Production Of Uremic Toxins Research Articles

Blueberry, cranberry, raspberry, and strawberry as modulators of the gut microbiota: target for treatment of gut dysbiosis in chronic kidney disease? From current evidence to future possibilities.

Gut dysbiosis is common in patients with chronic kidney disease (CKD) and is associated with uremic toxin production, inflammation, oxidative stress, and cardiovascular disease development. Therefore, healthy dietary patterns are essential modulators of gut microbiota. In this context, studies suggest that consuming berry fruits, rich in polyphenols and nutrients, may positively affect the gut microbiota, promoting the selective growth of beneficial bacteria and improving clinical status. However, studies on the effects of berry fruits on gut microbiota in CKD are scarce, and a better understanding of the possible mechanisms of action of berry fruits on gut microbiota is needed to guide future clinical studies and clinical practice in CKD. The objective was to discuss how berry fruits (blueberry, cranberry, raspberry, and strawberry) could be a therapeutic strategy to modulate the gut microbiota and possibly reverse the dysbiosis in CKD. Overall, available evidence shows that berry fruits can promote an increase in diversity by affecting the abundance of mucus-producing bacteria and short-chain fatty acids. Moreover, these fruits can increase the expression of mRNA involved in tight junctions in the gut such as occludin, tight junction protein 1 (TJP1), and mucin. Studies on the exact amount of berries leading to these effects show heterogeneous findings. However, it is known that, with 5 mg/day, it is already possible to observe some effects in animal models. Wild berries could possibly improve the uremic condition by reducing the levels of uremic toxins via modulation of the gut microbiota. In the long term, this could be an excellent strategy for patients with CKD. Therefore, clinical studies are encouraged to evaluate better these effects on CKD as well as the safe amount of these fruits in order to promote a better quality of life or even the survival of these patients.

The state of the intestinal microbial-tissue complex in patients with chronic kidney disease

The gut microbiota plays a fundamental role in maintaining normal organism homeostasis, regulating a wide range of metabolic, biosynthetic, and immune functions. This complex ecosystem, together with cellular, and stromal components of the intestinal wall, forms the intestinal microbial-tissue complex, which pathology is considered a universal mechanism for the development of many diseases, including chronic kidney disease. Accumulation of nitrogen metabolism products in the intestine, specific diet, polypharmacy, sedentary lifestyle, limited fluid intake, and violation of gastrointestinal motility in patients with chronic kidney disease lead to a decrease in the number of bacteria synthesizing short-chain fatty acids with crucial physiological effects, along with an increase in the content of anaerobic proteolytic bacteria expressing uricase, urease, and p-cresol-, and indole-forming enzymes. The features of gut dysbiosis depend on the etiology of chronic kidney disease and severity of renal insufficiency and differ significantly in individuals receiving various renal replacement therapies (hemodialysis, peritoneal dialysis, kidney transplant recipients). Abnormal microbial metabolism enhances the production and accumulation of microbial-derived uremic toxins: p-cresyl sulfate, indoxyl sulfate, and trimethylamine-N-oxide. Renal insufficiency, through mechanisms mainly associated with the hydrolysis of accumulated in the lumen of the intestine urea, leads to inflammation, and swelling of the intestinal wall, which is accompanied by disorders of the immune tolerance of the mucous layer and disorganization of intercellular junctional complexes, which are critical modulators of intestinal intercellular transepithelial transport. Uremia-induced impairment of the gut epithelial barrier integrity induces the systemic translocation of numerous immunogenic substances generated by the aberrant microbiota, followed by the development of oxidative stress and chronic subclinical inflammation that causes the progression of chronic kidney disease and related complications. The most pronounced changes were observed in people with end-stage chronic kidney disease. Further study of the bidirectional relationship between the kidneys and intestinal microbial-tissue complex will contribute to the development of new directions of pathogenetic therapy and prevention of adverse outcomes in patients with chronic kidney disease.

Berberine ameliorates chronic kidney disease through inhibiting the production of gut-derived uremic toxins in the gut microbiota.

At present, clinical interventions for chronic kidney disease are very limited, and most patients rely on dialysis to sustain their lives for a long time. However, studies on the gut-kidney axis have shown that the gut microbiota is a potentially effective target for correcting or controlling chronic kidney disease. This study showed that berberine, a natural drug with low oral availability, significantly ameliorated chronic kidney disease by altering the composition of the gut microbiota and inhibiting the production of gut-derived uremic toxins, including p-cresol. Furthermore, berberine reduced the content of p-cresol sulfate in plasma mainly by lowering the abundance of g_Clostridium_sensu_stricto_1 and inhibiting the tyrosine-p-cresol pathway of the intestinal flora. Meanwhile, berberine increased the butyric acid producing bacteria and the butyric acid content in feces, while decreased the renal toxic trimethylamine N-oxide. These findings suggest that berberine may be a therapeutic drug with significant potential to ameliorate chronic kidney disease through the gut-kidney axis.

Plant-Dominant Low Protein Diet: A Potential Alternative Dietary Practice for Patients with Chronic Kidney Disease.

Dietary protein restriction has long been a cornerstone of nutritional therapy for patients with chronic kidney diseases (CKD). However, the recommended amount of dietary protein intake is different across guidelines. This is partly because previous randomized controlled trials have reported conflicting results regarding the efficacy of protein restriction in terms of kidney outcomes. Interestingly, a vegetarian, very low protein diet has been shown to reduce the risk of kidney failure among patients with advanced CKD, without increasing the incidence of hyperkalemia. This finding suggests that the source of protein may also influence the kidney outcomes. Furthermore, a plant-dominant low-protein diet (PLADO) has recently been proposed as an alternative dietary therapy for patients with CKD. There are several potential mechanisms by which plant-based diets would benefit patients with CKD. For example, plant-based diets may reduce the production of gut-derived uremic toxins by increasing the intake of fiber, and are useful for correcting metabolic acidosis and hyperphosphatemia. Plant proteins are less likely to induce glomerular hyperfiltration than animal proteins. Furthermore, plant-based diets increase magnesium intake, which may prevent vascular calcification. More evidence is needed to establish the efficacy, safety, and feasibility of PLADO as a new adjunct therapy in real-world patients with CKD.

Plant-based diets: a fad or the future of medical nutrition therapy for children with chronic kidney disease?

Plant-based diets are growing in popularity worldwide due to the importance of reducing the population's ecological footprint as well as an emerging role in the prevention and treatment of chronic human diseases. In adults, plant-based diets have been shown to be beneficial for preventing and controlling conditions that are common in patients with chronic kidney disease (CKD), such as obesity, hypertension, type 2 diabetes, dyslipidemia, and metabolic acidosis. Emerging evidence suggests that the higher fiber content of plant-based diets may help to modulate production of uremic toxins through beneficial shifts in the gut microbiome. The effects of the plant-based diet on progression of CKD remain controversial, and there are no data to support this in children. However, knowledge that the bioavailability of potassium and phosphorus from plant-based foods is reduced has led to recent changes in international kidney-friendly diet recommendations for children with CKD. The new guidelines advise that high potassium fruits and vegetables should no longer be automatically excluded from the kidney-friendly diet. In fact, a plant-based diet can be safely implemented in children with CKD through building the diet around whole, high fiber foods, avoiding processed foods and using recommended cooking methods to control potassium. The health benefits of the plant-based diet compared to omnivorous diets in children with CKD need investigation.

The benefits of dietary fiber: the gastrointestinal tract and beyond.

Dietary fiber is considered an essential constituent of a healthy child's diet. Diets of healthy children with adequate dietary fiber intake are characterized by a higher diet quality, a higher nutrient density, and a higher intake of vitamins and minerals in comparison to the diets of children with poor dietary fiber intake. Nevertheless, a substantial proportion of children do not meet the recommended dietary fiber intake. This is especially true in those children with kidney diseases, as traditional dietary recommendations in kidney diseases have predominantly focused on the quantities of energy and protein, and often restricting potassium and phosphate, while overlooking the quality and diversity of the diet. Emerging evidence suggests that dietary fiber and, by extension, a plant-based diet with its typically higher dietary fiber content are just as important for children with kidney diseases as for healthy children. Dietary fiber confers several health benefits such as prevention of constipation and fewer gastrointestinal symptoms, reduced inflammatory state, and decreased production of gut-derived uremic toxins. Recent studies have challenged the notion that a high dietary fiber intake confers an increased risk of hyperkalemia or nutritional deficits in children with kidney diseases. There is an urgent need of new studies and revised guidelines that address the dietary fiber intake in children with kidney diseases.

Indole and p-cresol in feces of healthy subjects: Concentration, kinetics, and correlation with microbiome.

Indole and p-cresol are precursors of the most important uremic toxins, generated from the fermentation of amino acids tryptophan and tyrosine by the proteolytic community of intestinal bacteria. The present study focused on the relationship between the microbiome composition, the fecal levels of indole and p-cresol, and their kinetics of generation/degradation in fecal cultures. The concentration of indole and p-cresol, the volatilome, the dry weight, and the amount of ammonium and carbohydrates were analyzed in the feces of 10 healthy adults. Indole and p-cresol widely differed among samples, laying in the range of 1.0-19.5μg/g and 1.2-173.4μg/g, respectively. Higher fecal levels of indole and p-cresol were associated with lower carbohydrates and higher ammonium levels, that are markers of a more pronounced intestinal proteolytic metabolism. Positive relationship was observed also with the dry/wet weight ratio, indicator of prolonged intestinal retention of feces. p-cresol and indole presented a statistically significant negative correlation with OTUs of uncultured Bacteroidetes and Firmicutes, the former belonging to Bacteroides and the latter to the families Butyricicoccaceae (genus Butyricicoccus), Monoglobaceae (genus Monoglobus), Lachnospiraceae (genera Faecalibacterium, Roseburia, and Eubacterium ventriosum group). The kinetics of formation and/or degradation of indole and p-cresol was investigated in fecal slurries, supplemented with the precursor amino acids tryptophan and tyrosine in strict anaerobiosis. The presence of the precursors bursted indole production but had a lower effect on the rate of p-cresol formation. On the other hand, supplementation with indole reduced the net rate of formation. The taxa that positively correlated with fecal levels of uremic toxins presented a positive correlation also with p-cresol generation rate in biotransformation experiments. Moreover other bacterial groups were positively correlated with generation rate of p-cresol and indole, further expanding the range of taxa associated to production of p-cresol (Bacteroides, Alistipes, Eubacterium xylanophylum, and Barnesiella) and indole (e.g., Bacteroides, Ruminococcus torques, Balutia, Dialister, Butyricicoccus). The information herein presented contributes to disclose the relationships between microbiota composition and the production of uremic toxins, that could provide the basis for probiotic intervention on the gut microbiota, aimed to prevent the onset, hamper the progression, and alleviate the impact of nephropaties.

Homeostasis in the Gut Microbiota in Chronic Kidney Disease.

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.

The Dual Roles of Protein-Bound Solutes as Toxins and Signaling Molecules in Uremia.

In patients with severe kidney disease, renal clearance is compromised, resulting in the accumulation of a plethora of endogenous waste molecules that cannot be removed by current dialysis techniques, the most often applied treatment. These uremic retention solutes, also named uremic toxins, are a heterogeneous group of organic compounds of which many are too large to be filtered and/or are protein-bound. Their renal excretion depends largely on renal tubular secretion, by which the binding is shifted towards the free fraction that can be eliminated. To facilitate this process, kidney proximal tubule cells are equipped with a range of transport proteins that cooperate in cellular uptake and urinary excretion. In recent years, innovations in dialysis techniques to advance uremic toxin removal, as well as treatments with drugs and/or dietary supplements that limit uremic toxin production, have provided some clinical improvements or are still in progress. This review gives an overview of these developments. Furthermore, the role protein-bound uremic toxins play in inter-organ communication, in particular between the gut (the side where toxins are produced) and the kidney (the side of their removal), is discussed.

MO563: Effect of Probiotics on Uremic Toxins Production and Inflammation in Patients Suffering from CKD Stage 3 and 4

Abstract BACKGROUND AND AIMS Probiotics are being coprescribed in the management of chronic kidney disease (CKD). Few studies have reported that probiotics could slow down the progression of CKD by regulating the intestinal flora and by reducing the uremic toxins. [1,2] Objective of our study is to assess the effect of probiotics on uremic toxins production and inflammation in patient suffering from CKD stage 3 and 4. METHOD Patients of either sex, aged 18–75 years, suffering from CKD stage 3 and 4 were enrolled. Study was conducted at Department of Nephrology, Guwahati Medical College and Hospital (GMCH), Guwahati, Assam. Patients received 1 capsule containing 45 billion of colony forming units of probiotics twice a day for 180 days. Patients were evaluated at day 0, 90 and 180. Parameters such as serum creatinine, blood urea, uric acid, C-reactive protein (CRP), hemoglobin and albumin were recorded at each visit. RESULTS During period of May 2019 to May 2020, 102 patients were enrolled and followed for 180 days. Significantly higher number of males 67 (66%) than 35 (34%) females is reported (P = 0.024). CKD stage 3 and 4 is reported in 41 (40% ) and 61 (60%), respectively. Insignificant drop of serum creatinine of -0.17 (on day 90, P = 0.146) and -0.23 (on day 180, P = 0.135) compared with baseline Sr. creatinine 2.53 ± 0.56 (mean ± SD) is reported. Significant drop in blood urea is reported on day 90 (-2.97, P = 0.014) and on day 180 (-3.60, P < 0.001) compared with baseline 52.11 ± 26.90 (mean ± SD). The reduction in CRP on day 90 and day 180 from baseline was found to be statistically significant (P = 0.037, 0.011). However, reduction in uric acid and increase in hemoglobin and albumin did not reach significance on day 90 and day 180. CONCLUSION Probiotics supplementation lead to decrease in blood urea and CRP. However, its effect on serum creatinine, hemoglobin, uric acid and albumin did not reach statistical significance. More randomized controlled trials are required to prove the efficacy of probiotics to retard CKD progression.

Uremic Toxin-Producing Bacteroides Species Prevail in the Gut Microbiota of Taiwanese CKD Patients: An Analysis Using the New Taiwan Microbiome Baseline.

Rationale and ObjectiveGut microbiota have been targeted by alternative therapies for non-communicable diseases. We examined the gut microbiota of a healthy Taiwanese population, identified various bacterial drivers in different demographics, and compared them with dialysis patients to associate kidney disease progression with changes in gut microbiota.Study DesignThis was a cross-sectional cohort study.Settings and ParticipantsFecal samples were obtained from 119 healthy Taiwanese volunteers, and 16S rRNA sequencing was done on the V3-V4 regions to identify the bacterial enterotypes. Twenty-six samples from the above cohort were compared with fecal samples from 22 peritoneal dialysis and 16 hemodialysis patients to identify species-level bacterial biomarkers in the dysbiotic gut of chronic kidney disease (CKD) patients.ResultsSpecific bacterial species were identified pertaining to different demographics such as gender, age, BMI, physical activity, and sleeping habits. Dialysis patients had a significant difference in gut microbiome composition compared to healthy controls. The most abundant genus identified in CKD patients was Bacteroides, and at the species level hemodialysis patients showed significant abundance in B. ovatus, B. caccae, B. uniformis, and peritoneal dialysis patients showed higher abundance in Blautia producta (p ≤ 0.05) than the control group. Pathways pertaining to the production of uremic toxins were enriched in CKD patients. The abundance of the bacterial species depended on the type of dialysis treatment.ConclusionThis study characterizes the healthy gut microbiome of a Taiwanese population in terms of various demographics. In a case-control examination, the results showed the alteration in gut microbiota in CKD patients corresponding to different dialysis treatments. Also, this study identified the bacterial species abundant in CKD patients and their possible role in complicating the patients’ condition.

Effects of an SGLT Inhibitor on the Production, Toxicity, and Elimination of Gut-Derived Uremic Toxins: A Call for Additional Evidence.

Sodium–glucose cotransporter (SGLT) inhibitors are a class of oral hypoglycemic agents, which, in recent years, have been shown to improve renal and cardiovascular outcomes in patients with diabetic and non-diabetic chronic kidney disease. There remains considerable debate regarding the potential glucose-independent mechanisms by which these benefits are conferred. SGLT inhibitors, to a variable extent, impair small intestinal glucose absorption, facilitating the delivery of glucose into the colon. This suppresses protein fermentation, and thus the generation of uremic toxins such as phenols and indoles. It is acknowledged that such a shift in gut microbial metabolism yields health benefits for the host. SGLT inhibition, in addition, may be hypothesized to foster the renal clearance of protein-bound uremic toxins. Altered generation and elimination of uremic toxins may be in the causal pathway between SGLT inhibition and improved cardiometabolic health. Present review calls for additional research.

The Role of Dietary Fiber and Gut Microbiome Modulation in Progression of Chronic Kidney Disease.

Nutrition is one of the fundamental approaches to promoting and preventing all kinds of diseases, especially kidney diseases. Dietary fiber forms a significant aspect of renal nutrition in treating chronic kidney disease (CKD). Dietary fiber intake influences the composition and metabolism of the gut microbiome with proven roles in reducing uremic toxin production, preserving kidney function, and retarding the progression of CKD through mechanisms of regulating metabolic, immunological, and inflammatory processes. Understanding dietary fiber’s pathogenesis and mechanistic action in modulating host and microbiome interactions provides a potential adjunct therapeutic target for preventing, controlling, and treating CKD patients. In this regard, a recommendation of adequate and appropriate dietary fiber intake to restore beneficial gut microbiota composition would reduce the risks and complications associated with CKD. This mini review summarizes current evidence of the role of dietary fiber intake in modulating the gut microbiome to improve kidney health.

The Effects of Resistant Starch Consumption in Adult Patients With Chronic Kidney Disease: A Systematic Review.

Background:Resistant starches (RSs) are not digested by human digestive enzymes and pass through the upper digestive tract to become substrates for colonic bacteria. Resistant starch supplementation has shown promising results in altering the microbiota of animal models of chronic kidney disease (CKD). Resistant starch consumption may influence the production of uremic toxins in CKD.Objective:To conduct a systematic review to determine whether the consumption of RS reduces the progression of kidney disease in adult patients with CKD.Design:We included randomized controlled trials comparing RS supplementation to placebo, no treatment, or standard care. Cochrane Central, Embase, MEDLINE, Web of Science, and CINAHL databases were searched. There was no limitation on publication date, but only English manuscripts were included. The search was conducted in July 2020.Patients:Adult outpatient populations with CKD, using any recognized diagnostic criteria.Measurements:The primary outcome was change in glomerular filtration rate (GFR) from baseline through the end of the trial in patients not on dialysis; secondary outcomes included change in uremic toxin concentrations (p-cresol/p-cresyl sulfate [p-CS], indoxyl sulfate [IS]) and inflammatory markers (tumor necrosis factor alpha [TNF-α], C-reactive protein [CRP], interleukin 6 [IL-6]) from baseline through the end of the trial, and changes in self-reported symptom scores.Methods:The Cochrane Collaboration Risk of Bias tool was used to assess risk of bias in included studies. The systematic review results are reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.Results:We identified 4 unique studies, reported in 9 publications that met our inclusion criteria, including a total of 215 enrolled participants. Results were calculated using data from the longest reported follow-up time. The primary outcome of changes in kidney function markers was only studied in 1 trial; this trial reported an increase in creatinine and a decrease in blood urea nitrogen; no changes in GFR were reported. A review of the secondary outcomes showed an overall decline in IS, TNF-α, and IL-6, in RS groups, but with mixed results in p-CS and CRP/high-sensitivity CRP. Safety data showed that RS was well tolerated with no reports of excessive side effects.Limitations:We determined a meta-analysis was not feasible due to clinical heterogeneity between study populations and differences in reported outcomes in the included studies.Conclusion:There is limited and inconsistent evidence on the impact of RS in adult patients with CKD. Further research is needed to determine the safety and efficacy of RS supplementation in this population.

Novel intestinal dialysis interventions and microbiome modulation to control uremia.

In patients with chronic kidney disease (CKD), the gut plays a key role in the homeostasis of fluid and electrolyte balance and the production and disposal of uremic toxins. This review summarizes the current evidence on the gut-targeted interventions to control uremia, fluid overload, hyperkalemia and hyperphosphatemia in CKD. Studies have emerged that support the concept of intestinal dialysis, such as colonic perfusion with a Malone antegrade continence enema stoma or colonic irrigation with a rectal catheter, as a promising adjuvant approach to control uremia in CKD, although most findings are preliminary. The use of AST-120, an oral adsorbent, has been shown to reduce circulating levels of indoxyl sulfate and p-cresol sulfate and have potential renoprotective benefits in patients with advanced CKD. Diarrhea or inducing watery stools may modulate fluid retention and potassium and phosphorus load. Accumulating evidence indicates that plant-based diets, low-protein diets, and pre-, pro-, and synbiotic supplementation may lead to favorable alterations of the gut microbiota, contributing to reduce uremic toxin generation. The effects of these gut-targeted interventions on kidney and cardiovascular outcomes are still limited and need to be tested in future studies including clinical trials. Interventions aimed at enhancing bowel elimination of uremic toxins, fluid and electrolytes and at modulating gut microbiota may represent novel therapeutic strategies for the management of uremia in patients with CKD.

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

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 some key uremic toxins production (such as PCS and IS), with a lower risk of malnutrition.

Fiber intake and health in people with chronic kidney disease.

Emerging evidence suggests that diet, particularly one that is rich in dietary fiber, may prevent the progression of chronic kidney disease (CKD) and its associated complications in people with established CKD. This narrative review summarizes the current evidence and discusses the opportunities for increasing fiber intake in people with CKD to improve health and reduce disease complications. A higher consumption of fiber exerts multiple health benefits, such as increasing stool output, promoting the growth of beneficial microbiota, improving the gut barrier and decreasing inflammation, as well decreasing uremic toxin production. Despite this, the majority of people with CKD consume less than the recommended dietary fiber intake, which may be due in part to the competing dietary potassium concern. Based on existing evidence, we see benefits from adopting a higher intake of fiber-rich food, and recommend cooperation with the dietitian to ensure an adequate diet plan. We also identify knowledge gaps for future research and suggest means to improve patient adherence to a high-fiber diet.

Administration of Lactobacillus reuteri Combined with Clostridium butyricum Attenuates Cisplatin-Induced Renal Damage by Gut Microbiota Reconstitution, Increasing Butyric Acid Production, and Suppressing Renal Inflammation.

Cisplatin-induced nephrotoxicity is associated with gut microbiota disturbance. The present study aimed to investigate whether supplementation of Lactobacillus reuteri and Clostridium butyricum (LCs) had a protective effect on cisplatin-induced nephrotoxicity through reconstruction of gut microbiota. Wistar rats were given different treatments: control, cisplatin (Cis), cisplatin + C. butyricum and L. reuteri (Cis+LCs), and C. butyricum and L. reuteri (LCs). We observed that cisplatin-treated rats supplemented with LCs exhibited significantly decreased renal inflammation (KIM-1, F4/80, and MPO), oxidative stress, fibrosis (collagen IV, fibronectin, and a-SMA), apoptosis, concentration of blood endotoxin and indoxyl sulfate, and increased fecal butyric acid production compared with those without supplementation. In addition, LCs improved the cisplatin-induced microbiome dysbiosis by maintaining a healthy gut microbiota structure and diversity; depleting Escherichia-Shigella and the Enterobacteriaceae family; and enriching probiotic Bifidobacterium, Ruminococcaceae, Ruminiclostridium_9, and Oscillibacter. Moreover, the LCs intervention alleviated the cisplatin-induced intestinal epithelial barrier impairment. This study indicated LCs probiotic serves as a mediator of the gut–kidney axis in cisplatin-induced nephrotoxicity to restore the intestinal microbiota composition, thereby suppressing uremic toxin production and enhancing butyrate production. Furthermore, the renoprotective effect of LCs is partially mediated by increasing the anti-inflammatory effects and maintaining the integrity of the intestinal barrier.

Dietary Phosphorus Differentially Alters Uremic Toxin Production in a Rat Model of Chronic Kidney Disease

ObjectivesChronic kidney disease (CKD) is characterized by declining kidney function, limiting the kidney’s ability to efficiently remove metabolic waste products from circulation. Byproducts of gut microbial protein metabolism, termed uremic retention solutes (URS), accumulate in CKD patients and are associated with accelerating kidney decline. The gut microbes responsible for generating URS are dependent upon phosphorus (P) for growth and survival. As dietary P restriction is a cornerstone of CKD treatment, we hypothesized that changes in dietary P loads would alter URS production. MethodsTo evaluate this, 8-week-old male Sprague Dawley rats underwent 5/6th nephrectomy (Nx, n = 24) or sham operation (n = 20) and were maintained on a 0.6% P diet (w/w) for three weeks. Animals were then randomized to receive either low (0.1% (w/w)) or high (1.2% (w/w)) P diets for 4h/d for 7d. Blood was collected at the start and end of the 7d diet (baseline and sacrifice, respectively). Serum was analyzed for blood urea nitrogen (BUN) and URS, including trimethylamine oxide (TMAO), indoxyl sulfate (IS), and p-cresol sulfate (pCS), via LC-MS. ResultsNx rats had significantly elevated BUN compared to sham controls (38.9 ± 5.9 vs 23.1 ± 5.1 mg/dL, p < 0.0001). Additionally, the presence of significantly enlarged kidney tissue in Nx animals verified the progression of kidney decline. At sacrifice, all URS were elevated in Nx animals as compared to sham controls (p < 0.0001), though changes in dietary P loads only affected IS production (low vs. high, p = 0.0003). When comparing baseline to sacrifice, TMAO decreased, IS remained consistent, and pCS increased in all rats. ConclusionsOur results indicate that dietary P loads may differentially affect the production of some URS in a rat model of CKD. As dietary P restriction is one of the cornerstones of CKD treatment, we posit that this dietary strategy influences URS production, CKD progression, and, ultimately, health outcomes. Funding SourcesASBMR, NIH K01.

MO137DIFFERENCES IN GUT MICROBIOTA PROFILES AND FUNCTIONS BETWEEN END-STAGE KIDNEY DISEASE AND HEALTHY POPULATIONS

Abstract Background and Aims Patients with end-stage kidney disease (ESKD) are characterized by altered gut microbiota, impaired intestinal barrier function, and experienced gut microbiota-derived metabolites related to systemic complications. However, limited studies evaluated the microbial diversity and function in ESKD patients previously. Method Compared to age- and gender-matched subjects without kidney disease, 82 ESKD patients in the discovery cohort and 58 ESKD patients in the validation cohort were investigated for the microbial richness, biodiversity, gut dysbiosis, microbial composition differences, and the functional changes by gut metabolic module analysis. Bacterial derived free form protein-bound uremic toxins were analyzed by mass spectrometry and their association with microbial richness in ESKD patients was determined. Results Compared to controls, an increased α-diversity and distinct β-diversity were found in ESKD (Figure). The increase in α-diversity was correlated with protein-bound uremic toxins, particularly hippuric acid. A higher microbial dysbiosis index (MDI) was found in ESKD patients with the following enriched genera: Facealibacterium, Ruminococcus, Fusobacterium, Dorea, Anaerovorax, Sarcina, Akkermansia, Streptococcus, and Dysgonomonas. MDI at the genus level successfully differentiated between ESKD and controls in the discovery cohort (area under the curve [AUC] of 81.9%) and the validation cohort (AUC of 83.2%). Regarding functional enrichment analysis with gut metabolic modules, ESKD subjects presented with gut microbial function of increased saccharide and amino acid metabolism compared with matched controls. Conclusion An enriched but dysbiotic gut microbiota was presented in ESKD patients, in which the bacteria that were present increase amino acid metabolism linked to the production of protein-bound uremic toxins.