory effects of IS on osteoblast viability and differentiation, and osteoblastic signaling via the parathyroid hormone. Excessive ROS and inflammatory cytokine releases caused by IS directly inhibit myocyte growth in muscle wasting via myokines’ effects. Moreover, IS triggers eryptosis via ROS-mediated oxidative stress, and elevates hepcidin levels in order to prevent iron flux in circulation in renal anemia. Thus, IS-induced oxidative stress underlies the mechanisms in CKD-related complications. This review summarizes the underlying mechanisms of how IS mediates oxidative stress in the pathogenesis of CKD’s complications. Furthermore, we also discuss the potential role of oral AST-120 in attenuating IS-mediated oxidative stress after gastrointestinal adsorption of the IS precursor indole.

MO460ASSOCIATION BETWEEN CARBAMYLATED ALBUMIN, GUT MICROBIOTA AND THEIR DERIVED METABOLITES IN CHRONIC KIDNEY DISEASE

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Mieke Steenbeke ◽  
Sophie Valkenburg ◽  
Wim Van Biesen ◽  
Joris Delanghe ◽  
Marijn Speeckaert ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Gut Microbiota ◽  
Plasma Levels ◽  
Pearson Correlation ◽  
Bacterial Species ◽  
Study Cohort ◽  
Gut Dysbiosis ◽  
Symmetry Factor ◽  
Cardiovascular Morbidity And Mortality

Abstract Background and Aims Chronic kidney disease (CKD) is characterized by gut dysbiosis. We recently demonstrated a decrease of short-chain fatty acid (SCFA) producing bacterial species with the progression of CKD. Besides, levels of protein-bound uremic toxins (PBUTs) and post-translational modifications of protein are increased in CKD, both are risk factors for accelerated cardiovascular morbidity and mortality. The link between the gut-kidney axis and protein carbamylation is unclear. The aim of the study was to explore the relation between carbamylated albumin, estimated by the albumin symmetry factor, and plasma levels of PBUTs, fecal levels of SCFAs (ongoing), and the abundance of related gut microbiota in different stages of CKD (1-5). Method The study cohort includes 103 non-dialyzed CKD patients (stages 1-5). Serum proteins were detected by capillary electrophoresis and UV absorbance at 214 nm with the symmetry factor as a marker of albumin carbamylation [the lower the symmetry factor, the more carbamylated albumin]. The quantification of PBUTs and SCFAs in plasma and fecal samples, respectively, using validated UPLC methods. Results The Pearson correlation coefficient (r) shows a positive correlation between the albumin symmetry factor and the estimated glomerular filtration rate (eGFR) (r=0.3025; p=0.0019). The albumin symmetry factor correlates positively with the abundance of Butyricicoccus spp. (r= 0.3211; p=0.0009), Faecalibacterium prausnitzii (r=0.2765; p=0.0047) and Roseburia spp. (r=0.2527; p=0.0100) and negatively with the PBUTs, p-cresyl sulfate (pCS) (r=-0.2819; p=0.0039), p-cresyl glucuronide (pCG) (r=-0.2819; p=0.0039) and indoxyl sulfate (IxS) (r=-0.2650; p=0.0068). Conclusion The decreased abundance of SCFA producing gut bacteria with the progression of CKD can evoke unfavorable conditions in the gut. This can contribute to increased plasma levels of PBUTs potentially (indirectly) playing a role in albumin carbamylation. It will be further explored whether fecal levels of SCFAs are affected in parallel and could be potential targets to restore gut dysbiosis and uremia.

scholarly journals The Association between Gut Microbiota and Uremia of Chronic Kidney Disease

2020 ◽  
Vol 8 (6) ◽  
pp. 907 ◽  
Author(s):  
Ji Eun Kim ◽  
Hyo-Eun Kim ◽  
Ji In Park ◽  
Hyunjeong Cho ◽  
Min-Jung Kwak ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Gut Microbiota ◽  
Kidney Function ◽  
Kidney Diseases ◽  
Toxin Production ◽  
Positive Interactions ◽  
Uremic Toxin ◽  
Serum Concentrations ◽  
Pyruvate Metabolism

Chronic kidney disease (CKD)-associated uremia aggravates—and is aggravated by—gut dysbiosis. However, the correlation between CKD severity and gut microbiota and/or their uremic metabolites is unclear. We enrolled 103 CKD patients with stage 1 to 5 and 46 healthy controls. We analyzed patients’ gut microbiota by MiSeq system and measured the serum concentrations of four uremic metabolites (p-cresyl sulfate, indoxyl sulfate, p-cresyl glucuronide, and trimethylamine N-oxide) by liquid chromatography–tandem mass spectrometry. Serum concentrations of the uremic metabolites increased with kidney function deterioration. Gut microbial diversity did not differ among the examined patient and control groups. In moderate or higher stage CKD groups, Oscillibacter showed positive interactions with other microbiota, and the proportions of Oscillibacter were positively correlated with those of the uremic metabolites. The gut microbiota, particularly Oscillibacter, was predicted to contribute to pyruvate metabolism which increased with CKD progression. Relative abundance of Oscillibacter was significantly associated with both serum uremic metabolite levels and kidney function. Predicted functional analysis suggested that kidney-function-associated changes in the contribution of Oscillibacter to pyruvate metabolism in CKD may greatly affect the gut environment according to kidney function, resulting in dysbiosis concomitant with uremic toxin production. The gut microbiota could be associated with uremia progression in CKD. These results may provide basis for further metagenomics analysis of kidney diseases.

scholarly journals Maternal Adenine-Induced Chronic Kidney Disease Programs Hypertension in Adult Male Rat Offspring: Implications of Nitric Oxide and Gut Microbiome Derived Metabolites

2020 ◽  
Vol 21 (19) ◽  
pp. 7237 ◽  
Author(s):  
Chien-Ning Hsu ◽  
Hung-Wei Yang ◽  
Chih-Yao Hou ◽  
Guo-Ping Chang-Chien ◽  
Sufan Lin ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Gut Microbiota ◽  
Adult Male ◽  
Male Offspring ◽  
Uremic Toxin ◽  
Microbiota Composition ◽  
Adverse Pregnancy ◽  
Gut Microbiota Composition

Maternal chronic kidney disease (CKD) during pregnancy causes adverse fetal programming. Nitric oxide (NO) deficiency, gut microbiota dysbiosis, and dysregulated renin-angiotensin system (RAS) during pregnancy are linked to the development of hypertension in adult offspring. We examined whether maternal adenine-induced CKD can program hypertension and kidney disease in adult male offspring. We also aimed to identify potential mechanisms, including alterations of gut microbiota composition, increased trimethylamine-N-oxide (TMAO), reduced NO bioavailability, and dysregulation of the RAS. To construct a maternal CKD model, female Sprague-Dawley rats received regular chow (control group) or chow supplemented with 0.5% adenine (CKD group) for 3 weeks before pregnancy. Mother rats were sacrificed on gestational day 21 to analyze placentas and fetuses. Male offspring (n = 8/group) were sacrificed at 12 weeks of age. Adenine-fed rats developed renal dysfunction, glomerular and tubulointerstitial damage, hypertension, placental abnormalities, and reduced fetal weights. Additionally, maternal adenine-induced CKD caused hypertension and renal hypertrophy in adult male offspring. These adverse pregnancy and offspring outcomes are associated with alterations of gut microbiota composition, increased uremic toxin asymmetric and symmetric dimethylarginine (ADMA and SDMA), increased microbiota-derived uremic toxin TMAO, reduced microbiota-derived metabolite acetate and butyrate levels, and dysregulation of the intrarenal RAS. Our results indicated that adenine-induced maternal CKD could be an appropriate model for studying uremia-related adverse pregnancy and offspring outcomes. Targeting NO pathway, microbiota metabolite TMAO, and the RAS might be potential therapeutic strategies to improve maternal CKD-induced adverse pregnancy and offspring outcomes.

scholarly journals P0921ROLE OF UREMIC TOXIN, INDOXYL SULFATE IN SARCOPENIA OF NONDIALYSIS DEPENDENT-CHRONIC KIDNEY DISEASE PATIENTS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Jun Chul Kim ◽  
Seok Hui Kang ◽  
Miyeun Han ◽  
Su-Hyun Kim ◽  
Ran-Hui Cha ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Muscle Mass ◽  
Bioelectrical Impedance ◽  
Impedance Analysis ◽  
Indoxyl Sulfate ◽  
High Rate ◽  
Uremic Toxin ◽  
Inverse Association

Abstract Background and Aims Sarcopenia in patients with chronic kidney disease (CKD) is highly prevalent and leads to high rate of morbidity and mortality. The role of indoxyl sulfate (IS) to develop muscle wasting has been researched and proved in several animal model studies. However, there is no human data showing this relationship in CKD population. The aim of the present study was to evaluate the association between serum IS levels and each component of sarcopenia in nondialysis dependent-CKD (NDD-CKD) patients. Method We enrolled 150 NDD-CKD adult patients from 6 medical centers and collected data of demographics, blood chemistry such as indoxyl sulfate, interleukin (IL)-6, and estimated glomerular filtration rate using MDRD equation (eGFR), and body mass index (BMI, kg/m2). We also measured hand-grip strength (HGS, kg), walking speed (WS, m/s), skeletal muscle mass (SMM, kg) by bioelectrical impedance analysis (BIA). Results The numbers of male sex was 97 (64.7%). Mean age was 63.7±10.8 years old. The numbers of patients with diabetes mellitus was 77 (52.0%). Charlson comorbidity index (CCI) score was 3.9 ± 1.9. The stage of CKD ranged from 3 to 5 (eGFR=33.7±12.0 ml/min/1.73m2, mean±SD). Correlation coefficients with indoxyl sulfate levels were 0.211 for serum IL-6 level (P = 0.010), -0.212 for HGS (P = 0.009), -0.188 for WS (P = 0.021), -0.237 for SMM (P = 0.004), and -0.168 for BMI (P = 0.041), respectively. Correlation analysis showed that indoxyl sulfate levels had inverse association significantly with HGS, WS, SMM, and BMI and were positively associated with serum IL-6 levels. Conclusion Our study shows that higher serum indoxyl sulfate level was significantly associated with lower levels of muscle mass, strength, and physical performance function and higher inflammation status in non-dialysis dependent CKD patients. We suggest that the role of AST120 in prevention or treatment of sarcopenia be studied in this CKD population.

scholarly journals The gut microbiota profile of adults with kidney disease: A systematic review of the literature

2019 ◽  
Author(s):  
Jordan Stanford ◽  
Karen Charlton ◽  
Anita Stefoska-Needham ◽  
Rukayat Ibrahim ◽  
Kelly Lambert
Keyword(s):  
Systematic Review ◽  
Kidney Disease ◽  
Gut Microbiota ◽  
Cochrane Library ◽  
Uremic Toxin ◽  
Healthy Controls ◽  
Microbiota Composition ◽  
Dietary Intakes ◽  
Microbial Composition ◽  
Gut Microbiota Composition

Abstract Background There is mounting evidence that individuals with kidney disease have an abnormal gut microbiota composition. No studies to date have summarised the evidence to categorise how the gut microbiota profile of individuals with kidney disease may differ from healthy controls. Synthesis of this evidence is important to inform future clinical trials. This systematic review aims to characterise differences of the gut microbiota composition in adults with kidney disease, as well as to describe the functional capacity of the gut microbiota and reporting of diet as a confounder in these studies. Methods Included studies were those that investigated the gut microbial community in adults with any type of kidney disease and compared this to the profile of healthy controls. Six scientific databases (CINHAL, Medline, PubMed, Scopus, Web of Science, Cochrane Library) as well as selected grey literature sources were searched up until August 2018. Quality assessment was undertaken independently by three authors. The system of evidence level criteria was employed to quantitatively evaluate the alteration of microbiota by strictly considering the number, methodological quality and consistency of the findings. Additional findings relating to altered functions of the gut microbiota, dietary intakes and dietary methodologies used were qualitatively summarised. Results Sixteen articles, reporting 15 studies met the eligibility criteria and included a total of 540 adults with kidney disease and 1117 healthy controls. Compared to healthy controls, individuals with kidney disease had increased abundances of Enterobacteriaceae, and decreased abundances of Coprococcus and Prevotella. Adults with kidney stones also had an altered microbial composition with variations to Bacteroides, Lachnospiraceae NK4A136 group, Ruminiclostridium 5 group, Dorea, Enterobacter, Christensenellaceae and its genus Christensenellaceae R7 group. Altered microbial functions in adults with kidney disease were reported, particularly in the context of metabolic pathways relating to urea and uremic toxin generation. Only three of the 16 articles accounted for diet, and of these studies only two used a valid dietary assessment method. Conclusions The gut microbiota profile of adults with kidney disease differs from healthy controls. Future study designs should include adequate reporting of important confounders such as dietary intakes to assist with interpretation of findings.

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