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Current Urology Reports

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01-01-2018 | Pediatric Urology (D Weiss, Section Editor)

The Role of the Genitourinary Microbiome in Pediatric Urology: a Review

Authors: Daniel Gerber, Catherine S. Forster, Michael Hsieh

Published in: Current Urology Reports | Issue 1/2018

Abstract

Purpose of Review

In this review, we highlight the effects of the microbiome on urologic diseases that affect the pediatric patient.

Recent Findings

Perturbations in the urinary microbiome have been shown to be associated with a number of urologic diseases affecting children, namely urinary tract infection, overactive bladder/urge urinary incontinence, and urolithiasis.

Summary

Recently, improved cultivation and sequencing technologies have allowed for the discovery of a significant and diverse microbiome in the bladder, previously assumed to be sterile. Early studies aimed to identify the resident bacterial species and demonstrate the efficacy of sequencing and enhanced quantitative urine culture. More recently, research has sought to elucidate the association between the microbiome and urologic disease, as well as to demonstrate effects of manipulation of the microbiome on various urologic pathologies. With an improved appreciation for the impact of the urinary microbiome on urologic disease, researchers have begun to explore the impact of these resident bacteria in pediatric urology.

Aragón IM, Herrera-Imbroda B, Queipo-Ortuño MI, Castillo E, del Moral JSG, Gómez-Millán J, et al. The urinary tract microbiome in health and disease. European Urology Focus. 2016; https://doi.org/10.1016/j.euf.2016.11.001.

Brubaker L, Wolfe AJ. The new world of the urinary microbiota in women. Am J Obstet Gynecol. 2015;213(5):644–9. https://doi.org/10.1016/j.ajog.2015.05.032.CrossRefPubMedPubMedCentral

Alfano M, et al. The interplay of extracellular matrix and microbiome in urothelial bladder cancer. Nat Rev Urol. 2015;13:77–90.CrossRefPubMed

• Pearce MM. et al. The female urinary microbiome: a comparison of women with and without urgency urinary incontinence. MBio. 2014;5. Pearce et al. (2014) was of importance because it not only demonstrated differences in the urinary microbiome between patients with and without UUI but it also showed that there was variation in species of Lactobacillus in these patients. Importantly, Lactobacillus species that produce more lactic acid are more common in patients without UUI, while those that produce less lactic acid are more common in UUI sufferers. This suggests acification of the bladder microbiome could be protective, mirroring a similar hypothesis in the vaginal microbiome.

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.05852-11.CrossRefPubMedPubMedCentral

Lewis DA, Brown R, Williams J, White P, Jacobson SK, Marchesi JR, et al. The human urinary microbiome; bacterial DNA in voided urine of asymptomatic adults. Front Cell Infect Microbiol. 2013;3 https://doi.org/10.3389/fcimb.2013.00041.

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 Pelvic Floor Dysfunct. 2016;27(5):723–33. https://doi.org/10.1007/s00192-015-2847-x.CrossRef

• Hilt EE, 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;52:871–6. Hilt et al. was of importance because it was instrumental in establishing the protocol for expanded quantitative urine culture (EQUC) and showing strong concordance between bacterial species identified by sequencing and expanded cultureCrossRefPubMedPubMedCentral

Kliman HJ. Comment on ‘the placenta harbors a unique microbiome’. Sci Transl Med. 2014;6(254):254le4. https://doi.org/10.1126/scitranslmed.3009864.CrossRefPubMed

10.

Pearce MM, Zilliox MJ, Rosenfeld AB, Thomas-White KJ, Richter HE, Nager CW, et al. The female urinary microbiome in urgency urinary incontinence. Am J Obstet Gynecol. 2015;213(3):347e1–347e11. https://doi.org/10.1016/j.ajog.2015.07.009.CrossRef

11.

Nelson DE, Dong Q, van der Pol B, Toh E, Fan B, Katz BP, et al. Bacterial communities of the coronal sulcus and distal urethra of adolescent males. PLoS One. 2012;7(5):e36298. https://doi.org/10.1371/journal.pone.0036298.CrossRefPubMedPubMedCentral

12.

Khasriya R, Sathiananthamoorthy S, Ismail S, Kelsey M, Wilson M, Rohn JL, et al. Spectrum of bacterial colonization associated with urothelial cells from patients with chronic lower urinary tract symptoms. J Clin Microbiol. 2013;51(7):2054–62. https://doi.org/10.1128/JCM.03314-12.CrossRefPubMedPubMedCentral

13.

• Asnicar F, et al. Studying Vertical Microbiome Transmission from Mothers to Infants by Strain-Level Metagenomic Profiling. mSystems. 2017;2:e00164–16. Asnicar et al. was of importance because it used metatranscriptomics to demonstrate that vertical transmission of the microbiome results in an active microbiome in various sites in the infant. These results demonstrate the importance of vertical transmission of the microbiome and may allow for future studies examining the role of vertical transmission in the urinary microbiomeCrossRefPubMedPubMedCentral

14.

Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci. 2010;107(26):11971–5. https://doi.org/10.1073/pnas.1002601107.CrossRefPubMedPubMedCentral

15.

• Hickey, RJ, et al. Vaginal microbiota of adolescent girls prior to the onset of menarche resemble those of reproductive-age women. MBio. 2015;6. Hickey et al. was of importance because it demonstrates that Lactobacillus exists in the vaginal microbiome of premenarcheal girls. This finding is in contrast to much of the other literature in the area that suggests that Lactobacillus is rarely a member of the premenarcheal vaginal microbiome. Hickey et al. do note, however, that pubertal development is associated with more representation by lactic acid-producing bacteria in the vaginal microbiome, with a corresponding decrease in vaginal pH. This suggests that the acquisition of the female “adult-form” microbiome is more of a maturation of the microbiome, rather than a transition in the species representation as had been previously asserted.

16.

•• Barr-Beare E, et al. The interaction between enterobacteriaceae and calcium oxalate deposits. PLoS One. 2015;10. Barr-Bear et al. was of outstanding importance because it is the only study examined that analyzed the microbiome of uroliths from pediatric patients. Further, it demonstrated that the microbiome of stones may exist independent of the bacteria of the upper tract urine, and providing evidence that bacteria may contribute to formation of all stone types rather than solely struvite stones.

17.

Alvarez-Olmos MI, Barousse MM, Rajan L, van der Pol BJ, Fortenberry D, Orr D, et al. Vaginal lactobacilli in adolescents. Sex Transm Dis. 2004;31(7):393–400. https://doi.org/10.1097/01.OLQ.0000130454.83883.E9.CrossRefPubMed

18.

Yamamoto T, Zhou X, Williams CJ, Hochwalt A, Forney LJ. Bacterial populations in the vaginas of healthy adolescent women. J Pediatr Adolesc Gynecol. 2009;22(1):11–8. https://doi.org/10.1016/j.jpag.2008.01.073.CrossRefPubMed

19.

•• Nienhouse V, et al. Interplay between bladder microbiota and urinary antimicrobial peptides: mechanisms for human urinary tract infection risk and symptom severity. PLoS One. 2014;9. Nienhouse et al. was of outstanding importance because it provides evidence for the pathophysiological basis for dysbiosis of the urinary microbiome associated with urinatry tract infection. They describe the interplay between the microbiome and innate immunity.

20.

Chapman CMC, Gibson GR, Rowland I. Anaerobe effects of single- and multi-strain probiotics on bio fi lm formation and in vitro adhesion to bladder cells by urinary tract pathogens. Anaerobe. 2014;27:1–6.CrossRef

21.

Fouts DE, Pieper R, Szpakowski S, Pohl H, Knoblach S, Suh MJ, et al. 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. 2012;10(1):174. https://doi.org/10.1186/1479-5876-10-174.CrossRefPubMedPubMedCentral

22.

Xu W, Yang L, Lee P, Huang WC, Nossa C, Ma Y, et al. Mini-review: perspective of the microbiome in the pathogenesis of urothelial carcinoma. Am J Clin Exp Urol. 2014;2(1):57–61.PubMedPubMedCentral

23.

Siddiqui H, Lagesen K, Nederbragt AJ, Jeansson SL, Jakobsen KS. Alterations of microbiota in urine from women with interstitial cystitis. BMC Microbiol. 2012;12(1):205. https://doi.org/10.1186/1471-2180-12-205.CrossRefPubMedPubMedCentral

24.

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.CrossRefPubMed

25.

Nelson DE, van der Pol B, Dong Q, Revanna KV, Fan B, Easwaran S, et al. Characteristic male urine microbiomes associate with asymptomatic sexually transmitted infection. PLoS One. 2010;5(11):e14116. https://doi.org/10.1371/journal.pone.0014116.CrossRefPubMedPubMedCentral

26.

Roberts KB. Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics. 2011;128(3):595–610. https://doi.org/10.1542/peds.2011-1330.CrossRefPubMed

27.

Horwitz D, et al. Decreased microbiota diversity associated with urinary tract infection in a trial of bacterial interference. J Inf Secur. 2015;71:358–67.

28.

Day AS, Keenan JI. Probiotic-mediated modulation of host inflammation. Expert Rev Gastroenterol Hepatol. 2011;5(3):319–21. https://doi.org/10.1586/egh.11.34.CrossRefPubMed

29.

Schierack P, Kleta S, Tedin K, Babila JT, Oswald S, Oelschlaeger TA, et al. E. coli Nissle 1917 affects Salmonella adhesion to porcine intestinal epithelial cells. PLoS One. 2011;6(2):e14712. https://doi.org/10.1371/journal.pone.0014712.CrossRefPubMedPubMedCentral

30.

Trautner BW, Hull RA, Darouiche RO. Colicins prevent colonization of urinary catheters. J Antimicrob Chemother. 2005;56(2):413–5. https://doi.org/10.1093/jac/dki228.CrossRefPubMedPubMedCentral

31.

Darouiche RO, Thornby JI, Cerra-Stewart C, Donovan WH, Hull RA. Bacterial interference for prevention of urinary tract infection: a prospective, randomized, placebo-controlled, double-blind pilot trial. Clin Infect Dis. 2005;41(10):1531–4. https://doi.org/10.1086/497272.CrossRefPubMed

32.

Wullt B, Bergsten G, Connell H, Röllano P, Gebretsadik N, Hull R, et al. P fimbriae enhance the early establishment of Escherichia coli in the human urinary tract. Mol Microbiol. 2000;38(3):456–64. https://doi.org/10.1046/j.1365-2958.2000.02165.x.CrossRefPubMed

33.

Cadieux PA, Burton JP, Devillard E, Reid G. Lactobacillus by-products inhibit the growth and virulence of uropathogenic Escherichia coli. J Physiol Pharmacol. 2009;60:13–8.PubMed

34.

McMillan A, Dell M, Zellar MP, Cribby S, Martz S, Hong E, et al. Disruption of urogenital biofilms by lactobacilli. Colloids Surfaces B Biointerfaces. 2011;86(1):58–64. https://doi.org/10.1016/j.colsurfb.2011.03.016.CrossRefPubMed

35.

Chromek M, Slamová Z, Bergman P, Kovács L, Podracká L, Ehrén I, et al. The antimicrobial peptide cathelicidin protects the urinary tract against invasive bacterial infection. Nat Med. 2006;12(6):636–41. https://doi.org/10.1038/nm1407.CrossRefPubMed

36.

Morrison G, Kilanowski F, Davidson D, Dorin J. Characterization of the mouse beta defensin 1, Defb1, mutant mouse model. Infect Immun. 2002;70(6):3053–60. https://doi.org/10.1128/IAI.70.6.3053-3060.2002.CrossRefPubMedPubMedCentral

37.

Yamasaki K. Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin. FASEB J. 2006;20(12):2068–80. https://doi.org/10.1096/fj.06-6075com.CrossRefPubMed

38.

Groah SL, Pérez-Losada M, Caldovic L, Ljungberg IH, Sprague BM, Castro-Nallar E, et al. Redefining healthy urine: a cross-sectional exploratory metagenomic study of people with and without bladder dysfunction. J Urol. 2016;196(2):579–87. https://doi.org/10.1016/j.juro.2016.01.088.CrossRefPubMed

39.

Bossa L, Kline K, McDougald D, Lee BB, Rice SA. Urinary catheter-associated microbiota change in accordance with treatment and infection status. PLoS One. 2017;12:1–20.CrossRef

40.

Trautner BW, Hull RA, Thornby JI, Darouiche RO. Coating urinary catheters with an avirulent strain of Escherichia coli as a means to establish asymptomatic colonization. Infect Control Hosp Epidemiol. 2007;28(01):92–4. https://doi.org/10.1086/510872.CrossRefPubMed

41.

Prasad A, Cevallos ME, Riosa S, Darouiche RO, Trautner BW. A bacterial interference strategy for prevention of UTI in persons practicing intermittent catheterization. Spinal Cord. 2009;47(7):565–9. https://doi.org/10.1038/sc.2008.166.CrossRefPubMedPubMedCentral

42.

Darouiche RO, Green BG, Donovan WH, Chen D, Schwartz M, Merritt J, et al. Multicenter randomized controlled trial of bacterial interference for prevention of urinary tract infection in patients with neurogenic bladder. Urology. 2011;78(2):341–7. https://doi.org/10.1016/j.urology.2011.03.062.CrossRefPubMed

43.

• Karstens L, et al. Does the urinary microbiome play a role in urgency urinary incontinence and its severity? Front Cell Infect Microbiol. 2016;6. Karstens et al. was of importance because it was instrumental in showing the variation in species of the urinary microbiome associated with urge urinary incontinence. Importantly, they found that the bladder microbiome of women with UUI symptoms was overrepresented by at least 5 known uropathogens, suggesting a possible causative role of the microbiome in the pathology of UUI/OAB.

44.

Hashim H, Abrams P. Is the bladder a reliable witness for predicting detrusor overactivity? J Urol. 2006;175(1):191–4. https://doi.org/10.1016/S0022-5347(05)00067-4.CrossRefPubMed

45.

Santos JC, Telo E. Solifenacin: scientific evidence in the treatment of overactive bladder. Arch Esp Urol. 2010;63:197–213.PubMed

46.

Sorrentino F, Cartwright R, Digesu GA, Tolton L, Franklin L, Singh A, et al. Associations between individual lower urinary tract symptoms and bacteriuria in random urine samples in women. Neurourol Urodyn. 2015;34(5):429–33. https://doi.org/10.1002/nau.22607.CrossRefPubMed

47.

Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SSK, McCulle SL, et al. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci. 2011;108(Supplement_1):4680–7. https://doi.org/10.1073/pnas.1002611107.CrossRefPubMed

48.

Brubaker L, Nager CW, Richter HE, Visco A, Nygaard I, Barber MD, et al. Urinary bacteria in adult women with urgency urinary incontinence. Int Urogynecol J. 2014;25(9):1179–84. https://doi.org/10.1007/s00192-013-2325-2.CrossRefPubMedPubMedCentral

49.

Broomfield RJ, Morgan SD, Khan A, Stickler DJ. Crystalline bacterial biofilm formation on urinary catheters by urease-producing urinary tract pathogens: a simple method of control. J Med Microbiol. 2009;58(10):1367–75. https://doi.org/10.1099/jmm.0.012419-0.CrossRefPubMed

50.

Wang X, Krambeck AE, Williams JC, Tang X, Rule AD, Zhao F, et al. Distinguishing characteristics of idiopathic calcium oxalate kidney stone formers with low amounts of randall’s plaque. Clin J Am Soc Nephrol. 2014;9(10):1757–63. https://doi.org/10.2215/CJN.01490214.CrossRefPubMedPubMedCentral

51.

Tavichakorntrakool R, Prasongwattana V, Sungkeeree S, Saisud P, Sribenjalux P, Pimratana C, et al. Extensive characterizations of bacteria isolated from catheterized urine and stone matrices in patients with nephrolithiasis. Nephrol Dial Transplant. 2012;27(11):4125–30. https://doi.org/10.1093/ndt/gfs057.CrossRefPubMed

52.

Knight J, Deora R, Assimos DG, Holmes RP. The genetic composition of Oxalobacter formigenes and its relationship to colonization and calcium oxalate stone disease. Urol Res. 2013;41:187–96.

53.

Siener R, Bangen U, Sidhu H. The role of Oxalobacter formigenes colonization in calcium oxalate stone disease. Kidney Int. 2013;83(6):1144–9. https://doi.org/10.1038/ki.2013.104.CrossRefPubMed

54.

Kaufman DW, Kelly JP, Curhan GC, Anderson TE, Dretler SP, Preminger GM, et al. Oxalobacter formigenes may reduce the risk of calcium oxalate kidney stones. J Am Soc Nephrol. 2008;19(6):1197–203. https://doi.org/10.1681/ASN.2007101058.CrossRefPubMedPubMedCentral

55.

Hatch M, Cornelius J, Allison M, Sidhu H, Peck A, Freel RW. Oxalobacter sp. reduces urinary oxalate excretion by promoting enteric oxalate secretion. Kidney Int. 2006;69(4):691–8. https://doi.org/10.1038/sj.ki.5000162.CrossRefPubMed

56.

Duncan SH, Richardson AJ, Kaul P, Holmes RP, Allison MJ, Stewart CS. Oxalobacter formigenes and its potential role in human health. Appl Environ Microbiol. 2002;68(8):3841–7. https://doi.org/10.1128/AEM.68.8.3841-3847.2002.CrossRefPubMedPubMedCentral

57.

Milliner D, Hoppe B, Groothoff J. A randomised phase II/III study to evaluate the efficacy and safety of orally administered Oxalobacter formigenes to treat primary hyperoxaluria. Urolithiasis. 2017:1–11. https://doi.org/10.1007/s00240-017-0998-6.

58.

Hoppe B, Groothoff JW, Hulton SA, Cochat P, Niaudet P, Kemper MJ, et al. Efficacy and safety of Oxalobacter formigenes to reduce urinary oxalate in primary hyperoxaluria. Nephrol Dial Transplant. 2011;26(11):3609–15. https://doi.org/10.1093/ndt/gfr107.CrossRefPubMed

59.

Lieske JC, Tremaine WJ, de Simone C, O’Connor HM, Li X, Bergstralh EJ, et al. Diet, but not oral probiotics, effectively reduces urinary oxalate excretion and calciumoxalate supersaturation. Kidney Int. 2010;78(11):1178–85. https://doi.org/10.1038/ki.2010.310.CrossRefPubMedPubMedCentral

60.

•• Miller AW, Dale C, Dearing MD. The induction of oxalate metabolism in vivo is more effective with functional microbial communities than with functional microbial species. mSystems. 2017;2:e00088–17. Miller et al. was of outstanding importance because it not only demonstrated an effective probiotic treatment that may reduce urolithiasis, but established a new path for future research on the use of probiotics to target the urinary system. Authors demonstrated that in rats, fecal transplants with complete microbial communities containing oxalate-metabolizing bacteria were significantly more effective in reducing oxalate excretion. Further, this benefit was maintained after reduction in dietary oxalate, suggesting formation of a stable community of bacteria following fecal transplant CrossRefPubMedPubMedCentral

61.

Mittal RD, Kumar R, Bid HK, Mittal B. Effect of antibiotics on Oxalobacter formigenes colonization of human gastrointestinal tract. J Endourol. 2005;19(1):102–6. https://doi.org/10.1089/end.2005.19.102.CrossRefPubMed

62.

Kelly JP, Curhan GC, Cave DR, Anderson TE, Kaufman DW. Factors related to colonization with oxalobacter formigenes in U.S. adults. J Urol. 2011;186:577–8.

63.

Lange JN, Wood KD, Wong H, Otto R, Mufarrij PW, Knight J, et al. Sensitivity of human strains of Oxalobacter formigenes to commonly prescribed antibiotics. Urology. 2012;79(6):1286–9. https://doi.org/10.1016/j.urology.2011.11.017.CrossRefPubMedPubMedCentral

64.

Ackerman AL, Underhill DM. The mycobiome of the human urinary tract: potential roles for fungi in urology. Ann Transl Med. 2017;5(2):31. https://doi.org/10.21037/atm.2016.12.69.CrossRefPubMedPubMedCentral

Title: The Role of the Genitourinary Microbiome in Pediatric Urology: a Review
Authors: Daniel Gerber
Catherine S. Forster
Michael Hsieh
Publication date: 01-01-2018
Publisher: Springer US
Published in: Current Urology Reports / Issue 1/2018
Print ISSN: 1527-2737
Electronic ISSN: 1534-6285
DOI: https://doi.org/10.1007/s11934-018-0763-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

The Role of the Genitourinary Microbiome in Pediatric Urology: a Review

Abstract

Purpose of Review

Recent Findings

Summary

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose of Review

Recent Findings

Summary

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