By Katherine Lawless on May 20, 2020 1:15:00 PM
Bacteriophages, also known informally as phages, are the most abundant organism in the biosphere and considered the ‘natural enemies’ of bacteria. They are viruses that prey on bacteria, keeping them in check. Bacteriophages, can be found in soil, sewage, water, and other places where bacteria tend to be abundant. Bacteriophages infect and replicate within bacteria by binding to the bacteria and injects their genes and copies itself inside the bacteria (they can make up to about 1000 new viruses in each bacterium). Finally, the bacteriophage breaks open the bacteria, releasing new phage viruses. Bacteriophages have been used to treat bacterial infections for 100 years, and led to several central discoveries such as that mutations are at the basis of genetic variations, that DNA is the basis for genetic transmission, as well as the discovery of restriction enzymes as a matter of bacterial resistance to their bacteriophage predators.
However it wasn’t until recently that bacteriophage therapy became an interest in the medical community again. 
According to an article by Jean-Paul Pirnay, Daniel De Vos, and Gilbert Verbeken in Microbiology Australia (March 2019) , PubMed search results for the terms “phage therapy” and “bacteriophage therapy” has increased in phage-related literature:
- 1997-2001: 15
- 2002-2006: 76
- 2007-2011: 161
- Past 5 years: 616
Bacteriophage therapy and microbiome research
Research is now investigating the study of bacteriophage therapy, including microbiome research.
“Bacteriophages are naturally present within the human gut, oral and nasal cavity, genital tract, and eye, in collection with other bacteria, fungi, and protozoa. Most bacteriophages naturally present in the human body are temperate phages and many thus bacteria in our microbiome harbor prophages.”
A prophage is a bacteriophage genome inserted and integrated into the bacterial DNA chromosome or exists as an extrachromosomal plasmid. The viral genes are now present in the bacterium without causing disruption of the bacterial cell until specifically activated for the production of new phages.
Interference with these prophages can lead to disturbance of the balance of the microbiome and dysbiosis (imbalance between organisms within the microbiome). These inductions can be caused by diet, lifestyle or other therapies like chemotherapy. The control of the induction of prophages can be used as an approach to control the human microbiome dysbiosis and could be regarded as a ‘next-generation phage therapy.
Because bacteriophages have the natural ability to highly target specific bacteria, they can be used as tools for microbiome therapy for various bacterial diseases associated with microbiome dysbiosis.
Studies, such as Zuo et al., have found that recent fecal transplant research has pointed out that using bacteriophages to tweak the microbiome can help improve disease outcomes for fecal transplant treatments. 
According to an article in the Microbiome Times in Jan 2019, the use of bacteriophages as therapeutics for bacterial infections and microbiome tweaking agents has yet to be commercialized in some countries. However, next-generation sequencing (NGS) can sequence entire phages and microbiomes at reasonable prices and high throughput allowing the researchers to better understand bacteriophage therapy and its role with the microbiome.
Bacteriophages affecting the microbiome and metabolome
Bryan Hsu and colleagues at Brigham and Women’s Hospital and the Wyss Institute wanted to investigate how the bacteriophage behaves in the gut microbiome – where it is found naturally. They colonized gut samples from mice and added bacteriophages, tracking the growth of each microbe. They found that bacteriophages have a large impact on the dynamic of the gut microbiome by creating a ‘ripple effect’ in the gut microbiome ecosystem. 
“Using high throughput sequencing and computational analyses, the team found that the phage caused attritions of the species they preyed upon as expected, but with a rippling effect on the rest of the ecosystem including blooms of non-targeted species.” 
They also found targeted changes in the metabolome. Senior author Dr. George Greber told the Microbiome Times in an interview, that this change in the metabolome raised the question if this could be an intervention for conditions such as depression, where you would want to change neurotransmitter levels. Dr. Greber stated that this study could be a good tool to understand the potential effects of other therapeutics that alter the microbiome.
Applications for bacteriophage therapy
It is important to note that the potential clinical applications of bacteriophage therapy is still being investigated by researchers. For example, phage therapy could be very important to treat infections that don’t respond well to antibiotics, such as the Staphylococcus (Staph) bacterial infection called MRSA . It could also be used to help patients with infected ulcers, and in the past was used to treat infected burns and wound infections. 
In addition to clinical applications, bacteriophage therapy can be very useful in the food industry, regarding bacteria that can cause food poisoning, such as salmonella, E.coli, Mycobacterium tuberculosis, and more. 
The future of bacteriophage therapy
Research on bacteriophage therapy has increased so drastically that conferences are now being dedicated solely to research of bacteriophages and phage therapy, such as 2018 French Phage Network Annual Conference in Paris, and the 2019 Bacteriophage Therapy Summit in Boston.
The future seems bright for bacteriophage research as the development of novel bacteriophage therapeutics could be the key to reduce mortality rate due to bacterial infection or target antibiotic-resistant bacteria.
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 Froissart R et al. “French Phage Network” Annual Conference 2018- Fourth Meeting Report. Viruses 11:470 (2019).
 Luria S.E., Delbrück M. Mutations of Bacteria from Virus Sensitivity to Virus Resistance. Genetics. 1943;28:491–511.
 Hershey A.D., Chase M. Independent Functions of Viral Protein and Nucleic Acid in Growth of Bacteriophage. J. Gen. Physiol. 1952;36:39–56. doi: 10.1085/jgp.36.1.39.
 How restriction enzymes became the workhorses of molecular biology. Proc. Natl. Acad. Sci. USA. 2005;102:5905–5908. doi: 10.1073/pnas.0500923102.
 Jean-Paul Pirnay, Daniel De Vos, and Gilbert Verbeken. Clinical application of bacteriophages in Europe. Microbiology Australia. 40(1): 8-14 (2019).
 Gansehan SD, and Hosseinidoust Z. Phage Therapy with a Focus on the Human Microbiota. Antibiotics. 8:131 (2019).
 Sacher, J. A Bright Outlook for Bacteriophage Applications. Microbiome Times. 7:135 (2019)
 Just a phage? How bacteria’s predators can shape the gut microbiome. Microbiome Times. 2: 13-15 (2019).