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Bacteriophages of the lower urinary tract

Nature Reviews Urology (2019) | Download Citation


The discovery of bacteria in the female urinary bladder has fundamentally changed current dogma regarding the urinary tract and related urinary disorders. Previous research characterized many of the bacterial components of the female urinary tract, but the viral fraction of this community is largely unknown. Viruses within the human microbiota far outnumber bacterial cells, with the most abundant viruses being those that infect bacteria (bacteriophages). Similar to observations within the microbiota of the gut and oral cavity, preliminary surveys of the urinary tract and bladder microbiota indicate a rich diversity of uncharacterized bacteriophage (phage) species. Phages are vital members of the microbiota, having critical roles in shaping bacterial metabolism and community structure. Although phages have been discovered in the urinary tract, such as phages that infect Escherichia coli, sampling them is challenging owing to low biomass, possible contamination when using non-invasive methods and the invasiveness of methods that reduce the potential for contamination. Phages could influence bladder health, but an understanding of the association between phage communities, bacterial populations and bladder health is in its infancy. However, evidence suggests that phages can defend the host against pathogenic bacteria and, therefore, modulation of the microbiome using phages has therapeutic potential for lower urinary tract symptoms. Furthermore, as natural predators of bacteria, phages have garnered renewed interest for their use as antimicrobial agents, for instance, in the treatment of urinary tract infections.

Key points

  • Bacteriophages (phages) are abundant members of the microbiota of the lower urinary tract.

  • Active or lytic phages have been isolated from urine samples, but the majority of phages within the urinary microbiota persist through dormant infections, the lysogenic life cycle.

  • Evidence suggests that phages have a role in modulating the composition of the urinary microbiota, similar to that observed in microbiota of other organs of the human body.

  • Phage therapy, or the use of phages to treat pathogenic bacterial infections, is an active area of research within urology given their potential use to treat urinary tract infections.

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  1. 1.

    Chibani-Chennoufi, S., Bruttin, A., Dillmann, M.-L. & Brussow, H. Phage-host interaction: an ecological perspective. J. Bacteriol. 186, 3677–3686 (2004).

  2. 2.

    Breitbart, M., Bonnain, C., Malki, K. & Sawaya, N. A. Phage puppet masters of the marine microbial realm. Nat. Microbiol. 3, 754–766 (2018).

  3. 3.

    Williamson, K. E., Radosevich, M. & Wommack, K. E. Abundance and diversity of viruses in six Delaware soils. Appl. Environ. Microbiol. 71, 3119–3125 (2005).

  4. 4.

    Williamson, K. E., Fuhrmann, J. J., Wommack, K. E. & Radosevich, M. Viruses in soil ecosystems: an unknown quantity within an unexplored territory. Annu. Rev. Virol. 4, 201–219 (2017).

  5. 5.

    Bruder, K. et al. Freshwater metaviromics and bacteriophages: a current assessment of the state of the art in relation to bioinformatic challenges. Evol. Bioinform. Online 12, 25–33 (2016).

  6. 6.

    Prestel, E., Regeard, C., Salamitou, S., Neveu, J. & Dubow, M. S. The bacteria and bacteriophages from a Mesquite Flats site of the Death Valley desert. Antonie Van Leeuwenhoek 103, 1329–1341 (2013).

  7. 7.

    Luhtanen, A.-M. et al. Isolation and characterization of phage–host systems from the Baltic Sea ice. Extremophiles 18, 121–130 (2014).

  8. 8.

    Nigro, O. D. et al. Viruses in the oceanic basement. mBio 8, e02129–16 (2017).

  9. 9.

    Koskella, B. & Parr, N. The evolution of bacterial resistance against bacteriophages in the horse chestnut phyllosphere is general across both space and time. Phil. Trans. R. Soc. B 370, 20140297 (2015).

  10. 10.

    Pramono, A. K. et al. Discovery and complete genome sequence of a bacteriophage from an obligate intracellular symbiont of a cellulolytic protist in the termite gut. Microbes Environ. 32, 112–117 (2017).

  11. 11.

    Moreno, P. S. et al. Characterisation of the canine faecal virome in healthy dogs and dogs with acute diarrhoea using shotgun metagenomics. PLOS ONE 12, e0178433 (2017).

  12. 12.

    Barr, J. J. A bacteriophages journey through the human body. Immunol. Rev. 279, 106–122 (2017).

  13. 13.

    Navarro, F. & Muniesa, M. Phages in the human body. Front. Microbiol. 8, 566 (2017).

  14. 14.

    Nguyen, S. et al. Bacteriophage transcytosis provides a mechanism to cross epithelial cell layers. mBio 8, e01874–17 (2017).

  15. 15.

    Górski, A. et al. Bacteriophage translocation. FEMS Immunol. Med. Microbiol. 46, 313–319 (2006).

  16. 16.

    Hayes, S., Mahony, J., Nauta, A. & van Sinderen, D. Metagenomic approaches to assess bacteriophages in various environmental niches. Viruses 9, 127 (2017).

  17. 17.

    Kim, K.-H. & Bae, J.-W. Amplification methods bias metagenomic libraries of uncultured single-stranded and double-stranded DNA viruses. Appl. Environ. Microbiol. 77, 7663–7668 (2011).

  18. 18.

    Parras-Moltó, M., Rodríguez-Galet, A., Suárez-Rodríguez, P. & López-Bueno, A. Evaluation of bias induced by viral enrichment and random amplification protocols in metagenomic surveys of saliva DNA viruses. Microbiome 6, 119 (2018).

  19. 19.

    Yilmaz, S., Allgaier, M. & Hugenholtz, P. Multiple displacement amplification compromises quantitative analysis of metagenomes. Nat. Methods 7, 943–944 (2010).

  20. 20.

    Kristensen, D. M. et al. Orthologous gene clusters and taxon signature genes for viruses of prokaryotes. J. Bacteriol. 195, 941–950 (2013).

  21. 21.

    Adriaenssens, E. M. & Cowan, D. A. Using signature genes as tools to assess environmental viral ecology and diversity. Appl. Environ. Microbiol. 80, 4470–4480 (2014).

  22. 22.

    Roux, S., Hallam, S. J., Woyke, T. & Sullivan, M. B. Viral dark matter and virus-host interactions resolved from publicly available microbial genomes. eLife 4, e08490 (2015).

  23. 23.

    Paez-Espino, D. et al. IMG/VR: a database of cultured and uncultured DNA viruses and retroviruses. Nucleic Acids Res. 45, D457–D465 (2017).

  24. 24.

    Paez-Espino, D. et al. Uncovering Earth’s virome. Nature 536, 425–430 (2016).

  25. 25.

    Minot, S. et al. Rapid evolution of the human gut virome. Proc. Natl Acad. Sci. USA 110, 12450–12455 (2013).

  26. 26.

    Minot, S. et al. The human gut virome: inter-individual variation and dynamic response to diet. Genome Res. 21, 1616–1625 (2011).

  27. 27.

    Norman, J. M. et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 160, 447–460 (2015).

  28. 28.

    Lim, E. S. et al. Early life dynamics of the human gut virome and bacterial microbiome in infants. Nat. Med. 21, 1228–1234 (2015).

  29. 29.

    Ogilvie, L. A. & Jones, B. V. The human gut virome: a multifaceted majority. Front. Microbiol. 6, 918 (2015).

  30. 30.

    Manrique, P. et al. Healthy human gut phageome. Proc. Natl Acad. Sci. USA 113, 10400–10405 (2016).

  31. 31.

    Manrique, P., Dills, M. & Young, M. The human gut phage community and its implications for health and disease. Viruses 9, 141 (2017).

  32. 32.

    Rani, A. et al. A diverse virome in kidney transplant patients contains multiple viral subtypes with distinct polymorphisms. Sci. Rep. 6, 33327 (2016).

  33. 33.

    Garretto, A., Thomas-White, K., Wolfe, A. J. & Putonti, C. Detecting viral genomes in the female urinary microbiome. J. Gen. Virol. 99, 1141–1146 (2018).

  34. 34.

    Thannesberger, J. et al. Viruses comprise an extensive pool of mobile genetic elements in eukaryote cell cultures and human clinical samples. FASEB J. 31, 1987–2000 (2017).

  35. 35.

    Santiago-Rodriguez, T. M., Ly, M., Bonilla, N. & Pride, D. T. The human urine virome in association with urinary tract infections. Front. Microbiol. 6, 14 (2015).

  36. 36.

    Moustafa, A. et al. Microbial metagenome of urinary tract infection. Sci. Rep. 8, 4333 (2018).

  37. 37.

    Huttenhower, C. et al. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).

  38. 38.

    Aagaard, K. et al. The Human Microbiome Project strategy for comprehensive sampling of the human microbiome and why it matters. FASEB J. 27, 1012–1022 (2013).

  39. 39.

    Thomas-White, K., Brady, M., Wolfe, A. J. & Mueller, E. R. The bladder is not sterile: history and current discoveries on the urinary microbiome. Curr. Bladder Dysfunct. Rep. 11, 18–24 (2016).

  40. 40.

    Fouts, D. E. 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. 10, 174 (2012).

  41. 41.

    Wolfe, A. J. et al. Evidence of uncultivated bacteria in the adult female bladder. J. Clin. Microbiol. 50, 1376–1383 (2012).

  42. 42.

    Brubaker, L. et al. Urinary bacteria in adult women with urgency urinary incontinence. Int. Urogynecol. J. 25, 1179–1184 (2014).

  43. 43.

    Hilt, E. E. 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. 52, 871–876 (2014).

  44. 44.

    Pearce, M. M. et al. The female urinary microbiome: a comparison of women with and without urgency urinary incontinence. mBio 5, e01283–14 (2014).

  45. 45.

    Pearce, M. M. et al. The female urinary microbiome in urgency urinary incontinence. Am. J. Obstet. Gynecol. 213, 347.e1–347.e11 (2015).

  46. 46.

    Thomas-White, K., Fok, C., Mueller, E. R., Wolfe, A. J. & Brubaker, L. Pre-operative urinary microbiome reveals post-operative urinary tract infection risk. Neurourol. Urodynam. 34, S21–S22 (2015).

  47. 47.

    Karstens, L. et al. Does the urinary microbiome play a role in urgency urinary incontinence and its severity? Front. Cell. Infect. Microbiol. 6, 78 (2016).

  48. 48.

    Ackerman, A. L. & Underhill, D. M. The mycobiome of the human urinary tract: potential roles for fungi in urology. Ann. Transl Med. 5, 31–31 (2017).

  49. 49.

    Whiteside, S. A., Razvi, H., Dave, S., Reid, G. & Burton, J. P. The microbiome of the urinary tract — a role beyond infection. Nat. Rev. Urol. 12, 81–90 (2015).

  50. 50.

    Fok, C. S. et al. Day of surgery urine cultures identify urogynecologic patients at increased risk for postoperative urinary tract infection. J. Urol. 189, 1721–1724 (2013).

  51. 51.

    Nienhouse, V. et al. Interplay between bladder microbiota and urinary antimicrobial peptides: mechanisms for human urinary tract infection risk and symptom severity. PLOS ONE 9, e114185 (2014).

  52. 52.

    Thomas-White, K. J. et al. Incontinence medication response relates to the female urinary microbiota. Int. Urogynecol. J. 27, 723–733 (2016).

  53. 53.

    Fok, C. S. et al. Urinary symptoms are associated with certain urinary microbes in urogynecologic surgical patients. Int. Urogynecol. J. 29, 1765–1771 (2018).

  54. 54.

    Thomas-White, K. J. et al. Urinary microbes and postoperative urinary tract infection risk in urogynecologic surgical patients. Int. Urogynecol. J. 29, 1797–1805 (2018).

  55. 55.

    Brubaker, L. & Wolfe, A. J. Microbiota in 2016: associating infection and incontinence with the female urinary microbiota. Nat. Rev. Urol. 14, 72–74 (2017).

  56. 56.

    Mueller, E. R., Wolfe, A. J. & Brubaker, L. Female urinary microbiota. Curr. Opin. Urol. 27, 282–286 (2017).

  57. 57.

    Thomas-White, K. Culturing of female bladder bacteria reveals an interconnected urogenital microbiome. Nat. Commun. 9, 8350 (2018).

  58. 58.

    Wylie, K. M. et al. Metagenomic analysis of double-stranded DNA viruses in healthy adults. BMC Biol. 12, 71 (2014).

  59. 59.

    Lloyd-Price, J., Abu-Ali, G. & Huttenhower, C. The healthy human microbiome. Genome Med. 8, 51 (2016).

  60. 60.

    Wagner, J. et al. Bacteriophages in gut samples from pediatric Crohn’s disease patients: metagenomic analysis using 454 Pyrosequencing. Inflamm. Bowel Dis. 19, 1598–1608 (2013).

  61. 61.

    Zuo, T. et al. Gut mucosal virome alterations in ulcerative colitis. Gut (2019).

  62. 62.

    Ma, Y., You, X., Mai, G., Tokuyasu, T. & Liu, C. A human gut phage catalog correlates the gut phageome with type 2 diabetes. Microbiome 6, 24 (2018).

  63. 63.

    Foulongne, V. et al. Human skin microbiota: high diversity of DNA viruses identified on the human skin by high throughput sequencing. PLOS ONE 7, e38499 (2012).

  64. 64.

    Pride, D. T. et al. Evidence of a robust resident bacteriophage population revealed through analysis of the human salivary virome. ISME J. 6, 915–926 (2012).

  65. 65.

    Ly, M. et al. Altered oral viral ecology in association with periodontal disease. mBio 5, e01133–14 (2014).

  66. 66.

    Hannigan, G. D. et al. The human skin double-stranded DNA virome: topographical and temporal diversity, genetic enrichment, and dynamic associations with the host microbiome. mBio 6, e01578–15 (2015).

  67. 67.

    Hannigan, G. D. et al. Evolutionary and functional implications of hypervariable loci within the skin virome. PeerJ 5, e2959 (2017).

  68. 68.

    Pérez-Brocal, V. & Moya, A. The analysis of the oral DNA virome reveals which viruses are widespread and rare among healthy young adults in Valencia (Spain). PLOS ONE 13, e0191867 (2018).

  69. 69.

    Thomas-White, K. J. et al. Evaluation of the urinary microbiota of women with uncomplicated stress urinary incontinence. Am J. Obstet. Gynecol. 216, 55.e1–55.e16 (2017).

  70. 70.

    Bajic, P. et al. Male bladder microbiome relates to lower urinary tract symptoms. Eur. Urol. Focus (2018).

  71. 71.

    Kramer, H. et al. Diversity of the midstream urine microbiome in adults with chronic kidney disease. Int. Urol. Nephrol. 50, 1123–1130 (2018).

  72. 72.

    Hobbs, Z. & Abedon, S. T. Diversity of phage infection types and associated terminology: the problem with ‘Lytic or lysogenic’. FEMS Microbiol. Lett. 363, fnw047 (2016).

  73. 73.

    Koskella, B. & Meaden, S. Understanding bacteriophage specificity in natural microbial communities. Viruses 5, 806–823 (2013).

  74. 74.

    Young, R. Phage lysis: Three steps, three choices, one outcome. J. Microbiol. 52, 243–258 (2014).

  75. 75.

    Little, J. in Phages Their Role in Bacterial Pathogenesis and Biotechnology (eds Waldor, M., Friedman, D. & Adhya, S.) 37–54 (ASM Press, 2005).

  76. 76.

    Abedon, S. T. Bacteriophage Ecology: Population Growth, Evolution, and Impact of Bacterial Viruses (Cambridge Univ. Press, 2008).

  77. 77.

    Erez, Z. et al. Communication between viruses guides lysis-lysogeny decisions. Nature 541, 488–493 (2017).

  78. 78.

    Calendar, R. The Bacteriophages (Oxford Univ. Press, 2006).

  79. 79.

    Fuhrman, J. A. Marine viruses and their biogeochemical and ecological effects. Nature 399, 541–548 (1999).

  80. 80.

    Suttle, C. A. Viruses in the sea. Nature 437, 356–361 (2005).

  81. 81.

    Clokie, M. R. J., Millard, A. D., Letarov, A. V. & Heaphy, S. Phages in nature. Bacteriophage 1, 31–45 (2011).

  82. 82.

    Buckling, A. & Rainey, P. B. Antagonistic coevolution between a bacterium and a bacteriophage. Proc. Biol. Sci. 269, 931–936 (2002).

  83. 83.

    Rodriguez-Valera, F. et al. Explaining microbial population genomics through phage predation. Nat. Rev. Microbiol. 7, 828–836 (2009).

  84. 84.

    Koskella, B. & Brockhurst, M. A. Bacteria-phage coevolution as a driver of ecological and evolutionary processes in microbial communities. FEMS Microbiol. Rev. 38, 916–931 (2014).

  85. 85.

    Tellier, A., Moreno-Gámez, S. & Stephan, W. Speed of adaptation and genomic footprints of host-parasite coevolution under arms race and trench warfare dynamics. Evolution 68, 2211–2224 (2014).

  86. 86.

    Braga, L. P. P., Soucy, S. M., Amgarten, D. E., da Silva, A. M. & Setubal, J. C. Bacterial diversification in the light of the interactions with phages: the genetic symbionts and their role in ecological speciation. Front. Ecol. Evol. 6, 6 (2018).

  87. 87.

    Scanlan, P. D. Bacteria–bacteriophage coevolution in the human gut: implications for microbial diversity and functionality. Trends Microbiol. 25, 614–623 (2017).

  88. 88.

    Hosseinidoust, Z., van de Ven, T. G. M. & Tufenkji, N. Evolution of Pseudomonas aeruginosa virulence as a result of phage predation. Appl. Environ. Microbiol. 79, 6110–6116 (2013).

  89. 89.

    Wendling, C. C. et al. Tripartite species interaction: eukaryotic hosts suffer more from phage susceptible than from phage resistant bacteria. BMC Evol. Biol. 17, 98 (2017).

  90. 90.

    Wagner, P. L. & Waldor, M. K. Bacteriophage control of bacterial virulence. Infect. Immun. 70, 3985–3993 (2002).

  91. 91.

    Casas, V. & Maloy, S. Role of bacteriophage-encoded exotoxins in the evolution of bacterial pathogens. Future Microbiol. 6, 1461–1473 (2011).

  92. 92.

    Starr, M. et al. Hemolytic-uremic syndrome following urinary tract infection with enterohemorrhagic Escherichia coli: case report and review. Clin. Infect. Dis. 27, 310–315 (1998).

  93. 93.

    Gadea, M. et al. Two cases of urinary tract infection caused by Shiga toxin-producing Escherichia coli O157:H7 strains. Rev. Argent. Microbiol. 44, 94–96 (2012).

  94. 94.

    Toval, F. et al. Characterization of urinary tract infection-associated shiga toxin-producing Escherichia coli. Infect. Immun. 82, 4631–4642 (2014).

  95. 95.

    Harrison, E. & Brockhurst, M. A. Ecological and evolutionary benefits of temperate phage: what does or doesn’t kill you makes you stronger. BioEssays 39, 1700112 (2017).

  96. 96.

    Touchon, M., Moura de Sousa, J. A. & Rocha, E. P. Embracing the enemy: the diversification of microbial gene repertoires by phage-mediated horizontal gene transfer. Curr. Opin. Microbiol. 38, 66–73 (2017).

  97. 97.

    Drexler, H. Transduction by bacteriophage T1. Proc. Natl Acad. Sci. USA 66, 1083–1088 (1970).

  98. 98.

    Modi, S. R., Lee, H. H., Spina, C. S. & Collins, J. J. Antibiotic treatment expands the resistance reservoir and ecological network of the phage metagenome. Nature 499, 219–222 (2013).

  99. 99.

    Abeles, S. R., Ly, M., Santiago-Rodriguez, T. M. & Pride, D. T. Effects of long term antibiotic therapy on human oral and fecal viromes. PLOS ONE 10, e0134941 (2015).

  100. 100.

    Enault, F. et al. Phages rarely encode antibiotic resistance genes: a cautionary tale for virome analyses. ISME J. 11, 237–247 (2017).

  101. 101.

    Lood, R., Ertürk, G. & Mattiasson, B. Revisiting antibiotic resistance spreading in wastewater treatment plants — bacteriophages as a much neglected potential transmission vehicle. Front. Microbiol. 8, 2298 (2017).

  102. 102.

    Keen, E. C. et al. Novel “superspreader” bacteriophages promote horizontal gene transfer by transformation. mBio 8, e02115–16 (2017).

  103. 103.

    Hatfull, G. F. Dark matter of the biosphere: the amazing world of bacteriophage diversity. J. Virol. 89, 8107–8110 (2015).

  104. 104.

    Wang, J., Gao, Y. & Zhao, F. Phage-bacteria interaction network in human oral microbiome: Human oral virome. Environ. Microbiol. 18, 2143–2158 (2016).

  105. 105.

    Shapiro, J. W. & Putonti, C. Gene co-occurrence networks reflect bacteriophage ecology and evolution. mBio 9, e01870–17 (2018).

  106. 106.

    Echavarria, M., Forman, M., Ticehurst, J., Dumler, J. S. & Charache, P. PCR method for detection of adenovirus in urine of healthy and human immunodeficiency virus-infected individuals. J. Clin. Microbiol. 36, 3323–3326 (1998).

  107. 107.

    Lion, T. Adenovirus infections in immunocompetent and immunocompromised patients. Clin. Microbiol. Rev. 27, 441–462 (2014).

  108. 108.

    Tan, S. K., Relman, D. A. & Pinsky, B. A. The human virome: implications for clinical practice in transplantation medicine. J. Clin. Microbiol. 55, 2884–2893 (2017).

  109. 109.

    Chang, H. et al. High incidence of JC viruria in JC-seropositive older individuals. J. Neurovirol. 8, 447–451 (2002).

  110. 110.

    Hirsch, H. H., Kardas, P., Kranz, D. & Leboeuf, C. The human JC polyomavirus (JCPyV): virological background and clinical implications. APMIS 121, 685–727 (2013).

  111. 111.

    Rinaldo, C. H., Tylden, G. D. & Sharma, B. N. The human polyomavirus BK (BKPyV): virological background and clinical implications. APMIS 121, 728–745 (2013).

  112. 112.

    Tshomo, U. et al. Evaluation of the performance of human papillomavirus testing in paired urine and clinician-collected cervical samples among women aged over 30 years in Bhutan. Virol. J. 14, 74 (2017).

  113. 113.

    Iwasawa, A. et al. Presence of human papillomavirus 6/11 DNA in condyloma acuminatum of the urinary bladder. Urol. Int. 48, 235–238 (1992).

  114. 114.

    Karim, R. Z., Rose, B. R., Brammah, S. & Scolyer, R. A. Condylomata acuminata of the urinary bladder with HPV 11. Pathology 37, 176–178 (2005).

  115. 115.

    Chrisofos, M., Skolarikos, A., Lazaris, A., Bogris, S. & Deliveliotis, C. HPV 16/18-associated condyloma acuminatum of the urinary bladder: first international report and review of literature. Int. J. STD AIDS 15, 836–838 (2004).

  116. 116.

    Murray, A. J., Bivalacqua, T. J. & Sopko, N. A. Innumerable Condyloma Acuminatum tumors of the bladder. Urol. Case Rep. 12, 76–77 (2017).

  117. 117.

    Ma, Y. et al. Human papillomavirus community in healthy persons, defined by metagenomics analysis of Human Microbiome Project shotgun sequencing data sets. J. Virol. 88, 4786–4797 (2014).

  118. 118.

    d’Herelle, F. Sur un microbe invisible antagoniste des bacilles dysenteriques [French]. C. R. Acad. Sci. 165, 373 (1917).

  119. 119.

    Brown-Jaque, M., Muniesa, M. & Navarro, F. Bacteriophages in clinical samples can interfere with microbiological diagnostic tools. Sci. Rep. 6, 33000 (2016).

  120. 120.

    Jalil, M. B., Al-Hmudi, H. A., Al-Alsaad, L. A. & Abdul-Hussein, Z. R. Isolation and characterization of bacteriophages against multiple drug resistant Pseudomonas aeruginosa with using the bacteriophage as a therpy in the mice model. Int. J. Dev. Res. 7, 11519 (2017).

  121. 121.

    Dallas, S. D. & Kingsbery, L. Bacteriophage plaques on primary isolation media of a urine culture growing Escherichia coli. Clin. Microbiol. Newsl. 19, 53–56 (1997).

  122. 122.

    Malki, K. et al. Seven bacteriophages isolated from the female urinary microbiota. Genome Announc. 4, e01003–16 (2016).

  123. 123.

    Smith, R., O’Hara, M., Hobman, J. L. & Millard, A. D. Draft genome sequences of 14 Escherichia coli phages isolated from cattle slurry. Genome Announc. 3, e01364–15 (2015).

  124. 124.

    Putonti, C., Garretto, A., Shapiro, J. W. & Wolfe, A. J. The role of bacterial viruses in the female urinary microbiome. Female Pelv. Med. Reconstr. Surg. 23, S39–S40 (2017).

  125. 125.

    Edlund, A., Santiago-Rodriguez, T. M., Boehm, T. K. & Pride, D. T. Bacteriophage and their potential roles in the human oral cavity. J. Oral Microbiol. 7, 27423 (2015).

  126. 126.

    Kim, M.-S. & Bae, J.-W. Lysogeny is prevalent and widely distributed in the murine gut microbiota. ISME J. 12, 1127–1141 (2018).

  127. 127.

    Price, T. K. et al. Genome sequences and annotation of two urinary isolates of E. coli. Stand. Genomic Sci. 11, 79 (2016).

  128. 128.

    Malki, K. et al. Genomes of Gardnerella strains reveal an abundance of prophages within the bladder microbiome. PLOS ONE 11, e0166757 (2016).

  129. 129.

    Miller-Ensminger, T. et al. Bacteriophages of the urinary microbiome. J. Bacteriol. 200, e00738–17 (2018).

  130. 130.

    Lewis, D. A. et al. The human urinary microbiome; bacterial DNA in voided urine of asymptomatic adults. Front. Cell. Infect. Microbiol. 3, 41 (2013).

  131. 131.

    Gottschick, C. et al. The urinary microbiota of men and women and its changes in women during bacterial vaginosis and antibiotic treatment. Microbiome 5, 99 (2017).

  132. 132.

    Perkins, D., Metwally, A. & Finn, P. Microbes everywhere. Presented at the 2017 Great Lakes Bioinformatics Conference 2017 at the University of Illinois, Chicago, IL, USA (2017).

  133. 133.

    Khasriya, R. et al. Spectrum of bacterial colonization associated with urothelial cells from patients with chronic lower urinary tract symptoms. J. Clinl Microbiol. 51, 2054–2062 (2013).

  134. 134.

    Price, T. K. et al. The clinical urine culture: enhanced techniques improve detection of clinically relevant microorganisms. J. Clin. Microbiol. 54, 1216–1222 (2016).

  135. 135.

    Bao, Y. et al. Questions and challenges associated with studying the microbiome of the urinary tract. Ann. Transl Med. 5, 33–33 (2017).

  136. 136.

    Gangping, L. et al. Diversity of duodenal and rectal microbiota in biopsy tissues and luminal contents in healthy volunteers. J. Microbiol. Biotechnol. 25, 1136–1145 (2015).

  137. 137.

    Kim, D. et al. Optimizing methods and dodging pitfalls in microbiome research. Microbiome 5, 52 (2017).

  138. 138.

    Panek, M. et al. Methodology challenges in studying human gut microbiota — effects of collection, storage, DNA extraction and next generation sequencing technologies. Sci. Rep. 8, 2045–2322 (2018).

  139. 139.

    Holm, A. & Rune, A. Urine sampling techniques in symptomatic primary-care patients: a diagnostic accuracy review. BMC Fam. Pract. 17, 72 (2016).

  140. 140.

    Southworth, E. et al. A cross-sectional pilot cohort study comparing standard urine collection to the Peezy midstream device for research studies involving women. Female Pelv. Med. Reconstr. Surg. 25, e28–e33 (2019).

  141. 141.

    Łusiak-Szelachowska, M., Weber-Dabrowska, B., Jonczyk-Matysiak, E., Wojciechowska, R. & Górski, A. Bacteriophages in the gastrointestinal tract and their implications. Gut Pathog. 9, 44 (2017).

  142. 142.

    Barr, J. J. et al. Bacteriophage adhering to mucus provide a non-host-derived immunity. Proc. Natl Acad. Sci. USA 110, 10771–10776 (2013).

  143. 143.

    Shan, J. et al. Bacteriophages are more virulent to bacteria with human cells than they are in bacterial culture; insights from HT-29 cells. Sci. Rep. 8, 5091 (2018).

  144. 144.

    Dabrowska, K. et al. Antitumor activity of bacteriophages in murine experimental cancer models caused possibly by inhibition of beta3 integrin signaling pathway. Acta Virol. 48, 241–248 (2004).

  145. 145.

    Duerkop, B. A. & Hooper, L. V. Resident viruses and their interactions with the immune system. Nat. Immunol. 14, 654–659 (2013).

  146. 146.

    Nieth, A., Verseux, C. & Römer, W. A. Question of attire: dressing up bacteriophage therapy for the battle against antibiotic-resistant intracellular bacteria. Springer Sci. Rev. 3, 1–11 (2015).

  147. 147.

    Zhang, L. et al. Intracellular Staphylococcus aureus control by virulent bacteriophages within MAC-T bovine mammary epithelial cells. Antimicrob. Agents Chemother. 61, e01990–16 (2017).

  148. 148.

    Górski, A. et al. Phages and immunomodulation. Future Microbiol. 12, 905–914 (2017).

  149. 149.

    Górski, A. et al. Bacteriophages and transplantation tolerance. Transplant. Proc. 38, 331–333 (2006).

  150. 150.

    Dabrowska, K. et al. Immunogenicity studies of proteins forming the T4 phage head surface. J. Virol. 88, 12551–12557 (2014).

  151. 151.

    Tothova, L. et al. Phage therapy of Cronobacter-induced urinary tract infection in mice. Med. Sci. Monit. 17, BR173–BR178 (2011).

  152. 152.

    Duerkop, B. A., Clements, C. V., Rollins, D., Rodrigues, J. L. M. & Hooper, L. V. A composite bacteriophage alters colonization by an intestinal commensal bacterium. Proc. Natl Acad. Sci. USA 109, 17621–17626 (2012).

  153. 153.

    Gama, J. A. et al. Temperate bacterial viruses as double-edged swords in bacterial warfare. PLOS ONE 8, e59043 (2013).

  154. 154.

    Lin, D. M., Koskella, B. & Lin, H. C. Phage therapy: an alternative to antibiotics in the age of multi-drug resistance. World J. Gastrointest. Pharmacol. Ther. 8, 162 (2017).

  155. 155.

    Caldwell, J. A. Bacteriophagy in urinary infections following the administration of the bacteriophage therapeutically. Arch. Intern. Med. 41, 189 (1928).

  156. 156.

    Gill, G. & Young, R. F. in Emerging Trends in Antibacterial Discovery (eds Miller, A. A. & Miller, P. F.) 367–407 (Caister Academic Press, 2011).

  157. 157.

    Sybesma, W. et al. Bacteriophages as potential treatment for urinary tract infections. Front. Microbiol. 7, 465 (2016).

  158. 158.

    Khawaldeh, A. et al. Bacteriophage therapy for refractory Pseudomonas aeruginosa urinary tract infection. J. Med. Microbiol. 60, 1697–1700 (2011).

  159. 159.

    Leitner, L. et al. Bacteriophages for treating urinary tract infections in patients undergoing transurethral resection of the prostate: a randomized, placebo-controlled, double-blind clinical trial. BMC Urol. 17, 90 (2017).

  160. 160.

    US National Library of Medicine. (2017).

  161. 161.

    Ujmajuridze, A. et al. Adapted bacteriophages for treating urinary tract infections. Front. Microbiol. 9, 1832 (2018).

  162. 162.

    Siddiq, D. M. & Darouiche, R. O. New strategies to prevent catheter-associated urinary tract infections. Nat. Rev. Urol. 9, 305–314 (2012).

  163. 163.

    Fu, W. et al. Bacteriophage cocktail for the prevention of biofilm formation by Pseudomonas aeruginosa on catheters in an in vitro model system. Antimicrob. Agents Chemother. 54, 397–404 (2010).

  164. 164.

    Melo, L. D. R. et al. Development of a phage cocktail to control Proteus mirabilis catheter-associated urinary tract infections. Front. Microbiol. 7, 1024 (2016).

  165. 165.

    Liao, K. S., Lehman, S. M., Tweardy, D. J., Donlan, R. M. & Trautner, B. W. Bacteriophages are synergistic with bacterial interference for the prevention of Pseudomonas aeruginosa biofilm formation on urinary catheters. J. Appl. Microbiol. 113, 1530–1539 (2012).

  166. 166.

    Abedon, S. T., Kuhl, S. J., Blasdel, B. G. & Kutter, E. M. Phage treatment of human infections. Bacteriophage 1, 66–85 (2011).

  167. 167.

    Schooley, R. T. et al. Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant Acinetobacter baumannii infection. Antimicrob. Agents Chemother. 61, e00954–17 (2017).

  168. 168.

    Chan, B. K. et al. Phage treatment of an aortic graft infected with Pseudomonas aeruginosa. Evol. Med. Public Health 2018, 60–66 (2018).

  169. 169.

    Sirha, N. et al. Nonantibiotic prevention and management of recurrent urinary tract infection. Nat. Rev. Urol. 15, 750–776 (2018).

  170. 170.

    Nobrega, F. L. et al. Targeting mechanisms of tailed bacteriophages. Nat. Rev. Microbiol. 16, 760–773 (2018).

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This work was supported by the NIH (R01 DK104718 to A.J.W.). A.G. is supported by the Carbon Research Fellowship at Loyola University Chicago. T.M.-E. was supported by a Loyola University Chicago Interdisciplinary Research Fellowship. The authors thank J. Shapiro for critical reading of the manuscript and assistance with generating the transmission electron microscopy image.

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Nature Reviews Urology thanks A. Górski and other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Bioinformatics Program, Loyola University Chicago, Chicago, IL, USA

    • Andrea Garretto
    • , Taylor Miller-Ensminger
    •  & Catherine Putonti
  2. Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA

    • Alan J. Wolfe
    •  & Catherine Putonti
  3. Department of Biology, Loyola University Chicago, Chicago, IL, USA

    • Catherine Putonti
  4. Department of Computer Science, Loyola University Chicago, Chicago, IL, USA

    • Catherine Putonti


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A.G. and T.M.-E. researched data for the article. All authors made substantial contribution to discussion of content, wrote the article and reviewed and edited the manuscript before submission.

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The authors declare no competing interests.

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Correspondence to Catherine Putonti.

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