Abstract
Bacteriophages (hence termed phages) are viruses that target bacteria and have long been considered as potential future treatments against antibiotic-resistant bacterial infection. However, the molecular nature of phage interactions with bacteria and the human host has remained elusive for decades, limiting their therapeutic application. While many phages and their functional repertoires remain unknown, the advent of next-generation sequencing has increasingly enabled researchers to decode new lytic and lysogenic mechanisms by which they attack and destroy bacteria. Furthermore, the last decade has witnessed a renewed interest in the utilization of phages as therapeutic vectors and as a means of targeting pathogenic or commensal bacteria or inducing immunomodulation. Importantly, the narrow host range, immense antibacterial repertoire, and ease of manipulating phages may potentially allow for their use as targeted modulators of pathogenic, commensal and pathobiont members of the microbiome, thereby impacting mammalian physiology and immunity along mucosal surfaces in health and in microbiome-associated diseases. In this review, we aim to highlight recent advances in phage biology and how a mechanistic understanding of phage–bacteria–host interactions may facilitate the development of novel phage-based therapeutics. We provide an overview of the challenges of the therapeutic use of phages and how these could be addressed for future use of phages as specific modulators of the human microbiome in a variety of infectious and noncommunicable human diseases.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Reyes, A. et al. Going viral: next-generation sequencing applied to phage populations in the human gut. Nat. Rev. Microbiol. 10, 607–617 (2012).
Suttle, C. A. Viruses in the sea. Nature 437, 356–361 (2005).
Zablocki, O., Adriaenssens, E. M. & Cowan, D. Diversity and ecology of viruses in hyperarid desert soils. Appl. Environ. Microbiol. 82, 770–777 (2015).
Howard-Varona, C. et al. Lysogeny in nature: mechanisms, impact and ecology of temperate phages. ISME J. 11, 1511–1520 (2017).
Weinbauer, M. G. Ecology of prokaryotic viruses. FEMS Microbiol. Rev. 28, 127–181 (2004).
Erez, Z. et al. Communication between viruses guides lysis–lysogeny decisions. Nature 541, 488–493 (2017).
Davidson, A. R. Phages make a group decision. Nature 541, 466–467 (2017).
Harms, A. & Diard, M. Crowd controlled-host quorum sensing drives phage decision. Cell Host Microbe 25, 179–181 (2019).
Zeng, L. et al. Decision making at a subcellular level determines the outcome of bacteriophage infection. Cell 141, 682–691 (2010).
Hynes, A. P. & Moineau, S. Phagebook: the social network. Mol. Cell 65, 963–964 (2017).
Bellas, C., Anesio, A. & Barker, G. Analysis of virus genomes from glacial environments reveals novel virus groups with unusual host interactions. Front. Microbiol. 6, 656 (2015).
Silpe, J. E. & Bassler, B. L. A host-produced quorum-sensing autoinducer controls a phage lysis-lysogeny decision. Cell 176, 268–280.e13 (2019).
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).
Galtier, M. et al. Bacteriophages targeting adherent invasive Escherichia coli strains as a promising new treatment for Crohn’s Disease. J. Crohn’s Colitis 11, 840–847 (2017).
Maura, D. et al. Virulent bacteriophages can target O104:H4 enteroaggregative Escherichia coli in the mouse intestine. Antimicrob. Agents Chemother. 56, 6235–6242 (2012).
Oh, J. et al. Temporal stability of the human skin microbiome. Cell 165, 854–866 (2016).
Oh, J. H. et al. Dietary fructose and microbiota-derived short-chain fatty acids promote bacteriophage production in the gut symbiont Lactobacillus reuteri. Cell Host Microbe 25, 273–284.e6 (2019).
Hsu, B. B. et al. Dynamic modulation of the gut microbiota and metabolome by bacteriophages in a mouse model. Cell Host Microbe 25, 803–814.e5 (2019).
d'Hérelle, F. Sur un microbe invisible antagoniste des bacilles dysentériques. C. R. Acad. Sci. 165, 373–375 (1917).
Sulakvelidze, A., Alavidze, Z. & Morris, J. G. Bacteriophage therapy. Antimicrobial Agents Chemother. 45, 649–659 (2001).
Krueger, A. P. & Scribner, E. J. Bacteriophage therapy. II. The bacteriophage: its nature and its therapeutic use. JAMA 19, 2160–2277 (1941).
Dixon, B. New dawn for phage therapy. Lancet Infect. Dis. 4, 186 (2004).
Pawluk, A., Davidson, A. R. & Maxwell, K. L. Anti-CRISPR: discovery, mechanism and function. Nat. Rev. Microbiol. 16, 12–17 (2018).
Hyman, P. & Abedon, S. T. Bacteriophage host range and bacterial resistance. Adv. Appl Microbiol 70, 217–248 (2010).
Bertin, A., de Frutos, M. & Letellier, L. Bacteriophage-host interactions leading to genome internalization. Curr. Opin. Microbiol. 14, 492–496 (2011).
Meyer, J. R. et al. Repeatability and contingency in the evolution of a key innovation in phage lambda. Science 335, 428–432 (2012).
Michel, A. et al. Bacteriophage PhiX174’s ecological niche and the flexibility of its Escherichia coli lipopolysaccharide receptor. Appl. Environ. Microbiol. 76, 7310–7313 (2010).
Latka, A. et al. Modeling the architecture of depolymerase-containing receptor binding proteins in Klebsiella phages. Front. Microbiol. 10, 2649 (2019).
Warren, R. A. Modified bases in bacteriophage DNAs. Annu. Rev. Microbiol. 34, 137–158 (1980).
Hill, C., Miller, L. A. & Klaenhammer, T. R. In vivo genetic exchange of a functional domain from a type II A methylase between lactococcal plasmid pTR2030 and a virulent bacteriophage. J. Bacteriol. 173, 4363 (1991).
Fineran, P. C. et al. The phage abortive infection system, ToxIN, functions as a protein-RNA toxin-antitoxin pair. Proc. Natl Acad. Sci. USA 106, 894–899 (2009).
Short, F. L. et al. The bacterial Type III toxin-antitoxin system, ToxIN, is a dynamic protein-RNA complex with stability-dependent antiviral abortive infection activity. Sci. Rep. 8, 1013 (2018).
Blower, T. R. et al. Viral evasion of a bacterial suicide system by RNA-based molecular mimicry enables infectious altruism. PLoS Genet. 8, e1003023 (2012).
Blower, T. R. et al. Viral molecular mimicry circumvents abortive infection and suppresses bacterial suicide to make hosts permissive for replication. Bacteriophage 2, 234–238 (2012).
Yanli Zheng, J. L. et al. Endogenous Type I CRISPR-Cas: from foreign DNA defense to prokaryotic engineering. Front. Bioeng. Biotechnol. 8, 62 (2020).
van Houte, S. et al. The diversity-generating benefits of a prokaryotic adaptive immune system. Nature 532, 385–388 (2016).
Rollie, C. et al. Targeting of temperate phages drives loss of type I CRISPR–Cas systems. Nature 578, 149–153 (2020).
Stern, A. et al. CRISPR targeting reveals a reservoir of common phages associated with the human gut microbiome. Genome Res. 22, 1985–1994 (2012).
Stanley, S. Y. & Maxwell, K. L. Phage-encoded anti-CRISPR defenses. Annu. Rev. Genet. 52, 445–464 (2018).
Borges, A. L. et al. Bacteriophage cooperation suppresses CRISPR-Cas3 and Cas9 immunity. Cell 174, 917–925.e10 (2018).
Landsberger, M. et al. Anti-CRISPR phages cooperate to overcome CRISPR-Cas immunity. Cell 174, 908–916.e12 (2018).
Alseth, E. O. et al. Bacterial biodiversity drives the evolution of CRISPR-based phage resistance. Nature 574, 549–552 (2019).
Cohen, D. et al. Cyclic GMP–AMP signalling protects bacteria against viral infection. Nature 574, 691–695 (2019).
Ofir, G. et al. DISARM is a widespread bacterial defence system with broad anti-phage activities. Nat. Microbiol. 3, 90–98 (2018).
Koskella, B. et al. The costs of evolving resistance in heterogeneous parasite environments. Proc. Biol. Sci. 279, 1896–1903 (2012).
Rodriguez-Valera, F. et al. Explaining microbial population genomics through phage predation. Nat. Rev. Microbiol 7, 828–836 (2009).
Arumugam, M. et al. Enterotypes of the human gut microbiome. Nature 473, 174–180 (2011).
Hoyles, L. et al. Characterization of virus-like particles associated with the human faecal and caecal microbiota. Res Microbiol 165, 803–812 (2014).
Kim, M. S. et al. Diversity and abundance of single-stranded DNA viruses in human feces. Appl Environ. Microbiol 77, 8062–8070 (2011).
d’Humières, C. et al. A simple, reproducible and cost-effective procedure to analyse gut phageome: from phage isolation to bioinformatic approach. Sci. Rep. 9, 11331 (2019).
Kang, H. S. et al. Prophage genomics reveals patterns in phage genome organization and replication. https://www.biorxiv.org/content/10.1101/114819v1 (2017).
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).
Minot, S. et al. The human gut virome: inter-individual variation and dynamic response to diet. Genome Res. 21, 1616–1625 (2011).
Reyes, A. et al. Viruses in the faecal microbiota of monozygotic twins and their mothers. Nature 466, 334–338 (2010).
Moreno-Gallego, J. L. et al. Virome diversity correlates with intestinal microbiome diversity in adult monozygotic twins. Cell Host Microbe 25, 261–272.e5 (2019).
Minot, S. et al. Rapid evolution of the human gut virome. Proc. Natl Acad. Sci. USA 110, 12450–12455 (2013).
Kapusinszky, B., Minor, P. & Delwart, E. Nearly constant shedding of diverse enteric viruses by two healthy infants. J. Clin. Microbiol. 50, 3427–3434 (2012).
Witsø, E. et al. High prevalence of human enterovirus a infections in natural circulation of human enteroviruses. J. Clin. Microbiol 44, 4095–4100 (2006).
Manrique, P. et al. Healthy human gut phageome. Proc. Natl Acad. Sci. USA 113, 10400–10405 (2016).
McCann, A. et al. Viromes of one year old infants reveal the impact of birth mode on microbiome diversity. PeerJ 6, e4694 (2018).
Dutilh, B. E. et al. A highly abundant bacteriophage discovered in the unknown sequences of human faecal metagenomes. Nat. Commun. 5, 4498 (2014).
Shkoporov, A. N. et al. ΦCrAss001 represents the most abundant bacteriophage family in the human gut and infects Bacteroides intestinalis. Nat. Commun. 9, 4781 (2018).
Kim, M. S. & Bae, J. W. Lysogeny is prevalent and widely distributed in the murine gut microbiota. ISME J. 12, 1127–1141 (2018).
Reyes, A. et al. Gut DNA viromes of Malawian twins discordant for severe acute malnutrition. Proc. Natl Acad. Sci. USA 112, 11941–11946 (2015).
Norman, J. M. et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 160, 447–460 (2015).
Lim, E. S. et al. Early life dynamics of the human gut virome and bacterial microbiome in infants. Nat. Med. 21, 1228–1234 (2015).
Duerkop, B. A. et al. Murine colitis reveals a disease-associated bacteriophage community. Nat. Microbiol. 3, 1023–1031 (2018).
Martinez-Hernandez, F. et al. Single-virus genomics reveals hidden cosmopolitan and abundant viruses. Nat. Commun. 8, 15892 (2017).
Deng, L. et al. Viral tagging reveals discrete populations in Synechococcus viral genome sequence space. Nature 513, 242–245 (2014).
Dion, M. B., Oechslin, F. & Moineau, S. Phage diversity, genomics and phylogeny. Nat. Rev. Microbiol. 18, 125–138 (2020).
Jong, E. C., Ko, H. L. & Pulverer, G. Studies on bacteriophages of Propionibacterium acnes. Med Microbiol Immunol. 161, 263–271 (1975).
Webster, G. F. & Cummins, C. S. Use of bacteriophage typing to distinguish Propionibacterium acne types I and II. J. Clin. Microbiol. 7, 84–90 (1978).
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).
Liu, J. et al. The diversity and host interactions of Propionibacterium acnes bacteriophages on human skin. ISME J. 9, 2116 (2015).
Marples, R. R. The microflora of the face and acne lesions. J. Investig. Dermatol. 62, 326–331 (1974).
Zierdt, C. H. Properties of Corynebacterium acnes bacteriophage and description of an interference phenomenon. J. Virol. 14, 1268–7 (1974).
Lood, R. et al. Inducible Siphoviruses in superficial and deep tissue isolates of Propionibacterium acnes. BMC Microbiol 8, 139 (2008).
Marinelli, L. J. et al. Propionibacterium acnes bacteriophages display limited genetic diversity and broad killing activity against bacterial skin isolates. mBio 3, e00279–12 (2012).
Pulverer, G., Sorgo, W. & Ko, H. L. [Bacteriophages of Propionibacterium acnes (author’s transl)]. Zentralbl Bakteriol. Orig. A 225, 353–363 (1973).
Allen, E. K. et al. Characterization of the nasopharyngeal microbiota in health and during rhinovirus challenge. Microbiome 2, 22 (2014).
McCaskill, J. G. et al. Pulmonary immune responses to Propionibacterium acnes in C57BL/6 and BALB/c mice. Am. J. Respir. Cell Mol. Biol. 35, 347–356 (2006).
Li, Y. et al. Altered respiratory virome and serum cytokine profile associated with recurrent respiratory tract infections in children. Nat. Commun. 10, 2288 (2019).
Willner, D. et al. Metagenomic analysis of respiratory tract DNA viral communities in cystic fibrosis and non-cystic fibrosis individuals. PLoS ONE 4, e7370 (2009).
Gregory, A. C. et al. Smoking is associated with quantifiable differences in the human lung DNA virome and metabolome. Respiratory Res. 19, 174 (2018).
Damelin, L. H. et al. Identification of predominant culturable vaginal Lactobacillus species and associated bacteriophages from women with and without vaginal discharge syndrome in South Africa. J. Med. Microbiol. 60, 180–183 (2011).
Pavlova, S. I. et al. Phage infection in vaginal lactobacilli: an in vitro study. Infect. Dis. Obstet. Gynecol. 5, 36–44 (1997).
Huttenhower, C. et al. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012).
Fethers, K. A. et al. Sexual risk factors and bacterial vaginosis: a systematic review and meta-analysis. Clin. Infect. Dis. 47, 1426–1435 (2008).
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).
Jakobsen, R. R. et al. Characterization of the vaginal DNA virome in health and dysbiosis: an opening study in patients with non-female factor infertility. https://www.biorxiv.org/content/10.1101/755710v1 (2019).
Lev-Sagie, A. et al. Vaginal microbiome transplantation in women with intractable bacterial vaginosis. Nat. Med. 25, 1500–1504 (2019).
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).
Bachrach, G. et al. Bacteriophage isolation from human saliva. Lett. Appl. Microbiol. 36, 50–53 (2003).
Hitch, G., Pratten, J. & Taylor, P. W. Isolation of bacteriophages from the oral cavity. Lett. Appl. Microbiol. 39, 215–219 (2004).
Atarashi, K. et al. Ectopic colonization of oral bacteria in the intestine drives T(H)1 cell induction and inflammation. Science 358, 359–365 (2017).
Willner, D. et al. Metagenomic detection of phage-encoded platelet-binding factors in the human oral cavity. Proc. Natl Acad. Sci. USA 108, 4547–4553 (2011).
Wang, J., Gao, Y. & Zhao, F. Phage-bacteria interaction network in human oral microbiome. Environ. Microbiol 18, 2143–2158 (2016).
Carr, V. R. et al. The human oral phageome is highly diverse and rich in jumbo phages. https://www.biorxiv.org/content/10.1101/2020.07.06.186817v1 (2020).
Hansen, M. F. et al. Big impact of the tiny: bacteriophage-bacteria interactions in biofilms. Trends Microbiol. 27, 739–752 (2019).
Reyes, A. et al. Gnotobiotic mouse model of phage-bacterial host dynamics in the human gut. Proc. Natl Acad. Sci. USA 110, 20236–20241 (2013).
Goodrich, J. K. et al. Human genetics shape the gut microbiome. Cell 159, 789–799 (2014).
Rothschild, D. et al. Environment dominates over host genetics in shaping human gut microbiota. Nature 555, 210–215 (2018).
Pannaraj, P. S. et al. Shared and distinct features of human milk and infant stool viromes. Front. Microbiol. 9, 1162 (2018).
Garmaeva, S. et al. Studying the gut virome in the metagenomic era: challenges and perspectives. BMC Biol. 17, 84 (2019).
Howe, A. et al. Divergent responses of viral and bacterial communities in the gut microbiome to dietary disturbances in mice. ISME J. 10, 1217–1227 (2016).
Duerkop, B. A. et al. A composite bacteriophage alters colonization by an intestinal commensal bacterium. Proc. Natl Acad. Sci. USA 109, 17621–17626 (2012).
Chatterjee, A. & Duerkop, B. A. Sugar and fatty acids Ack-celerate prophage induction. Cell Host Microbe 25, 175–176 (2019).
Deehan, E. C. & Walter, J. The fiber gap and the disappearing gut microbiome: implications for human nutrition. Trends Endocrinol. Metab. 27, 239–242 (2016).
Van Belleghem, J. D. et al. Interactions between Bacteriophage, Bacteria, and the Mammalian Immune System. Viruses 11, 10 (2018).
Frobisher, M. & B., J. Transmissible toxicogenicity of Streptococci. Bull. Johns. Hopkins Hosp. 41, 167–173 (1927).
Feiner, R. et al. A new perspective on lysogeny: prophages as active regulatory switches of bacteria. Nat. Rev. Microbiol 13, 641–650 (2015).
Rabinovich, L. et al. Prophage excision activates Listeria competence genes that promote phagosomal escape and virulence. Cell 150, 792–802 (2012).
Pasechnek, A. et al. Active lysogeny in Listeria monocytogenes is a bacteria-phage adaptive response in the mammalian environment. Cell Rep. 32, 107956 (2020).
Cenens, W. et al. Phage-host interactions during pseudolysogeny: lessons from the Pid/dgo interaction. Bacteriophage 3, e25029 (2013).
Latino, L. et al. Investigation of Pseudomonas aeruginosa strain PcyII-10 variants resisting infection by N4-like phage Ab09 in search for genes involved in phage adsorption. PLoS ONE 14, e0215456 (2019).
Nguyen, S. et al. Bacteriophage transcytosis provides a mechanism to cross epithelial cell layers. mBio 8, e01874-17 (2017).
Krut, O. & Bekeredjian-Ding, I. Contribution of the immune response to phage therapy. J. Immunol. 200, 3037–3044 (2018).
Dufour, N. et al. Phage therapy of pneumonia is not associated with an overstimulation of the inflammatory response compared to antibiotic treatment in mice. Antimicrob. Agents Chemother. 63, e00379-19 (2019).
Gogokhia, L. et al. Expansion of bacteriophages is linked to aggravated intestinal inflammation and colitis. Cell Host Microbe 25, 285–299 e8 (2019).
Miernikiewicz, P. et al. T4 phage and its head surface proteins do not stimulate inflammatory mediator production. PLoS ONE 8, e71036 (2013).
Hodyra-Stefaniak, K. et al. Mammalian host-versus-phage immune response determines phage fate in vivo. Sci. Rep. 5, 14802 (2015).
Barr, J. J. et al. Bacteriophage adhering to mucus provide a non-host-derived immunity. Proc. Natl Acad. Sci. USA 110, 10771–10776 (2013).
Tetz, G. & Tetz, V. Bacteriophage infections of microbiota can lead to leaky gut in an experimental rodent model. Gut Pathog. 8, 33 (2016).
Jahn, M. T. et al. A phage protein aids bacterial symbionts in eukaryote immune evasion. Cell Host Microbe 26, 542–550.e5 (2019).
Sweere, J. M. et al. Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection. Science 363, eaat9691 (2019).
Hosseinidoust, Z., van de Ven, T. G. & Tufenkji, N. Evolution of Pseudomonas aeruginosa virulence as a result of phage predation. Appl. Environ. Microbiol. 79, 6110–6116 (2013).
Secor, P. R. et al. Filamentous bacteriophage produced by Pseudomonas aeruginosa alters the inflammatory response and promotes noninvasive infection in vivo. Infect. Immun. 85, e00648-16 (2017).
Roach, D. R. et al. Synergy between the host immune system and bacteriophage is essential for successful phage therapy against an acute respiratory pathogen. Cell Host Microbe 22, 38–47.e4 (2017).
Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).
Edwards, R. A. et al. Global phylogeography and ancient evolution of the widespread human gut virus crAssphage. Nat. Microbiol. 4, 1727–1736 (2019).
Rodriguez-Brito, B. et al. Viral and microbial community dynamics in four aquatic environments. ISME J. 4, 739–751 (2010).
Sutton, T. D. S. et al. Choice of assembly software has a critical impact on virome characterisation. Microbiome 7, 12 (2019).
Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).
Blacher, E. et al. Potential roles of gut microbiome and metabolites in modulating ALS in mice. Nature 572, 474–480 (2019).
Le Roy, T. et al. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice. Gut 62, 1787–1794 (2013).
Kåhrström, C. T., Pariente, N. & Weiss, U. Intestinal microbiota in health and disease. Nature 535, 47–47 (2016).
Kostic, A. D., Xavier, R. J. & Gevers, D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology 146, 1489–1499 (2014).
Zuo, T. et al. Gut mucosal virome alterations in ulcerative colitis. Gut 68, 1169–1179 (2019).
Cornuault, J. K. et al. Phages infecting Faecalibacterium prausnitzii belong to novel viral genera that help to decipher intestinal viromes. Microbiome 6, 65 (2018).
Eaton, M. D. & B.-J., S. Bacteriophage therapy. Review of the principles and results of the use of bacteriophage in the treatment of infections. JAMA 23, 1769–1776 (1934).
Debattista, J. Phage therapy: where East meets West. Expert Rev. Anti Infect. Ther. 2, 815–819 (2004).
Watanabe, R. et al. Efficacy of bacteriophage therapy against gut-derived sepsis caused by Pseudomonas aeruginosa in mice. Antimicrob. Agents Chemother. 51, 446–452 (2007).
Lood, R. et al. Novel phage lysin capable of killing the multidrug-resistant Gram-negative bacterium Acinetobacter baumannii in a mouse bacteremia model. Antimicrobial Agents Chemother. 59, 1983–1991 (2015).
Jun, J. W. et al. Bacteriophage therapy of a Vibrio parahaemolyticus infection caused by a multiple-antibiotic-resistant O3:K6 pandemic clinical strain. J. Infect. Dis. 210, 72–78 (2014).
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).
Wills, Q. F., Kerrigan, C. & Soothill, J. S. Experimental bacteriophage protection against Staphylococcus aureus abscesses in a rabbit model. Antimicrob. Agents Chemother. 49, 1220–1221 (2005).
Wang, J. et al. Therapeutic effectiveness of bacteriophages in the rescue of mice with extended spectrum beta-lactamase-producing Escherichia coli bacteremia. Int. J. Mol. Med. 17, 347–355 (2006).
Biswas, B. et al. Bacteriophage therapy rescues mice bacteremic from a clinical isolate of vancomycin-resistant Enterococcus faecium. Infect. Immun. 70, 204–210 (2002).
Wang, J. et al. Use of bacteriophage in the treatment of experimental animal bacteremia from imipenem-resistant Pseudomonas aeruginosa. Int J. Mol. Med. 17, 309–317 (2006).
Dąbrowska, K. & Abedon, S. T. Pharmacologically aware phage therapy: pharmacodynamic and pharmacokinetic obstacles to phage antibacterial action in animal and human bodies. Microbiol. Mol. Biol. Rev. 83, e00012–e00019 (2019).
Capparelli, R. et al. Selection of an Escherichia coli O157:H7 bacteriophage for persistence in the circulatory system of mice infected experimentally. Clin. Microbiol. Infect. 12, 248–253 (2006).
Hodyra-Stefaniak, K. et al. Bacteriophages engineered to display foreign peptides may become short-circulating phages. Microb. Biotechnol. 12, 730–741 (2019).
Chhibber, S., Kaur, S. & Kumari, S. Therapeutic potential of bacteriophage in treating Klebsiella pneumoniae B5055-mediated lobar pneumonia in mice. J. Med. Microbiol. 57, 1508–1513 (2008).
Wolochow, H., Hildebrand, G. J. & Lamanna, C. Translocation of microorganisms across the intestinal wall of the rat: effect of microbial size and concentration. J. Infect. Dis. 116, 523–528 (1966).
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).
Bruttin, A. & Brüssow, H. Human volunteers receiving Escherichia coli phage T4 orally: a safety test of phage therapy. Antimicrob. Agents Chemother. 49, 2874–2878 (2005).
Cao, F. et al. Evaluation of the efficacy of a bacteriophage in the treatment of pneumonia induced by multidrug resistance Klebsiella pneumoniae in mice. BioMed. Res. Int. 2015, 752930 (2015).
Debarbieux, L. et al. Bacteriophages can treat and prevent Pseudomonas aeruginosa lung infections. J. Infect. Dis. 201, 1096–1104 (2010).
Liu, K. Y. et al. Inhalation study of mycobacteriophage D29 aerosol for mice by endotracheal route and nose-only exposure. J. Aerosol Med. Pulm. Drug Deliv. 29, 393–405 (2016).
Nishikawa, H. et al. T-even-related bacteriophages as candidates for treatment of Escherichia coli urinary tract infections. Arch. Virol. 153, 507–515 (2008).
Nobrega, F. L. et al. Targeting mechanisms of tailed bacteriophages. Nat. Rev. Microbiol. 16, 760–773 (2018).
Rhoads, D. D. et al. Bacteriophage therapy of venous leg ulcers in humans: results of a phase I safety trial. J. Wound Care 18, 237–238 (2009).
Sarker, S. A. et al. Oral T4-like phage cocktail application to healthy adult volunteers from Bangladesh. Virology 434, 222–232 (2012).
Ando, H. et al. Engineering modular viral scaffolds for targeted bacterial population editing. https://www.biorxiv.org/content/10.1101/020891v1.full (2015).
Mahichi, F. et al. Site-specific recombination of T2 phage using IP008 long tail fiber genes provides a targeted method for expanding host range while retaining lytic activity. FEMS Microbiol. Lett. 295, 211–217 (2009).
Yoichi, M. et al. Alteration of tail fiber protein gp38 enables T2 phage to infect Escherichia coli O157:H7. J. Biotechnol. 115, 101–107 (2005).
Kelly, C. R. et al. Fecal microbiota transplant for treatment of Clostridium difficile infection in immunocompromised patients. Am. J. Gastroenterol. 109, 1065–1071 (2014).
van Nood, E. et al. Duodenal infusion of donor feces for recurrent clostridium difficile. N. Engl. J. Med. 368, 407–415 (2013).
Allegretti, J. R. et al. Fecal microbiota transplantation in patients with primary sclerosing cholangitis: a pilot clinical trial. Am. J. Gastroenterol. 114, 1071–1079 (2019).
Aroniadis, O. C. et al. Faecal microbiota transplantation for diarrhoea-predominant irritable bowel syndrome: a double-blind, randomised, placebo-controlled trial. Lancet Gastroenterol. Hepatol. 4, 675–685 (2019).
Huttner, B. D. et al. A 5-day course of oral antibiotics followed by faecal transplantation to eradicate carriage of multidrug-resistant Enterobacteriaceae: a randomized clinical trial. Clin. Microbiol Infect. 25, 830–838 (2019).
Yu, E. W. et al. Fecal microbiota transplantation for the improvement of metabolism in obesity: The FMT-TRIM double-blind placebo-controlled pilot trial. PLoS Med 17, e1003051 (2020).
Broecker, F. et al. Stable core virome despite variable microbiome after fecal transfer. Gut Microbes 8, 214–220 (2017).
Draper, L. A. et al. Long-term colonisation with donor bacteriophages following successful faecal microbial transplantation. Microbiome 6, 220 (2018).
Zuo, T. et al. Bacteriophage transfer during faecal microbiota transplantation in Clostridium difficile infection is associated with treatment outcome. Gut 67, 634–643 (2018).
Lin, D. M. et al. Transplanting fecal virus-like particles reduces high-fat diet-induced small intestinal bacterial overgrowth in mice. Front. Cell Infect. Microbiol. 9, 348 (2019).
Džunková, M. et al. Defining the human gut host-phage network through single-cell viral tagging. Nat. Microbiol. 4, 2192–2203 (2019).
Johnson, C. N. & Duerkop, B. A. Dyeing to connect. Nat. Microbiol. 4, 2033–2034 (2019).
Moelling, K., Broecker, F. & Willy, C. A wake-up call: we need phage therapy now. Viruses 10, 688 (2018).
Chaudhry, W. N. et al. Synergy and order effects of antibiotics and phages in killing Pseudomonas aeruginosa biofilms. PLoS ONE 12, e0168615 (2017).
Oechslin, F. et al. Synergistic interaction between phage therapy and antibiotics clears Pseudomonas aeruginosa Infection in endocarditis and reduces virulence. J. Infect. Dis. 215, 703–712 (2017).
Regeimbal, J. M. et al. Personalized therapeutic cocktail of wild environmental phages rescues mice from Acinetobacter baumannii wound infections. Antimicrob. Agents Chemother. 60, 5806–5816 (2016).
Horváth, M. et al. Identification of a newly isolated lytic bacteriophage against K24 capsular type, carbapenem resistant Klebsiella pneumoniae isolates. Sci. Rep. 10, 5891 (2020).
Bao, J. et al. Non-active antibiotic and bacteriophage synergism to successfully treat recurrent urinary tract infection caused by extensively drug-resistant Klebsiella pneumoniae. Emerg. Microbes Infect. 9, 771–774 (2020).
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. Antimicrobial Agents Chemother. 61, e00954–17 (2017).
Chan, B. K. et al. Phage treatment of an aortic graft infected with Pseudomonas aeruginosa. Evol. Med. Public Health 2018, 60–66 (2018).
Dedrick, R. M. et al. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat. Med. 25, 730–733 (2019).
Cooper, C. J., Khan Mirzaei, M. & Nilsson, A. S. Adapting drug approval pathways for bacteriophage-based therapeutics. Front Microbiol 7, 1209 (2016).
Furfaro, L. L., Payne, M. S. & Chang, B. J. Bacteriophage therapy: clinical trials and regulatory hurdles. Front. Cell. Infect. Microbiol. 8, 376 (2018).
Pelfrene, E. et al. Bacteriophage therapy: a regulatory perspective. J. Antimicrobial Chemother. 71, 2071–2074 (2016).
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).
Parracho, H. M. et al. The role of regulated clinical trials in the development of bacteriophage therapeutics. J. Mol. Genet. Med. 6, 279–286 (2012).
Dąbrowska, K. et al. Immunogenicity studies of proteins forming the T4 phage head surface. J. Virol. 88, 12551–12557 (2014).
Górski, A. et al. Phage as a modulator of immune responses: practical implications for phage therapy. Adv. Virus Res. 83, 41–71 (2012).
Beaudoin, J. & Pratt, D. Antiserum inactivation of electrophoretically purified M13 diploid virions: model for the F-specific filamentous bacteriophages. J. Virol. 13, 466–469 (1974).
Araya, D. V. et al. Deletion of a prophage-like element causes attenuation of Salmonella enterica serovar Enteritidis and promotes protective immunity. Vaccine 28, 5458–5466 (2010).
Capparelli, R. et al. Bacteriophage-resistant Staphylococcus aureus mutant confers broad immunity against staphylococcal infection in mice. PLoS ONE 5, e11720 (2010).
Won, G. et al. A Salmonella Typhi ghost induced by the E gene of phage phiX174 stimulates dendritic cells and efficiently activates the adaptive immune response. J. Vet. Sci. 19, 536–542 (2018).
Yang, H. et al. Staphylococcus aureus virulence attenuation and immune clearance mediated by a phage lysin-derived protein. EMBO J. 37, e98045 (2018)
Yang, Y. et al. A small mycobacteriophage-derived peptide and its improved isomer restrict mycobacterial infection via dual mycobactericidal-immunoregulatory activities. J. Biol. Chem. 294, 7615–7631 (2019).
Tian, M. et al. B cell-intrinsic MyD88 signaling promotes initial cell proliferation and differentiation to enhance the germinal center response to a virus-like particle. J. Immunol. 200, 937–948 (2018).
Chen, F. et al. Recombinant phage elicits protective immune response against systemic S. globosa infection in mouse model. Sci. Rep. 7, 42024 (2017).
Sartorius, R. et al. Antigen delivery by filamentous bacteriophage fd displaying an anti-DEC-205 single-chain variable fragment confers adjuvanticity by triggering a TLR9-mediated immune response. EMBO Mol. Med. 7, 973–988 (2015).
Barksdale, L. & Arden, S. B. Persisting bacteriophage infections, lysogeny, and phage conversions. Annu. Rev. Microbiol. 28, 265–299 (1974).
Freeman, V. J. Studies on the virulence of bacteriophage-infected strains of Corynebacterium diphtheriae. J. Bacteriol. 61, 675–688 (1951).
Wang, X. et al. Cryptic prophages help bacteria cope with adverse environments. Nat. Commun. 1, 147 (2010).
Beutin, L., Stroeher, U. H. & Manning, P. A. Isolation of enterohemolysin (Ehly2)-associated sequences encoded on temperate phages of Escherichia coli. Gene 132, 95–99 (1993).
Hayashi, T. et al. Molecular analysis of a cytotoxin-converting phage, phi CTX, of Pseudomonas aeruginosa: structure of the attP-cos-ctx region and integration into the serine tRNA gene. Mol. Microbiol. 7, 657–667 (1993).
Coleman, D. C. et al. Staphylococcus aureus bacteriophages mediating the simultaneous lysogenic conversion of beta-lysin, staphylokinase and enterotoxin A: molecular mechanism of triple conversion. J. Gen. Microbiol. 135, 1679–1697 (1989).
Clark, C. A., Beltrame, J. & Manning, P. A. The oac gene encoding a lipopolysaccharide O-antigen acetylase maps adjacent to the integrase-encoding gene on the genome of Shigella flexneri bacteriophage Sf6. Gene 107, 43–52 (1991).
McShan, W. M. & Ferretti, J. J. Genetic diversity in temperate bacteriophages of Streptococcus pyogenes: identification of a second attachment site for phages carrying the erythrogenic toxin A gene. J. Bacteriol. 179, 6509–6511 (1997).
Figueroa-Bossi, N. et al. Variable assortment of prophages provides a transferable repertoire of pathogenic determinants in Salmonella. Mol. Microbiol. 39, 260–271 (2001).
Figueroa-Bossi, N., Ammendola, S. & Bossi, L. Differences in gene expression levels and in enzymatic qualities account for the uneven contribution of superoxide dismutases SodCI and SodCII to pathogenicity in Salmonella enterica. Microbes Infect. 8, 1569–1578 (2006).
Pelludat, C., Mirold, S. & Hardt, W. D. The SopEPhi phage integrates into the ssrA gene of Salmonella enterica serovar Typhimurium A36 and is closely related to the Fels-2 prophage. J. Bacteriol. 185, 5182–5191 (2003).
Strauch, E., Lurz, R. & Beutin, L. Characterization of a Shiga toxin-encoding temperate bacteriophage of Shigella sonnei. Infect. Immun. 69, 7588–7595 (2001).
Das, B., Bischerour, J. & Barre, F. X. Molecular mechanism of acquisition of the cholera toxin genes. Indian J. Med. Res. 133, 195–200 (2011).
Krom, R. J. et al. Engineered phagemids for nonlytic, targeted antibacterial therapies. Nano Lett. 15, 4808–4813 (2015).
Sarker, S. A. & Brüssow, H. From bench to bed and back again: phage therapy of childhood Escherichia coli diarrhea. Ann. N. Y. Acad. Sci. 1372, 42–52 (2016).
Schneider, G. et al. Kinetics of targeted phage rescue in a mouse model of systemic Escherichia coli K1. BioMed. Res. Int. 2018, 7569645 (2018).
Kumari, S., Harjai, K. & Chhibber, S. Efficacy of bacteriophage treatment in murine burn wound infection induced by Klebsiella pneumoniae. J. Microbiol Biotechnol. 19, 622–628 (2009).
Takemura-Uchiyama, I. et al. Experimental phage therapy against lethal lung-derived septicemia caused by Staphylococcus aureus in mice. Microbes Infect. 16, 512–517 (2014).
Kishor, C. et al. Phage therapy of staphylococcal chronic osteomyelitis in experimental animal model. Indian J. Med. Res. 143, 87–94 (2016).
McVay, C. S., Velásquez, M. & Fralick, J. A. Phage therapy of Pseudomonas aeruginosa infection in a mouse burn wound model. Antimicrobial agents Chemother. 51, 1934–1938 (2007).
Wright, A. et al. 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).
Cafora, M. et al. Phage therapy against Pseudomonas aeruginosa infections in a cystic fibrosis zebrafish model. Sci. Rep. 9, 1527 (2019).
Mai, V. et al. Bacteriophage administration significantly reduces Shigella colonization and shedding by Shigella-challenged mice without deleterious side effects and distortions in the gut microbiota. Bacteriophage 5, e1088124 (2015).
Hurwitz, B. L. et al. Evaluation of methods to concentrate and purify ocean virus communities through comparative, replicated metagenomics. Environ. Microbiol. 15, 1428–1440 (2013).
Parras-Moltó, M. et al. Evaluation of bias induced by viral enrichment and random amplification protocols in metagenomic surveys of saliva DNA viruses. Microbiome 6, 119 (2018).
Solonenko, S. A. & Sullivan, M. B. Preparation of metagenomic libraries from naturally occurring marine viruses. Methods Enzymol. 531, 143–165 (2013).
Kleiner, M., Hooper, L. V. & Duerkop, B. A. Evaluation of methods to purify virus-like particles for metagenomic sequencing of intestinal viromes. BMC Genom. 16, 7 (2015).
Rosseel, T. et al. Evaluation of convenient pretreatment protocols for RNA virus metagenomics in serum and tissue samples. J. Virol. Methods 222, 72–80 (2015).
Sachsenröder, J. et al. Simultaneous identification of DNA and RNA viruses present in pig faeces using process-controlled deep sequencing. PLoS ONE 7, e34631 (2012).
Conceição-Neto, N. et al. Modular approach to customise sample preparation procedures for viral metagenomics: a reproducible protocol for virome analysis. Sci. Rep. 5, 16532 (2015).
Stinson, L. F., Keelan, J. A. & Payne, M. S. Identification and removal of contaminating microbial DNA from PCR reagents: impact on low-biomass microbiome analyses. Lett. Appl. Microbiol. 68, 2–8 (2019).
Džunková, M., D’Auria, G. & Moya, A. Direct sequencing of human gut virome fractions obtained by flow cytometry. Front. Microbiol. 6, 955 (2015).
Hurwitz, B. L., U’Ren, J. M. & Youens-Clark K. Computational prospecting the great viral unknown. FEMS Microbiol. Lett. 363, fnw077 (2016).
Sutton, T. D. S. & Hill, C. Gut bacteriophage: current understanding and challenges. Front. Endocrinol. 10, 784 (2019).
Acknowledgements
We thank the members of the Elinav laboratory for discussions and apologize for authors whose work was not cited because of space constraints. S.P.N is funded by an EMBO Long-term Fellowship ALTF 767–2017. E.E. is the incumbent of the Sir Marc and Lady Tania Feldmann Professorial Chair, a senior fellow at the Canadian Institute of Advanced Research (CIFAR) and an international scholar at the Bill & Melinda Gates Foundation and the Howard Hughes Medical Institute (HHMI).
Author information
Authors and Affiliations
Contributions
All authors performed an extensive literature research, contributed substantially to discussion of the content, and wrote and edited the manuscript.
Corresponding author
Ethics declarations
Competing interests
E.E. is a salaried scientific consultant for DayTwo and BiomX. S.F. and S.P.N. have nothing to declare.
Rights and permissions
About this article
Cite this article
Federici, S., Nobs, S.P. & Elinav, E. Phages and their potential to modulate the microbiome and immunity. Cell Mol Immunol 18, 889–904 (2021). https://doi.org/10.1038/s41423-020-00532-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41423-020-00532-4
Keywords
This article is cited by
-
Exploring the gut DNA virome in fecal immunochemical test stool samples reveals associations with lifestyle in a large population-based study
Nature Communications (2024)
-
Emerging applications of phage therapy and fecal virome transplantation for treatment of Clostridioides difficile infection: challenges and perspectives
Gut Pathogens (2023)
-
Utilization of the microbiome in personalized medicine
Nature Reviews Microbiology (2023)
-
Rheinheimera faecalis sp. nov., isolated from Ceratotherium simum feces
Archives of Microbiology (2023)
-
Engineered reporter phages for detection of Escherichia coli, Enterococcus, and Klebsiella in urine
Nature Communications (2023)
