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Increasing numbers of pyelonephritis-associated uropathogenic Escherichia coli (UPEC) are exhibiting high resistance to antibiotic therapy. They include a particular clonal group, the CTX-M-15-producing O25b:H4-ST131 clone, which has been shown to have a high dissemination potential. Here we show that a representative isolate of this E. coli clone, referred to as TN03, has enhanced metabolic capacities, acts as a potent intestine- colonizing strain, and displays the typical features of UPEC strains. In a modified streptomycin-treated mouse model of intestinal colonization where streptomycin was stopped 5 days before inoculation, we show that TN03 outcompetes the commensal E. coli strains K-12 MG1655, IAI1, and ED1a at days 1 and 7. Using an experimental model of ascending UTI in C3H/HeN mice, we then show that TN03 colonized the urinary tract. One week after the transurethral inoculation of the TN03 isolates, the bacterial loads in the bladder and kidneys were significantly greater than those of two other UPEC strains (CFT073 and HT7) belonging to the same B2 phylogenetic group. The differences in bacterial loads did not seem to be directly linked to differences in the inflammatory response, since the intrarenal expression of chemokines and cytokines and the number of polymorphonuclear neutrophils attracted to the site of inflammation was the same in kidneys colonized by TN03, CFT073, or HT7. Lastly, we show that in vitro TN03 has a high maximum growth rate in both complex (Luria-Bertani and human urine) and minimum media. In conclusion, our findings indicate that TN03 is a potent UPEC strain that colonizes the intestinal tract and may persist in the kidneys of infected hosts.

Dysbiosis represents changes in composition and structure of the gut microbiome community (microbiome), which may dictate the physiological phenotype (health or disease). Recent technological advances and efforts in metagenomic and metabolomic analyses have led to a dramatical growth in our understanding of microbiome, but still, the mechanisms underlying gut microbiome–host interactions in healthy or diseased state remain elusive and their elucidation is in infancy. Disruption of the normal gut microbiota may lead to intestinal dysbiosis, intestinal barrier dysfunction, and bacterial translocation. Excessive uremic toxins are produced as a result of gut microbiota alteration, including indoxyl sulphate, p -cresyl sulphate, and trimethylamine-N-oxide, all implicated in the variant processes of kidney diseases development. This review focuses on the pathogenic association between gut microbiota and kidney diseases (the gut–kidney axis), covering CKD, IgA nephropathy, nephrolithiasis, hypertension, acute kidney injury, hemodialysis and peritoneal dialysis in clinic. Targeted interventions including probiotic, prebiotic and symbiotic measures are discussed for their potential of re-establishing symbiosis, and more effective strategies for the treatment of kidney diseases patients are suggested. The novel insights into the dysbiosis of the gut microbiota in kidney diseases are helpful to develop novel therapeutic strategies for preventing or attenuating kidney diseases and complications.

Background: The microbiota composition is now considered as one of the main modifiable risk factors for health. No controlled study has been performed on the association between microbiota composition and renal function. We applied Mendelian randomization (MR) to estimate the casual impact of eight microbiota genera on renal function and the risk of chronic kidney disease (CKD). Methods: MR was implemented by using summary-level data from the largest-ever genome-wide association studies (GWAS) conducted on microbiota genera, CKD and renal function parameters. The inverse-variance weighted method (IVW), weighted median (WM)-based method, MR-Egger, MR-Robust Adjusted Profile Score (RAPS), MR-Pleiotropy RESidual Sum and Outlier (PRESSO) were applied. A sensitivity analysis was conducted using the leave-one-out method. Results: The Anaerostipes genus was associated with higher estimated glomerular filtration rate (eGFR) in the overall population (IVW: β = 0.003, p = 0.021) and non-diabetes mellitus (DM) subgroup (IVW: β = 0.003, p = 0.033), while it had a non-significant association with the risk of CKD and eGFR in DM patients. Subjects with higher abundance of Desulfovibrio spp. had a significantly lower level of eGFR (IVW: β = −0.001, p = 0.035); the same results were observed in non-DM (IVW: β = −0.001, p = 0.007) subjects. Acidaminococcus, Bacteroides, Bifidobacterium, Faecalibacterium, Lactobacillus and Megamonas had no significant association with eGFR in the overall population, DM and non-DM subgroups (IVW: p > 0.105 for all groups); they also presented no significant association with the risk of CKD (IVW: p > 0.201 for all groups). Analyses of MR-PRESSO did not highlight any outlier. The pleiotropy test, with very negligible intercept and insignificant p-value, also indicated no chance of pleiotropy for all estimations. The leave-one-out method demonstrated that the observed links were not driven by single single-nucleotide polymorphism. Conclusions: Our results suggest an adverse association of Desulfovibrio spp. and a beneficial association of Anaerostipes spp. with eGFR. Further studies using multiple robust instruments are needed to confirm these results.

The gut microbiota (GM) can affect the immune system, which can lead to a variety of diseases, as confirmed by many studies. However, the exact mechanism by which GM affects kidney stone incidence through the immune system remains unclear. This study used a two-step, two-sample Mendelian randomization (MR) analysis by inverse variance weighting (IVW) method as well as Bayesian weighting (BWMR) to find out how the gut microbiota and inflammatory cytokines contribute to kidney stones, followed by a mediated MR analysis to exploreHow inflammatory cytokines are involved in the connection with the gut microbiota and kidney stones. MR analysis revealed that seven intestinal flora were protective against kidney stones, including family. Actinomycetaceae, family.Clostridiaceae1, genus.Clostridiumsensustricto1, genus. Hungatella, genus.LachnospiraceaeUCG001, genus.LachnospiraceaeUCG008 and order. Actinomycetales, while four intestinal flora, including genus. Haemophilus, genus. RuminococcaceaeUCG010, order.Rhodospirillales and phylum.Actinobacteria may increase the risk of kidney stones. In addition, it was confirmed that seven Inflammatory cytokines DNER, IL-18, IL-1α, SLAMF1, STAMPB, CST5 and FGF-5 in association with kidney stones. Notably, the mediating MR indicated the causal effect of phylum. Actinobacteria and order. Rhodospirillales gut group on kidney stones was mainly modulated by IL-18 levels, with mediating effects accounting for 15.8% and 12.8% of the total effect, respectively. The present study demonstrates this phylum. Actinobacteria and order. Rhodospirillales flora have an important role in reducing the risk of kidney stones and act mainly by modulating IL-18 levels.

Staphylococcus aureus causes acute and chronic infections resulting in significant morbidity. Urease, an enzyme that generates NH3 and CO2 from urea, is key to pH homeostasis in bacterial pathogens under acidic stress and nitrogen limitation. However, the function of urease in S. aureus niche colonization and nitrogen metabolism has not been extensively studied. We discovered that urease is essential for pH homeostasis and viability in urea-rich environments under weak acid stress. The regulation of urease transcription by CcpA, Agr, and CodY was identified in this study, implying a complex network that controls urease expression in response to changes in metabolic flux. In addition, it was determined that the endogenous urea derived from arginine is not a significant contributor to the intracellular nitrogen pool in non-acidic conditions. Furthermore, we found that during a murine chronic renal infection, urease facilitates S. aureus persistence by promoting bacterial fitness in the low-pH, urea-rich kidney. Overall, our study establishes that urease in S. aureus is not only a primary component of the acid response network but also an important factor required for persistent murine renal infections.

Studies suggest a link between the gut microbiome and metastatic renal cell carcinoma (mRCC) outcomes, including evidence that mRCC patients possess a lower abundance of Bifidobacterium spp. compared to healthy adults. We sought to assess if a Bifidobacterium‐containing yogurt product could modulate the gut microbiome and clinical outcome from vascular endothelial growth factor‐tyrosine kinase inhibitors (VEGF‐TKIs). mRCC patients initiating VEGF‐TKIs, regardless of the line of therapy, were randomized to probiotic‐supplemented (two 4 oz. servings of the probiotic yogurt product daily) or probiotic‐restricted arms. Stool samples were collected prior to therapy and at weeks 2, 3, 4, and 12. Microbiome composition was assessed using whole‐metagenome sequencing. A total of 20 patients were randomized. Bifidobacterium animalis, the active ingredient of the probiotic supplement, reached detectable levels in all patients in the probiotic‐supplemented arm versus two patients in the probiotic‐restricted arm. Clinical benefit rate was similar in probiotic‐supplemented versus probiotic‐restricted arms (70% vs. 80%, p = 0.606). Linear discriminant analysis (LDA) effect size analysis of MetaPhIAn2 abundance data predicted 25 enriched species demonstrating an LDA score >3 in either clinical benefit or no clinical benefit. In patients with clinical benefit (vs. no clinical benefit), Barnesiella intestinihominis and Akkermansia muciniphila were significantly more abundant (p = 7.4 × 10−6 and p = 5.6 × 10−3, respectively). This is the first prospective randomized study demonstrating modulation of the gut microbiome with a probiotic in mRCC. Probiotic supplementation successfully increased the Bifidobacterium spp. levels. Analysis of longitudinal stool specimens identified an association between B. intestinihominis, A. muciniphila, and clinical benefit with therapy. Trial Registration: NCT02944617 Our study provides novel evidence regarding gut microbiome modulation with a Bifidobacterium‐containing yogurt in metastatic renal cell carcinoma patients receiving targeted therapies and specifies the microbiota members (Barnesiella intestinihominis, Akkermansia muciniphila) associated with clinical benefit from targeted therapies in mRCC.

Background The dogma that urine is sterile in healthy individuals has been overturned by recent studies applying molecular-based methods. Mounting evidences indicate that dysbiosis of the urinary microbiota is associated with several urological diseases. In this study, we aimed to investigate the urinary microbiome of male patients with calcium-based kidney stones and compare it with those of healthy individuals. Results The diversity of the urinary microbiota in kidney stone patients was significantly lower than that of healthy controls based on the Shannon and Simpson index ( P  < 0.001 for both indices). The urinary microbiota structure also significantly differed between kidney stone patients and healthy controls (ANOSIM, R = 0.11, P  < 0.001). Differential representation of inflammation associated bacteria (e.g., Acinetobacter ) and several enriched functional pathways were identified in the urine of kidney stones patients. Meanwhile, we found the species diversity, overall composition of microbiota and predicted functional pathways were similar between bladder urine and renal pelvis urine in kidney stone patients. Conclusions A marked dysbiosis of urinary microbiota in male patients with calcium-based kidney stones was observed, which may be helpful to interpret the association between bacteria and calcium-based kidney stones.

Introduction Increasing evidence indicates an important role of microbiota in cancer development and progression, while little is known about the correlation between microbiota and renal cell carcinoma (RCC). Thus, we performed this study to profile the intratumoral microbiota possibly associated with RCC. Materials and methods Paired RCC and adjacent normal tissue samples were collected from 24 patients with RCC. V3-V4 variable region of microbial 16S rRNA gene was sequenced using Illumina MiSeq. Sequencing reads were processed using QIIME. Differentially abundant bacterial taxa between groups were identified by LEfSe, and their potential functions were inferred by PICRUSt. Results Decreased species diversity was presented in RCC tissues (Simpson index, P  = 0.0340), and the composition of the bacterial community in RCC tissues was significantly distinct from that in normal tissues (unweighted UniFrac distance, P  = 0.026; weighted UniFrac distance, P  = 0.017). Compared with normal tissues, 25 taxa increased and 47 reduced taxa were identified in RCC tissues. Among these taxa, the class Chloroplast (AUC = 0.91, P  < 0.0001) and the order Streptophyta (AUC = 0.89, P  < 0.0001) showed high indication accuracy to discriminate RCC tissues from normal tissues. Furthermore, nine altered pathways were identified in RCC tissues to reveal the potential microbial function. Conclusions Our results have uncovered the presence of distinct microbiota in RCC and adjacent normal tissues and provided a better understanding of the possible role of the intratumoral microbiota in RCC. Further studies are required to confirm our results and determine the real correlation between microbiota and RCC.

Shiga toxin-producing Escherichia coli -associated haemolytic uraemic syndrome (STEC-HUS) is associated with renal and neurological injury. This Review summarizes the pathophysiology and clinical presentation of STEC-HUS and its acute and long-term effects on the kidney and central nervous system. The authors also describe the experience of a single centre that was affected by the STEC-HUS outbreak in Germany in 2011. Shiga toxin-producing Escherichia coli -associated haemolytic uraemic syndrome (STEC-HUS) is one of the most important causes of acute kidney injury in patients of all ages, especially in children. It can occur sporadically or in outbreaks. STEC-HUS is a systemic illness caused by toxin-mediated injury to the vascular endothelium and a generalized inflammatory response. The kidney and the brain are the two primary target organs. Nearly 40% of patients with STEC-HUS require at least temporary renal replacement therapy and up to 20% will have permanent residual kidney dysfunction. Neurological injury can be sudden and severe and is the most frequent cause of acute mortality in patients with STEC-HUS. Over the past 30 years, a wide range of inflammatory mediators have been linked to the pathogenesis of STEC-HUS and associated renal and neurological complications. Recently, evidence has accumulated that abnormal activation of the alternative pathway of complement occurs in patients with STEC-HUS. In the large outbreak of STEC-HUS caused by E. coli O104:H4 that occurred in Germany in May 2011, a large number of patients received eculizumab, a monoclonal antibody directed against C5, in an open-label manner. We describe the experience with eculizumab under these emergent circumstances at one large centre. Key Points The kidney and the brain are the two principal target organs in patients with Shiga toxin-producing Escherichia coli -associated haemolytic uraemic syndrome (STEC-HUS) Outbreaks of enteritis and STEC-HUS caused by novel bacterial strains continue to occur and might be associated with unique clinical features The pathophysiology of organ injury in the kidney and the brain might differ and could influence the response to treatment and long-term outcomes Nearly 40% of patients with STEC-HUS require renal replacement therapy and brain involvement is the most frequent cause of fatalities Activation of the alternative complement pathway may contribute to the pathogenesis of STEC-HUS and further clinical research is needed to determine if blockade of this pathway attenuates the disease

Gut microbiota plays a central role in programming host metabolic function and immune modulation in both health and disease. Microbial dysbiosis leads to an increase in opportunistic pathogens and a reduction in beneficial bacteria, which collectively result in the excessive production of detrimental metabolites, particularly uremic toxins such as indoxyl sulfate and trimethylamine-N-oxide, while concurrently decreasing beneficial metabolites, such as short-chain fatty acids and tryptophan catabolites, including indole-3-aldehyde. The accumulation of harmful metabolites and depletion of protective metabolites contribute to fibrosis progression through various mediators, including the renin-angiotensin system, reactive oxygen species, Toll-like receptor 4, aryl hydrocarbon receptor, inhibitor of kappa B/nuclear factor kappa B, and Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 pathways. This review highlights the pathogenic link between gut microbiota and kidney damage via the gut-kidney axis, encompassing acute kidney injury (AKI) and chronic kidney disease (CKD). Innovative therapeutic strategies, including microbial therapeutics (such as probiotics, prebiotics, and synbiotics), natural products (such as neohesperidin, isoquercitrin, and polysaccharides), and fecal microbiota transplantation, have been proposed to restore microbial balance and improve kidney function. Targeted modulation of the gut microbiota offers a promising strategy for developing novel treatments in AKI, CKD, and the transition from AKI-to-CKD. This approach has the potential to prevent or mitigate these conditions and their complications.