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Key Points Despite nearly four decades of clinical experience with Bacillus Calmette–Guérin (BCG) for bladder cancer, the mechanism of its therapeutic effect is still under investigation The requirements for effective BCG therapy include an intact immune system, live BCG, and close contact of BCG with bladder cancer cells Important constituents of the cellular inflammatory response to BCG include CD4 + and CD8 + lymphocytes, natural killer cells, and granulocytes Important elements of the humoral immune response to BCG include TRAIL (tumour necrosis factor-related apoptosis-inducing ligand), IL-2, IL-8, IL-18, IL-12, interferon (IFN)-γ, and tumour necrosis factor (TNF) Bladder cancer cells and benign urothelial cells might have a role in the initial recognition and processing of BCG, leading to immune system recruitment Future investigation will hopefully lead to the discovery of clinically useful predictors of response to BCG and development of recombinant BCG strains with improved efficacy and decreased toxicity Intravesical BCG instillation is a longstanding therapy for bladder cancer, but its mode of action is still under investigation. This Review summarises the current understanding of the requirements for effective BCG therapy, and the putative roles of normal and malignant bladder cells, as well as the immune system, in the response to BCG. Bacillus Calmette–Guérin (BCG) has been used to treat non-muscle-invasive bladder cancer for more than 30 years. It is one of the most successful biotherapies for cancer in use. Despite long clinical experience with BCG, the mechanism of its therapeutic effect is still under investigation. Available evidence suggests that urothelial cells (including bladder cancer cells themselves) and cells of the immune system both have crucial roles in the therapeutic antitumour effect of BCG. The possible involvement of bladder cancer cells includes attachment and internalization of BCG, secretion of cytokines and chemokines, and presentation of BCG and/or cancer cell antigens to cells of the immune system. Immune system cell subsets that have potential roles in BCG therapy include CD4 + and CD8 + lymphocytes, natural killer cells, granulocytes, macrophages, and dendritic cells. Bladder cancer cells are killed through direct cytotoxicity by these cells, by secretion of soluble factors such as TRAIL (tumour necrosis factor-related apoptosis-inducing ligand), and, to some degree, by the direct action of BCG. Several gaps still exist in our knowledge that should be addressed in future efforts to understand this biotherapy of cancer.

Mounting evidence indicates that microbiome plays an important role in the development and progression of cancer. The dogma that urine in healthy individuals must be sterile has been overturned. Dysbiosis of the urinary microbiome has been revealed responsible for various urological disorders, including prostate cancer. The link between chronic inflammation, microbiome and solid tumors has been established for various neoplastic diseases. However, a detailed and comprehensive analysis of urinary microenvironment of bladder cancer has not been yet reported. We performed this study to characterize the potential urinary microbial community possibly associated with bladder cancer. Mid-stream urine was collected from 31 male patients with bladder cancer and 18 non-neoplastic controls. DNA was extracted from urine pellet samples and processed for high throughput 16S rRNA amplicon sequencing of the V4 region using Illumina MiSeq. Sequencing reads were filtered using QIIME and clustered using UPARSE. We observed increased bacterial richness (Observed Species, Chao 1 and Ace indexes; cancer vs. control; 120.0 vs. 56.0; 134.5 vs. 68.3; and 139.6 vs. 72.9, respectively), enrichment of some bacterial genera (e.g., ) and decrease of some bacterial genera (e.g., , and ) in cancer group when compared to non-cancer group. Significant difference in beta diversity was found between cancer and non-cancer group, among different risk level, but not among different tumor grade. Enrichment of , and was observed in cancer patients with high risk of recurrence and progression, which means these genera maybe potential biomarkers for risk stratification. The PICRUSt showed that various functional pathways were enriched in cancer group, including infection, glycerolipid metabolism and retinol metabolism. To our knowledge, we performed the most comprehensive study to date to characterize the urinary microbiome associated with bladder cancer. A better understanding of the role of microbiome in the development and progression of bladder cancer could pave a new way for exploring new therapeutic options and biomarkers.

The microbiota isolated from the urine of bladder carcinoma patients exhibits significantly increased compositional abundance of some bacterial genera compared to the urine of healthy patients. Our aim was to compare the microbiota composition of cancerous tissues and urine samples collected from the same set of patients in order to improve the accuracy of diagnostic measures. Tissue samples were collected from patients during cancer tissue removal by transurethral resection. In parallel, urine samples were obtained by transurethral resectoscopy from the same patients. The V3–V4 region of the bacterial 16S rRNA gene was sequenced and analyzed using the Kraken pipeline. In the case of four patients, duplicate microbiota analysis from distant parts of the cancerous tissues was highly reproducible, and independent of the site of tissue collection of any given patient. Akkermansia, Bacteroides, Clostridium sensu stricto , Enterobacter and Klebsiella, as “five suspect genera”, were over-represented in tissue samples compared to the urine. To our knowledge, this is the first study comparing urinary and bladder mucosa-associated microbiota profiles in bladder cancer patients. More accurate characterization of changes in microbiota composition during bladder cancer progression could provide new opportunities in the development of appropriate screening or monitoring methods.

The human bladder hosts a resident, low-biomass microbial community (urobiota) that has only become the subject of intense investigation in the last 15 years. The advantages that the urobiota may confer to the bladder, in contrast to the microbiota of other mucosal sites, remain to be elucidated. Alterations in the urobiota have been associated with various pathological urogenital conditions, including urinary tract infections (UTIs) and recurrent UTIs. A potential link between bladder cancer (BC), the ninth most common human cancer by incidence worldwide, and a dysbiotic urobiota is still unclear and represents an emerging field of study. In this review, we focus on recent studies that not only analyzed the urobiota of BC patients using urine specimens to identify biomarkers and microbial signatures of the disease, but also monitored therapeutic responses to therapies. We also discuss novel techniques of culturing, such as culturomics, animal models of BC, and 3D organotypic models. Furthermore, we review studies on the gut–bladder axis which, though still limited, already suggest that diet- and gut-derived bacterial metabolites can influence BC progression and individual responses to therapy.

Purpose The recent discovery of the urinary microbiome has led to an emerging field of investigation about the potential role of microorganisms in the pathogenesis of urinary bladder cancer. Few preliminary data have been reported so far implicating urobiome as causative and prognostic factor of bladder tumorigenesis. In the present study, a review of the current evidence is presented about microbiome composition among patients with bladder cancer and healthy individuals as well as possible implications of microbiome on urothelial carcinoma of the bladder. Methods A literature review was conducted using PubMed/MEDLINE, Scopus, and the Cochrane library until December 2023. Search algorithm was constructed using the following terms and their associated Mesh terms and Boolean operators: “urinary microbiome” and “urinary microbiota”. Studies written in English language, identifying, and comparing urinary microbiome among bladder cancer patients and healthy control group were included in the review. Results A total of 2,356 reports were identified. From this total 16 articles complied with the inclusion criteria were selected for analysis. These articles represent a total of about 486 bladder cancer patients. Conclusion Recent studies revealed the colonization of the urinary tract and the bladder by micro-organisms using both enhanced culture- and molecular-based techniques for microbial characterization. However, several limitations exist in the literature decreasing the reliability of the current reports. As a result, urinary microbiome consist an ambitious era in bladder cancer research with an increasing number of evidence about its potential pathogenetic, prognostic and therapeutic role.

The catheter-associated uropathogen Proteus mirabilis frequently causes urinary stones, but little has been known about the initial stages of bladder colonization and stone formation. We found that P. mirabilis rapidly invades the bladder urothelium, but generally fails to establish an intracellular niche. Instead, it forms extracellular clusters in the bladder lumen, which form foci of mineral deposition consistent with development of urinary stones. These clusters elicit a robust neutrophil response, and we present evidence of neutrophil extracellular trap generation during experimental urinary tract infection. We identified two virulence factors required for cluster development: urease, which is required for urolithiasis, and mannoseresistant Proteus-like fimbriae. The extracellular cluster formation by P. mirabilis stands in direct contrast to uropathogenic Escherichia coli, which readily formed intracellular bacterial communities but not luminal clusters or urinary stones. We propose that extracellular clusters are a key mechanism of P. mirabilis survival and virulence in the bladder.

Background To examine the microbial profiles in parenchyma tissues in bladder cancer. Methods Tissue samples of cancerous bladder mucosa were collected from patients diagnosed with bladder cancer (22 carcinoma tissues and 12 adjacent normal tissues). The V3‐V4 region of the bacterial 16S rRNA gene was PCR amplified, followed by sequencing on an Illumina MiSeq platform. Bioinformatics analysis for microbial classification and functional assessment was performed to assess bladder microbiome diversity and variations. Results The predominant phylum in both tissues was Proteobacteria. The cancerous tissues exhibited lower species richness and diversity. Beta diversity significantly differed between the cancerous and normal tissues. Lower relative abundances of the microbial genera Lactobacillus, Prevotella_9, as well as Ruminococcaceae were observed, whereas those of Cupriavidus spp., an unknown genus of family Brucellaceae, and Acinetobacter, Anoxybacillus, Escherichia‐Shigella, Geobacillus, Pelomonas, Ralstonia, and Sphingomonas were higher in the cancerous tissues. These findings indicate that these genera may be potentially utilized as biomarkers for bladder cancer. PICRUSt analysis revealed that several pathways involved in the metabolism of harmful chemical compounds were enriched in the cancer tissues, thereby providing evidence that environmental factors are strongly associated with bladder cancer etiology. Conclusion This is the first study that has described and analyzed the dysbiotic motifs of urinary microbiota in the parenchymatous tissues of bladder cancer via 16S rRNA gene sequencing. Our results suggest that changes in the bladder microbiome may serve as biomarkers for bladder cancer, possibly assisting in disease screening and monitoring. This is the first study describing and analyzing the dysbiosis signatures of urinary microbiota within the parenchyma in bladder cancer using a 16S rRNA gene sequencing method. The study reveals previously undescribed bacterial diversity present in human bladder. The bladder microbiome changes could be a biomarker of bladder cancer that could be used to help in screening for the disease. Analysis of the inferred bladder cancer metagenome identified the strongest association with the harmful chemical products that may be metabolized.

Urinary bladder cancer (BC) inflicts a significant impairment of life quality and poses a high mortality risk. Schistosoma haematobium infection can cause BC, and the urinary microbiota of BC patients differs from healthy controls. Importantly, intravesical instillation of the bacterium Bacillus Calmette-Guerin stands as the foremost therapy for non-muscle invasive BC. Hence, studying the receptors and signaling molecules orchestrating bacterial recognition and the cellular response in the context of BC is of paramount importance. Thus, we challenged Toll-like receptor 4 (Tlr4) and myeloid differentiation factor 88 (Myd88) knock-out (KO) mice with N-butyl-N-(4-hydroxylbutyl)-nitrosamine (BBN), a well-known urinary bladder carcinogen. Gut microbiota, gene expression, and urinary bladder pathology were followed. Acute exposure to BBN did not reveal a difference in bladder pathology despite differences in the animal’s ability to recognize and react to bacteria. However, chronic treatment resulted in reduced cancer invasiveness among Myd88KO mice while the absence of functional Tlr4 did not influence BC development or progression. These differences correlate with a heightened abundance of the Faecalibaculum genus and the lowest microbial diversity observed among Myd88KO mice. The presented data underscore the important role of microbiota composition and MyD88-mediated signaling during bladder carcinogenesis.

Background Previous research on urinary microbiomes in bladder cancer patients has yielded inconsistent results, highlighting the need for further investigation. This study aims to analyze microbiome dysbiosis in bladder cancer patients by comparing multiple sample types, incorporating negative controls, and assessing sex-based variations. Fifty patients who required transurethral resection of bladder tumor for treatment were selected. Three types of specimens were collected from each patient: midstream urine, catheterized urine, and normal bladder mucosal tissue. Microbiome was analyzed via 16 S rRNA gene amplificon sequencing. Results Beta diversity analysis revealed significant differences in microbiome composition between mucosal tissue and urine samples, while no significant variation was observed between midstream and catheterized urine samples. Due to the low biomass of mucosal tissue—characterized by dominance of a few taxa and high variability across extraction kit lots—its susceptibility to contamination compromised reproducibility, leading to a focus on urine samples for further analysis. Midstream urine samples showed significant sex-related microbiome differences, whereas catheterized urine exhibited no such differences, suggesting midstream urine may not be ideal for bladder-specific microbiome studies. Catheterized urine analysis identified Curvibacter , particularly Curvibacter gracilis , as significantly more abundant in bladder cancer patients compared to controls, while overall microbiome composition remained unchanged between the groups. Curvibacter prevalence was not directly correlated with any single clinical marker but increased with bladder cancer severity when patients were classified into high-risk and low-risk groups based on biopsy and clinical criteria. Conclusions This study highlights the importance of selecting appropriate sample types for bladder microbiome analysis, with catheterized urine emerging as the most reliable option. The findings suggest that Curvibacter may be associated with bladder cancer severity, warranting further investigation into its potential role as a biomarker. Future research should focus on validating these findings in larger cohorts and exploring the mechanistic link between microbiome alterations and bladder cancer progression.

Escherichia coli entry into the bladder is met with potent innate defenses, including neutrophil influx and epithelial exfoliation. Bacterial subversion of innate responses involves invasion into bladder superficial cells. We discovered that the intracellular bacteria matured into biofilms, creating pod-like bulges on the bladder surface. Pods contained bacteria encased in a polysaccharide-rich matrix surrounded by a protective shell of uroplakin. Within the biofilm, bacterial structures interacted extensively with the surrounding matrix, and biofilm associated factors had regional variation in expression. The discovery of intracellular biofilm-like pods explains how bladder infections can persist in the face of robust host defenses.