Impact of Gut Dysbiosis on Neurohormonal Pathways in Chronic Kidney Disease

Chronic kidney disease (CKD) is a worldwide major health problem. Traditional risk factors for CKD are hypertension, obesity, and diabetes mellitus. Recent studies have identified gut dysbiosis as a novel risk factor for the progression CKD and its complications. Dysbiosis can worsen systemic inflammation, which plays an important role in the progression of CKD and its complications such as cardiovascular diseases. In this review, we discuss the beneficial effects of the normal gut microbiota, and then elaborate on how alterations in the biochemical environment of the gastrointestinal tract in CKD can affect gut microbiota. External factors such as dietary restrictions, medications, and dialysis further promote dysbiosis. We discuss the impact of an altered gut microbiota on neuroendocrine pathways such as the hypothalamus–pituitary–adrenal axis, the production of neurotransmitters and neuroactive compounds, tryptophan metabolism, and the cholinergic anti-inflammatory pathway. Finally, therapeutic strategies including diet modification, intestinal alpha-glucosidase inhibitors, prebiotics, probiotics and synbiotics are reviewed.

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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.

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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.

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Could the beneficial effects of dietary calcium on obesity and diabetes control be mediated by changes in intestinal microbiota and integrity?

British Journal Of Nutrition ◽

10.1017/s0007114515003608 ◽

2015 ◽

Vol 114 (11) ◽

pp. 1756-1765 ◽

Cited By ~ 23

Author(s):

J. M. G. Gomes ◽

J. A. Costa ◽

R. C. Alfenas

Keyword(s):

Gut Microbiota ◽

Metabolic Diseases ◽

Beneficial Effects ◽

Body Weight Reduction ◽

Intestinal Integrity ◽

Obesity And Diabetes ◽

Supplementation Period ◽

Inflammatory State ◽

The Impact

AbstractEvidence from animal and human studies has associated gut microbiota, increased translocation of lipopolysaccharide (LPS) and reduced intestinal integrity (II) with the inflammatory state that occurs in obesity and type 2 diabetes mellitus (T2DM). Consumption of Ca may favour body weight reduction and glycaemic control, but its influence on II and gut microbiota is not well understood. Considering the impact of metabolic diseases on public health and the role of Ca on the pathophysiology of these diseases, this review critically discusses possible mechanisms by which high-Ca diets could affect gut microbiota and II. Published studies from 1993 to 2015 about this topic were searched and selected from Medline/PubMed, Scielo and Lilacs databases. High-Ca diets seem to favour the growth of lactobacilli, maintain II (especially in the colon), reduce translocation of LPS and regulate tight-junction gene expression. We conclude that dietary Ca might interfere with gut microbiota and II modulations and it can partly explain the effect of Ca on obesity and T2DM control. However, further research is required to define the supplementation period, the dose and the type of Ca supplement (milk or salt) required for more effective results. As Ca interacts with other components of the diet, these interactions must also be considered in future studies. We believe that more complex mechanisms involving extraintestinal disorders (hormones, cytokines and other biomarkers) also need to be studied.

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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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Vitamin D supplementation on anemia markers and the impact on PTH in patients with chronic kidney disease

Research Society and Development ◽

10.33448/rsd-v10i9.17752 ◽

2021 ◽

Vol 10 (9) ◽

pp. e53310917752

Author(s):

Letícya Thaís Mendes Viana ◽

Larissa Lages Rodrigues ◽

Jurandy do Nascimento Silva ◽

Maria Márcia Dantas de Sousa ◽

Fhanuel Silva Andrade ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Vitamin D ◽

Kidney Disease ◽

Vitamin D Supplementation ◽

Beneficial Effects ◽

Search And Selection ◽

The Impact ◽

Anemia Of Inflammation ◽

Selection Of

Chronic Kidney Disease (CKD) is an injury that causes progressive impairment of exocrine and endocrine renal functions. A very common complication is anemia, caused by reduced erythropoietin production, iron deficiency and inflammation. Evidence demonstrates that vitamin D has effects on anemia of inflammation, through the increase in erythrocytes and decrease in pro-inflammatory cytokines. This study aims to review the effects of vitamin D supplementation on 25(OH)D2 concentrations, on anemia markers and on PTH levels. This is an integrative review carried out through the search and selection of original publications, in english and portuguese, indexed in PubMed, Web of Science and Science Direct databases belonging to the 2010-2020 range. The results pointed to 25(OH)D2 concentrations compatible with normality after vitamin D supplementation. In five studies, there was no change in hemoglobin and PTH levels, and in four studies there was a reduction in the dose of EPO or erythroid stimulating agent, attributing such effect on the role of calcitriol as a substrate for bone marrow erythropoietic cells. The study concluded that vitamin D supplementation had beneficial effects for correction of 25(OH)D2 deficiency, however, it reinforces the controversy about the behavior of vitamin D on the improvement of anemia markers and PTH levels in patients with DRC. Therefore, it is suggested that the beneficial effect of vitamin D on anemia in renal patients may be independent of PTH suppression.

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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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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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Targeted Inhibition of Gut Microbial Trimethylamine N-Oxide Production Reduces Renal Tubulointerstitial Fibrosis and Functional Impairment in a Murine Model of Chronic Kidney Disease

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314139 ◽

2020 ◽

Vol 40 (5) ◽

pp. 1239-1255 ◽

Cited By ~ 10

Author(s):

Nilaksh Gupta ◽

Jennifer A. Buffa ◽

Adam B. Roberts ◽

Naseer Sangwan ◽

Sarah M. Skye ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Renal Function ◽

Kidney Disease ◽

Gut Microbiota ◽

Functional Impairment ◽

Tubulointerstitial Fibrosis ◽

Intestinal Microbes ◽

Renal Tubulointerstitial Fibrosis ◽

Selective Targeting ◽

The Impact

Objective: Gut microbial metabolism of dietary choline, a nutrient abundant in a Western diet, produces trimethylamine (TMA) and the atherothrombosis- and fibrosis-promoting metabolite TMA-N-oxide (TMAO). Recent clinical and animal studies reveal that elevated TMAO levels are associated with heightened risks for both cardiovascular disease and incident chronic kidney disease development. Despite this, studies focusing on therapeutically targeting gut microbiota-dependent TMAO production and its impact on preserving renal function are limited. Approach and Results: Herein we examined the impact of pharmacological inhibition of choline diet-induced gut microbiota-dependent production of TMA, and consequently TMAO, on renal tubulointerstitial fibrosis and functional impairment in a model of chronic kidney disease. Initial studies with a gut microbial choline TMA-lyase mechanism-based inhibitor, iodomethylcholine, confirmed both marked suppression of TMA generation, and consequently TMAO levels, and selective targeting of the gut microbial compartment (ie, both accumulation of the drug in intestinal microbes and limited systemic exposure in the host). Dietary supplementation of either choline or TMAO significantly augmented multiple indices of renal functional impairment and fibrosis associated with chronic subcutaneous infusion of isoproterenol. However, the presence of the gut microbiota-targeting inhibitor iodomethylcholine blocked choline diet-induced elevation in TMAO, and both significantly improved decline in renal function, and significantly attenuated multiple indices of tubulointerstitial fibrosis. Iodomethylcholine treatment also reversed many choline diet-induced changes in cecal microbial community composition associated with TMAO and renal functional impairment. Conclusions: Selective targeting of gut microbiota-dependent TMAO generation may prevent adverse renal structural and functional alterations in subjects at risk for chronic kidney disease.

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The challenge of early glomerular filtration rate decline in response to antihypertensive treatment and chronic kidney disease outcomes

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa171 ◽

2020 ◽

Author(s):

Lorenzo Signorini ◽

Gianluigi Zaza ◽

Giovanni Gambaro

Keyword(s):

Chronic Kidney Disease ◽

Glomerular Filtration Rate ◽

Kidney Disease ◽

Glomerular Filtration ◽

Filtration Rate ◽

Enzyme Inhibitor ◽

Response To Treatment ◽

Beneficial Effects ◽

Cv Disease ◽

The Impact

Abstract Hypertension and chronic kidney disease (CKD) are closely linked pathological processes. Combating high blood pressure (BP) is an essential part of preventing CKD progression and reducing cardiovascular (CV) risk. Data from recent randomized controlled trials on patients at high CV risk showed the beneficial effects of intensive action to meet BP targets on mortality related to CV disease. The impact of meeting such targets on renal function is still unclear, however, particularly for patients with CKD. This issue has been the object of several post hoc analyses because lowering BP definitely has a nephroprotective role, but the early decline in glomerular filtration rate (GFR) associated with antihypertensive therapies and strict BP targets is still a concern in nephrology clinical practice. The present review discusses the results of studies on this topic, focusing specifically on the clinical significance of early GFR decline in response to treatment with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, or to different BP targets, in terms of renal and CV outcomes, and how this tips the balance towards continuing or discontinuing antihypertensive therapy.

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