Abstract
Traditionally, the healthy urinary bladder has been considered to be sterile. Several teams have used metagenomic (DNA-dependent) and metaculturomic (culture-dependent) methods to debunk this longstanding dogma. In fact, resident microbial communities (urobiome) have been detected in both adult females and males. Although the field is young, several observations have been made. For example, the urobiome differs between men and women, likely due to anatomical and hormonal differences. Importantly, the urobiome has been associated with a variety of lower urinary tract disorders, including overactive bladder and post-operative urinary tract infection, raising the possibility that clinicians might one day treat symptoms by modifying the urobiome instead of killing the suspected uropathogen. Little is known concerning the relationship between the urobiome and host genetics; so far, only a single paper has reported such a study. However, major efforts have gone into understanding the genomics of the urobiome itself, a process facilitated by the fact that many urobiome studies have used metaculturomic methods to detect and identify microbes. In this narrative review, we will introduce the urobiome with separate sections on the female and male urobiomes, discuss challenges specific to the urobiome, describe newly discovered associations between the urobiome and lower urinary tract symptoms, and highlight the one study that has attempted to relate host genetics and the urobiome. We will finish with a section on how metagenomic surveys and whole genome sequencing of bacterial isolates are improving our understanding of the urobiome and its relationship to lower urinary tract health and disorders.
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Abelson B, Sun D, Que L, Nebel RA, Baker D, Popiel P, Amundsen CL, Chai T, Close C, DiSanto M, Fraser MO, Kielb SJ, Kuchel G, Mueller ER, Palmer MH, Parker-Autry C, Wolfe AJ, Damaser MS (2018) Sex differences in lower urinary tract biology and physiology. Biol Sex Differ 9:45
Ackerman AL, Underhill DM (2017) The mycobiome of the human urinary tract: potential roles for fungi in urology. Ann Transl Med 5:31
Adebayo AS, Ackermann G, Bowyer RCE, Wells PM, Humphrey G, Knight R, Spector TD, Steves CJ (2020) The urinary tract microbiome in older women exhibits host genetics and environmental influences. Cell Host Microbe 28:298-305.e3
Bajic P, Wolfe AJ, Gupta GN (2019) Old instillations and new implications for bladder cancer: the urinary microbiome and intravesical BCG. BJU Int 124:7–8
Bajic P, Van Kuiken ME, Burge BK, Kirshenbaum EJ, Joyce CJ, Wolfe AJ, Branch JD, Bresler L, Farooq AV (2020) Male bladder microbiome relates to lower urinary tract symptoms. Eur Urol Focus 6:376–382
Brubaker L, Wolfe A (2016) The urinary microbiota: a paradigm shift for bladder disorders? Curr Opin Obstet Gynecol 28:407–412
Chen SL, Hung CS, Xu J, Reigstad CS, Magrini V, Sabo A, Blasiar D, Bieri T, Meyer RR, Ozersky P, Armstrong JR, Fulton RS, Latreille JP, Spieth J, Hooton TM, Mardis ER, Hultgren SJ, Gordon JI (2006) Identification of genes subject to positive selection in uropathogenic strains of Escherichia coli: a comparative genomics approach. Proc Natl Acad Sci USA 103:5977–5982
Chen YB, Hochstedler B, Pham TT, Acevedao Alvarez M, Mueller ER, Wolfe AJ (2020) The urethral microbiota: a missing link in the female urinary microbiota. J Urol 204:303–309
Coorevits L, Heytens S, Boelens J, Claeys G (2016) The resident microflora of voided midstream urine of healthy controls: standard versus expanded urine culture protocols. Eur J Clin Microbiol Infect Dis 36:635–639
Dong Q, Nelson DE, Toh E, Diao L, Gao X, Fortenberry JD, Van der Pol B (2011) The microbial communities in male first catch urine are highly similar to those in paired urethral swab specimens. PLoS ONE 6:e19709
Flint HJ, Scott KP, Louis P, Duncan SH (2012) The role of the gut microbiota in nutrition and health. Nat Rev Gastroenterol Hepatol 9:577–589
Fok CS, Gao X, Lin H, Thomas-White KJ, Mueller ER, Wolfe AJ, Dong Q, Brubaker L (2018) Urinary symptoms are associated with certain urinary microbes in urogynecologic surgical patients. Int Urogynecol J 29:1765–1771
Fouts DE, Pieper R, Szpakowski S, Pohl H, Knoblach S, Suh MJ, Huang ST, Ljungberg I, Sprague BM, Lucas SK, Torralba M, Nelson KE, Groah SL (2012) Integrated next-generation sequencing of 16S rDNA and metaproteomics differentiate the healthy urine microbiome from asymptomatic bacteriuria in neuropathic bladder associated with spinal cord injury. J Transl Med 10:174
Frølund M, Wikström A, Lidbrink P, Abu Al-Soud W, Larsen N, Harder CB, Sørensen S, Jensen JS, Ahrens P (2018) The bacterial microbiota in first-void urine from men with and without idiopathic urethritis. PLoS ONE 13:e0201380
Garretto A, Thomas-White K, Wolfe AJ, Putonti C (2018) Detecting viral genomes in the female urinary microbiome. J Gen Virol 99:1141–1146
Garretto A, Miller-Ensminger T, Wolfe AJ, Putonti C (2019) Bacteriophages of the lower urinary tract. Nat Rev Urol 16:422–432
Garretto A, Miller-Ensminger T, Ene A, Merchant Z, Shah A, Gerodias A, Biancofiori A, Canchola S, Castillo E, Chowdhury T, Gandhi N, Hamilton S, Hatton K, Hyder S, Krull K, Lagios D, Lam T, Mitchell K, Mortensen C, Murphy A, Richburg J, Rokas M, Ryclik S, Sulit P, Szwajnos T, Widuch M, Willis J, Woloszyn M, Brassil B, Johnson G, Mormando R, Maskeri L, Batrich M, Stark N, Shapiro JW, Montelongohernandez S, Banerjee S, Wolfe AJ, Putonti C (2020) Genomic survey of E. coli. From the bladders of women with and without lower urinary tract symptoms. Front Microbiol 11:2094
Hilt EE, McKinley K, Pearce MM, Rosenfeld AB, Zilliox MJ, Mueller ER, Brubaker L, Gai X, Wolfe AJ, Schreckenberger PC (2014) Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder. J Clin Microbiol 52:871–876
Karstens L, Asquith M, Davin S, Stauffer P, Fair D, Gregory WT, Rosenbaum JT, McWeeney SK, Nardos R (2016) Does the urinary microbiome play a role in urgency urinary incontinence and its severity? Front Cell Infect Microbiol 6:78
Khasriya R, Sathiananthamoorthy S, Ismail S, Kelsey M, Wilson M, Rohn JL, Malone-Lee J (2013) Spectrum of bacterial colonization associated with urothelial cells from patients with chronic lower urinary tract symptoms. J Clin Microbiol 51:2054–2062
Komesu YM, Richter HE, Carper B, Dinwiddie DL, Lukacz ES, Siddiqui NY, Sung VW, Zyczynski HM, Ridgeway B, Rogers RG, Arya LA, Mazloomdoost D, Gantz MG, Disorders NPF (2018) The urinary microbiome in women with mixed urinary incontinence compared to similarly aged controls. Int Urogynecol J 29:1785–1795
Lloyd-Price J, Abu-Ali G, Huttenhower C (2016) The healthy human microbiome. Genome Med 8:51
Mändar R, Punab M, Korrovits P, Türk S, Ausmees K, Lapp E, Preem JK, Oopkaup K, Salumets A, Truu J (2017) Seminal microbiome in men with and without prostatitis. Int J Urol 24:211–216
Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre M-L, Luke JJ, Gajewski TF (2018) The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359:104–108
McMillan A, Macklaim JM, Burton JP, Reid G (2013) Adhesion of Lactobacillus iners AB-1 to human fibronectin: a key mediator for persistence in the vagina? Reprod Sci 20:791–796
Moustafa A, Li W, Singh H, Moncera KJ, Torralba MG, Yu Y, Manuel O, Biggs W, Venter JC, Nelson KE, Pieper R, Telenti A (2018) Microbial metagenome of urinary tract infection. Sci Rep 8:4333
Mueller ER, Wolfe AJ, Brubaker L (2017) Female urinary microbiota. Curr Opin Urol 27:282–286
Nelson DE, Van Der Pol B, Dong Q, Revanna KV, Fan B, Easwaran S, Sodergren E, Weinstock GM, Diao L, Fortenberry JD (2010) Characteristic male urine microbiomes associate with asymptomatic sexually transmitted infection. PLoS ONE 5:e14116
Nickel JC, Stephens A, Landis JR, Chen J, Mullins C, van Bokhoven A, Lucia MS, Melton-Kreft R, Ehrlich GD (2015) Search for microorganisms in men with urologic chronic pelvic pain syndrome: a culture-independent analysis in the mapp research network. J Urol 194:127–135
Nielsen KL, Dynesen P, Larsen P, Frimodt-Møller N (2014) Faecal Escherichia coli from patients with E. coli urinary tract infection and healthy controls who have never had a urinary tract infection. J Med Microbiol 63:582–589
Nunn KL, Forney LJ (2016) Unraveling the dynamics of the human vaginal microbiome. Yale J Biol Med 89:331–337
Olomu IN, Pena-Cortes LC, Long RA, Vyas A, Krichevskiy O, Luellwitz R, Singh P, Mulks MH (2020) Elimination of “kitome” and “splashome” contamination results in lack of detection of a unique placental microbiome. BMC Microbiol 20:157
Pearce MM, Hilt EE, Rosenfeld AB, Zilliox MJ, Thomas-White K, Fok C, Kliethermes S, Schreckenberger PC, Brubaker L, Gai X, Wolfe AJ (2014) The female urinary microbiome: a comparison of women with and without urgency urinary incontinence. MBio 5:e01283-e1314
Pearce MM, Zilliox MJ, Rosenfeld AB, Thomas-White KJ, Richter HE, Nager CW, Visco AG, Nygaard IE, Barber MD, Schaffer J, Moalli P, Sung VW, Smith AL, Rogers R, Nolen TL, Wallace D, Meikle SF, Gai X, Wolfe AJ, Brubaker L, Disorders NPF (2015) The female urinary microbiome in urgency urinary incontinence. Am J Obstet Gynecol 213(347):e1-11
Popović VB, Šitum M, Chow C-ET, Chan LS, Roje B, Terzić J (2018) The urinary microbiome associated with bladder cancer. Sci Rep 8:12157
Price TK, Dune T, Hilt EE, Thomas-White KJ, Kliethermes S, Brincat C, Brubaker L, Wolfe AJ, Mueller ER, Schreckenberger P (2016) The clinical urine culture: enhanced techniques improve detection of clinically relevant microorganisms. J Clin Microbiol 54:1216–1222
Price TK, Hilt EE, Dune TJ, Mueller ER, Wolfe AJ, Brubaker L (2017) Urine trouble: should we think differently about UTI? Int Urogynecol J 29:205–210
Price TK, Hilt EE, Thomas-White K, Mueller ER, Wolfe AJ, Brubaker L (2019) The urobiome of continent adult women: a cross-sectional study. BJOG 127:193–201
Price TK, Lin H, Gao X, Thomas-White KJ, Hilt EE, Mueller ER, Wolfe AJ, Dong Q, Brubaker L (2020a) Bladder bacterial diversity differs in continent and incontinent women: a cross-sectional study. Am J Obstet Gynecol S0002–9378:30512–30513
Price TK, Wolff B, Halverson T, Limeira R, Brubaker L, Dong Q, Mueller ER, Wolfe AJ (2020b) Temporal dynamics of the adult female lower urinary tract microbiota. MBio 11:e00475-e520
Sharon G, Sampson TR, Geschwind DH, Mazmanian SK (2016) The central nervous system and the gut microbiome. Cell 167:915–932
Shoskes DA, Altemus J, Polackwich AS, Tucky B, Wang H, Eng C (2016) 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 92:26–32
Shrestha E, White JR, Yu SH, Kulac I, Ertunc O, De Marzo AM, Yegnasubramanian S, Mangold LA, Partin AW, Sfanos KS (2018) Profiling the urinary microbiome in men with positive versus negative biopsies for prostate cancer. J Urol 199:161–171
Siddiqui H, Nederbragt AJ, Lagesen K, Jeansson SL, Jakobsen KS (2011) Assessing diversity of the female urine microbiota by high throughput sequencing of 16S rDNA amplicons. BMC Microbiol 11:244
Southworth E, Hochstedler B, Price TK, Joyce C, Wolfe AJ, Mueller ER (2019) A cross-sectional pilot cohort study comparing standard urine collection to the Peezy midstream device for research studies involving women. Female Pelvic Med Reconstr Surg 25:e28–e33
Stinson LF, Keelan JA, Payne MS (2019) Identification and removal of contaminating microbial DNA from PCR reagents: impact on low-biomass microbiome analyses. Lett Appl Microbiol 68:2–8
Thomas-White KJ, Hilt EE, Fok C, Pearce MM, Mueller ER, Kliethermes S, Jacobs K, Zilliox MJ, Brincat C, Price TK, Kuffel G, Schreckenberger P, Gai X, Brubaker L, Wolfe AJ (2016a) Incontinence medication response relates to the female urinary microbiota. Int Urogynecol J 27:723–733
Thomas-White KJ, Kliethermes S, Rickey L, Lukacz ES, Richter HE, Moalli P, Zimmern P, Norton P, Kusek JW, Wolfe AJ, Brubaker L, Diabetes National Institute of, Digestive, and Network Kidney Diseases Urinary Incontinence Treatment (2016b) Evaluation of the urinary microbiota of women with uncomplicated stress urinary incontinence. Am J Obstet Gynecol 216:55.e1-55.e16
Thomas-White K, Forster SC, Kumar N, Van Kuiken M, Putonti C, Stares MD, Hilt EE, Price TK, Wolfe AJ, Lawley TD (2018a) Culturing of female bladder bacteria reveals an interconnected urogenital microbiota. Nat Commun 9:1557
Thomas-White KJ, Gao X, Lin H, Fok CS, Ghanayem K, Mueller ER, Dong Q, Brubaker L, Wolfe AJ (2018b) Urinary microbes and postoperative urinary tract infection risk in urogynecologic surgical patients. Int Urogynecol J 29:1797–1805
Verdi S, Abbasian G, Bowyer RCE, Lachance G, Yarand D, Christofidou P, Mangino M, Menni C, Bell JT, Falchi M, Small KS, Williams FMK, Hammond CJ, Hart DJ, Spector TD, Steves CJ (2019) TwinsUK: the UK adult twin registry update. Twin Res Hum Genet 22:523–529
Whiteside SA, Razvi H, Dave S, Reid G, Burton JP (2015) The microbiome of the urinary tract–a role beyond infection. Nat Rev Urol 12:81–90
Wolfe AJ, Brubaker L (2018) Urobiome updates: advances in urinary microbiome research. Nat Rev Urol 16:73–74
Wolfe AJ, Toh E, Shibata N, Rong R, Kenton K, Fitzgerald M, Mueller ER, Schreckenberger P, Dong Q, Nelson DE, Brubaker L (2012) Evidence of uncultivated bacteria in the adult female bladder. J Clin Microbiol 50:1376–1383
Wu P, Zhang G, Zhao J, Chen J, Chen Y, Huang W, Zhong J, Zeng J (2018) Profiling the urinary microbiota in male patients with bladder cancer in China. Front Cell Infect Microbiol 8:167
Xu Z, Malmer D, Langille MG, Way SF, Knight R (2014) Which is more important for classifying microbial communities: who’s there or what they can do? ISME J 8:2357–2359
Yamamoto S, Tsukamoto T, Terai A, Kurazono H, Takeda Y, Yoshida O (1997) Genetic evidence supporting the fecal-perineal-urethral hypothesis in cystitis caused by Escherichia coli. J Urol 157:1127–1129
Acknowledgements
We would like to thank the members of the Loyola Urinary Education and Research Collaborative for their contributions to the work described.
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The authors gratefully acknowledge the following funding: AJW and LB by NIH Grant R01 DK104718, QD by NIH Grant 5R01AI116706 (subcontracted from Indiana University School of Medicine, PI, David Nelson), and CP by NSF Grant 1661357. No funding, supplies, or services were received from any commercial organization.
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LB, CP, QD and AJW wrote and edited the manuscript.
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Dr. Wolfe discloses research support from the NIH, the DOD, Astellas Scientific and Medical Affairs and Kimberly Clark Corporation. He also discloses membership on the advisory board for Urobiome Therapeutics. Dr. Brubaker discloses research funding from NIH and editorial stipends from Female Pelvic Medicine & Reconstructive Surgery, UpToDate and JAMA. The remaining authors report no disclosures.
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Brubaker, L., Putonti, C., Dong, Q. et al. The human urobiome. Mamm Genome 32, 232–238 (2021). https://doi.org/10.1007/s00335-021-09862-8
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DOI: https://doi.org/10.1007/s00335-021-09862-8