Bacteriophages, known as “phages” are bacteria-infecting viruses that have been used in medical treatments in Russia for decades, treating bacterial infections that regular antibiotics can’t heal. As well as regulating the bacterial life in our gut, bacteriophages pose as an effective weapon in our recent battle against rapidly evolving antibiotic-resistant bacteria.
The word “bacteriophage” translates exactly to “bacteria eater”. These microbes are the most abundant entity found in nature, outnumbering every other living creature combined. Phages are approximately 50 times smaller than bacteria, and although we can’t detect them using normal microscopes, their entire collective biomass outweighs that of all of humanity. They reside in soil, water, and aerosolized particles in the air. Right now, trillions of phages are currently preying upon a multitude of bacterial species in your gut.
Humans coevolved with trillions of microbes that live within our bodies and create adaptive ecosystems. Healthy gut flora contains a fine balance of bacterial species that help us to digest food and contribute to the operation of the immune system — commensal bacteria directly influence host immunity to help ward off invasive pathogens.
Disruption of this equilibrium — a state known as dysbiosis — underpins an array of autoimmune conditions from multiple sclerosis to rheumatoid arthritis. Phages appear to help to control certain populations of bacteria through predator-prey cycles that would otherwise grow out of control.
First discovered in 1915, phage therapy has been successfully used since World War II by Russian physicians cut off from the developing field of antibiotics. Phages are more successful at penetrating the biofilm around cells, and are more specific in targeting specific areas of the human body, so they don’t kill good bacteria with the bad. Their drawback is in their specificity – they need to match the bacteria, but to combat this phages are often delivered as part of a “cocktail” to target a wider diversity.
However, not all phages strive to refine bacterial species in our bellies. Elevated levels of certain phages may create a shift in the microbiota that drive diseases such as ulcerative colitis, diabetes, and some forms of cancer.
Life cycle and hunting mechanics
After coming into contact with a bacterial cell, phages attach themselves to the cell membrane. They use their tail fibres like legs to move across the surface in search of an appropriate place to insert their genetic material. Once satisfied, they penetrate the cell membrane with the spike positioned at the tip of the tail. This device breaches the interior of the cell and inserts the DNA housed in the capsid.
Once the viral DNA enters the cell, phages choose one of two life cycle pathways. The lytic cycle involves immediate viral replication and death of the bacterial cell. The strands of phage DNA and accompanying capsid proteins hijack cellular organelles known as ribosomes. They use these tools to program the creation of new proteins to build more versions of themselves.
Once the cell reaches a maximum capacity of newly formed phages, the internal pressure causes the cell to rupture. The increased number of phages leave the initial prey and begin hunting for more bacteria to start the process over again.
The second life cycle seeks to keep the host cell alive and kicking. Known as the lysogenic cycle, this approach utilizes the genetic code of the target bacteria as storage for the phage’s genome.
Here, the phage integrates its genetic material with bacterial chromosomes, turns into a prophage, and enters a state of lysogeny. Phages can remain suspended in this way for many bacterial generations, and eventually emerge to conduct the lytic cycle when external environmental factors favour them.
But bacteria aren’t simply sitting ducks. They acknowledge phages as their biggest threat and adapt accordingly. Certain species have developed adaptive responses to minimize death at the hands of viruses, such as thick coatings of mucous to keep phages from docking at their membranes.
Phages and the human gut
Just as we possess bacterial microbiota, we also harbour a virome — an assembly of viruses associated with a particular organism. With every breath we take, our bodies remain a battleground for competitive microbes.
Phages play a key role in keeping a lid on the bacterial communities inside of us. Just as wolves keep deer from devouring forests, the predator-prey cycle within our bodies keeps microbes from running amok. Far from just targeting and killing specific bacteria, phages drive biochemical changes that ripple out into the microbiome, changing its composition.
Despite their role in mediating bacterial colonies, phages themselves can often become overly successful, resulting in a microbial imbalance that has a consequence on human health. Elevated levels of certain phages may drive gut pathology through overly aggressive action against some bacteria.
However, researchers have yet to determine how the first dominoes fall in these cases. Such imbalances — currently thought to stem from phage activity — may have roots in initial shifts in microbiota composition.
Aside from bacteria, phages also influence the host immune system. By fuelling changes in both innate and adaptive immunity, phages may contribute towards some forms of inflammatory disease. Conversely, in some instances, these viruses appear to team up with host cells to defend against bacterial infections — an act of phage-animal synergy.
Scientists have known about the impact of diet on the microbiome for quite some time, and nutrition serves as a directly modifiable factor to influence populations of gut bacteria. Now, researchers have discovered that nutrition also impacts the nature of our virome. Specific compounds wake prophages up and cause them to depart from storage in bacterial chromosomes.
A study conducted at San Diego State University in 2019 set out to observe how certain foods impact phage activity. The team discovered that clove, propolis, and stevia all increased phage populations. In particular, stevia increased the number of viral particles by over 400 percent in some species of bacteria.
They also found coffee, rhubarb, and oregano to reduce the numbers of viral particles. Furthermore, the application of grapefruit seed extract and pomegranate boosted phage activity associated with some bacteria, while reducing it in others.
Scientists are just getting to grips with how diet impacts the complex world of phages. As more developments unfold, the influence of diet on the human virome may sway our eating decisions in the future, ultimately helping to landscape our microbiome in a way that fuels health and negates disease.
In 2019, the FDA (Food and Drug Administration) greenlighted the first US clinical trial for IV therapy with bacteriophages. In July 2020 Yale University conducted a double blind, placebo controlled study using phages for treating infections in Cystic Fibrosis sufferers. And as the long history of safe usage of phages is disseminated in the West, phage therapy now offers a dynamic way to counter bacteria that are becoming resistant to antibiotics.
Luke Sumpter is a freelance journalist that specializes in health, wellness, and alternative therapies. Currently, he’s working on a dissertation exploring the emerging role of the endocannabinoid system in orthopaedic medicine.