scholarly journals Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins

2018 ◽  
Vol 132 (5) ◽  
pp. 509-522 ◽  
Author(s):  
Wei Ling Lau ◽  
Javad Savoj ◽  
Michael B. Nakata ◽  
Nosratola D. Vaziri
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Gut Microbiome ◽  
Short Chain Fatty Acids ◽  
Intestinal Wall ◽  
Uremic Toxins ◽  
Blood Levels ◽  
Systemic Effects ◽  
Kidney Fibrosis ◽  
Microbial Dysbiosis

In chronic kidney disease (CKD), influx of urea and other retained toxins exerts a change in the gut microbiome. There is decreased number of beneficial bacteria that produce short-chain fatty acids, an essential nutrient for the colonic epithelium, concurrent with an increase in bacteria that produce uremic toxins such as indoxyl sulphate, p-cresyl sulphate, and trimethylamine-N-oxide (TMAO). Due to intestinal wall inflammation and degradation of intercellular tight junctions, gut-derived uremic toxins translocate into the bloodstream and exert systemic effects. In this review, we discuss the evidence supporting a role for gut-derived uremic toxins in promoting multiorgan dysfunction via inflammatory, oxidative stress, and apoptosis pathways. End-organ effects include vascular calcification, kidney fibrosis, anemia, impaired immune system, adipocyte dysfunction with insulin resistance, and low turnover bone disease. Higher blood levels of gut-derived uremic toxins are associated with increased cardiovascular events and mortality in the CKD population. Clinical trials that have examined interventions to trap toxic products or reverse gut microbial dysbiosis via oral activated charcoal AST-120, prebiotics and probiotics have not shown impact on cardiovascular or survival outcomes but were limited by sample size and short trials. In summary, the gut microbiome is a major contributor to adverse cardiovascular outcomes and progression of CKD.

Abstract 17220: Effects of the Oral Adsorbent of AST-120 in Patients with both Chronic Heart Failure and Chronic Kidney Disease

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Miki Imazu ◽  
Masanori Asakura ◽  
Takuya Hasegawa ◽  
Hiroshi Asanuma ◽  
Shin Ito ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Kidney Disease ◽  
Chronic Heart Failure ◽  
Kidney Disease ◽  
Diastolic Dysfunction ◽  
Uremic Toxins ◽  
Control Group ◽  
Blood Levels ◽  
Uremic Toxin ◽  
Oral Adsorbent

Background: One of uremic toxins, indoxyl sulfate (IS) is related to the progression of chronic kidney disease (CKD) and the worse cardiovascular outcomes. We have previously reported the relationship between IS levels and the severity of chronic heart failure (CHF), but the question arises as to whether the treatment of uremic toxin is beneficial in patients with CHF. This study aimed to elucidate whether the treatment with the oral adsorbent which reduces uremic toxin improved the cardiac function of the patients with CHF. Methods: First of all, we retrospectively enrolled 49 patients with both CHF and stage ≤3 CKD in our institute compared with the healthy subjects without CHF or CKD in the resident cohort study of Arita. Secondly, we retrospectively enrolled 16 CHF outpatients with stage 3-5 CKD. They were treated with and without the oral adsorbent of AST-120 for one year termed as the treatment and control groups, respectively. We underwent both blood test and echocardiography before and after the treatment. Results: First of all, among 49 patients in CHF patients, plasma IS levels increased to 1.38 ± 0.84 μg/ml from the value of 0.08 ± 0.06 μg/ml in Arita-cho as a community-living matched with gender and eGFR of CHF patients. We found both fractional shortening (FS) and E/e’, an index of diastolic function were decreased (25.0 ± 12.7%) and increased (13.7 ± 7.5), respectively in CHF patients compared with the value of FS and E/e’ in Arita-cho (FS: 41.8 ± 8.3%, E/e’: 8.8 ± 2.1). Secondly, in the treatment group, the plasma IS levels and the serum creatinine and brain natriuretic peptide levels decreased (1.40 ± 0.17 to 0.92 ± 0.15 μg/ml; p<0.05, 1.91 ± 0.16 to 1.67 ± 0.12 mg/dl; p<0.05, 352 ± 57 to 244 ± 49 pg/ml; p<0.05, respectively) and both FS and E/e’ were improved following the treatment with AST-120 (28.8 ± 2.8 to 32.9 ± 2.6%; p<0.05, 18.0 ± 2.0 to 11.8 ± 1.0; p<0.05). However, these parameters did not change in the control group. Conclusions: The treatment to decrease the blood levels of uremic toxins improved not only renal dysfunction but cardiac systolic and diastolic dysfunction in patients with chronic heart failure. Oral adsorbents might be a new treatment of heart failure especially with diastolic dysfunction.

scholarly journals Kidneys and microbiota

2019 ◽  
pp. 48-57
Author(s):  
Zh. Semydotska ◽  
I. Chernyakova ◽  
O. Avdeyeva
Keyword(s):  
Chronic Kidney Disease ◽  
Fatty Acids ◽  
Kidney Disease ◽  
Intestinal Microbiota ◽  
General Circulation ◽  
Short Chain Fatty Acids ◽  
Uremic Toxins ◽  
Short Chain ◽  
Intestinal Lumen ◽  
Chain Fatty Acids

 The review article analyzes the results of studies of the bi-directional relationship of the intestinal microbiota and kidneys, the so-called colorenal interactive axis of interaction.  The intestinal microbiota is considered as a kind of organ that influences the brain, cardiovascular and immune systems, as well as the kidneys of the "host".  Short-chain fatty acids (SCFA) formed in the colon as the result of microbial metabolism from plant components of dietary fiber and acting as ligands for the olfactory receptor, paired G-proteins in the kidneys are recognized as the markers of this symbiosis.  With the help of modern omix technologies, the development of dysbiosis taking into account patients with chronic kidney disease (CKD) has been proved, which leads to the accumulation of precursors of uremic toxins, a decrease in the production of SCFA, which have nephroprotective properties and play a key role in energy homeostasis.  Changes in the composition of the intestinal microbiota in CKD, an increase in the content of uremic toxins in the intestinal lumen contribute to the appearance of the “leaky” intestinal barrier syndrome, the movement of bacteria from the intestine into the general circulation, the development of systemic inflammation, oxidative stress, comorbidity, the progression of CKD, and an increase in mortality. Diets with restriction of protein and potassium quotas, violation of nutritional status lead to the development of dysbiosis in CKD.  A decrease in the diet of vegetables and fruit causes the expansion of bacteria producing uricase and urease, which are enzymes in the formation of uremic toxins and reduce the number and variety of bacteria producing short-chain fatty acids.  Potential targeted effects on the axis of “intestinal microbiota - chronic kidney disease” are being discussed: the use of a diet enriched in plant fibers, heat-treated, then chilled potatoes and rice as prebiotics (sources of resistant starch), nuts, plant seeds, and pro-, pre-, synbiotics, fecal transplantation.  Most of the proposed interventions in the structure and functions of the microbiota are not dangerous, side effects are minimal.

scholarly journals A low aromatic amino-acid diet improves renal function and prevent kidney fibrosis in mice with chronic kidney disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Christophe Barba ◽  
Bérengère Benoit ◽  
Emilie Bres ◽  
Stéphanie Chanon ◽  
Aurélie Vieille-Marchiset ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Amino Acid ◽  
Kidney Disease ◽  
Aromatic Amino Acid ◽  
Aromatic Amino Acids ◽  
Uremic Toxins ◽  
Kidney Fibrosis ◽  
Acid Diet ◽  
Chemically Induced ◽  
Amino Acid Diet

AbstractDespite decades of use of low protein diets (LPD) in the management of chronic kidney disease (CKD), their mechanisms of action are unclear. A reduced production of uremic toxins could contribute to the benefits of LPDs. Aromatic amino-acids (AA) are precursors of major uremic toxins such as p-cresyl sulfate (PCS) and indoxyl sulfate (IS). We hypothesize that a low aromatic amino acid diet (LA-AAD, namely a low intake of tyrosine, tryptophan and phenylalanine) while being normoproteic, could be as effective as a LPD, through the decreased production of uremic toxins. Kidney failure was chemically induced in mice with a diet containing 0.25% (w/w) of adenine. Mice received three different diets for six weeks: normoproteic diet (NPD: 14.7% proteins, aromatic AAs 0.019%), LPD (5% proteins, aromatic AAs 0.007%) and LA-AAD (14% proteins, aromatic AAs 0.007%). Both LPD and LA-AAD significantly reduced proteinuria, kidney fibrosis and inflammation. While LPD only slightly decreased plasma free PCS and free IS compared to NPD; free fractions of both compounds were significantly decreased by LA-AAD. These results suggest that a LA-AAD confers similar benefits of a LPD in delaying the progression of CKD through a reduction in some key uremic toxins production (such as PCS and IS), with a lower risk of malnutrition.

scholarly journals Gut Microbiome Profiling Uncovers a Lower Abundance of Butyricicoccus in Advanced Stages of Chronic Kidney Disease

2021 ◽  
Vol 11 (11) ◽  
pp. 1118
Author(s):  
Tessa Gryp ◽  
Karoline Faust ◽  
Wim Van Biesen ◽  
Geert R. B. Huys ◽  
Francis Verbeke ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Gut Microbiome ◽  
Amplicon Sequencing ◽  
Uremic Toxins ◽  
Microbial Composition ◽  
Cross Sectional ◽  
Organ Systems ◽  
Significant Difference ◽  
Advanced Stages

Chronic kidney disease (CKD) is characterized by the accumulation of uremic toxins which exert deleterious effects on various organ systems. Several of these uremic toxins originate from the bacterial metabolization of aromatic amino acids in the colon. This study assessed whether the gut microbial composition varies among patients in different stages of CKD. Uremic metabolites were quantified by UPLC/fluorescence detection and microbial profiling by 16S rRNA amplicon sequencing. Gut microbial profiles of CKD patients were compared among stages 1–2, stage 3 and stages 4–5. Although a substantial inter-individual difference in abundance of the top 15 genera was observed, no significant difference was observed between groups. Bristol stool scale (BSS) correlated negatively with p-cresyl sulfate and hippuric acid levels, irrespective of the intake of laxatives. Butyricicoccus, a genus with butyrate-generating properties, was decreased in abundance in advanced stages of CKD compared to the earlier stages (p = 0.043). In conclusion, in this cross-sectional study no gradual differences in the gut microbial profile over the different stages of CKD were observed. However, the decrease in the abundance of Butyricicoccus genus with loss of kidney function stresses the need for more in-depth functional exploration of the gut microbiome in CKD patients not on dialysis.

scholarly journals Bacterial metabolites and cardiovascular risk in children with chronic kidney disease

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Julia Schlender ◽  
Felix Behrens ◽  
Victoria McParland ◽  
Dominik Müller ◽  
Nicola Wilck ◽  
...  
Keyword(s):  
Risk Factors ◽  
Chronic Kidney Disease ◽  
Cardiovascular Risk ◽  
Kidney Disease ◽  
Gut Microbiome ◽  
Short Chain Fatty Acids ◽  
Underlying Disease ◽  
Human Gut ◽  
Endogenous Factors ◽  
Human Gut Microbiome

AbstractCardiovascular complications are the major cause of the marked morbidity and mortality associated with chronic kidney disease (CKD). The classical cardiovascular risk factors such as diabetes and hypertension undoubtedly play a role in the development of cardiovascular disease (CVD) in adult CKD patients; however, CVD is just as prominent in children with CKD who do not have these risk factors. Hence, the CKD-specific pathophysiology of CVD remains incompletely understood. In light of this, studying children with CKD presents a unique opportunity to analyze CKD-associated mechanisms of CVD more specifically and could help to unveil novel therapeutic targets.Here, we comprehensively review the interaction of the human gut microbiome and the microbial metabolism of nutrients with host immunity and cardiovascular end-organ damage. The human gut microbiome is evolutionary conditioned and modified throughout life by endogenous factors as well as environmental factors. Chronic diseases, such as CKD, cause significant disruption to the composition and function of the gut microbiome and lead to disease-associated dysbiosis. This dysbiosis and the accompanying loss of biochemical homeostasis in the epithelial cells of the colon can be the result of poor diet (e.g., low-fiber intake), medications, and underlying disease. As a result of dysbiosis, bacteria promoting proteolytic fermentation increase and those for saccharolytic fermentation decrease and the integrity of the gut barrier is perturbed (leaky gut). These changes disrupt local metabolite homeostasis in the gut and decrease productions of the beneficial short-chain fatty acids (SCFAs). Moreover, the enhanced proteolytic fermentation generates unhealthy levels of microbially derived toxic metabolites, which further accumulate in the systemic circulation as a consequence of impaired kidney function. We describe possible mechanisms involved in the increased systemic inflammation in CKD that is associated with the combined effect of SCFA deficiency and accumulation of uremic toxins. In the future, a more comprehensive and mechanistic understanding of the gut–kidney–heart interaction, mediated largely by immune dysregulation and inflammation, might allow us to target the gut microbiome more specifically in order to attenuate CKD-associated comorbidities.

Metagenomic profiling of gut microbiome in early chronic kidney disease

2020 ◽  
Author(s):  
Noriaki Sato ◽  
Masanori Kakuta ◽  
Takanori Hasegawa ◽  
Rui Yamaguchi ◽  
Eiichiro Uchino ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Gut Microbiome ◽  
Short Chain Fatty Acids ◽  
Toxin Production ◽  
Metagenomic Sequencing ◽  
Stool Samples ◽  
The Mean ◽  
Estimated Glomerular Filtration Rates ◽  
The Relationship

Abstract Background The relationship between chronic kidney disease (CKD) and the gut microbiome, which interact through chronic inflammation, uraemic toxin production and immune response regulation, has gained interest in the development of CKD therapies. However, reports using shotgun metagenomic analysis of the gut microbiome are scarce, especially for early CKD. Here we characterized gut microbiome differences between non-CKD participants and ones with early CKD using metagenomic sequencing. Methods In total, 74 non-CKD participants and 37 participants with early CKD were included based on propensity score matching, controlling for various factors including dietary intake. Stool samples were collected from participants and subjected to shotgun sequencing. Bacterial and pathway abundances were profiled at the species level with MetaPhlAn2 and HUMAnN2, respectively, and overall microbiome differences were determined using Bray–Curtis dissimilarities. Diabetic and non-diabetic populations were analysed separately. Results For diabetic and non-diabetic participants, the mean estimated glomerular filtration rates of the CKD group were 53.71 [standard deviation (SD) 3.87] and 53.72 (SD 4.44), whereas those of the non-CKD group were 72.63 (SD 7.72) and 76.10 (SD 9.84), respectively. Alpha and beta diversities were not significantly different between groups. Based on taxonomic analysis, butyrate-producing species Roseburia inulinivorans, Ruminococcus torques and Ruminococcus lactaris were more abundant in the non-CKD group, whereas Bacteroides caccae and Bacteroides coprocora were more abundant in the non-diabetic CKD group. Conclusions Although gut microbiome changes in individuals with early CKD were subtle, the results suggest that changes related to producing short-chain fatty acids can already be observed in early CKD.

scholarly journals Chronic Kidney Disease, Gut Dysbiosis, and Constipation: A Burdensome Triplet

2020 ◽  
Vol 8 (12) ◽  
pp. 1862
Author(s):  
Ryota Ikee ◽  
Naomi Sasaki ◽  
Takuji Yasuda ◽  
Sawako Fukazawa
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Inflammatory Responses ◽  
Bacterial Species ◽  
Short Chain Fatty Acids ◽  
Uremic Toxins ◽  
Fermentation Products ◽  
Bacterial Fermentation ◽  
Gut Dysbiosis ◽  
Multiple Drugs

Gut dysbiosis has been implicated in the progression of chronic kidney disease (CKD). Alterations in the gut environment induced by uremic toxins, the dietary restriction of fiber-rich foods, and multiple drugs may be involved in CKD-related gut dysbiosis. CKD-related gut dysbiosis is considered to be characterized by the expansion of bacterial species producing precursors of harmful uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, and the contraction of species generating beneficial short-chain fatty acids, such as butyrate. Gut-derived uremic toxins cause oxidative stress and pro-inflammatory responses, whereas butyrate exerts anti-inflammatory effects and contributes to gut epithelial integrity. Gut dysbiosis is associated with the disruption of the gut epithelial barrier, which leads to the translocation of endotoxins. Research on CKD-related gut dysbiosis has mainly focused on chronic inflammation and consequent cardiovascular and renal damage. The pathogenic relationship between CKD-related gut dysbiosis and constipation has not yet been investigated in detail. Constipation is highly prevalent in CKD and affects the quality of life of these patients. Under the pathophysiological state of gut dysbiosis, altered bacterial fermentation products may play a prominent role in intestinal dysmotility. In this review, we outline the factors contributing to constipation, such as the gut microbiota and bacterial fermentation; introduce recent findings on the pathogenic link between CKD-related gut dysbiosis and constipation; and discuss potential interventions. This pathogenic link needs to be elucidated in more detail and may contribute to the development of novel treatment options not only for constipation, but also cardiovascular disease in CKD.

scholarly journals Canagliflozin reduces plasma uremic toxins and alters the intestinal microbiota composition in a chronic kidney disease mouse model

2018 ◽  
Vol 315 (4) ◽  
pp. F824-F833 ◽  
Author(s):  
Eikan Mishima ◽  
Shinji Fukuda ◽  
Yoshitomi Kanemitsu ◽  
Daisuke Saigusa ◽  
Chikahisa Mukawa ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Failure ◽  
Kidney Disease ◽  
Therapeutic Option ◽  
Short Chain Fatty Acids ◽  
Inhibitory Effect ◽  
Uremic Toxins ◽  
Indoxyl Sulfate ◽  
Vehicle Group ◽  
Microbiota Composition

Accumulation of uremic toxins, which exert deleterious effects in chronic kidney disease, is influenced by the intestinal environment; the microbiota contributes to the production of representative uremic toxins, including p-cresyl sulfate and indoxyl sulfate. Canagliflozin is a sodium-glucose cotransporter (SGLT) 2 inhibitor, and it also exerts a modest inhibitory effect on SGLT1. The inhibition of intestinal SGLT1 can influence the gastrointestinal environment. We examined the effect of canagliflozin on the accumulation of uremic toxins in chronic kidney disease using adenine-induced renal failure mice. Two-week canagliflozin (10 mg/kg po) treatment did not influence the impaired renal function; however, it significantly reduced the plasma levels of p-cresyl sulfate and indoxyl sulfate in renal failure mice (a 75% and 26% reduction, respectively, compared with the vehicle group). Additionally, canagliflozin significantly increased cecal short-chain fatty acids in the mice, suggesting the promotion of bacterial carbohydrate fermentation in the intestine. Analysis of the cecal microbiota showed that canagliflozin significantly altered microbiota composition in the renal failure mice. These results indicate that canagliflozin exerts intestinal effects that reduce the accumulation of uremic toxins including p-cresyl sulfate. Reduction of accumulated uremic toxins by canagliflozin could provide a potential therapeutic option in chronic kidney disease.

scholarly journals A Low Aromatic Amino-Acid Diet Improves Renal Function and Prevent Kidney Fibrosis in Mice with Chronic Kidney Disease

2021 ◽  
Author(s):  
Christophe Barba ◽  
Bérengère Benoit ◽  
Bres Emilie ◽  
Stéphanie Chanon ◽  
Aurélie Vieille-Marchiset ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Amino Acid ◽  
Kidney Disease ◽  
Aromatic Amino Acid ◽  
Aromatic Amino Acids ◽  
Uremic Toxins ◽  
Kidney Fibrosis ◽  
Acid Diet ◽  
Chemically Induced ◽  
Amino Acid Diet

Abstract Despite decades of use of low protein diets (LPD) in the management of chronic kidney disease (CKD), their mechanisms of action are unclear. A reduced production of uremic toxins could contribute to the benefits of LPDs. Aromatic amino-acids (AA) are precursors of major uremic toxins such as p-cresyl sulfate (PCS) and indoxyl sulfate (IS). We hypothesize that a low aromatic amino acid diet (LA-AAD, namely a low intake of tyrosine, tryptophan and phenylalanine) while being normoproteic, could be as effective as a LPD, through the decreased production of uremic toxins. Kidney failure was chemically induced in mice with a diet containing 0.25% (w/w) of adenine. Mice received three different diets for six weeks: normoproteic diet (NPD: 14.7% proteins, aromatic AAs 0.019%), LPD (5% proteins, aromatic AAs 0.007%) and LA-AAD (14% proteins, aromatic AAs 0.007%). Both LPD and LA-AAD significantly reduced proteinuria, kidney fibrosis and inflammation. While LPD only slightly decreased plasma free PCS and free IS compared to NPD; free fractions of both compounds were significantly decreased by LA-AAD. These results suggest that a LA-AAD confers similar benefits of a LPD in delaying the progression of CKD through a reduction in uremic toxins production, with a lower risk of malnutrition.

scholarly journals The Effects of Gum Acacia on the Composition of the Gut Microbiome and Plasma Levels of Short-Chain Fatty Acids in a Rat Model of Chronic Kidney Disease

2020 ◽  
Vol 11 ◽  
Author(s):  
Maha Al-Asmakh ◽  
Muhammad Umar Sohail ◽  
Ola Al-Jamal ◽  
Banan Mosaad Shoair ◽  
Asmaa Yousef Al-Baniali ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Fatty Acids ◽  
Renal Function ◽  
Kidney Disease ◽  
Gut Microbiome ◽  
Plasma Levels ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Biochemical Indicators ◽  
Chain Fatty Acids

Chronic kidney disease (CKD) may be fatal for its victims and is an important long-term public health problem. The complicated medical procedures and diet restrictions to which patients with CKD are subjected alter the gut microbiome in an adverse manner, favoring over-accumulation of proteolytic bacteria that produce ammonia and other toxic substances. The present study aimed to investigate the effect of GA on 1) the composition of the gut microbiome and 2) on plasma levels of short-chain fatty acids. Male Wister rats were divided into four groups (six each) and treated for 4 weeks based on the following: control, dietary adenine (0.75%, w/w) to induce CKD, GA in the drinking water (15%, w/v), and both adenine and GA. At the end of the treatment period, plasma, urine, and fecal samples were collected for determination of several biochemical indicators of renal function and plasma levels of short-chain fatty acids (SCFAs) as well as characterization of the gut microbiome. Dietary adenine induced the typical signs of CKD, i.e., loss of body weight and impairment of renal function, while GA alleviated these effects. The intestine of the rats with CKD contained an elevated abundance of pathogenic Proteobacteria, Actinobacteria, and Verrucomicrobia but lowered proportions of Lactobacillaceae belonging to the Firmicutes phylum. Plasma levels of propionate and butyrate were lowered by dietary adenine and restored by GA. A negative association (Spearman’s p-value ≤ 0.01, r ≤ 0.5) was observed between Firmicutes and plasma creatinine, urea, urine N-acetyl-beta-D-glucosaminidase (NAG) and albumin. Phylum Proteobacteria on the other hand was positively associated with these markers while Phylum Bacteroidetes was positively associated with plasma SCFAs. In conclusion, the adverse changes in the composition of the gut microbiome, plasma levels of SCFAs, and biochemical indicators of renal function observed in the rats with CKD induced by dietary adenine were mitigated by GA. These findings are indicative of a link between uremia and the composition of the microbiome in connection with this disease. Dietary administration of GA to patients with CKD may improve their renal function via modulating the composition of their microbiome—a finding that certainly warrants further investigation.

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