Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Ménage à trois in the human gut: interactions between host, bacteria and phages

Key Points

  • The human gut is home to dense bacterial and phage populations that are involved in regulating human health.

  • Phages regulate bacterial abundance, diversity and metabolism in numerous ecosystems, but their effects in the human gut remain largely unexplored.

  • Despite high bacterial abundance and metabolism, the majority of described phages in the gut are integrated within their bacterial hosts, which suggests dynamic interactions that are specific to this system.

  • Different bacteria–phage interactions occur depending on the health status and development stage of the human host. Characterization of these interactions would provide unique ways to improve disease or developmental outcomes.

  • Further research on phage replication cycles and phage pharmacodynamics is essential before considering their therapeutic use for human health.

Abstract

The human gut is host to one of the densest microbial communities known, the gut microbiota, which contains bacteria, archaea, viruses, fungi and other microbial eukaryotes. Bacteriophages in the gut are largely unexplored, despite their potential to regulate bacterial communities and thus human health. In addition to helping us understand gut homeostasis, applying an ecological perspective to the study of bacterial and phage communities in the gut will help us to understand how this microbial system functions. For example, temporal studies of bacteria, phages and host immune cells in the gut during health and disease could provide key information about disease development and inform therapeutic treatments, whereas understanding the regulation of the replication cycles of phages could help harness the gut microbiota to improve disease outcomes. As the most abundant biological entities in our gut, we must consider bacteriophages in our pursuit of personalized medicine.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Overview of bacteria and bacteriophage communities in the healthy adult gut.
Figure 2: Gut health and development are linked to different bacteria–bacteriophage dynamics.
Figure 3: Biotic and abiotic parameters that affect bacteria and bacteriophage interactions.
Figure 4: Overview of phage manipulation of the gut microbiome using phage cocktails.

References

  1. 1

    Rohwer, F., Prangishvili, D. & Lindell, D. Roles of viruses in the environment. Environ. Microbiol. 11, 2771–2774 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Mills, S. et al. Movers and shakers: influence of bacteriophages in shaping the mammalian gut microbiota. Gut Microbes 4, 4–16 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    De Smet, J. et al. High coverage metabolomics analysis reveals phage-specific alterations to Pseudomonas aeruginosa physiology during infection. ISME J. 10, 1823–1835 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    Parfrey, L. W., Walters, W. A. & Knight, R. Microbial eukaryotes in the human microbiome: ecology, evolution, and future directions. Front. Microbiol. 2, 153 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Hoffmann, C. et al. Archaea and fungi of the human gut microbiome: correlations with diet and bacterial residents. PLoS ONE 8, e66019 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).

  9. 9

    Hewitson, J. P. & Maizels, R. M. Vaccination against helminth parasite infections. Expert Rev. Vaccines 13, 473–487 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Tlaskalova-Hogenova, H. et al. The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases. Cell. Mol. Immunol. 8, 110–120 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Wilson, M. in Bacteriology of Humans: An Ecological Perspective 278–279 (Wiley-Blackwell, 2008).

    Google Scholar 

  12. 12

    Blaut, M. Ecology and physiology of the intestinal tract. Curr. Top. Microbiol. Immunol. 358, 247–272 (2013).

    PubMed  PubMed Central  Google Scholar 

  13. 13

    Cotillard, A. et al. Dietary intervention impact on gut microbial gene richness. Nature 500, 585–588 (2013).

    CAS  Article  Google Scholar 

  14. 14

    Kamada, N., Seo, S. U., Chen, G. Y. & Nunez, G. Role of the gut microbiota in immunity and inflammatory disease. Nat. Rev. Immunol. 13, 321–335 (2013).

    CAS  Article  Google Scholar 

  15. 15

    Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Sommer, F. & Backhed, F. The gut microbiota — masters of host development and physiology. Nat. Rev. Microbiol. 11, 227–238 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Ley, R. E., Peterson, D. A. & Gordon, J. I. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124, 837–848 (2006). A review that identifies possible ecological rules governing the diversity of the bacterial communities in the human gut.

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Faith, J. J. et al. The long-term stability of the human gut microbiota. Science 341, 1237439 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Frank, D. N. et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl Acad. Sci. USA 104, 13780–13785 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Qin, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012).

    CAS  Article  Google Scholar 

  22. 22

    David, L. A. et al. Host lifestyle affects human microbiota on daily timescales. Genome Biol. 15, R89 (2014). This study provides a comprehensive time-series analysis of gut and oral bacterial communities in two healthy individuals over the course of 1 year.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Ley, R. E. et al. Evolution of mammals and their gut microbes. Science 320, 1647–1651 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Lozupone, C. A., Stombaugh, J. I., Gordon, J. I., Jansson, J. K. & Knight, R. Diversity, stability and resilience of the human gut microbiota. Nature 489, 220–230 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Breitbart, M. et al. Metagenomic analyses of an uncultured viral community from human feces. J. Bacteriol. 185, 6220–6223 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Norman, J. M. et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 160, 447–460 (2015). This study details a comparison between the gut viromes of patients with IBD, showing disease-specific changes in virome diversity that are not explained by the changes in bacterial communities.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Reyes, A. et al. Gut DNA viromes of Malawian twins discordant for severe acute malnutrition. Proc. Natl Acad. Sci. USA 112, 11941–11946 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Reyes, A. et al. Viruses in the faecal microbiota of monozygotic twins and their mothers. Nature 466, 334–338 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    Reyes, A., Wu, M., McNulty, N. P., Rohwer, F. L. & Gordon, J. I. Gnotobiotic mouse model of phage–bacterial host dynamics in the human gut. Proc. Natl Acad. Sci. USA 110, 20236–20241 (2013). This study shows that mice that are colonized by a specific bacterial community isolated from the human gut and are infected by phages have reproducible and non-simultaneous bacterial infection patterns.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Zhang, T. et al. RNA viral community in human feces: prevalence of plant pathogenic viruses. PLoS Biol. 4, e3 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Minot, S. et al. Rapid evolution of the human gut virome. Proc. Natl Acad. Sci. USA 110, 12450–12455 (2013). A temporal study of the healthy human gut virome over 2.5 years, which shows long-term stability of diversity in the gut virome and the rapid evolution of some long-term members of the gut virome.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Browne, H. P. et al. Culturing of 'unculturable' human microbiota reveals novel taxa and extensive sporulation. Nature 533, 543–546 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Myhrvold, C., Kotula, J. W., Hicks, W. M., Conway, N. J. & Silver, P. A. A distributed cell division counter reveals growth dynamics in the gut microbiota. Nat. Commun. 6, 10039 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37

    Breitbart, M. et al. Viral diversity and dynamics in an infant gut. Res. Microbiol. 159, 367–373 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Sharon, I. et al. Time series community genomics analysis reveals rapid shifts in bacterial species, strains, and phage during infant gut colonization. Genome Res. 23, 111–120 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Koenig, J. E. et al. Succession of microbial consortia in the developing infant gut microbiome. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4578–4585 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Dominguez-Bello, M. G. et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl Acad. Sci. USA 107, 11971–11975 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Thingstad, T. F. Elements of a theory for the mechanisms controlling abundance, diversity, and biogeochemical role of lytic bacterial viruses in aquatic systems. Limnol. Oceanogr. 45, 1320–1328 (2000).

    Article  Google Scholar 

  43. 43

    Weinbauer, M. G. & Rassoulzadegan, F. Are viruses driving microbial diversification and diversity? Environ. Microbiol. 6, 1–11 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Mahana, D. et al. Antibiotic perturbation of the murine gut microbiome enhances the adiposity, insulin resistance, and liver disease associated with high-fat diet. Genome Med. 8, 48 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Charbonneau, M. R. et al. Sialylated milk oligosaccharides promote microbiota-dependent growth in models of infant undernutrition. Cell 164, 859–871 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Harrison, E., Laine, A. L., Hietala, M. & Brockhurst, M. A. Rapidly fluctuating environments constrain coevolutionary arms races by impeding selective sweeps. Proc. Biol. Sci. 280, 20130937 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Gomez, P. & Buckling, A. Bacteria–phage antagonistic coevolution in soil. Science 332, 106–109 (2011). This study in soil microcosms illustrates that bacteria–phage coevolution in soil leads to fluctuating selection dynamics between bacteria and phages.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Hall, A. R., Scanlan, P. D., Morgan, A. D. & Buckling, A. Host–parasite coevolutionary arms races give way to fluctuating selection. Ecol. Lett. 14, 635–642 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    van Houte, S., Buckling, A. & Westra, E. R. Evolutionary ecology of prokaryotic immune mechanisms. Microbiol. Mol. Biol. Rev. 80, 745–763 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Lopez Pascua, L. et al. Higher resources decrease fluctuating selection during host–parasite coevolution. Ecol. Lett. 17, 1380–1388 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    Williamson, K. E., Radosevich, M., Smith, D. W. & Wommack, K. E. Incidence of lysogeny within temperate and extreme soil environments. Environ. Microbiol. 9, 2563–2574 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Weinbauer, M. G., Brettar, I. & Hofle, M. G. Lysogeny and virus-induced mortality of bacterioplankton in surface, deep, and anoxic marine waters. Limnol. Oceanogr. 48, 1457–1465 (2003).

    Article  Google Scholar 

  53. 53

    Weinbauer, M. G. Ecology of prokaryotic viruses. FEMS Microbiol. Rev. 28, 127–181 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Silveira, C. B. & Rohwer, F. L. Piggyback-the-Winner in host-associated microbial communities. NPJ Biofilms Microbiomes 2, 16010 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  55. 55

    Lenski, R. E. Dynamics of interactions between bacteria and virulent bacteriophage. Adv. Microb. Ecol. 10, 1–44 (1988).

    CAS  Article  Google Scholar 

  56. 56

    Knowles, B. et al. Lytic to temperate switching of viral communities. Nature 531, 466–470 (2016). This study proposes the piggyback-the-winner model in host-associated microbial communities.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Touchon, M., Bernheim, A. & Rocha, E. P. Genetic and life-history traits associated with the distribution of prophages in bacteria. ISME J. 10, 2744–2754 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58

    Peterson, D. A., Frank, D. N., Pace, N. R. & Gordon, J. I. Metagenomic approaches for defining the pathogenesis of inflammatory bowel diseases. Cell Host Microbe 3, 417–427 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59

    Perez-Brocal, V. et al. Study of the viral and microbial communities associated with Crohn's disease: a metagenomic approach. Clin. Transl Gastroenterol. 4, e36 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Lepage, P. et al. Dysbiosis in inflammatory bowel disease: a role for bacteriophages? Gut 57, 424–425 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Brockhurst, M. A., Morgan, A. D., Fenton, A. & Buckling, A. Experimental coevolution with bacteria and phage. The Pseudomonas fluorescens–Φ2 model system. Infect. Genet. Evol. 7, 547–552 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Maranger, R. & Bird, D. F. Viral abundance in aquatic systems — a comparison between marine and fresh-waters. Mar. Ecol. Prog. Ser. 121, 217–226 (1995).

    Article  Google Scholar 

  63. 63

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 64

    Hodyra-Stefaniak, K. et al. Mammalian host-versus-phage immune response determines phage fate in vivo. Sci. Rep. 5, 14802 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65

    Majewska, J. et al. Oral application of T4 phage induces weak antibody production in the gut and in the blood. Viruses 7, 4783–4799 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Miernikiewicz, P. et al. T4 phage tail adhesin Gp12 counteracts LPS-induced inflammation in vivo. Front. Microbiol. 7, 1112 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    Barr, J. J. et al. Bacteriophage adhering to mucus provide a non-host-derived immunity. Proc. Natl Acad. Sci. USA 110, 10771–10776 (2013). This study shows that phage immunoglobulin-like proteins enable increased phage adherence to mucosal surfaces of metazoan hosts, including human intestinal cells, and provide a first line of defence against bacterial pathogens.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69

    Mogensen, T. H. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin. Microbiol. Rev. 22, 240–273 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Fischbach, M. A. & Sonnenburg, J. L. Eating for two: how metabolism establishes interspecies interactions in the gut. Cell Host Microbe 10, 336–347 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71

    Rossmann, F. S. et al. Phage-mediated dispersal of biofilm and distribution of bacterial virulence genes is induced by quorum sensing. PLoS Pathog. 11, e1004653 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Erez, Z. et al. Communication between viruses guides lysis–lysogeny decisions. Nature 541, 488–493 (2017). This study characterizes three phage genes that are involved in a phage-specific peptide communication system to coordinate the lysis–lysogeny decision of phages from the SPbeta group.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Jonczyk, E., Klak, M., Miedzybrodzki, R. & Gorski, A. The influence of external factors on bacteriophages — review. Folia Microbiol. (Praha) 56, 191–200 (2011).

    CAS  Article  Google Scholar 

  74. 74

    Verthe, K., Possemiers, S., Boon, N., Vaneechoutte, M. & Verstraete, W. Stability and activity of an Enterobacter aerogenes-specific bacteriophage under simulated gastro-intestinal conditions. Appl. Microbiol. Biotechnol. 65, 465–472 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    Ma, Y. et al. Microencapsulation of bacteriophage felix O1 into chitosan-alginate microspheres for oral delivery. Appl. Environ. Microbiol. 74, 4799–4805 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76

    Maura, D., Galtier, M., Le Bouguenec, C. & Debarbieux, L. Virulent bacteriophages can target O104:H4 enteroaggregative Escherichia coli in the mouse intestine. Antimicrob. Agents Chemother. 56, 6235–6242 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Turnbaugh, P. J., Backhed, F., Fulton, L. & Gordon, J. I. Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 3, 213–223 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78

    Kim, M. S. & Bae, J. W. Spatial disturbances in altered mucosal and luminal gut viromes of diet-induced obese mice. Environ. Microbiol. 18, 1498–1510 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    United Nations Children's Fund, World Health Organization & The World Bank. UNICEF–WHO–World Bank joint child malnutrition estimates. World Health Organization http://www.who.int/nutgrowthdb/jme_unicef_who_wb.pdf (2012).

  80. 80

    Subramanian, S. et al. Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature 510, 417–421 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81

    Maurice, C. F., Haiser, H. J. & Turnbaugh, P. J. Xenobiotics shape the physiology and gene expression of the active human gut microbiome. Cell 152, 39–50 (2013). This in vitro study identifies the rapid effects of therapeutic compounds on the gene expression, physiology and community structure of healthy gut bacterial communities, including the higher transcription of prophage induction genes.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82

    Pavlova, S. I. & Tao, L. Induction of vaginal Lactobacillus phages by the cigarette smoke chemical benzo[a]pyrene diol epoxide. Mutat. Res. 466, 57–62 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83

    Willner, D. et al. Metagenomic detection of phage-encoded platelet-binding factors in the human oral cavity. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4547–4553 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Taguer, M. & Maurice, C. F. The complex interplay of diet, xenobiotics, and microbial metabolism in the gut: implications for clinical outcomes. Clin. Pharmacol. Ther. 99, 588–599 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    Mylon, S. E. et al. Influence of salts and natural organic matter on the stability of bacteriophage MS2. Langmuir 26, 1035–1042 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86

    Lenzi, L. J., Lucchesi, P. M., Medico, L., Burgan, J. & Kruger, A. Effect of the food additives sodium citrate and disodium phosphate on shiga toxin-producing Escherichia coli and production of stx-phages and Shiga toxin. Front. Microbiol. 7, 992 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  87. 87

    Allen, H. K. et al. Antibiotics in feed induce prophages in swine fecal microbiomes. mBio 2, e00260-11 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  88. 88

    DeMarini, D. M. & Lawrence, B. K. Prophage induction by DNA topoisomerase II poisons and reactive-oxygen species: role of DNA breaks. Mutat. Res. 267, 1–17 (1992).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89

    Wegrzyn, G. & Wegrzyn, A. Genetic switches during bacteriophage λ development. Prog. Nucleic Acid Res. Mol. Biol. 79, 1–48 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 91

    Los, J. M., Los, M., Wegrzyn, G. & Wegrzyn, A. Differential efficiency of induction of various lambdoid prophages responsible for production of Shiga toxins in response to different induction agents. Microb. Pathog. 47, 289–298 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. 92

    Volkova, V. V., Lu, Z., Besser, T. & Grohn, Y. T. Modeling the infection dynamics of bacteriophages in enteric Escherichia coli: estimating the contribution of transduction to antimicrobial gene spread. Appl. Environ. Microbiol. 80, 4350–4362 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Sarker, S. A. et al. Oral phage therapy of acute bacterial diarrhea with two coliphage preparations: a randomized trial in children from Bangladesh. EBioMedicine 4, 124–137 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  94. 94

    Nailor, M. D. & Sobel, J. D. Antibiotics for Gram-positive bacterial infections: vancomycin, teicoplanin, quinupristin/dalfopristin, oxazolidinones, daptomycin, dalbavancin, and telavancin. Infect. Dis. Clin. North Am. 23, 965–982 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  95. 95

    Ross, A., Ward, S. & Hyman, P. More is better: selecting for broad host range bacteriophages. Front. Microbiol. 7, 1352 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  96. 96

    Bruttin, A. & Brussow, H. Human volunteers receiving Escherichia coli phage T4 orally: a safety test of phage therapy. Antimicrob. Agents Chemother. 49, 2874–2878 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97

    Galtier, M. et al. Bacteriophages to reduce gut carriage of antibiotic resistant uropathogens with low impact on microbiota composition. Environ. Microbiol. 18, 2237–2245 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. 98

    Wright, A., Hawkins, C. H., Anggard, E. E. & Harper, D. R. A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Clin. Otolaryngol. 34, 349–357 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02116010 (2015).

  100. 100

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02664740 (2016).

  101. 101

    Lu, T. K. & Collins, J. J. Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy. Proc. Natl Acad. Sci. USA 106, 4629–4634 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. 102

    Libis, V. K. et al. Silencing of antibiotic resistance in E. coli with engineered phage bearing small regulatory RNAs. ACS Synth. Biol. 3, 1003–1006 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. 103

    Chan, B. K. et al. Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa. Sci. Rep. 6, 26717 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. 104

    Alang, N. & Kelly, C. R. Weight gain after fecal microbiota transplantation. Open Forum Infect. Dis. 2, ofv004 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  105. 105

    Sheth, R. U., Cabral, V., Chen, S. P. & Wang, H. H. Manipulating bacterial communities by in situ microbiome engineering. Trends Genet. 32, 189–200 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106

    Cooper, C., Khan Mirzaei, M. & Nilsson, A. S. Adapting drug approval pathways for bacteriophage-based therapeutics. Front. Microbiol. 7, 1209 (2016).

    PubMed  PubMed Central  Google Scholar 

  107. 107

    Nale, J. Y. et al. Bacteriophage combinations significantly reduce Clostridium difficile growth in vitro and proliferation in vivo. Antimicrob. Agents Chemother. 60, 968–981 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. 108

    Abedon, S. T., Kuhl, S. J., Blasdel, B. G. & Kutter, E. M. Phage treatment of human infections. Bacteriophage 1, 66–85 (2011). A review of historical and contemporary research on the use of phages to treat human infections.

    Article  PubMed  PubMed Central  Google Scholar 

  109. 109

    Manichanh, C., Borruel, N., Casellas, F. & Guarner, F. The gut microbiota in IBD. Nat. Rev. Gastroenterol. Hepatol. 9, 599–608 (2012).

    CAS  Article  Google Scholar 

  110. 110

    Pirnay, J. P. et al. The phage therapy paradigm: pret-a-porter or sur-mesure? Pharm. Res. 28, 934–937 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. 111

    Nilsson, A. S. Phage therapy — constraints and possibilities. Ups. J. Med. Sci. 119, 192–198 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  112. 112

    Swidsinski, A., Weber, J., Loening-Baucke, V., Hale, L. P. & Lochs, H. Spatial organization and composition of the mucosal flora in patients with inflammatory bowel disease. J. Clin. Microbiol. 43, 3380–3389 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  113. 113

    Bull, J. J. & Gill, J. J. The habits of highly effective phages: population dynamics as a framework for identifying therapeutic phages. Front. Microbiol. 5, 618 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  114. 114

    Khan Mirzaei, M. & Nilsson, A. S. Isolation of phages for phage therapy: a comparison of spot tests and efficiency of plating analyses for determination of host range and efficacy. PLoS ONE 10, e0118557 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Dutilh, B. E. et al. A highly abundant bacteriophage discovered in the unknown sequences of human faecal metagenomes. Nat. Commun. 5, 4498 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  116. 116

    Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 117

    Paul, J. H. Prophages in marine bacteria: dangerous molecular time bombs or the key to survival in the seas? ISME J. 2, 579–589 (2008). This study identifies phage-encoded repressors and transcriptional regulators of bacterial metabolism that enable the survival of the bacterial host in unfavourable environmental conditions in marine systems.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118

    Brussow, H., Canchaya, C. & Hardt, W. D. Phages and the evolution of bacterial pathogens: from genomic rearrangements to lysogenic conversion. Microbiol. Mol. Biol. Rev. 68, 560–602 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Smeal, S. W., Schmitt, M. A., Pereira, R. R., Prasad, A. & Fisk, J. D. Simulation of the M13 life cycle I: assembly of a genetically-structured deterministic chemical kinetic simulation. Virology 500, 259–274 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. 120

    Cenens, W., Makumi, A., Mebrhatu, M. T., Lavigne, R. & Aertsen, A. Phage–host interactions during pseudolysogeny: lessons from the Pid/dgo interaction. Bacteriophage 3, e25029 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  121. 121

    Feiner, R. et al. A new perspective on lysogeny: prophages as active regulatory switches of bacteria. Nat. Rev. Microbiol. 13, 641–650 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. 122

    Reyesa, A. et al. Gut DNA viromes of Malawian twins discordant for severe acute malnutrition. Proc. Natl Acad. Sci. USA 112, 11941–11946 (2015).

    Article  CAS  Google Scholar 

  123. 123

    Thingstad, T. F. & Lignell, R. Theoretical models for the control of bacterial growth rate, abundance, diversity and carbon demand. Aquat. Microb. Ecol. 13, 19–27 (1997).

    Article  Google Scholar 

  124. 124

    Maurice, C. F. et al. Disentangling the relative influence of bacterioplankton phylogeny and metabolism on lysogeny in reservoirs and lagoons. ISME J. 5, 831–842 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. 125

    Bibby, K. Improved bacteriophage genome data is necessary for integrating viral and bacterial ecology. Microb. Ecol. 67, 242–244 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  126. 126

    Labrie, S. J., Samson, J. E. & Moineau, S. Bacteriophage resistance mechanisms. Nat. Rev. Microbiol. 8, 317–327 (2010).

    CAS  Article  Google Scholar 

  127. 127

    Samson, J. E., Magadan, A. H., Sabri, M. & Moineau, S. Revenge of the phages: defeating bacterial defences. Nat. Rev. Microbiol. 11, 675–687 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  128. 128

    Stern, A. & Sorek, R. The phage–host arms race: shaping the evolution of microbes. Bioessays 33, 43–51 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. 129

    Weitz, J. S., Hartman, H. & Levin, S. A. Coevolutionary arms races between bacteria and bacteriophage. Proc. Natl Acad. Sci. USA 102, 9535–9540 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Canada Research Chair Program and the Bill and Melinda Gates Foundation (OPP1139814). The authors thank members of the Maurice laboratory and E. Haggård-ljungquist for constructive comments on this manuscript.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Corinne F. Maurice.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Microbiome

The collective genomes of all microorganisms in an ecosystem.

Microbiota

The collection of all microorganisms that exist in an ecosystem.

Xenobiotics

Chemical substances that are foreign to an ecosystem.

Dysbiosis

An imbalance in microbial diversity that is usually characterized by a decrease in specific members of the Firmicutes and an increase in members of the Proteobacteria.

Genome annotation

The process of identifying, characterizing and annotating all coding and non-coding regions in a genome.

Cryptic phages

Defective prophages that lack the ability to return to the lytic cycle.

Kill-the-winner

(KTW). A specific case of Lotka–Volterra dynamics that is applied to bacterial and phage communities. The KTW hypothesis models the frequency-dependent viral infection of temporally abundant and active bacterial taxa, allowing for high bacterial diversity.

Restriction–modification

(R–M). A bacterial defence system against invading foreign unmethylated DNA; for example, from phages and plasmids. Unmethylated DNA sites are recognized and cleaved by specific bacterial restriction endonucleases.

Selective sweeps

The reduction or elimination of genetic variation in regions linked to a recently fixed beneficial mutation that increases host fitness.

Fluctuating selection dynamics

A model of co-evolutionary dynamics that is characterized by the fluctuation of the selection pressure on genes, phenotypes or species in variable environments over time. In this model, there is maintenance of within-population genetic diversity over time, with variants that might become advantageous under appropriate environmental conditions.

Piggyback-the-winner model

A recent model of bacteria–phage interactions, whereby phages integrate as prophages and undergo the lysogenic replication cycle instead of the lytic cycle when bacterial density and activity increase.

Abortive infection system

(Abi system). Phage infection that leads to bacterial death and loss of the phage genome, without the production of any phages.

Competitive exclusion

A mechanism whereby two (or more) related species that are competing for the same resources cannot stably coexist in the same environment and must specialize.

Quorum sensing

A system of bacteria-produced molecular stimuli and responses that coordinate bacterial gene expression (of genes that are involved in biofilm formation, virulence and antibiotic resistance), according to the local density of the bacterial population.

Gnotobiotic mice

Germ-free mice or antibiotic-treated mice that are colonized with predefined bacterial species or communities.

Chronic otitis

A term that is used to describe various symptoms that result from the long-term damage of the middle ear by infection and inflammation.

Pharmacodynamics

The study of the effects and mechanisms of action of a compound (typically therapeutic drugs) on a living organism.

Pharmacokinetics

The study of the absorption, distribution, metabolism and excretion of a compound, typically applied to the study of therapeutic drugs.

Temperate phages

Phages that replicate through lysogenic or lytic replication.

Latency period

The time between phage infection and bacterial lysis with the release of new progeny.

Burst size

The number of progeny produced per infecting phage.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mirzaei, M., Maurice, C. Ménage à trois in the human gut: interactions between host, bacteria and phages. Nat Rev Microbiol 15, 397–408 (2017). https://doi.org/10.1038/nrmicro.2017.30

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing