Chronic kidney disease, uremic milieu, and its effects on gut bacterial microbiota dysbiosis

Several lines of evidence suggest that gut bacterial microbiota is altered in patients with chronic kidney disease (CKD), though the mechanism of which this dysbiosis takes place is not well understood. Recent studies delineated changes in gut microbiota in both CKD patients and experimental animal models using microarray chips. We present 16S ribosomal RNA gene sequencing of both stool pellets and small bowel contents of C57BL/6J mice that underwent a remnant kidney model and establish that changes in microbiota take place in the early gastrointestinal tract. Increased intestinal urea concentration has been hypothesized as a leading contributor to dysbiotic changes in CKD. We show that urea transporters (UT)-A and UT-B mRNA are both expressed throughout the whole gastrointestinal tract. The noted increase in intestinal urea concentration appears to be independent of UTs’ expression. Urea supplementation in drinking water resulted in alteration in bacterial gut microbiota that is quite different than that seen in CKD. This indicates that increased intestinal urea concentration might not fully explain the CKD- associated dysbiosis.

Download Full-text

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.

Download Full-text

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

Cells ◽

10.3390/cells10010114 ◽

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.

Download Full-text

Microbiome–metabolomics reveals gut microbiota associated with glycine-conjugated metabolites and polyamine metabolism in chronic kidney disease

Cellular and Molecular Life Sciences ◽

10.1007/s00018-019-03155-9 ◽

2019 ◽

Vol 76 (24) ◽

pp. 4961-4978 ◽

Cited By ~ 23

Author(s):

Ya-Long Feng ◽

Gang Cao ◽

Dan-Qian Chen ◽

Nosratola D. Vaziri ◽

Lin Chen ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Polyamine Metabolism ◽

Conjugated Metabolites

Download Full-text

Association of Sarcopenia and Gut Microbiota Composition in Older Patients with Advanced Chronic Kidney Disease, Investigation of the Interactions with Uremic Toxins, Inflammation and Oxidative Stress

Toxins ◽

10.3390/toxins13070472 ◽

2021 ◽

Vol 13 (7) ◽

pp. 472

Author(s):

Elisabetta Margiotta ◽

Lara Caldiroli ◽

Maria Luisa Callegari ◽

Francesco Miragoli ◽

Francesca Zanoni ◽

...

Keyword(s):

Oxidative Stress ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Inflammatory Cytokines ◽

Interleukin 10 ◽

Uremic Toxins ◽

Interleukin 12 ◽

European Working ◽

And Oxidative Stress

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.

Download Full-text

The Role of Gut Microbiota and Diet on Uremic Retention Solutes Production in the Context of Chronic Kidney Disease

Toxins ◽

10.3390/toxins10040155 ◽

2018 ◽

Vol 10 (4) ◽

pp. 155 ◽

Cited By ~ 21

Author(s):

Laetitia Koppe ◽

Denis Fouque ◽

Christophe Soulage

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota

Download Full-text

Effect of cranberry supplementation on toxins produced by the gut microbiota in chronic kidney disease patients: a pilot randomized placebo-controlled trial

Clinical Nutrition ESPEN ◽

10.1016/j.clnesp.2021.11.012 ◽

2021 ◽

Author(s):

Karla Thaís Resende Teixeira ◽

Laís de Souza Gouveia Moreira ◽

Natalia Alvarenga Borges ◽

Isabela Brum ◽

Bruna R. de Paiva ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Controlled Trial

Download Full-text

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

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab090.0022 ◽

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.

Download Full-text

Alterations in the gut microbiota can elicit hypertension in rats

Physiological Genomics ◽

10.1152/physiolgenomics.00081.2016 ◽

2017 ◽

Vol 49 (2) ◽

pp. 96-104 ◽

Cited By ~ 118

Author(s):

Sareema Adnan ◽

James W. Nelson ◽

Nadim J. Ajami ◽

Venugopal R. Venna ◽

Joseph F. Petrosino ◽

...

Keyword(s):

Blood Pressure ◽

Gut Microbiota ◽

Systolic Blood Pressure ◽

Ribosomal Rna ◽

Shr Rats ◽

Spontaneously Hypertensive ◽

Gut Dysbiosis ◽

16S Ribosomal Rna Gene ◽

Previously Treated ◽

Normotensive Strain

Gut dysbiosis has been linked to cardiovascular diseases including hypertension. We tested the hypothesis that hypertension could be induced in a normotensive strain of rats or attenuated in a hypertensive strain of rats by exchanging the gut microbiota between the two strains. Cecal contents from spontaneously hypertensive stroke prone rats (SHRSP) were pooled. Similarly, cecal contents from normotensive WKY rats were pooled. Four-week-old recipient WKY and SHR rats, previously treated with antibiotics to reduce the native microbiota, were gavaged with WKY or SHRSP microbiota, resulting in four groups; WKY with WKY microbiota (WKY g-WKY), WKY with SHRSP microbiota (WKY g-SHRSP), SHR with SHRSP microbiota (SHR g-SHRSP), and SHR with WKY microbiota (SHR g-WKY). Systolic blood pressure (SBP) was measured weekly using tail-cuff plethysmography. At 11.5 wk of age systolic blood pressure increased 26 mmHg in WKY g-SHRSP compared with that in WKY g-WKY (182 ± 8 vs. 156 ± 8 mmHg, P = 0.02). Although the SBP in SHR g-WKY tended to decrease compared with SHR g-SHRSP, the differences were not statistically significant. Fecal pellets were collected at 11.5 wk of age for identification of the microbiota by sequencing the 16S ribosomal RNA gene. We observed a significant increase in the Firmicutes:Bacteroidetes ratio in the hypertensive WKY g-SHRSP, as compared with the normotensive WKY g-WKY ( P = 0.042). Relative abundance of multiple taxa correlated with SBP. We conclude that gut dysbiosis can directly affect SBP. Manipulation of the gut microbiota may represent an innovative treatment for hypertension.

Download Full-text

The Association between Gut Microbiota and Uremia of Chronic Kidney Disease

Microorganisms ◽

10.3390/microorganisms8060907 ◽

2020 ◽

Vol 8 (6) ◽

pp. 907 ◽

Cited By ~ 1

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.

Download Full-text