Insights into the Interplay between the Urinary Microbiome and Bladder Cancer: A Comprehensive Review
Abstract
:1. Introduction
2. Methods
3. Revisiting the “Core” Urinary Microbiome
4. The Urinary Microbiome in Bladder Cancer
5. Microbiome Influence on the Extracellular Matrix
6. Microbiome Influence on Gene Expression
7. Microbiome Modulation through Bacillus Calmette–Guérin (BCG) Instillation Therapy
8. Overlooked Components of the Urinary Microbiome and Its Implications on Therapeutic Responses
9. Metabolic Implications of the Microbiome in Bladder Cancer
10. Discussion
11. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Disease Stage | Findings | Methods | Population | Sample Collection | Author |
---|---|---|---|---|---|
Primary or recurrent NMIBC | No differences in alpha diversity or Simpson index between groups (182 OTUs for NMIBC vs. 184 for patients without bladder cancer). Firmicutes, Actinobacteria, Bacteroidetes, and Proteobacteria were the most abundant phyla. Patients with bladder cancer showed enriched OTUs: Ruminococcaceae family, Campylobacter hominis, Actinobaculum massiliense, and Jonquetella anthropi. | DNA extraction with PowerSoil® (MoBio Laboratories, Inc. Radnor, PA, USA). DNA quantification via Qubit® (Thermo Fisher Scientific, Waltham, MA, USA) 16S rRNA (V4 region) gene library preparation and MiSeq sequencing (Illumina, Inc. San Diego, CA, USA). Sequenced paired-end reads processing with USEARCH into OTUs. PERMANOVA analysis for risk association. Bladder cancer tissue analysis through F. nucleatum PCR. | Total of 23 men: 12 NMIBC and 11 healthy individuals. | Urine specimens. Bladder cancer tissue. | Bučević Popović (2018) [9] |
Primary or recurrent bladder cancer | No differences found in the urinary microbiome between bladder cancer group and controls without bladder cancer at the alpha and beta diversity levels. Both groups showed that Firmicutes, Proteobacteria, and Actinobacteria were the most dominant phyla. At the genus level, Lactobacillus was more common in patients undergoing BCG therapy. Genera Howardella and Streptococcus anginosus were more common in female patients. | DNA extraction with QIAamp DNA Micro Kit (QIAGEN, Hilden, Germany). 16s rRNA sequencing (V3 and V4). Sequenced paired-end reads processing with QIAseq (QIAGEN) 16s/ITS kit. Quantitative analysis with QuantiFlour® (Promega, Madison, WI, USA) QIIME2 for bioinformatic analysis. | Total of 25 patients: 18 with bladder cancer and 7 patients without bladder cancer; 73% were men. | Midstream urine sample | Chorbinska (2023) [10] |
Bladder cancer: either NMIBC or MIBC. Eleven receiving BCG. | No difference in alpha diversity. Differences in beta diversity at the genus level and phylum levels: Actinobacteria and Proteobacteria showed higher representations in patients with bladder cancer. Phylum level: Firmicutes and Deinococcus-Thermus were more abundant in controls. Genus level: Actinomyces, Achromobacter, Brevibacterium, and Brucella. These were more abundant in bladder cancer. Patients responding to BCG showed no differences in alpha or beta diversity. | DNA extraction with CAT# 47050. DNA sequencing with 16S rRNA of V3 and V4 rDNAs. Analysis in OTUs using QIIME software and polishing with ChimeraSlayer. OTUs were summarized at the Genus level. Assessment of alpha diversity and beta diversity scores using PERNAOVA. | Total of 43 patients with bladder cancer and 10 controls without bladder cancer. | Cases: transurethral. Controls and cases not undergoing a procedure: clean-catch midstream samples. | Hussein (2020) [11] |
Bladder cancer comparing NMIBC and MIBC. | Statistically significant differences in alpha and beta diversity between groups. Analysis at the phylum level in both MIBC and NMIBC showed a major representation of Proteobacteria (68.45% and 39.09%), Firmicutes (14.76% and 19.17%), and Actinobacteria (12.98% and 14.92%, respectively). Analysis of differential abundance in MIBC at the phylum level showed abundance of Proteobacteria and decreased Bacteroidetes and Firmicutes. At the species level, Ralstonia was an important marker of MIBC. | DNA extraction with TIANamp MicroDNA kit (TIANGEN Biotech, Beijing, China). Sequencing was processed based on the recognition of Type IIB restriction endonuclease. Cleaned readings were assessed using the 2bRAD-M tags for library identification. Alpha diversity was calculated with the CHao1, Shannon, and Simpson indexes. Beta diversity was assessed with Bray–Curtis, Binary Jaccard, and Euclidean distances. | Total of 22 subjects: 7 with NMIBC and 15 with MIBC. | Bladder tissue | Jian-Xuan (2023) [18] |
Three groups: patients without cancer (benign urologic conditions), patients with NMIBC, and patients with MIBC. | Controls showed higher diversity and richness when compared to patients with NMIBC and MIBC, as well as when compared to high-grade and low-grade samples. Bacteroidetes, Lachnoclostridium, and Burkolderia were mostly represented in control samples, while MIBC showed a major representation of Bacteroides and Faecalbacterium. | DNA isolation with using the ZymoBIOMICS (Zymo Research Corporation, Irvine, CA, USA) DNA/RNA kit. PCR products were analyzed on a 2% agarose E-Gel and products were purified with QIAquick gel extraction kit (QIAGEN). Sequences were analyzed for taxonomy using the silva version 132 classifier. Alpha and beta diversity were measured. | Total of 37 subjects: 10 in noncancer group; 15 in muscle-invasive group; 12 in non-muscle-invasive group. | Midstream samples | Chipollini (2020) [15] |
Subjects without bladder cancer compared to patients with bladder cancer, either NMIBC or MIBC. | A consistent representation of five genera was observed: Streptococcus, Bifidobacterium, Lactobacillus, Veillonella, and Actinomyces. Of these, general Actinomyces showed a higher representation in the group with bladder cancer, suggesting a positive correlation with bladder cancer. Within this genus, A. europaneus was higher compared to in the control group. | DNA extraction and 16S rDNA sequencing, PCR amplification of V3–V4 region. Sequencing reads were processed using QIIME, from which alpha diversity was calculated. Sequences were organized into OTUs and assigned taxonomy using the Greengenes database. | Total of 55 patients: 29 patients with bladder cancer and 26 controls without bladder cancer. | Midstream clean-catch sample collection | Bi (2019) [12] |
Patients with cancer compared to patients without cancer. Patients with cancer included those with NMIBC and MIBC. | Comparison between patients with cancer and controls without bladder cancer at phylum level showed a major representation of Proteobacteria (39.7% vs. 49%), Firmicutes (32.8%, 28.1%), Actinobacteria (7% vs. 6.2%), and Bacteroidetes (3.9%, 9.4%); these differences were not statistically significant. At genus level Acinetobacter, Anaerococcus, and Rubrobacter were more represented in patients with cancer. | DNA sequencing with 16s rRNA from V4 regions (Dneasy kit, QIAGEN). OTUs were identified using UPARSE and aligned for a taxonomic analysis using the SILVA and Greengenes databases. Alpha and beta diversity was assessed using QIIME. | Total of 49 patients: 18 without bladder cancer and 31 with bladder cancer (26 with NMIBC and 5 with MIBC). | Midstream clean-catch urine sample collection | Wu (2018) [14] |
Disease Stage | Findings | Methods | Population | Sample Collection | Author |
---|---|---|---|---|---|
Intermediate-/high-risk NMIBC | No differences in microbiome diversity between patients with bladder cancer and controls. No association between bladder microbiota and tumor features. Lactobacillus, Streptococcus, and Cutibacterium were enriched in patients without persistent disease. BCG does not integrate to the bladder microbiota; BCG was observed in only 9% of maintenance samples. | DNA extraction with QI Aamp Kit (QIAGEN, Hilden, Germany). Amplicon sequencing with 16S rRNA. Paired-end reads were processed using QIIME 2, amplicon splice variants were taxonomically classified with Naive Bayes classifiers. Alpha diversity was assessed with the ASV richness, Gini–Simpson, and Shannon indexes. Beta diversity was assessed with ANCOM-BC. | A total of 32 male patients with intermediate-/high-risk NMIBC vs. 41 with benign prostatic hyperplasia. | Catheterized urine samples taken before BCG instillation (induction 1, 5, and 6; maintenance 1) and immediately before TURP for the control group. | Heidrich et al. (2024) [26] |
High-grade NMIBC | Significant differences in Shannon and Simpson indexes between patients who experienced recurrence and those who did not. The group that recurred showed more evenness in bacterial representations. Relative abundance of Aerococcus was higher in the recurrence group, whereas Escherichia/Shigella and Ureaplasma were higher for patients who did not experience recurrence. | DNA was extracted and sequenced with 16S rRNA, followed by amplification of the V4 region using Illumina MiSEq primers 515F and 806R (Illumina, Inc. San Diego, CA, USA). Taxonomy was assigned according to the SILVA database. Alpha diversity: evenness was computed with Pielou index; richness and evenness were assessed with the Shannon index; abundance was assessed with the Simpson index. | Total of 29 patients undergoing intravesical therapy for NMIBC: 27 received BCG, 2 patients received intravesical gemcitabine. | Catheterized urine samples prior to first and all six BCG = induction doses. A 7th specimen was obtained before the 3-month cystoscopy. | James et al. (2023) [29] |
High-risk patients | Most abundant phyla in both groups were Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria, and Tenericutes. An abundance of Proteobacteria was observed in patients with recurrence, Lactobacilalles were more abundant in patients with no recurrence. | 16s rRNA gene sequencing. Rest of methodology not specified. | Total of 31 patients were enrolled: 10 with recurrence and 21 with no recurrence at 6-month follow-up. | Catheterized urine samples | Sweis (2019) [27] |
Various stages of treatment | No significant difference in alpha diversity when comparing patients with cancer vs. controls. Beta diversity was different between groups: Actinobacteria and Proteobacteria were more abundant in patients with bladder cancer. Firmicutes and Deinococcus were more abundant in controls. At the genus level, Actinomyces, Achromobacter, Brevibacterium, and Brucella were more abundant in patients with bladder cancer. Salinococcus, Escherichia-Shigella, and Lactobacillus were more abundant in controls without bladder cancer. In BCG responders, the phyla Firmicutes and Proteobacteria were more abundant. At the genus level, Serratia, Escherichia-Shigella, and Pseudomonas were more abundant in the responders. | DNA extraction and sequencing with 16S rRNA. Paired-end reads were analyzed with QIIME, and OTUs were referenced with the SILVA database. Measurement of alpha diversity was conducted with the Chao1, Shannon, and Simpson indexes. Beta diversity was measured with the Bray–Curtis score and PERMANOVA. | Total of 43 samples from patients with bladder cancer and 10 samples from controls without bladder cancer. | Catheterized urine samples from patients with bladder cancer. Clean-catch midstream samples obtained from volunteers without bladder cancer and patients with bladder cancer that were not undergoing a procedure. | Hussein (2020) [11] |
Sample of Study | Microbiome Fingerprint | References |
---|---|---|
Men without bladder cancer | Phyla: Firmicutes, Actinobacteria, Fusobacteria, Proteobacteria, Bacteroidetes. Genus: Lactobacillus, Corynebacterium, streptococcus. | Nelson (2010) [4] |
Women without bladder cancer | Phyla: Firmicutes, Bacteroidetes, Actinobacteria, Fusobacteria. Genus: Lactobacillus, Prevotella, Gardnerella. | Siddiqui (2011) [5] |
Bladder cancer | Phyla: Firmicutes, Proteobacteria, and Actinobacteria, Bacteroidetes. OTUs: Fusobacteria, Actinobacteria, Facklamia and Campilobacter. Strain level: Campylobacter hominis, Actinobaculum massiliense, and Jonquetella antrophi. Species: Fusobacterium nucleatum. | Bučević Popović (2018) [9], Chorbińska (2023) [10], Hussein (2021) [11], Bi (2021) [12], Sun (2023) [13], Wu (2018) [14], Chipollini (2020) [15] |
PD-1-positive | Phylum: Fusobacteria, Proteobacteria. Genus: Actinomyces, and Leptotrichia. | Chen (2022) [22] |
BCG responders | Genus: Lactobacillus, Streptococcus and Cutibacterium. Revisar: Escherichia/Shigella, Ureaplasma | James (2023) [29], Sweis (2019) [27], Heidrich (2024) [26] |
Virome | HCMV, EBV, HHV-6, HPV, BKPyV, TTV. | Hrbáček (2023) [31] |
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Pallares-Mendez, R.; Brassetti, A.; Bove, A.M.; Simone, G. Insights into the Interplay between the Urinary Microbiome and Bladder Cancer: A Comprehensive Review. J. Clin. Med. 2024, 13, 4927. https://doi.org/10.3390/jcm13164927
Pallares-Mendez R, Brassetti A, Bove AM, Simone G. Insights into the Interplay between the Urinary Microbiome and Bladder Cancer: A Comprehensive Review. Journal of Clinical Medicine. 2024; 13(16):4927. https://doi.org/10.3390/jcm13164927
Chicago/Turabian StylePallares-Mendez, Rigoberto, Aldo Brassetti, Alfredo Maria Bove, and Giuseppe Simone. 2024. "Insights into the Interplay between the Urinary Microbiome and Bladder Cancer: A Comprehensive Review" Journal of Clinical Medicine 13, no. 16: 4927. https://doi.org/10.3390/jcm13164927