Illustration of bacteriophages infecting a bacterium.
The role of bacteria and our microbiome in health and disease is at the forefront of medical research.
We are a long way from answering the many questions posed by recent findings, but it is now firmly established that without our personal fleet of "friendly" microorganisms — our microbiome — we would not thrive.
Medical science, however, does not sit on its haunches; its eyes are always fixed on the horizon, straining to describe the shape of things hidden in the far distance.
As we struggle to unpick the almost unbearably complex interactions between bacteria and health, the next challenge is already waiting in the wings: the role of the virome.
What is the virome?
When we hear the word "microbiome," we immediately think of bacteria, but technically, the microbiome is the sum of all microorganisms in a particular environment. Some scientists use the term to refer to the sum of the genetic material of these microorganisms.
So, aside from bacteria, the microbiome also includes viruses (the virome) and fungi (the mycobiome), among other visitors. To date, scientists have paid comparatively little attention to the virome or mycobiome.
Viruses have made themselves at home in a range of ecological niches in the human body, especially on mucosal surfaces, such as the insides of the nose and mouth and the lining of the gut.
In this feature, we will concentrate on the gut virome because it hosts the greatest number of viral occupants and has been investigated the most.
Of course, viruses are most famous for causing diseases, such as smallpox, hepatitis, HIV, and rabies. Because of the urgency associated with viral disease, this aspect has taken up the lion's share of researchers' time. However, many viruses do not have the slightest interest in human cells.
Introducing the bacteriophage
Scientists consider the virome to be "the largest, the most diverse, and the most dynamic part of [the] microbiome," and the majority of the viruses in our guts are bacteriophages. Wherever there are bacteria, there are bacteriophages in abundance.
As other researchers explain: "Phages are the most abundant life forms on Earth, being virtually omnipresent. [...] Some freshwater sources may contain up to 10 billion per [milliliter]."
Bacteriophages infect bacteria, commandeer their cell machinery, and use it to replicate their genetic material.
It is now abundantly clear that gut bacteria influence health and disease, so it is no surprise that viruses that infect gut bacteria may have a significant influence, too.
From the 1920s to the 1950s, scientists investigated whether bacteriophages could be used to treat bacterial infections. After all, these viruses are adept at destroying human pathogens.
Scientists found that phage therapy was both effective and, importantly, free from side effects.
When antibiotics were discovered, phage therapy faded into the background. Antibiotics could be manufactured with relative ease, and they killed a broad spectrum of bacterial species.
However, with today's hi-tech capabilities and the fearsome backdrop of antibiotic resistance, interest in phage therapy may enjoy a resurgence.
One factor that makes phage therapy attractive is its specificity. Often, antibiotics wipe out a wide spectrum of bacterial species. Now that we know that "good" bacteria live in the gut, however, it is clear that this is not ideal.
Bacteriophages, meanwhile, only target a narrow range of strains within the same bacterial species.
Plus, they only replicate if their target bacteria are in the local area. Taken together, this means that they only attack the desired bacterium, and they continue to replicate until they have wiped out the infection.
Friends for life
Bacteriophages join the human journey at an early stage. One study examined meconium — a newborn's first poop — and found no evidence of viruses.
However, just 1 week after birth, each gram of a baby's poop contained about 100 million virus particles, most of which were bacteriophages. Our virome truly is a lifelong companion.
Each human has a distinct selection of bacteriophages, which is collectively referred to as the phageome. People who have roughly the same diet share more similarities, but overall, each individual's phageome varies wildly.
From symbiosis to dysbiosis
Bacteriophages, as mentioned, destroy bacteria. However, in some situations, bacteriophages can benefit populations of bacteria.
In the gut, bacteriophages predominantly exist as prophages. In this stage, their genetic code is incorporated into a bacterium's genome, ready to produce bacteriophages if activated.
At this point in their life, a bacteriophage is not harmful to a bacterium — they exist in symbiosis.
Because bacteria can exchange genetic material with each other, the genetic code of prophages can also be transferred between individual bacteria.
They can exchange "genes associated with antibiotic resistance, virulence, or metabolic pathways between different bacterial species." This could benefit some bacterial species, potentially allowing them to broaden their niche. However, the growth could be at the expense of other colonies of bacteria in the gut.
"Prophages are symbiotic to their host bacteria, and these bacteria are symbiotic to our body. Therefore, phages can indirectly provide benefit to a multicellular organism like [a] human beyond what is experienced immediately by their host bacterial cells."
Once prophages are triggered to become active — for instance, in times of stress or if the host bacterium is in danger — they can cause a widespread change in the gut's microbial community.
The shift from harmless prophage to so-called lytic phage can wipe out communities of bacteria, potentially providing "bad" bacteria with some breathing space and allowing them to fill the void.
This is called community shuffling and can lead to dysbiosis — a microbial imbalance.
From dysbiosis to diagnosis
Dysbiosis is associated with a range of conditions, including inflammatory bowel disease, chronic fatigue syndrome, obesity, Clostridium difficile (C. diff) infection, and colitis. However, researchers are still unsure of the role of bacteriophages in these conditions.
In these cases, dysbiosis might occur via other mechanisms. Alternately, it might be a symptom of the conditions, rather than the cause.
Because bacteriophages outnumber the bacteria in our guts and rely on them to replicate, they must be either affected by or involved in any fluctuations.
Bacteriophages may not be driving changes in the gut — changes that, it must be added, may not be driving the disease. Instead, bacteriophage populations might just be altered, passively, by the changes in gut bacteria.
Whether the ebb and flow of bacteriophage communities is important in health and disease will be challenging to investigate. But even if it is not pivotal in the pathology of a disease, spotting these fluctuations might have other benefits.
As an example, there is the potential to use the virome as a diagnostic marker. For instance, scientists have identified disease-specific alterations in the gut virome in people with inflammatory bowel disease, which is a notoriously difficult condition to diagnose.
The trouble with viruses
Studying bacteria is far from easy; after all, they are incredibly small. Bacteria are generally 0.4–10 micrometers across. To provide some context: 10 micrometers is just one-hundredth of a millimeter or four ten-thousandths of an inch.
Viruses, however, are even smaller, at just 0.02–0.4 micrometers across.
Aside from the difficulties inherent in working on such a tiny scale, viruses pose other challenges.
If scientists want to understand which bacterial species are present in any given population, they extract genetic information.
From this, they isolate specific stretches of code and match them to existing databases; most commonly, they use the 16S rRNA gene. This particular gene can be found in almost all bacterial species, and over evolutionary time, it has remained relatively unchanged.
However, some regions of 16S RNA are considered hypervariable. Differences between these regions allow researchers to identify species.
Viruses, on the other hand, do not share any equivalent genes among species. This, until relatively recently, made studying the virome almost impossible, but advances in next-generation sequencing are slowly knocking down barriers.
At this stage, the role of viruses in human health is nowhere near as clear as their role in disease.
With that said, it also seems highly likely that viruses do play a substantial part in maintaining a healthy body. Only with advances in research techniques will their full impact be understood.
Given the immediate concerns of antibiotic resistance, perhaps renewed interest in the bacteriophage will see more time dedicated to this mysterious element of medical science.
Still, understanding the interplay between the components of our microbiome will be hard-won information; as one paper explains:
"The composition of the gut microbiome is not the same during the several stages of life, or even during the hours of the same day."
This is sure to be a long battle.