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Kidney Disease-Gut Dysbiosis: What Is the Role of Uremic Toxins?

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A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Uremic Toxins".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 46777

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Special Issue Editor

Prof. Dr. Griet Glorieux

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Guest Editor

Ghent University Hospital, Ghent University, 9000 Gent, Belgium
Interests: uremic toxins; protein-bound uremic toxins; chronic kidney disease; leukocyte/monocyte function; leukocyte–endothelial interaction; inflammation in CKD; dialysis fluid purity/endotoxins; gut–kidney axis
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Special Issue Information

Dear Colleagues,

The gut microbial composition is altered in patients with chronic kidney disease (CKD). These alterations are further enhanced by several uremia-related factors such as i) the gut influx of plasma urea, ii) colonic epithelial barrier disruption, iii) the gut influx of uric acid and oxalate from colonic epithelial cells, iv) prolonged intestinal transit time, v) impaired protein assimilation and malnutrition, vi) dietary restrictions, and vii) the intake of medication. In addition, the gut microbiota are a potential cause of change in the gut biochemical milieu and, in this way, can contribute to the complex clinical picture of CKD. In CKD, the homeostasis between the end-products of carbohydrate fermentation, such as short-chain fatty acids, and end-products of protein fermentation, among which are the precursors of well-known uremic toxins, is disrupted. To what extent this contributes to the increase in the plasma levels of uremic toxins is yet unclear. Nevertheless, gut microbiota and their metabolism are potential targets for reducing the circulating levels of uremic toxins and improving the outcomes of patients with CKD. Proof-of-concept studies are needed before potential therapeutic interventions such as dietary interventions and the administration of pre-, pro- and synbiotics can be further explored. In addition, studying the metabolism of intestinally generated uremic toxins along the gut–liver–kidney axis is desirable, and omics approaches are an important tool in this context.

This Special Issue entitled “Kidney Disease and Gut Dysbiosis: What Is the Role of Uremic Toxins?” focuses on the relationship between gut dysbiosis and uremic toxins in all its aspects: in vitro studies, animal studies and clinical studies. Original research papers and review articles describing novelties or overviews, respectively, are welcome.

Prof. Dr. Griet Glorieux
Guest Editor

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Keywords

kidney disease
cardiovascular disease
chronic kidney disease progression
gut microbiome
uremic toxins
short-chain fatty acids
intestinal barrier function
transporter proteins
omics approaches
gut–liver–kidney axis
diet and pre-, pro- and synbiotics

Published Papers (10 papers)

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Research

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10 pages, 434 KiB

Open AccessArticle

Serum Trimethylamine N-Oxide Level Is Associated with Peripheral Arterial Stiffness in Advanced Non-Dialysis Chronic Kidney Disease Patients

by Bang-Gee Hsu, Chih-Hsien Wang, Yu-Li Lin, Yu-Hsien Lai and Jen-Pi Tsai

Toxins 2022, 14(8), 526; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins14080526 - 31 Jul 2022

Cited by 5 | Viewed by 1735

Abstract

Trimethylamine N-oxide (TMAO) is a gut-derived uremic toxin involved in cardiovascular diseases (CVD). Peripheral arterial stiffness (PAS), measured by the brachial-ankle pulse wave velocity (baPWV) is a valuable indicator of the existence of CVD alongside other diseases. The study recruited 157 patients with chronic kidney disease (CKD) stages 3 to 5, and aimed to determine the correlation between serum TMAO and PAS, defined as a baPWV of >18.0 m/s. Patients with CKD who were diagnosed with PAS (68 patients, 43.3%) were older, had a higher percentage of hypertension or diabetes mellitus, higher systolic blood pressure, and higher fasting glucose, C-reactive protein, and TMAO levels. Furthermore, besides old age and SBP, patients with CKD who had higher serum TMAO were more likely to have PAS, with an odds ratio of 1.016 (95% confidence interval = 1.002–1.029, p = 0.021) by multivariate logistic regression analysis. Correlation analysis demonstrated that serum TMAO was positively correlated with C-reactive protein level and either left or right baPWV. Thus, we supposed that serum TMAO levels were associated with PAS in patients with advanced non-dialysis CKD. Full article

(This article belongs to the Special Issue Kidney Disease-Gut Dysbiosis: What Is the Role of Uremic Toxins?)

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11 pages, 736 KiB

Open AccessArticle

Lipid Profile Is Negatively Associated with Uremic Toxins in Patients with Kidney Failure—A Tri-National Cohort

by Sam Hobson, Henriette de Loor, Karolina Kublickiene, Joachim Beige, Pieter Evenepoel, Peter Stenvinkel and Thomas Ebert

Toxins 2022, 14(6), 412; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins14060412 - 16 Jun 2022

Cited by 5 | Viewed by 2234

Abstract

Patients with kidney failure (KF) have a high incidence of cardiovascular (CV) disease, partly driven by insufficient clearance of uremic toxins. Recent investigations have questioned the accepted effects of adverse lipid profile and CV risk in uremic patients. Therefore, we related a panel of uremic toxins previously associated with CV morbidity/mortality to a full lipid profile in a large, tri-national, cross-sectional cohort. Total, high-density lipoprotein (HDL), non-HDL, low-density lipoprotein (LDL), and remnant cholesterol, as well as triglyceride, levels were associated with five uremic toxins in a cohort of 611 adult KF patients with adjustment for clinically relevant covariates and other patient-level variables. Univariate analyses revealed negative correlations of total, non-HDL, and LDL cholesterol with all investigated uremic toxins. Multivariate linear regression analyses confirmed independent, negative associations of phenylacetylglutamine with total, non-HDL, and LDL cholesterol, while indole-3 acetic acid associated with non-HDL and LDL cholesterol. Furthermore, trimethylamine-N-Oxide was independently and negatively associated with non-HDL cholesterol. Sensitivity analyses largely confirmed findings in the entire cohort. In conclusion, significant inverse associations between lipid profile and distinct uremic toxins in KF highlight the complexity of the uremic milieu, suggesting that not all uremic toxin interactions with conventional CV risk markers may be pathogenic. Full article

(This article belongs to the Special Issue Kidney Disease-Gut Dysbiosis: What Is the Role of Uremic Toxins?)

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Graphical abstract

13 pages, 929 KiB

Open AccessEditor’s ChoiceArticle

Collagen-Derived Peptides in CKD: A Link to Fibrosis

by Emmanouil Mavrogeorgis, Harald Mischak, Agnieszka Latosinska, Antonia Vlahou, Joost P. Schanstra, Justyna Siwy, Vera Jankowski, Joachim Beige and Joachim Jankowski

Toxins 2022, 14(1), 10; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins14010010 - 23 Dec 2021

Cited by 14 | Viewed by 7959

Abstract

Collagen is a major component of the extracellular matrix (ECM) and has an imminent role in fibrosis, in, among others, chronic kidney disease (CKD). Collagen alpha-1(I) (col1a1) is the most abundant collagen type and has previously been underlined for its contribution to the disease phenotype. Here, we examined 5000 urinary peptidomic datasets randomly selected from healthy participants or patients with CKD to identify urinary col1a1 fragments and study their abundance, position in the main protein, as well as their correlation with renal function. We identified 707 col1a1 peptides that differed in their amino acid sequence and/or post-translational modifications (hydroxyprolines). Well-correlated peptides with the same amino acid sequence, but a different number of hydroxyprolines, were combined into a final list of 503 peptides. These 503 col1a1 peptides covered 69% of the full col1a1 sequence. Sixty-three col1a1 peptides were significantly and highly positively associated (rho > +0.3) with the estimated glomerular filtration rate (eGFR), while only six peptides showed a significant and strong, negative association (rho < −0.3). A similar tendency was observed for col1a1 peptides associated with ageing, where the abundance of most col1a1 peptides decreased with increasing age. Collectively the results show a strong association between collagen peptides and loss of kidney function and suggest that fibrosis, potentially also of other organs, may be the main consequence of an attenuation of collagen degradation, and not increased synthesis. Full article

(This article belongs to the Special Issue Kidney Disease-Gut Dysbiosis: What Is the Role of Uremic Toxins?)

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11 pages, 1680 KiB

Open AccessEditor’s ChoiceArticle

Gut Microbiota and Their Derived Metabolites, a Search for Potential Targets to Limit Accumulation of Protein-Bound Uremic Toxins in Chronic Kidney Disease

by Mieke Steenbeke, Sophie Valkenburg, Tessa Gryp, Wim Van Biesen, Joris R. Delanghe, Marijn M. Speeckaert and Griet Glorieux

Toxins 2021, 13(11), 809; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13110809 - 17 Nov 2021

Cited by 9 | Viewed by 4034

Abstract

Chronic kidney disease (CKD) is characterized by gut dysbiosis with a decrease in short-chain fatty acid (SCFA)-producing bacteria. Levels of protein-bound uremic toxins (PBUTs) and post-translational modifications (PTMs) of albumin increase with CKD, both risk factors for cardiovascular morbidity and mortality. The relationship between fecal metabolites and plasma concentrations of PBUTs in different stages of CKD (n = 103) was explored. Estimated GFR tends to correlate with fecal butyric acid (BA) concentrations (r_s = 0.212; p = 0.032), which, in its turn, correlates with the abundance of SCFA-producing bacteria. Specific SCFAs correlate with concentrations of PBUT precursors in feces. Fecal levels of p-cresol correlate with its derived plasma UTs (p-cresyl sulfate: r_s = 0.342, p < 0.001; p-cresyl glucuronide: r_s = 0.268, p = 0.006), whereas an association was found between fecal and plasma levels of indole acetic acid (r_s = 0.306; p = 0.002). Finally, the albumin symmetry factor correlates positively with eGFR (r_s = 0.274; p = 0.005). The decreased abundance of SCFA-producing gut bacteria in parallel with the fecal concentration of BA and indole could compromise the intestinal barrier function in CKD. It is currently not known if this contributes to increased plasma levels of PBUTs, potentially playing a role in the PTMs of albumin. Further evaluation of SCFA-producing bacteria and SCFAs as potential targets to restore both gut dysbiosis and uremia is needed. Full article

(This article belongs to the Special Issue Kidney Disease-Gut Dysbiosis: What Is the Role of Uremic Toxins?)

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Review

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23 pages, 1462 KiB

Open AccessEditor’s ChoiceReview

Food-Derived Uremic Toxins in Chronic Kidney Disease

by Mara Lauriola, Ricard Farré, Pieter Evenepoel, Saskia Adriana Overbeek and Björn Meijers

Toxins 2023, 15(2), 116; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins15020116 - 01 Feb 2023

Cited by 8 | Viewed by 3876

Abstract

Patients with chronic kidney disease (CKD) have a higher cardiovascular risk compared to the average population, and this is partially due to the plasma accumulation of solutes known as uremic toxins. The binding of some solutes to plasma proteins complicates their removal via conventional therapies, e.g., hemodialysis. Protein-bound uremic toxins originate either from endogenous production, diet, microbial metabolism, or the environment. Although the impact of diet on uremic toxicity in CKD is difficult to quantify, nutrient intake plays an important role. Indeed, most uremic toxins are gut-derived compounds. They include Maillard reaction products, hippurates, indoles, phenols, and polyamines, among others. In this review, we summarize the findings concerning foods and dietary components as sources of uremic toxins or their precursors. We then discuss their endogenous metabolism via human enzyme reactions or gut microbial fermentation. Lastly, we present potential dietary strategies found to be efficacious or promising in lowering uremic toxins plasma levels. Aligned with current nutritional guidelines for CKD, a low-protein diet with increased fiber consumption and limited processed foods seems to be an effective treatment against uremic toxins accumulation. Full article

(This article belongs to the Special Issue Kidney Disease-Gut Dysbiosis: What Is the Role of Uremic Toxins?)

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22 pages, 2020 KiB

Open AccessReview

Homeostasis in the Gut Microbiota in Chronic Kidney Disease

by Shruti Bhargava, Erik Merckelbach, Heidi Noels, Ashima Vohra and Joachim Jankowski

Toxins 2022, 14(10), 648; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins14100648 - 20 Sep 2022

Cited by 15 | Viewed by 6292

Abstract

The gut microbiota consists of trillions of microorganisms, fulfilling important roles in metabolism, nutritional intake, physiology and maturation of the immune system, but also aiding and abetting the progression of chronic kidney disease (CKD). The human gut microbiome consists of bacterial species from five major bacterial phyla, namely Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Verrucomicrobia. Alterations in the members of these phyla alter the total gut microbiota, with a decline in the number of symbiotic flora and an increase in the pathogenic bacteria, causing or aggravating CKD. In addition, CKD-associated alteration of this intestinal microbiome results in metabolic changes and the accumulation of amines, indoles and phenols, among other uremic metabolites, which have a feedforward adverse effect on CKD patients, inhibiting renal functions and increasing comorbidities such as atherosclerosis and cardiovascular diseases (CVD). A classification of uremic toxins according to the degree of known toxicity based on the experimental evidence of their toxicity (number of systems affected) and overall experimental and clinical evidence was selected to identify the representative uremic toxins from small water-soluble compounds, protein-bound compounds and middle molecules and their relation to the gut microbiota was summarized. Gut-derived uremic metabolites accumulating in CKD patients further exhibit cell-damaging properties, damage the intestinal epithelial cell wall, increase gut permeability and lead to the translocation of bacteria and endotoxins from the gut into the circulatory system. Elevated levels of endotoxins lead to endotoxemia and inflammation, further accelerating CKD progression. In recent years, the role of the gut microbiome in CKD pathophysiology has emerged as an important aspect of corrective treatment; however, the mechanisms by which the gut microbiota contributes to CKD progression are still not completely understood. Therefore, this review summarizes the current state of research regarding CKD and the gut microbiota, alterations in the microbiome, uremic toxin production, and gut epithelial barrier degradation. Full article

(This article belongs to the Special Issue Kidney Disease-Gut Dysbiosis: What Is the Role of Uremic Toxins?)

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21 pages, 1512 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Microbial-Derived Tryptophan Catabolites, Kidney Disease and Gut Inflammation

by Avra Melina Madella, Jeroen Van Bergenhenegouwen, Johan Garssen, Rosalinde Masereeuw and Saskia Adriana Overbeek

Toxins 2022, 14(9), 645; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins14090645 - 18 Sep 2022

Cited by 12 | Viewed by 3485

Abstract

Uremic metabolites, molecules either produced by the host or from the microbiota population existing in the gastrointestinal tract that gets excreted by the kidneys into urine, have significant effects on both health and disease. Tryptophan-derived catabolites are an important group of bacteria-produced metabolites with an extensive contribution to intestinal health and, eventually, chronic kidney disease (CKD) progression. The end-metabolite, indoxyl sulfate, is a key contributor to the exacerbation of CKD via the induction of an inflammatory state and oxidative stress affecting various organ systems. Contrastingly, other tryptophan catabolites positively contribute to maintaining intestinal homeostasis and preventing intestinal inflammation—activities signaled through nuclear receptors in particular—the aryl hydrocarbon receptor (AhR) and the pregnane X receptor (PXR). This review discusses the origins of these catabolites, their effect on organ systems, and how these can be manipulated therapeutically in the future as a strategy to treat CKD progression and gut inflammation management. Furthermore, the use of biotics (prebiotics, probiotics, synbiotics) as a means to increase the presence of beneficial short-chain fatty acids (SCFAs) to achieve intestinal homeostasis is discussed. Full article

(This article belongs to the Special Issue Kidney Disease-Gut Dysbiosis: What Is the Role of Uremic Toxins?)

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14 pages, 822 KiB

Open AccessReview

Gut–Kidney Axis Investigations in Animal Models of Chronic Kidney Disease

by Piotr Bartochowski, Nathalie Gayrard, Stéphanie Bornes, Céline Druart, Angel Argilés, Magali Cordaillat-Simmons and Flore Duranton

Toxins 2022, 14(9), 626; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins14090626 - 07 Sep 2022

Cited by 5 | Viewed by 3416

Abstract

Chronic kidney disease (CKD) is an incurable disease in which renal function gradually declines, resulting in no noticeable symptoms during the early stages and a life-threatening disorder in the latest stage. The changes that accompany renal failure are likely to influence the gut microbiota, or the ecosystem of micro-organisms resident in the intestine. Altered gut microbiota can display metabolic changes and become harmful to the host. To study the gut–kidney axis in vivo, animal models should ideally reproduce the disorders affecting both the host and the gut microbiota. Murine models of CKD, but not dog, manifest slowed gut transit, similarly to patient. Animal models of CKD also reproduce altered intestinal barrier function, as well as the resulting leaky gut syndrome and bacterial translocation. CKD animal models replicate metabolic but not compositional changes in the gut microbiota. Researchers investigating the gut–kidney axis should pay attention to the selection of the animal model (disease induction method, species) and the setting of the experimental design (control group, sterilization method, individually ventilated cages) that have been shown to influence gut microbiota. Full article

(This article belongs to the Special Issue Kidney Disease-Gut Dysbiosis: What Is the Role of Uremic Toxins?)

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17 pages, 2114 KiB

Open AccessReview

Postbiotics and Kidney Disease

by Chiara Favero, Laura Giordano, Silvia Maria Mihaila, Rosalinde Masereeuw, Alberto Ortiz and Maria Dolores Sanchez-Niño

Toxins 2022, 14(9), 623; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins14090623 - 06 Sep 2022

Cited by 4 | Viewed by 5547

Abstract

Chronic kidney disease (CKD) is projected to become the fifth global cause of death by 2040 as a result of key shortcomings in the current methods available to diagnose and treat kidney diseases. In this regard, the novel holobiont concept, used to describe an individual host and its microbial community, may pave the way towards a better understanding of kidney disease pathogenesis and progression. Microbiota-modulating or -derived interventions include probiotics, prebiotics, synbiotics and postbiotics. As of 2019, the concept of postbiotics was updated by the International Scientific Association of Probiotics and Prebiotics (ISAPP) to refer to preparations of inanimate microorganisms and/or their components that confer a health benefit to the host. By explicitly excluding purified metabolites without a cellular biomass, any literature making use of such term is potentially rendered obsolete. We now review the revised concept of postbiotics concerning their potential clinical applications and research in kidney disease, by discussing in detail several formulations that are undergoing preclinical development such as GABA-salt for diet-induced hypertension and kidney injury, sonicated Lactobacillus paracasei in high fat diet-induced kidney injury, GABA-salt, lacto-GABA-salt and postbiotic-GABA-salt in acute kidney injury, and O. formigenes lysates for hyperoxaluria. Furthermore, we provide a roadmap for postbiotics research in kidney disease to expedite clinical translation. Full article

(This article belongs to the Special Issue Kidney Disease-Gut Dysbiosis: What Is the Role of Uremic Toxins?)

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20 pages, 1838 KiB

Open AccessReview

Microbiome in Chronic Kidney Disease (CKD): An Omics Perspective

by Sonnal Lohia, Antonia Vlahou and Jerome Zoidakis

Toxins 2022, 14(3), 176; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins14030176 - 26 Feb 2022

Cited by 23 | Viewed by 7097

Abstract

Chronic kidney disease (CKD) is predominant in 10% of the world’s adult population, and is increasingly considered a silent epidemic. Gut microbiota plays an essential role in maintaining host energy homeostasis and gut epithelial integrity. Alterations in gut microbiota composition, functions and, specifically, production of metabolites causing uremic toxicity are often associated with CKD onset and progression. Here, we present the latest omics (transcriptomics, proteomics and metabolomics) studies that explore the connection between CKD and gut microbiome. A review of the available literature using PubMed was performed using the keywords “microb*”, “kidney”, “proteom”, “metabolom” and “transcript” for the last 10 years, yielding a total of 155 publications. Following selection of the relevant studies (focusing on microbiome in CKD), a predominance of metabolomics (n = 12) over transcriptomics (n = 1) and proteomics (n = 6) analyses was observed. A consensus arises supporting the idea that the uremic toxins produced in the gut cause oxidative stress, inflammation and fibrosis in the kidney leading to CKD. Collectively, findings include an observed enrichment of Eggerthella lenta, Enterobacteriaceae and Clostridium spp., and a depletion in Bacteroides eggerthii, Roseburia faecis and Prevotella spp. occurring in CKD models. Bacterial species involved in butyrate production, indole synthesis and mucin degradation were also related to CKD. Consequently, strong links between CKD and gut microbial dysbiosis suggest potential therapeutic strategies to prevent CKD progression and portray the gut as a promising therapeutic target. Full article

(This article belongs to the Special Issue Kidney Disease-Gut Dysbiosis: What Is the Role of Uremic Toxins?)

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