Uncovering specific taxonomic and functional alteration of gut microbiota in chronic kidney disease through 16S rRNA data.

Introduction: Chronic kidney disease (CKD) is worldwide healthcare burden with growing incidence and death rate. Emerging evidence demonstrated the compositional and functional differences of gut microbiota in patients with CKD. As such, gut microbial features can be developed as diagnostic biomarkers and potential therapeutic target for CKD. Methods: To eliminate the outcome bias arising from factors such as geographical distribution, sequencing platform, and data analysis techniques, we conducted a comprehensive analysis of the microbial differences between patients with CKD and healthy individuals based on multiple samples worldwide. A total of 980 samples from six references across three nations were incorporated from the PubMed, Web of Science, and GMrepo databases. The obtained 16S rRNA microbiome data were subjected to DADA2 processing, QIIME2 and PICRUSt2 analyses. Results: The gut microbiota of patients with CKD differs significantly from that of healthy controls (HC), with a substantial decrease in the microbial diversity among the CKD group. Moreover, a significantly reduced abundance of bacteria Faecalibacterium prausnitzii (F. prausnitzii) was detected in the CKD group through linear discriminant analysis effect size (LEfSe) analysis, which may be associated with the alleviating effects against CKD. Notably, we identified CKD-depleted F. prausnitzii demonstrated a significant negative correlation with three pathways based on predictive functional analysis, suggesting its potential role in regulating systemic acidbase disturbance and pro-oxidant metabolism. Discussion: Our findings demonstrated notable alterations of gut microbiota in CKD patients. Specific gut-beneficial microbiota, especially F. prausnitzii, may be developed as a preventive and therapeutic tool for CKD clinical management.

Yi-Shen-Hua-Shi regulates intestinal microbiota dysbiosis and protects against proteinuria in patients with chronic kidney disease: a randomized controlled study.

CONTEXT: Yi-Shen-Hua-Shi (YSHS) is a traditional Chinese medicine that treats chronic kidney disease (CKD). However, its efficacy in reducing proteinuria and underlying mechanisms is unknown. OBJECTIVE: This single-center randomized controlled trial explored whether YSHS could improve proteinuria and modulate the gut microbiota. MATERIALS AND METHODS: 120 CKD patients were enrolled and randomized to receive the renin-angiotensin-aldosterone system (RAAS) inhibitor plus YSHS (n = 56) or RAAS inhibitor (n = 47) alone for 4 months, and 103 patients completed the study. We collected baseline and follow-up fecal samples and clinical outcomes from participants. Total bacterial DNA was extracted, and the fecal microbiome was analyzed using bioinformatics. RESULTS: Patients in the intervention group had a significantly higher decrease in 24-h proteinuria. After 4 months of the YSHS intervention, the relative abundance of bacteria that have beneficial effects on the body, such as Faecalibacterium, Lachnospiraceae, Lachnoclostridium, and Sutterella increased significantly, while pathogenic bacteria such as the Eggerthella and Clostridium innocuum group decreased. However, we could not find these changes in the control group. Redundancy analysis showed that the decline in 24-h proteinuria during follow-up was significantly correlated with various taxa of gut bacteria, such as Lachnospiraceae and the Lachnoclostridium genus in the YSHS group. KEGG analysis also showed the potential role of YSHS in regulating glycan, lipid, and vitamin metabolism. DISCUSSION AND CONCLUSION: The YSHS granule reduced proteinuria associated with mitigating intestinal microbiota dysbiosis in CKD patients. The definite mechanisms of YSHS to improve proteinuria need to be further explored. TRIAL REGISTRATION: ChiCTR2300076136, retrospectively registered.

Prevotella copri promotes vascular calcification via lipopolysaccharide through activation of NF-κB signaling pathway.

Emerging evidence indicates that alteration of gut microbiota plays an important role in chronic kidney disease (CKD)-related vascular calcification (VC). We aimed to investigate the specific gut microbiota and the underlying mechanism involved in CKD-VC. We identified an increased abundance of Prevotella copri (P. copri) in the feces of CKD rats (induced by using 5/6 nephrectomy followed by a high calcium and phosphate diet) with aortic calcification via amplicon sequencing of 16S rRNA genes. In patients with CKD, we further confirmed a positive correlation between abundance of P. copri and aortic calcification scores. Moreover, oral administration of live P. copri aggravated CKD-related VC and osteogenic differentiation of vascular smooth muscle cells in vivo, accompanied by intestinal destruction, enhanced expression of Toll-like receptor-4 (TLR4), and elevated lipopolysaccharide (LPS) levels. In vitro and ex vivo experiments consistently demonstrated that P. copri-derived LPS (Pc-LPS) accelerated high phosphate-induced VC and VSMC osteogenic differentiation. Mechanistically, Pc-LPS bound to TLR4, then activated the nuclear factor κB (NF-κB) and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome signals during VC. Inhibition of NF-κB reduced NLRP3 inflammasome and attenuated Pc-LPS-induced VSMC calcification. Our study clarifies a novel role of P. copri in CKD-related VC, by the mechanisms involving increased inflammation-regulating metabolites including Pc-LPS, and activation of the NF-κB/NLRP3 signaling pathway. These findings highlight P. copri and its-derived LPS as potential therapeutic targets for VC in CKD.

The urogenital microbiome in chronic kidney disease patients on peritoneal dialysis.

INTRODUCTION AND OBJECTIVES: Diabetes, dyslipidemia, older age, gender, urinary tract infections, and recent antibiotic intake have been associated with a decrease in the urobiome richness and other fluctuations in this microbiome. Gut and blood microbiome have been reported to be altered in patients with chronic kidney disease (CKD), and specifically in peritoneal dialysis (PD) patients. Still, there are currently no studies describing the urogenital microbiome in CKD-PD patients. In this study we characterized the urobiome profile in 46 PD patients and analyzed its clinical and inflammatory parameters. MATERIALS AND METHODS: Mid-stream urine, fecal and blood samples were collected from 46 patients undergoing PD at Centro Hospitalar Universitário de São João (CHUSJ) in Porto, Portugal. Exclusion criteria were age under 18 years old, inability to give informed consent, history of infection in the last three months, and antibiotic intake in the last three months. The microbiome communities were analyzed by amplification and sequencing of the V3-V4 region of the bacterial 16S rRNA gene. Correlations with the patients' clinical data and inflammatory profile were performed. RESULTS: CKD-PD patients presented a unique urobiome profile dominated by Bacillota, Actinomycetota and Pseudomonadota and characterized by a lower Shannon diversity than fecal and blood microbiome. The taxonomic profiles of urogenital samples were organized in multiple subtypes dominated by populations of Lactobacillus, Staphylococcus, Streptococcus, Gardnerella, Prevotella, Escherichia-Shigella, being similar to other non-PD-CKD patients. Gender, sCD14, residual diuresis and history of peritonitis were significantly associated to variations in the urobiome. Although not reaching statistical significance, diabetes and the time on PD also showed association with particular taxonomic groups. Depletion of Gardnerella, Staphylococcus, Corynebacterium, Lactobacillus or Dermabacter populations correlated with CKD-PD patients with history of diabetes, history of peritonitis and altered levels of sCD14. CONCLUSIONS: Our results highlight urogenital microbiome as a potential partner and/or marker in the overall health state of CKD-PD patients.

Sweet, bloody consumption - what we eat and how it affects vascular ageing, the BBB and kidney health in CKD.

In today's industrialized society food consumption has changed immensely toward heightened red meat intake and use of artificial sweeteners instead of grains and vegetables or sugar, respectively. These dietary changes affect public health in general through an increased incidence of metabolic diseases like diabetes and obesity, with a further elevated risk for cardiorenal complications. Research shows that high red meat intake and artificial sweeteners ingestion can alter the microbial composition and further intestinal wall barrier permeability allowing increased transmission of uremic toxins like p-cresyl sulfate, indoxyl sulfate, trimethylamine n-oxide and phenylacetylglutamine into the blood stream causing an array of pathophysiological effects especially as a strain on the kidneys, since they are responsible for clearing out the toxins. In this review, we address how the burden of the Western diet affects the gut microbiome in altering the microbial composition and increasing the gut permeability for uremic toxins and the detrimental effects thereof on early vascular aging, the kidney per se and the blood-brain barrier, in addition to the potential implications for dietary changes/interventions to preserve the health issues related to chronic diseases in future.

Changes in the Progression of Chronic Kidney Disease in Patients Undergoing Fecal Microbiota Transplantation.

Chronic kidney disease (CKD) is a progressive loss of renal function in which gut dysbiosis is involved. Fecal microbiota transplantation (FMT) may be a promising alternative for restoring gut microbiota and treating CKD. This study evaluated the changes in CKD progression in patients treated with FMT. Patients with diabetes and/or hypertension with CKD clinical stages 2, 3, and 4 in this single-center, double-blind, randomized, placebo-controlled clinical trial (NCT04361097) were randomly assigned to receive either FMT or placebo capsules for 6 months. Laboratory and stool metagenomic analyses were performed. A total of 28 patients were included (15 FMT and 13 placebo). Regardless of CKD stages, patients responded similarly to FMT treatment. More patients (53.8%) from the placebo group progressed to CKD than the FMT group (13.3%). The FMT group maintained stable renal function parameters (serum creatinine and urea nitrogen) compared to the placebo group. Adverse events after FMT treatment were mild or moderate gastrointestinal symptoms. The abundance of Firmicutes and Actinobacteria decreased whereas Bacteroidetes, Proteobacteria and Roseburia spp. increased in the FMT group. CKD patients showed less disease progression after FMT administration. The administration of oral FMT in patients with CKD is a safe strategy, does not represent a risk, and has potential benefits.

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.

Role of the gut microbiota and their metabolites in hemodialysis patients.

High serum phosphate levels in chronic kidney disease (CKD) are linked to adverse health outcomes, including cardiovascular disease, kidney disease progression, and all-cause mortality. This study is aimed to find out which microorganisms or microbial functions have a significant impact on higher calcium-phosphorus product (Ca x P) after they undergo hemodialysis (HD) treatment. Feces samples from 30 healthy controls, 15 dialysis patients with controlled Ca xP (HD), and 16 dialysis patients with higher Ca xP (HDHCP) were collected to perform in 16S amplicon sequencing. We found gut microbial composition was significantly different between hemodialysis patients and healthy controls. Three phyla including Firmicutes, Actinobacteria, and Proteobacteria were significantly enriched in hemodialysis patients. Although only one genus, Lachnospiraceae_FCS020_group, was significantly increased in higher Ca xP group, there were four metabolic pathways predicted by PICRUSt significantly increased in higher Ca xP group and associated with causing VC, including the pentose phosphate pathway, steroid biosynthesis, terpenoid backbone biosynthesis, and fatty acid elongation pathway. Characterizing dysbiosis of gut microbiome played the important role in hemodialysis patients.

Dysbiosis of Gut Microbiota Contributes to Uremic Cardiomyopathy via Induction of IFNγ-Producing CD4+ T Cells Expansion.

Uremic cardiomyopathy (UCM) correlates with chronic kidney disease (CKD)-induced morbidity and mortality. Gut microbiota has been involved in the pathogenesis of certain cardiovascular disease, but the role of gut microbiota in the pathogenesis of UCM remains unknown. Here, we performed a case-control study to compare the gut microbiota of patients with CKD and healthy controls by 16S rRNA (rRNA) gene sequencing. To test the causative relationship between gut microbiota and UCM, we performed fecal microbiota transplantation (FMT) in 5/6th nephrectomy model of CKD. We found that opportunistic pathogens, particularly Klebsiella pneumoniae (K. pneumoniae), are markedly enriched in patients with CKD. FMT from CKD patients aggravated diastolic dysfunction in the mouse model. The diastolic dysfunction was associated with microbiome-dependent increases in heart-infiltrating IFNγ+ CD4+ T cells. Monocolonization with K. pneumoniae increased cardiac IFNγ+ CD4+ T cells infiltration and promoted UCM development of the mouse model. A probiotic Bifidobacterium animalis decreased the relative abundance of K. pneumoniae, reduced levels of cardiac IFNγ+ CD4+ T cells and ameliorated the severity of diastolic dysfunction in the mice. Thus, the aberrant gut microbiota in CKD patients, especially K. pneumoniae, contributed to UCM pathogenesis through the induction of heart-infiltrating IFNγ+ CD4+ T cells expansion, proposing that a Gut Microbiota-Gut-Kidney-Heart axis could play a critical role in elucidating the etiology of UCM, and suggesting that modulation of the gut bacteria may serve as a promising target for the amelioration of UCM. IMPORTANCE Uremic cardiomyopathy (UCM) correlates tightly with increased mortality in patients with chronic kidney disease (CKD), yet the pathogenesis of UCM remains incompletely understood, limiting therapeutic approaches. Our study proposed that a Gut Microbiota-Gut-Kidney-Heart axis could play a critical role in understanding etiology of UCM. There is a major need in future clinical trials of patients with CKD to explore if modulation of gut microbiota by fecal microbiota transplantation (FMT), probiotics or antibiotics can alleviate cardiac dysfunction, reduce mortality, and improve life quality.

Perturbed gut microbiome and fecal and serum metabolomes are associated with chronic kidney disease severity.

BACKGROUND: Chronic kidney disease (CKD) is a severe public health problem associated with a disordered gut microbiome. However, the functional alterations of microbiota and their cross talk with metabolism pathways based on disease severity remain unclear. RESULTS: We performed metagenomics and untargeted metabolomics in a cohort of 68 patients with CKD of differing severities and 20 healthy controls to characterize the complex interplay between the gut microbiome and fecal and serum metabolites during CKD progression. We identified 26 microbial species that significantly changed in patients with CKD; 18 species changed as the disease progressed, and eight species changed only in a specific CKD group. These distinct changes in gut microbiota were accompanied by functional alterations in arginine and proline, arachidonic acid, and glutathione metabolism and ubiquinone and other terpenoid-quinone biosynthesis pathways during CKD progression. Further metabolomic analyses revealed that the distributions of toxic and pro-oxidant metabolites from these four essential metabolic pathways varied in the feces and serum as CKD progressed. Furthermore, we observed a complex co-occurrence between CKD severity-related bacteria and the characterized metabolites from the four essential metabolic pathways. Notably, Ruminococcus bromii, fecal hydroquinone, and serum creatinine were identified as the main contributors to the integrated network, indicating their key roles in CKD progression. Moreover, a noninvasive model including R. bromii and fecal hydroquinone, L-cystine, and 12-keto-tetrahydro-LTB4 levels classified the CKD severity (area under the curve [AUC]: > 0.9) and had better performance than the serum creatinine level for mild CKD (AUC: 0.972 vs. 0.896). CONCLUSIONS: Perturbed CKD severity-related gut microbiota may contribute to unbalanced toxic and pro-oxidant metabolism in the gut and host, accelerating CKD progression, which may be an early diagnostic and therapeutic target for CKD. Video Abstract.

Akkermansia muciniphila ameliorates chronic kidney disease interstitial fibrosis via the gut-renal axis.

CONTEXT: Chronic kidney disease (CKD) affects approximately 10% of the global population. The abundance of Akkermansia muciniphila (AKK) is significantly reduced in CKD patients. OBJECTIVE: This study investigated the effects of AKK bacteria on kidney damage and the renal interstitium in rats with CKD. MATERIALS AND METHODS: CKD model 5/6 nephrectomy rats were used. CKD rats were supplemented with AKK (2 × 108 cfu/0.2 mL) for 8 weeks. RESULTS: AKK administration significantly suppressed epithelial-mesenchymal transition (EMT), and high-throughput 16S rRNA pyrosequencing showed that AKK supplementation restored the disordered intestinal microecology in CKD rats. AKK also enhanced the intestinal mucosal barrier function. AKK may regulate the intestinal microecology and reduce renal interstitial fibrosis by enhancing the abundance of probiotics and reducing damage to the intestinal mucosal barrier. CONCLUSION: The results suggest that AKK administration could be a novel therapeutic strategy for treating renal fibrosis and CKD.

Probiotic Bifidobacteria Mitigate the Deleterious Effects of para-Cresol in a Drosophila melanogaster Toxicity Model.

Renal impairment associated with chronic kidney disease (CKD) causes the buildup of uremic toxins that are deleterious to patient health. Current therapies that manage toxin accumulation in CKD offer an incomplete therapeutic effect against toxins such as para-cresol (p-cresol) and p-cresyl sulfate. Probiotic therapies can exploit the wealth of microbial diversity to reduce toxin accumulation. Using in vitro culture techniques, strains of lactobacilli and bifidobacteria from a 24-strain synbiotic were investigated for their ability to remove p-cresol. Four strains of bifidobacteria internalized p-cresol from the extracellular environment. The oral supplementation of these toxin-clearing probiotics was more protective than control strains in a Drosophila melanogaster toxicity model. Bifidobacterial supplementation was also associated with higher abundance of lactobacilli in the gut microbiota of p-cresol-exposed flies. The present findings suggest that these strains might reduce p-cresol in the gut in addition to increasing the prevalence of other beneficial bacteria, such as lactobacilli, and should be tested clinically to normalize the dysbiotic gut microbiota observed in CKD patients. IMPORTANCE Chronic kidney disease (CKD) affects approximately 10% of the global population and has limited treatment options. The accumulation of gut microbiota-derived uremic toxins, such as para-cresol (p-cresol) and p-cresyl sulfate, is associated with the onset of comorbidities (i.e., atherosclerosis and cognitive disorders) in CKD. Unfortunately, dialysis, the gold standard therapy is unable to remove these toxins from the bloodstream due to their highly protein-bound nature. Some strains of Bifidobacterium have metabolic properties that may be useful in managing uremic toxicity. Using a Drosophila model, the present work highlights why dosing with certain probiotic strains may be clinically useful in CKD management.

Strongyloides stercoralis infection induces gut dysbiosis in chronic kidney disease patients.

BACKGROUND: Strongyloides stercoralis infection typically causes severe symptoms in immunocompromised patients. This infection can also alter the gut microbiota and is often found in areas where chronic kidney disease (CKD) is common. However, the relationship between S. stercoralis and the gut microbiome in chronic kidney disease (CKD) is not understood fully. Recent studies have shown that gut dysbiosis plays an important role in the progression of CKD. Hence, this study aims to investigate the association of S. stercoralis infection and gut microbiome in CKD patients. METHODOLOGY/PRINCIPAL FINDINGS: Among 838 volunteers from Khon Kaen Province, northeastern Thailand, 40 subjects with CKD were enrolled and divided into two groups (S. stercoralis-infected and -uninfected) matched for age, sex and biochemical parameters. Next-generation technology was used to amplify and sequence the V3-V4 region of the 16S rRNA gene to provide a profile of the gut microbiota. Results revealed that members of the S. stercoralis-infected group had lower gut microbial diversity than was seen in the uninfected group. Interestingly, there was significantly greater representation of some pathogenic bacteria in the S. stercoralis-infected CKD group, including Escherichia-Shigella (P = 0.013), Rothia (P = 0.013) and Aggregatibacter (P = 0.03). There was also a trend towards increased Actinomyces, Streptococcus and Haemophilus (P > 0.05) in this group. On the other hand, the S. stercoralis-infected CKD group had significantly lower representation of SCFA-producing bacteria such as Anaerostipes (P = 0.01), Coprococcus_1 (0.043) and a non-significant decrease of Akkermansia, Eubacterium rectale and Eubacterium hallii (P > 0.05) relative to the uninfected group. Interesting, the genera Escherichia-Shigella and Anaerostipes exhibited opposing trends, which were significantly related to sex, age, infection status and CKD stages. The genus Escherichia-Shigella was significantly more abundant in CKD patients over the age of 65 years and infected with S. stercoralis. A correlation analysis showed inverse moderate correlation between the abundance of the genus of Escherichia-Shigella and the level of estimated glomerular filtration rate (eGFR). CONCLUSIONS/SIGNIFICANCE: Conclusion, the results suggest that S. stercoralis infection induced gut dysbiosis in the CKD patients, which might be involved in CKD progression.

Dysbiosis in Patients with Chronic Kidney Disease: Let Us Talk About Vitamin K.

PURPOSE OF REVIEW: This narrative review aimed to summarize the current evidence on the connection between dysbiosis and vitamin K deficiency in patients with chronic kidney disease (CKD). The presence of dysbiosis (perturbations in the composition of the microbiota) has been described in several non-communicable diseases, including chronic kidney disease, and it has been hypothesized that dysbiosis may cause vitamin K deficiency. Patients with CKD present both vitamin K deficiency and gut dysbiosis; however, the relationship between gut dysbiosis and vitamin K deficiency remains to be addressed. RECENT FINDINGS: Recently, few studies in animals have demonstrated that a dysbiotic environment is associated with low production of vitamin K by the gut microbiota. Vitamin K plays a vital role in blood coagulation as well as in the cardiovascular and bone systems. It serves as a cofactor for γ-glutamyl carboxylases and thus is essential for the post-translational modification and activation of vitamin K-dependent calcification regulators, such as osteocalcin, matrix Gla protein, Gla-rich protein, and proteins C and S. Additionally, vitamin K executes essential antioxidant and anti-inflammatory functions. Dietary intake is the main source of vitamin K; however, it also can be produced by gut microbiota. This review discusses the effects of uremia on the imbalance in gut microbiota, vitamin K-producing bacteria, and vitamin K deficiency in CKD patients, leading to a better understanding and raising hypothesis for future clinical studies.

Clostridium species diversity in gut microbiota of patients with renal failure.

The Pathology of digestive tract has long been known to be correlated with chronic kidney disease (CKD). The member of the major Firmicutes phylum especially Clostridium subcluster XIVa altered quantitatively and qualitatively in the gut microbiota of patients with End Stage Renal Disease (ESRD) and CKD. Therefore, in this study, the abundance of the species of Clostridium genus of Firmicutes phylum compared between intestine microbiota of patients with kidney failure and healthy individual. Fresh fecal specimens of 20 patients at different stages of CKD and 20 healthy individuals were collected. Bacterial DNA of samples were extracted to use for 16S ribosomal DNA sequencing targeting the V3-V4 region. Next generation sequencing (NGS) method at MiSeq system was used to find the diversity of gut microbiota composition. Totally, 11 (1.68%) of 651 bacterial strains which were isolated from forty fecal samples of both healthy volunteers and CKD/ESRD patients, were identified as Clostridium species. Eight genera of 11 Clostridium genera were related to Clostridium sensu stricto, and 3 other genera were as follows Vallitalea, Acidaminobacter and Caloramator. Among both group, the highest abundance was dedicated to Clostridium celatum genera. Sarcina maxima were not identified. The composition of Clostridium spp. showed the same frequency among CKD/ESRD and healthy groups (p < 0.05). The abundance of Clostridium spp. is virtually the same and not differs among healthy individuals and CKD/ESRD patients. Results of the present indicate despite of critical role of gut microbiota, some pathogens and their metabolites have no role on hemostasis and pathogenesis of kidney disorders.

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

Rationale and Objective: Gut 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 Design: This was a cross-sectional cohort study. Settings and Participants: Fecal 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. Results: Specific 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. Conclusion: This 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.

Probiotics-Supplemented Low-Protein Diet for Microbiota Modulation in Patients with Advanced Chronic Kidney Disease (ProLowCKD): Results from a Placebo-Controlled Randomized Trial.

The probiotics-supplemented low-protein diet in chronic kidney disease (ProLowCKD) was a single-centre, double-blind, placebo-controlled, randomised trial that was conducted to investigate whether the association between a low protein diet (LPD) and a new formulation of probiotics (Bifidobacterium longum and Lactobacillus reuteri) was effective at reducing traditional uremic, microbiota-derived, and proatherogenic toxins in sixty patients affected by advanced CKD. After 2 months of a LPD-a reduction in blood urea nitrogen (52 ± 17 vs. 46 ± 15 mg/dL, p = 0.003), total cholesterol (185 ± 41 vs. 171 ± 34 mg/dL, p = 0.001), and triglycerides (194 ± 148 vs. 161 ± 70 mg/dL, p = 0.03) was observed; 57 subjects were then randomized to receive probiotics or a placebo for the subsequent 3 months. A total of 27 patients in the placebo group showed increased serum values of total cholesterol (169 ± 36 vs. 185 ± 40 mg/dL, p = 0.01), LDL cholesterol (169 ± 36 vs. 185 ± 40 mg/dL, p = 0.02), lipoprotein-associated phospholipase A2 (155.4 ± 39.3 vs. 167.5 ± 51.4 nmol/mL/min, p = 0.006), and indoxyl-sulphate (30.1 ± 17.6 vs. 34.5 ± 20.2 µM, p = 0.026), while the 24 subjects in the probiotics group showed a trend in the reduction of microbiota toxins. A reduction of antihypertensive and diuretic medications was possible in the probiotics group. This study shows that associating probiotics to LPD may have an additional beneficial effect on the control and modulation of microbiota-derived and proatherogenic toxins in CKD patients.

Butyrate producing microbiota are reduced in chronic kidney diseases.

Chronic kidney disease is a major public health concern that affects millions of people globally. Alterations in gut microbiota composition have been observed in patients with chronic kidney disease. Nevertheless, the correlation between the gut microbiota and disease severity has not been investigated. In this study, we performed shot-gun metagenomics sequencing and identified several taxonomic and functional signatures associated with disease severity in patients with chronic kidney disease. We noted that 19 microbial genera were significantly associated with the severity of chronic kidney disease. The butyrate-producing bacteria were reduced in patients with advanced stages of chronic kidney diseases. In addition, functional metagenomics showed that two-component systems, metabolic activity and regulation of co-factor were significantly associated with the disease severity. Our study provides valuable information for the development of microbiota-oriented therapeutic strategies for chronic kidney disease.

Effects of Low Protein Diet on Modulating Gut Microbiota in Patients with Chronic Kidney Disease: A Systematic Review and Meta-analysis of International Studies.

Background: Although associations between low protein diet (LPD) and changes of gut microbiota have been reported; however, systematic discernment of the effects of LPD on diet-microbiome-host interaction in patients with chronic kidney disease (CKD) is lacking. Methods: We searched PUBMED and EMBASE for articles published on changes of gut microbiota associated with implementation of LPD in CKD patients until July 2021. Independent researchers extracted data and assessed risks of bias. We conducted meta-analyses of combine p-value, mean differences and random effects for gut microbiota and related metabolites. Study heterogeneity was measured by Tau2 and I2 statistic. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: Five articles met inclusion criteria. The meta-analyses of gut microbiota exhibited enrichments of Lactobacillaceae (meta-p= 0.010), Bacteroidaceae (meta-p= 0.048) and Streptococcus anginosus (meta-p< 0.001), but revealed depletion of Bacteroides eggerthii (p=0.017) and Roseburia faecis (meta-p=0.019) in LPD patients compared to patients undergoing normal protein diet. The serum IS levels (mean difference: 0.68 ug/mL, 95% CI: -8.38-9.68, p= 0.89) and pCS levels (mean difference: -3.85 ug/mL, 95% CI: -15.49-7.78, p < 0.52) did not change between groups. We did not find significant differences on renal function associated with change of microbiota between groups (eGFR, mean difference: -7.21 mL/min/1.73 m2, 95% CI: -33.2-18.79, p= 0.59; blood urea nitrogen, mean difference: -6.8 mg/dL, 95% CI: -46.42-32.82, p= 0.74). Other clinical (sodium, potassium, phosphate, albumin, fasting sugar, uric acid, total cholesterol, triglycerides, C-reactive protein and hemoglobin) and anthropometric estimates (body mass index, systolic blood pressure and diastolic blood pressure) did not differ between the two groups. Conclusions: This systematic review and meta-analysis suggested that the effects of LPD on the microbiota were observed predominantly at the families and species levels but minimal on microbial diversity or richness. In the absence of global compositional microbiota shifts, the species-level changes appear insufficient to alter metabolic or clinical outputs.

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

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 (rs = 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: rs = 0.342, p < 0.001; p-cresyl glucuronide: rs = 0.268, p = 0.006), whereas an association was found between fecal and plasma levels of indole acetic acid (rs = 0.306; p = 0.002). Finally, the albumin symmetry factor correlates positively with eGFR (rs = 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.