The Role of the Genitourinary Microbiome in Pediatric Urology: a Review
- 340 Downloads
Purpose of Review
In this review, we highlight the effects of the microbiome on urologic diseases that affect the pediatric patient.
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.
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.
KeywordsPediatric urology Genitourinary microbiome Urologic diseases Urinary incontinence Urolithiasis
The authors would like to thank Hans Pohl, M.D., for reviewing the manuscript.
Compliance with Ethical Standards
Conflict of Interest
Daniel Gerber, Catherine Forster, and Michael Hsieh each declare no potential conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.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.
- 4.• 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. Google Scholar
- 6.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.
- 8.• 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 cultureCrossRefPubMedPubMedCentralGoogle Scholar
- 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.CrossRefPubMedPubMedCentralGoogle Scholar
- 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 microbiomeCrossRefPubMedPubMedCentralGoogle Scholar
- 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.CrossRefPubMedPubMedCentralGoogle Scholar
- 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.Google Scholar
- 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. Google Scholar
- 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.CrossRefPubMedGoogle Scholar
- 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.Google Scholar
- 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.CrossRefPubMedPubMedCentralGoogle Scholar
- 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.CrossRefPubMedGoogle Scholar
- 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.Google Scholar
- 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.CrossRefPubMedGoogle Scholar
- 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.CrossRefPubMedGoogle Scholar
- 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. Google Scholar
- 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.CrossRefPubMedPubMedCentralGoogle Scholar
- 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.CrossRefPubMedGoogle Scholar
- 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.Google Scholar
- 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.
- 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.CrossRefPubMedPubMedCentralGoogle Scholar
- 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 CrossRefPubMedPubMedCentralGoogle Scholar
- 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.Google Scholar