Prospective observational study of the role of the microbiome in BCG responsiveness prediction (SILENT-EMPIRE): a study protocol

Uwe Bieri, Michael Scharl, Silvan Sigg, Barbara Maria Szczerba, Yasser Morsy, Jan Hendrik Rüschoff, Peter Hans Schraml, Michael Krauthammer, Lukas John Hefermehl, Daniel Eberli, Cédric Poyet, Uwe Bieri, Michael Scharl, Silvan Sigg, Barbara Maria Szczerba, Yasser Morsy, Jan Hendrik Rüschoff, Peter Hans Schraml, Michael Krauthammer, Lukas John Hefermehl, Daniel Eberli, Cédric Poyet

Abstract

Introduction: The human microbiota, the community of micro-organisms in different cavities, has been increasingly linked with inflammatory and neoplastic diseases. While investigation into the gut microbiome has been robust, the urinary microbiome has only recently been described. Investigation into the relationship between bladder cancer (BC) and the bladder and the intestinal microbiome may elucidate a pathophysiological relationship between the two. The bladder or the intestinal microbiome or the interplay between both may also act as a non-invasive biomarker for tumour behaviour. While these associations have not yet been fully investigated, urologists have been manipulating the bladder microbiome for treatment of BC for more than 40 years, treating high grade non-muscle invasive BC (NMIBC) with intravesical BCG immunotherapy. Neither the association between the microbiome sampled directly from bladder tissue and the response to BCG-therapy nor the association between response to BCG-therapy with the faecal microbiome has been studied until now. A prognostic tool prior to initiation of BCG-therapy is still needed.

Methods and analysis: In patients with NMIBC bladder samples will be collected during surgery (bladder microbiome assessment), faecal samples (microbiome assessment), instrumented urine and blood samples (biobank) will also be taken. We will analyse the microbial community by 16S rDNA gene amplicon sequencing. The difference in alpha diversity (diversity of species within each sample) and beta diversity (change in species diversity) between BCG-candidates will be assessed. Subgroup analysis will be performed which will lead to the development of a clinical prediction model estimating risk of BCG-response.

Ethics and dissemination: The study has been approved by the Cantonal Ethics Committee Zurich (2021-01783) and it is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Study results will be disseminated through peer-reviewed journals and national and international scientific conferences.

Trial registration number: NCT05204199.

Keywords: IMMUNOLOGY; MICROBIOLOGY; ONCOLOGY; Urological tumours.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Simulation-output of different effect sizes and calculations of the PERMANOVA power corresponding to the number of subjects per group. PERMANOVA, multivariate analysis of variance with permutation.

References

    1. IARC Publications Website - GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012 v1.0. Available: [Accessed 5 Jul 2020].
    1. Burger M, Catto JWF, Dalbagni G, et al. . Epidemiology and risk factors of urothelial bladder cancer. Eur Urol 2013;63:234–41. 10.1016/j.eururo.2012.07.033
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7–30. 10.3322/caac.21332
    1. Shariat SF, Sfakianos JP, Droller MJ, et al. . The effect of age and gender on bladder cancer: a critical review of the literature. BJU Int 2010;105:300–8. 10.1111/j.1464-410X.2009.09076.x
    1. Freedman ND, Silverman DT, Hollenbeck AR, et al. . Association between smoking and risk of bladder cancer among men and women. JAMA 2011;306:737–45. 10.1001/jama.2011.1142
    1. Vermeulen SH, Hanum N, Grotenhuis AJ, et al. . Recurrent urinary tract infection and risk of bladder cancer in the Nijmegen bladder cancer study. Br J Cancer 2015;112:594–600. 10.1038/bjc.2014.601
    1. Louis P, Hold GL, Flint HJ. The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol 2014;12:661–72. 10.1038/nrmicro3344
    1. Uchiyama K, Naito Y, Takagi T. Intestinal microbiome as a novel therapeutic target for local and systemic inflammation. Pharmacol Ther 2019;199:164–72. 10.1016/j.pharmthera.2019.03.006
    1. Lee KW, Song HY, Kim YH. The microbiome in urological diseases. Investig Clin Urol 2020;61:338. 10.4111/icu.2020.61.4.338
    1. Golombos DM, Ayangbesan A, O'Malley P, et al. . The role of gut microbiome in the pathogenesis of prostate cancer: a prospective, pilot study. Urology 2018;111:122–8. 10.1016/j.urology.2017.08.039
    1. Gill CIR, Rowland IR. Diet and cancer: assessing the risk. Br J Nutr 2002;88 Suppl 1:s73–87. 10.1079/BJN2002632
    1. Salgia NJ, Bergerot PG, Maia MC, et al. . Stool microbiome profiling of patients with metastatic renal cell carcinoma receiving anti-PD-1 immune checkpoint inhibitors. Eur Urol 2020;78:498–502. 10.1016/j.eururo.2020.07.011
    1. Whiteside SA, Razvi H, Dave S, et al. . The microbiome of the urinary tract--a role beyond infection. Nat Rev Urol 2015;12:81–90. 10.1038/nrurol.2014.361
    1. Thomas-White K, Brady M, Wolfe AJ, et al. . The bladder is not sterile: history and current discoveries on the urinary microbiome. Curr Bladder Dysfunct Rep 2016;11:18–24. 10.1007/s11884-016-0345-8
    1. Nelson DE, Van Der Pol B, Dong Q, et al. . Characteristic male urine microbiomes associate with asymptomatic sexually transmitted infection. PLoS One 2010;5:e14116. 10.1371/journal.pone.0014116
    1. Dong Q, Nelson DE, Toh E, et al. . The microbial communities in male first catch urine are highly similar to those in paired urethral swab specimens. PLoS One 2011;6:e19709. 10.1371/journal.pone.0019709
    1. Nelson DE, Dong Q, Van der Pol B, et al. . Bacterial communities of the coronal sulcus and distal urethra of adolescent males. PLoS One 2012;7:e36298. 10.1371/journal.pone.0036298
    1. Bajic P, Van Kuiken ME, Burge BK, et al. . Male bladder microbiome relates to lower urinary tract symptoms. Eur Urol Focus 2020;6:376–82. 10.1016/j.euf.2018.08.001
    1. Nickel JC, Stephens A, Landis JR, et al. . Search for microorganisms in men with urologic chronic pelvic pain syndrome: a culture-independent analysis in the MAPP research network. J Urol 2015;194:127–35. 10.1016/j.juro.2015.01.037
    1. Lewis DA, Brown R, Williams J, et al. . The human urinary microbiome; bacterial DNA in voided urine of asymptomatic adults. Front Cell Infect Microbiol 2013;3. 10.3389/fcimb.2013.00041
    1. Xu W, Yang L, Lee P, et al. . Mini-Review: perspective of the microbiome in the pathogenesis of urothelial carcinoma. Am J Clin Exp Urol 2014;2:57–61.
    1. Wu P, Zhang G, Zhao J. Profiling the urinary microbiota in male patients with bladder cancer in China. Front Cell Infect Microbiol 2018;8:1–10. 10.3389/fcimb.2018.00167
    1. Popović B, itum M, Chow CET. The urinary microbiome associated with bladder cancer. Sci Rep 2018;8. 10.1038/s41598-018-29054-w
    1. Bilski K, Dobruch J, Kozikowski M. Molecular sciences Urobiome in gender-related diversities of bladder cancer, 2020.
    1. Andolfi C, Bloodworth JC, Papachristos A, et al. . The urinary microbiome and bladder cancer: susceptibility and immune responsiveness. Bladder Cancer 2020;6:225–35. 10.3233/BLC-200277
    1. McConnell MJ, Actis L, Pachón J. Acinetobacter baumannii: human infections, factors contributing to pathogenesis and animal models. FEMS Microbiol Rev 2013;37:130–55. 10.1111/j.1574-6976.2012.00344.x
    1. Murphy EC, Frick I-M. Gram-positive anaerobic cocci--commensals and opportunistic pathogens. FEMS Microbiol Rev 2013;37:520–53. 10.1111/1574-6976.12005
    1. Alfano M, Canducci F, Nebuloni M, et al. . The interplay of extracellular matrix and microbiome in urothelial bladder cancer. Nat Rev Urol 2016;13:77–90. 10.1038/nrurol.2015.292
    1. Zeng J, Zhang G, Chen C, et al. . Alterations in Urobiome in patients with bladder cancer and implications for clinical outcome: a single-institution study. Front Cell Infect Microbiol 2020;10:555508. 10.3389/fcimb.2020.555508
    1. Bajic P, Wolfe AJ, Gupta GN. The urinary microbiome: implications in bladder cancer pathogenesis and therapeutics. Urology 2019;126:10–15. 10.1016/j.urology.2018.12.034
    1. Han J, Gu X, Li Y, et al. . Mechanisms of BCG in the treatment of bladder cancer-current understanding and the prospect. Biomed Pharmacother 2020;129:110393. 10.1016/j.biopha.2020.110393
    1. Herr HW, Morales A. History of Bacillus Calmette-Guerin and bladder cancer: an immunotherapy success story. J Urol 2008;179:53–6. 10.1016/j.juro.2007.08.122
    1. Alhunaidi O, Zlotta AR. The use of intravesical BCG in urothelial carcinoma of the bladder. Ecancermedicalscience 2019;13:905. 10.3332/ecancer.2019.905
    1. Cambier S, Sylvester RJ, Collette L, et al. . Eortc nomograms and risk groups for predicting recurrence, progression, and disease-specific and overall survival in non-muscle-invasive stage Ta-T1 urothelial bladder cancer patients treated with 1-3 years of maintenance Bacillus Calmette-Guérin. Eur Urol 2016;69:60–9. 10.1016/j.eururo.2015.06.045
    1. Babjuk M, Burger M, Compérat EM, et al. . European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (TaT1 and Carcinoma In Situ) - 2019 Update. Eur Urol 2019;76:639–57. 10.1016/j.eururo.2019.08.016
    1. Kulkarni GS, Hermanns T, Wei Y, et al. . Propensity score analysis of radical cystectomy versus Bladder-Sparing Trimodal therapy in the setting of a multidisciplinary bladder cancer clinic. J Clin Oncol 2017;35:2299–305. 10.1200/JCO.2016.69.2327
    1. Voskuilen CS, Oo HZ, Genitsch V, et al. . Multicenter validation of histopathologic tumor regression grade after neoadjuvant chemotherapy in muscle-invasive bladder carcinoma. Am J Surg Pathol 2019;43:1600–10. 10.1097/PAS.0000000000001371
    1. Golla V, Lenis AT, Faiena I, et al. . Intravesical therapy for non-muscle invasive bladder Cancer-Current and future options in the age of Bacillus Calmette-Guerin shortage. Rev Urol 2019;21:145–53.
    1. Sweis RF, Golan S, Barashi N, et al. . Association of the commensal urinary microbiome with response to Bacillus Calmette-Guérin (BCG) immunotherapy in nonmuscle invasive bladder cancer. JCO 2019;37:423. 10.1200/JCO.2019.37.7_suppl.423
    1. Turnbaugh PJ, Ley RE, Hamady M, et al. . The human microbiome project. Nature 2007;449:804–10. 10.1038/nature06244
    1. Integrative HMP (iHMP) Research Network Consortium . The integrative human microbiome project. Nature 2019;569:641–8. 10.1038/s41586-019-1238-8
    1. Kelly BJ, Gross R, Bittinger K, et al. . Power and sample-size estimation for microbiome studies using pairwise distances and PERMANOVA. Bioinformatics 2015;31:2461–8. 10.1093/bioinformatics/btv183
    1. Wolff RF, Moons KGM, Riley RD, et al. . PROBAST: a tool to assess the risk of bias and applicability of prediction model studies. Ann Intern Med 2019;170:51. 10.7326/M18-1376

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