The Bladder is Not Sterile: an Update on the Urinary Microbiome
Purpose of Review
The article discusses (1) techniques used to study bacterial urinary microbiota; (2) existence of non-bacterial urinary microbiota; (3) associations between changes in urinary microbiota and various benign lower urinary tract disorders.
Urine harbors a diverse microbial community that resides within it. A multitude of studies have identified differences in these communities associated with urologic conditions, suggesting that microbial communities may maintain normal bladder homeostasis. Technological advances in analytic approaches have improved our understanding of the urinary microbiome. The choice of urine sampling method (voided, catheterized, or aspirated) will significantly influence microbiome findings. Sex and age highly influence urinary microbiota; in addition to rigorous inclusion criteria, microbial studies must be sufficiently powered to overcome the substantial interindividual variability of urinary microbiota. Regardless of these complicating factors, studies have identified microbial patterns correlating with both urologic diagnoses and treatment responses.
Without a clear understanding of the variability of and exogenous influences on the urinary microbiota in the absence of disease, it has been challenging to reveal the microbial patterns responsible for disease pathophysiology. Host mechanisms in response to the urinary microbiome are also poorly understood. Additional research can address whether the manipulation of urinary microbiota will benefit lower urinary tract health.
KeywordsUrinary microbiome Benign lower urinary tract disorders
Compliance with Ethical Standards
Conflict of Interest
A. Lenore Ackerman has no conflict of interest. Toby C. Chai has no conflict of interest.
Human and Animal Rights and Informed Consent
The authors did not perform any studies with human or animal subjects in this review article.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 3.•• Karstens L, Asquith M, Caruso V, Rosenbaum JT, Fair DA, Braun J, et al. Community profiling of the urinary microbiota: considerations for low-biomass samples. Nat Rev Urol. 2018;15(12):735–49. https://doi.org/10.1038/s41585-018-0104-zThis is an in-depth exploration of the detailed decisions in the analysis of microbial sequence data that can influence the results and findings of microbiome studies of the urinary tract.CrossRefPubMedPubMedCentralGoogle Scholar
- 4.• Wolfe AJ, Toh E, Shibata N, Rong R, Kenton K, Fitzgerald M, et al. Evidence of uncultivated bacteria in the adult female bladder. J Clin Microbiol. 2012;50(4):1376–83. https://doi.org/10.1128/JCM.05852-11One of the first descriptions of the presence of bacteria within the urinary tract; it is also the only study to detail the profound differences in microbial communities detected with different methods of sampling the urinary tract.CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Caruso V, Song X, Asquith M, Karstens L. Performance of microbiome sequence inference methods in environments with varying biomass. mSystems. 2019;4(1). doi: https://doi.org/10.1128/mSystems.00163-18.
- 12.Earl JP, Adappa ND, Krol J, Bhat AS, Balashov S, Ehrlich RL, et al. Species-level bacterial community profiling of the healthy sinonasal microbiome using Pacific Biosciences sequencing of full-length 16S rRNA genes. Microbiome. 2018;6(1):190. https://doi.org/10.1186/s40168-018-0569-2.CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Zoetendal EG, von Wright A, Vilpponen-Salmela T, Ben-Amor K, Akkermans AD, de Vos WM. Mucosa-associated bacteria in the human gastrointestinal tract are uniformly distributed along the colon and differ from the community recovered from feces. Appl Environ Microbiol. 2002;68(7):3401–7. https://doi.org/10.1128/aem.68.7.3401-3407.2002.CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Momozawa Y, Deffontaine V, Louis E, Medrano JF. Characterization of bacteria in biopsies of colon and stools by high throughput sequencing of the V2 region of bacterial 16S rRNA gene in human. PLoS One. 2011;6(2):e16952. https://doi.org/10.1371/journal.pone.0016952.CrossRefPubMedPubMedCentralGoogle Scholar
- 16.•• Thomas-White K, Forster SC, Kumar N, Van Kuiken M, Putonti C, Stares MD, et al. Culturing of female bladder bacteria reveals an interconnected urogenital microbiota. Nat Commun. 2018;9(1):1557. https://doi.org/10.1038/s41467-018-03968-5Cross-sectional sampling of the urogenital tract in a cohort of female patients reveals strong interrelationship between the vaginal and urinary microbiome that may suggest an interconnected urogenital microbiome, at least in women.CrossRefPubMedPubMedCentralGoogle Scholar
- 20.• Thomas-White KJ, Hilt EE, Fok C, Pearce MM, Mueller ER, Kliethermes S, et al. Incontinence medication response relates to the female urinary microbiota. Int Urogynecol J. 2016;27(5):723–33. https://doi.org/10.1007/s00192-015-2847-xThe baseline urinary microbiome prior to treatment in a population of women with UUI was related to medication responses, providing the first evidence that the urinary microbiome may be a useful prognostic biomarker in the classification of patients with benign urologic conditions.CrossRefPubMedGoogle Scholar
- 21.Shoskes DA, Altemus J, Polackwich AS, Tucky B, Wang H, Eng C. The urinary microbiome differs significantly between patients with chronic prostatitis/chronic pelvic pain syndrome and controls as well as between patients with different clinical phenotypes. Urology. 2016;92:26–32. https://doi.org/10.1016/j.urology.2016.02.043.CrossRefPubMedGoogle Scholar
- 22.• Abernethy MG, Rosenfeld A, White JR, Mueller MG, Lewicky-Gaupp C, Kenton K. Urinary microbiome and cytokine levels in women with interstitial cystitis. Obstet Gynecol. 2017;129(3):500–6. https://doi.org/10.1097/AOG.0000000000001892This small study of a cohort of women with interstitial cystitis and age-matched controls identified alterations in the microbiome that also correlated with both increased inflammatory cytokine levels and worsening symptom scores, suggesting a functional consequence associated with shifts in urogenital microbial communities.CrossRefGoogle Scholar
- 28.Liu F, Ling Z, Xiao Y, Yang Q, Zheng L, Jiang P, et al. Characterization of the urinary microbiota of elderly women and the effects of type 2 diabetes and urinary tract infections on the microbiota. Oncotarget. 2017;8(59):100678–90. https://doi.org/10.18632/oncotarget.21126.CrossRefPubMedPubMedCentralGoogle Scholar
- 31.• Hilt EE, McKinley K, Pearce MM, Rosenfeld AB, Zilliox MJ, Mueller ER, et al. Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J Clin Microbiol. 2014;52(3):871–6. https://doi.org/10.1128/JCM.02876-13This paper describes the use of an enhanced culture technique to show that multiple genera of bacteria are culturable from urine obtained by catheterization from asymptomatic women.CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Nickel JC, Stephens A, Landis JR, Mullins C, van Bokhoven A, Anger JT, et al. Urinary fungi associated with urinary symptom severity among women with interstitial cystitis/bladder pain syndrome (IC/BPS). World J Urol. 2019. https://doi.org/10.1007/s00345-019-02764-0.
- 34.• Nickel JC, Stephens A, Landis JR, Mullins C, van Bokhoven A, Lucia MS, et al. Assessment of the lower urinary tract microbiota during symptom flare in women with urologic chronic pelvic pain syndrome: a MAPP network study. J Urol. 2016;195(2):356–62. https://doi.org/10.1016/j.juro.2015.09.075In a large cohort of patients with urologic chronic pelvic pain syndrome, an association of worsening symptoms, dubbed symptomatic “flares”, was associated with increased detection of urinary fungi, revealing an importance for non-bacterial organisms in disease is is being increasingly recognized for other organ systems.CrossRefPubMedGoogle Scholar
- 37.El-Jurdi N, Ghannoum MA. The mycobiome: impact on health and disease states. Microbiol Spectr. 2017;5(3). doi: https://doi.org/10.1128/microbiolspec.FUNK-0045-2016.
- 46.• Miller-Ensminger T, Garretto A, Brenner J, Thomas-White K, Zambom A, Wolfe AJ et al. Bacteriophages of the urinary microbiome. J Bacteriol. 2018;200(7). doi: https://doi.org/10.1128/JB.00738-17. This study provides early evidence of the existence of abundant and novel bacteriophages within the urinary tract that likely influence both the composition of the urinary microbiome as well as urologic disease.
- 49.Coyne KS, Sexton CC, Thompson CL, Milsom I, Irwin D, Kopp ZS, et al. The prevalence of lower urinary tract symptoms (LUTS) in the USA, the UK and Sweden: results from the Epidemiology of LUTS (EpiLUTS) study. BJU Int. 2009;104(3):352–60. https://doi.org/10.1111/j.1464-410X.2009.08427.x.CrossRefPubMedGoogle Scholar
- 54.Nickel JC, Stephens A, Landis JR, Chen J, Mullins C, van Bokhoven A, 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(1):127–35. https://doi.org/10.1016/j.juro.2015.01.037.CrossRefPubMedPubMedCentralGoogle Scholar
- 56.Nickel JC, Stephens-Shields AJ, Landis JR, Mullins C, van Bokhoven A, Lucia MS et al. A culture-independent analysis of the microbiota of female interstitial cystitis/bladder pain syndrome participants in the MAPP Research Network. J Clin Med. 2019;8(3). doi: https://doi.org/10.3390/jcm8030415.CrossRefGoogle Scholar
- 57.Meriwether KV, Lei Z, Singh R, Gaskins J, DTG H. Jala V. The vaginal and urinary microbiomes in premenopausal women with interstitial cystitis/bladder pain syndrome as compared to unaffected controls: a pilot cross-sectional study. Front Cell Infect Microbiol. 2019;9:92. https://doi.org/10.3389/fcimb.2019.00092.
- 60.De Gregorio PR, Silva JA, Marchesi A, Nader-Macias MEF. Anti-Candida activity of beneficial vaginal lactobacilli in in vitro assays and in a murine experimental model. FEMS Yeast Res. 2019;19(2). doi: https://doi.org/10.1093/femsyr/foz008.
- 67.Stork C, Kovacs B, Rozsai B, Putze J, Kiel M, Dorn A, et al. Characterization of asymptomatic bacteriuria Escherichia coli isolates in search of alternative strains for efficient bacterial interference against uropathogens. Front Microbiol. 2018;9:214. https://doi.org/10.3389/fmicb.2018.00214.CrossRefPubMedPubMedCentralGoogle Scholar
- 69.•• Schreiber HLt, Conover MS, Chou WC, Hibbing ME, Manson AL, Dodson KW et al. Bacterial virulence phenotypes of Escherichia coli and host susceptibility determine risk for urinary tract infections. Sci Transl Med. 2017;9(382). doi: https://doi.org/10.1126/scitranslmed.aaf1283. This comparative genomic study examining a panel of E. coli isolates from women with urinary tract infections revealed conserved functional, but not genomic, virulence patterns at the bacterial strain level, suggesting important host-pathogen interactions at the root of infection susceptibility. CrossRefGoogle Scholar
- 70.Krieger JN, Thumbikat P. Bacterial Prostatitis: Bacterial Virulence, Clinical outcomes, and new directions. Microbiol Spectr. 2016;4(1). doi: https://doi.org/10.1128/microbiolspec.UTI-0004-2012.
- 73.Stapleton AE. The vaginal microbiota and urinary tract infection. Microbiol Spectr. 2016;4(6). doi: https://doi.org/10.1128/microbiolspec.UTI-0025-2016.
- 74.• Gilbert NM, O'Brien VP, Lewis AL. Transient microbiota exposures activate dormant Escherichia coli infection in the bladder and drive severe outcomes of recurrent disease. PLoS Pathog. 2017;13(3):e1006238. https://doi.org/10.1371/journal.ppat.1006238In mice primed for recurrent urinary tract infections, intraurethral innoculation of Gardnerella, a bacterium associated in humans with bacterial vaginosis, can promote the development of E. coli urinary tract infection, suggesting that infection risk is a complex interplay not only between host and pathogen but that the microbial environment can also promote infection.CrossRefPubMedPubMedCentralGoogle Scholar
- 77.Kohler-Forsberg O, Petersen L, Gasse C, Mortensen PB, Dalsgaard S, Yolken RH, et al. A nationwide study in denmark of the association between treated infections and the subsequent risk of treated mental disorders in children and adolescents. JAMA Psychiatry. 2018. https://doi.org/10.1001/jamapsychiatry.2018.3428.CrossRefGoogle Scholar
- 78.Noverr MC, Falkowski NR, McDonald RA, McKenzie AN, Huffnagle GB. Development of allergic airway disease in mice following antibiotic therapy and fungal microbiota increase: role of host genetics, antigen, and interleukin-13. Infect Immun. 2005;73(1):30–8. https://doi.org/10.1128/IAI.73.1.30-38.2005.CrossRefPubMedPubMedCentralGoogle Scholar
- 79.• Mulder M, Radjabzadeh D, Hassing RJ, Heeringa J, Uitterlinden AG, Kraaij R, et al. The effect of antimicrobial drug use on the composition of the genitourinary microbiota in an elderly population. BMC Microbiol. 2019;19(1):9. https://doi.org/10.1186/s12866-018-1379-1Despite widespread use of antibiotics to treat uropathogens such as E. coli, this examination of older adults after treatment with antibiotics revealed decreases in the classic anti-inflammatory commensals such as Lactobacillus and increases in E. coli after treatment, which should caution the use of antimicrobials for “Eradication” of uropathogens, particularly in asymptomatic patients.CrossRefPubMedPubMedCentralGoogle Scholar
- 81.Modena BD, Milam R, Harrison F, Cheeseman JA, Abecassis MM, Friedewald JJ, et al. Changes in urinary microbiome populations correlate in kidney transplants with interstitial fibrosis and tubular atrophy documented in early surveillance biopsies. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2017;17(3):712–23. https://doi.org/10.1111/ajt.14038.CrossRefGoogle Scholar
- 84.Viljoen KS, Dakshinamurthy A, Goldberg P, Blackburn JM. Quantitative profiling of colorectal cancer-associated bacteria reveals associations between fusobacterium spp., enterotoxigenic Bacteroides fragilis (ETBF) and clinicopathological features of colorectal cancer. PLoS One. 2015;10(3):e0119462. https://doi.org/10.1371/journal.pone.0119462.CrossRefPubMedPubMedCentralGoogle Scholar
- 91.Suryavanshi MV, Bhute SS, Jadhav SD, Bhatia MS, Gune RP, Shouche YS. Hyperoxaluria leads to dysbiosis and drives selective enrichment of oxalate metabolizing bacterial species in recurrent kidney stone endures. Sci Rep. 2016;6:34712. https://doi.org/10.1038/srep34712.CrossRefPubMedPubMedCentralGoogle Scholar
- 92.Ticinesi A, Milani C, Guerra A, Allegri F, Lauretani F, Nouvenne A, et al. Understanding the gut-kidney axis in nephrolithiasis: an analysis of the gut microbiota composition and functionality of stone formers. Gut. 2018;67(12):2097–106. https://doi.org/10.1136/gutjnl-2017-315734.CrossRefPubMedGoogle Scholar
- 93.Dornbier RA, Bajic P, Van Kuiken M, Jardaneh A, Lin H, Gao X, et al. The microbiome of calcium-based urinary stones. Urolithiasis. 2019. https://doi.org/10.1007/s00240-019-01146-w.
- 94.Amimanan P, Tavichakorntrakool R, Fong-Ngern K, Sribenjalux P, Lulitanond A, Prasongwatana V, et al. Elongation factor Tu on Escherichia coli isolated from urine of kidney stone patients promotes calcium oxalate crystal growth and aggregation. Sci Rep. 2017;7(1):2953. https://doi.org/10.1038/s41598-017-03213-x.CrossRefPubMedPubMedCentralGoogle Scholar
- 98.De Ferrari ME, Macaluso M, Brunati C, Pozzoli R, Colussi G. Hypocitraturia and Ureaplasma urealyticum urinary tract infection in patients with idiopathic calcium nephrolithiasis. Nephrol Dial Transplant. 1996;11(6):1185. https://doi.org/10.1093/oxfordjournals.ndt.a027486.CrossRefPubMedGoogle Scholar