Protein-Bound Uremic Toxins from Gut Microbiota and Inflammatory Markers in Chronic Kidney Disease

Background: Sarcopenia is a prevalent condition in chronic kidney disease (CKD). We determined gut microbiota (gMB) composition in CKD patients with or without sarcopenia. Furthermore, we investigated whether in these patients, there was any association between gMB, uremic toxins, inflammation and oxidative stress. Methods: We analyzed gMB composition, uremic toxins (indoxyl sulphate and p-cresyl sulphate), inflammatory cytokines (interleukin 10, tumor necrosis factor α, interleukin 6, interleukin 17, interleukin 12 p70, monocyte chemoattractant protein-1 and fetuin-A) and oxidative stress (malondialdehyde) of 64 elderly CKD patients (10 < eGFR < 45 mL/min/1.73 m2, not on dialysis) categorized as sarcopenic and not-sarcopenic. Sarcopenia was defined according to European Working Group on Sarcopenia in Older People 2 criteria. Results: Sarcopenic patients had a greater abundance of the Micrococcaceae and Verrucomicrobiaceae families and of Megasphaera, Rothia, Veillonella, Akkermansia and Coprobacillus genera. They had a lower abundance of the Gemellaceae and Veillonellaceae families and of Acidaminococcus and Gemella genera. GMB was associated with uremic toxins, inflammatory cytokines and MDA. However, uremic toxins, inflammatory cytokines and MDA were not different in sarcopenic compared with not-sarcopenic individuals, except for interleukin 10, which was higher in not-sarcopenic patients. Conclusions: In older CKD patients, gMB was different in sarcopenic than in not-sarcopenic ones. Several bacterial families and genera were associated with uremic toxins and inflammatory cytokines, although none of these latter substantially different in sarcopenic versus not-sarcopenic patients.

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The Impact of CKD on Uremic Toxins and Gut Microbiota

Toxins ◽

10.3390/toxins13040252 ◽

2021 ◽

Vol 13 (4) ◽

pp. 252

Author(s):

Jacek Rysz ◽

Beata Franczyk ◽

Janusz Ławiński ◽

Robert Olszewski ◽

Aleksanda Ciałkowska-Rysz ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Microbial Community ◽

Kidney Disease ◽

Gut Microbiota ◽

Intestinal Inflammation ◽

Adverse Outcomes ◽

Uremic Toxins ◽

Dietary Interventions ◽

Stress Injury ◽

The Impact

Numerous studies have indicated that the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD) is strictly associated with the accumulation of toxic metabolites in blood and other metabolic compartments. This accumulation was suggested to be related to enhanced generation of toxins from the dysbiotic microbiome accompanied by their reduced elimination by impaired kidneys. Intestinal microbiota play a key role in the accumulation of uremic toxins due to the fact that numerous uremic solutes are generated in the process of protein fermentation by colonic microbiota. Some disease states, including CKD, are associated with the presence of dysbiosis, which can be defined as an “imbalanced intestinal microbial community with quantitative and qualitative changes in the composition and metabolic activities of the gut microbiota”. The results of studies have confirmed the altered composition and functions of gut microbial community in chronic kidney disease. In the course of CKD protein-bound uremic toxins, including indoxyl sulfate, p-cresyl glucuronide, p-cresyl sulfate and indole-3-acetic acid are progressively accumulated. The presence of chronic kidney disease may be accompanied by the development of intestinal inflammation and epithelial barrier impairment leading to hastened systemic translocation of bacterial-derived uremic toxins and consequent oxidative stress injury to the kidney, cardiovascular and endocrine systems. These findings offer new therapeutic possibilities for the management of uremia, inflammation and kidney disease progression and the prevention of adverse outcomes in CKD patients. It seems that dietary interventions comprising prebiotics, probiotics, and synbiotics could pose a promising strategy in the management of uremic toxins in CKD.

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Emodin via colonic irrigation modulates gut microbiota and reduces uremic toxins in rats with chronic kidney disease

Oncotarget ◽

10.18632/oncotarget.8160 ◽

2016 ◽

Vol 7 (14) ◽

pp. 17468-17478 ◽

Cited By ~ 22

Author(s):

Yu-Qun Zeng ◽

Zhenhua Dai ◽

Fuhua Lu ◽

Zhaoyu Lu ◽

Xusheng Liu ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Uremic Toxins ◽

Colonic Irrigation

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Gut-Derived Protein-Bound Uremic Toxins

Toxins ◽

10.3390/toxins12090590 ◽

2020 ◽

Vol 12 (9) ◽

pp. 590 ◽

Cited By ~ 1

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.

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Constipation in chronic kidney disease: it is time to reconsider

Renal Replacement Therapy ◽

10.1186/s41100-019-0246-3 ◽

2019 ◽

Vol 5 (1) ◽

Cited By ~ 1

Author(s):

Ryota Ikee ◽

Kazuhiro Yano ◽

Tomomi Tsuru

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Intestinal Motility ◽

Intestinal Inflammation ◽

Colonic Transit ◽

Uremic Toxins ◽

Phosphate Binders ◽

Limited Information ◽

Gut Dysbiosis

AbstractConstipation is highly prevalent in patients with chronic kidney disease (CKD) and is primarily characterized by decreased intestinal motility. This chronic disorder affects the quality of life of patients. However, nephrologist and dialysis clinicians have long had a disproportionately limited understanding of constipation. Accumulating evidence has revealed a relationship between constipation and cardiovascular disease and CKD. The pathogenesis of constipation in CKD patients is multifactorial: decreased physical activity, comorbidities affecting bowel movement, such as diabetes mellitus, cerebrovascular disease, and hyperparathyroidism, a restricted dietary intake of plant-based fiber-rich foods, and multiple medications, including phosphate binders and potassium-binding resins, have all been implicated. CKD is associated with alterations in the composition and function of the gut microbiota, so-called gut dysbiosis. Recent studies showed that CKD-related gut dysbiosis decreased intestinal motility via intestinal inflammation or the increased generation of gut-derived uremic toxins, such as indoxyl sulfate and p-cresyl sulfate. Furthermore, the gastrointestinal secretion of mucin was found to be decreased in CKD animal models, which may delay colonic transit by diminished lubrication in the alimentary tract. Thus, CKD-related gut dysbiosis may play a role in constipation, but limited information is currently available. Since constipation is often intractable, particularly in CKD patients, every available means needs to be employed in its treatment. The effects of probiotics, prebiotics, and synbiotics on the composition of the gut microbiota and gut-derived uremic toxins have been increasingly reported. However, their effects on stool consistency or frequency in CKD patients remain unclear. Some laxatives may be beneficial for improving not only bowel habits but also gut dysbiosis. Further studies are required to elucidate the CKD-specific pathogenesis of constipation and develop novel effective treatment options.

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Impact of Altered Intestinal Microbiota on Chronic Kidney Disease Progression

Toxins ◽

10.3390/toxins10070300 ◽

2018 ◽

Vol 10 (7) ◽

pp. 300 ◽

Cited By ~ 33

Author(s):

Esmeralda Castillo-Rodriguez ◽

Raul Fernandez-Prado ◽

Raquel Esteras ◽

Maria Perez-Gomez ◽

Carolina Gracia-Iguacel ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Molecular Mechanisms ◽

Kidney Diseases ◽

Toxin Production ◽

Uremic Toxins ◽

Uremic Toxin ◽

Ckd Progression ◽

Increased Risk

In chronic kidney disease (CKD), accumulation of uremic toxins is associated with an increased risk of CKD progression. Some uremic toxins result from nutrient processing by gut microbiota, yielding precursors of uremic toxins or uremic toxins themselves, such as trimethylamine N-Oxide (TMAO), p-cresyl sulphate, indoxyl sulphate and indole-3 acetic acid. Increased intake of some nutrients may modify the gut microbiota, increasing the number of bacteria that process them to yield uremic toxins. Circulating levels of nutrient-derived uremic toxins are associated to increased risk of CKD progression. This offers the opportunity for therapeutic intervention by either modifying the diet, modifying the microbiota, decreasing uremic toxin production by microbiota, increasing toxin excretion or targeting specific uremic toxins. We now review the link between nutrients, microbiota and uremic toxin with CKD progression. Specific focus will be placed on the generation specific uremic toxins with nephrotoxic potential, the decreased availability of bacteria-derived metabolites with nephroprotective potential, such as vitamin K and butyrate and the cellular and molecular mechanisms linking these toxins and protective factors to kidney diseases. This information provides a conceptual framework that allows the development of novel therapeutic approaches.

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The Impact of Uremia and Intestinal Dysbiosis on Hepatic Drug Metabolism in a Rat Model of Progressive Chronic Kidney Disease

10.1101/531939 ◽

2019 ◽

Author(s):

Emily D Hartjes ◽

Yong Jin Lim ◽

Thomas J Velenosi ◽

Kait F Al ◽

Jean M Macklaim ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Drug Metabolism ◽

Gut Microbiota ◽

Uremic Toxins ◽

Uremic Toxin ◽

Bacterial Microbiota ◽

Intestinal Dysbiosis ◽

Metabolite Profiles ◽

The Impact

AbstractNonrenal clearance pathways such as drug metabolism are decreased in chronic kidney disease (CKD). Although the mechanism remains elusive, uremic toxin retention and an altered gut microbiota are suspected to influence cytochrome P450s (CYPs) contributing to the unpredictable pharmacokinetics in patients with CKD. We characterized dysbiosis and uremia in CKD to elucidate associations between CYP expression and CKD progression. Rats fed control or CKD-inducing adenine diet were subsequently studied at five time points over 42 days. CYP expression and activity were compared to alterations in the 1) plasma and liver metabolome and 2) gut bacterial microbiota. CYP3A2 and CYP2C11 were downregulated in CKD by ≥76% (p<0.001) concurrently with or slightly prior to CKD onset as defined by serum creatinine. Metabolite profiles were altered prior to changes in the gut microbiota, and gut-derived uremic toxins including indoxyl sulfate, phenyl sulfate and 4-ethylphenyl sulfate correlated with CYP3A2 or CYP2C11 expression. Bacterial genera Turicibacter and Parabacteroides were identified as being characteristic of CKD. In conclusion, CYP3A2 and CYP2C11 are downregulated before dysbiosis and correlate with select uremic toxins.

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Aryl Hydrocarbon Receptor and Uremic Toxins from the Gut Microbiota in Chronic Kidney Disease Patients: Is There a Relationship between Them?

Biochemistry ◽

10.1021/acs.biochem.8b01305 ◽

2019 ◽

Vol 58 (15) ◽

pp. 2054-2060 ◽

Cited By ~ 9

Author(s):

Jessyca Sousa de Brito ◽

Natália Alvarenga Borges ◽

Juliana Saraiva dos Anjos ◽

Lia Sumie Nakao ◽

Milena Barcza Stockler-Pinto ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Aryl Hydrocarbon Receptor ◽

Uremic Toxins ◽

Aryl Hydrocarbon

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Effects of Uremic Toxins from the Gut Microbiota on Bone: A Brief Look at Chronic Kidney Disease

Therapeutic Apheresis and Dialysis ◽

10.1111/1744-9987.12307 ◽

2015 ◽

Vol 19 (5) ◽

pp. 436-440 ◽

Cited By ~ 7

Author(s):

Ana Paula Black ◽

Ludmila F M F Cardozo ◽

Denise Mafra

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Uremic Toxins

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The guanylate cyclase C agonist linaclotide ameliorates the gut–cardio–renal axis in an adenine-induced mouse model of chronic kidney disease

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfz126 ◽

2019 ◽

Cited By ~ 5

Author(s):

Fumika Nanto-Hara ◽

Yoshitomi Kanemitsu ◽

Shinji Fukuda ◽

Koichi Kikuchi ◽

Kei Asaji ◽

...

Keyword(s):

Cardiovascular Disease ◽

Chronic Kidney Disease ◽

Renal Function ◽

Kidney Disease ◽

Mouse Model ◽

Gut Microbiota ◽

Cardiac Fibrosis ◽

Cardiorenal Syndrome ◽

Uremic Toxins ◽

Guanylate Cyclase C

Abstract Background Cardiorenal syndrome is a major cause of mortality in patients with chronic kidney disease (CKD). However, the involvement of detrimental humoral mediators in the pathogenesis of cardiorenal syndrome is still controversial. Trimethylamine-N-oxide (TMAO), a hepatic metabolic product of trimethylamine generated from dietary phosphatidylcholine or carnitine derived by the gut microbiota, has been linked directly with progression of cardiovascular disease and renal dysfunction. Thus, targeting TMAO may be a novel strategy for the prevention of cardiovascular disease and chronic kidney disease. Methods Linaclotide, a guanylate cyclase C agonist, was administered to adenine-induced renal failure (RF) mice and changes in renal function and levels of gut-derived uremic toxins, as well as the gut microbiota community, were analyzed using metabolomic and metagenomic methods to reveal its cardiorenal effect. Results Linaclotide decreased the plasma levels of TMAO at a clinically used low dose of 10 μg/kg in the adenine-induced RF mouse model. At a high concentration of 100 μg/kg, linaclotide clearly improved renal function and reduced the levels of various uremic toxins. A reduction in TMAO levels following linaclotide treatment was also observed in a choline-fed pro-atherosclerotic model. Linaclotide ameliorated renal inflammation and fibrosis and cardiac fibrosis, as well as decreased the expression of collagen I, transforming growth factor-β, galectin-3 (Gal-3) and ST2 genes. Plasma levels of Gal-3 and ST2 were also reduced. Because exposure of cardiomyocytes to TMAO increased fibronectin expression, these data suggest that linaclotide reduced the levels of TMAO and various uremic toxins and may result in not only renal, but also cardiac, fibrosis. F4/80-positive macrophages were abundant in small intestinal crypts in RF mice, and this increased expression was decreased by linaclotide. Reduced colonic claudin-1 levels were also restored by linaclotide, suggesting that linaclotide ameliorated the ‘leaky gut’ in RF mice. Metagenomic analysis revealed that the microbial order Clostridiales could be responsible for the change in TMAO levels. Conclusion Linaclotide reduced TMAO and uremic toxin levels and could be a powerful tool for the prevention and control of the cardiorenal syndrome by modification of the gut–cardio–renal axis.

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