Viruses as ally? Are they going to optimize our gut flora?

Image by Gerd Altmann from Pixabay

Both good and bad bacteria in our gut affect our health. Can’t we kill those bad bacteria?

There I am, with a cotton swab in my hand, peering into the toilet bowl. I take a deep breath, pinch my nose with my left hand and push the cotton swab into my poop with my right. Never thought I would ever do that. The next day I bring my cotton swab, neatly in its case, to the laboratory. There they test whether my gut flora contains the benign bacteria Akkermansia muciniphila. This bacterium reduces the risk of intestinal diseases such as Crohn’s, and its presence indicates a healthy colon. In the lab the researchers perform all kinds of complicated tests with my bacteria. A few days later I receive the answer: I am Akkermansia positive – good news for my gut. If we want to make targeted modifications to bacteria in the gut, this type of testing may become standard procedure.

Bacteria killers

At the end of 2019, the scientific journal Nature reported that the poison-producing gut bacterium Enterococcus faecalis (E. faecalis) is a major cause of liver disorders in people who consume excessive amount of alcohol. One such disorder, cirrhosis of the liver, is one of the ten most common causes of death in the Western world and no treatment exists to date. The article also mentioned that researchers had succeeded in killing E. faecalis in the gut of mice, after which the mice developed less liver injury, even when administered a high dose of alcohol. By making adjustments to the gut flora, they were able to control the disease. The scientists used specific viruses to kill the pathogen: bacteriophages, or phages for short.

Why do doctors in the Netherlands still not prescribe phages to improve our gut flora?

Phages are viruses that attack and kill bacteria. Their anatomy is relatively simple: they consist of a protein head filled with genetic material (DNA or RNA), a body, and spider-like legs. Like other viruses, phages need a host to multiply. The phage’s legs come in handy here: they attach themselves firmly to their target. Once anchored, the phage injects its genetic material into the bacterium through its body. This material takes over control of the bacterial cell; the bacterium is now a phage factory that is rapidly producing new phages. This continues until the cell becomes overfilled with phages and bursts open. The phages that have been freed will then go on the prowl for new cells to infect.

E. faecalis and A. muciniphila are not the only gut bacteria that researchers know are affecting our health. Previous studies linked bacteria in the gut flora with, among other things, cancer, diabetes and Parkinson’s disease. The idea of ​​using phages as medication, or as an alternative to antibiotics, has been around since 1919. Now that more and more bacteria are being labled as influencers of disorders, targeted bactericides are attractive treatments. Why do doctors in the Netherlands still not prescribe phages to improve our gut flora?

Specificity

Phages are selective: they only infect one type of bacteria. Yet there are limits to their specificity. A species of bacteria contains different strains, just as a species of animal has several varieties. As a result, phages can also kill “good” bacteria, which are related to the pathogen. Although certain E. faecalis strains are responsible for liver disorders, others have been utilized in probiotics for over fifty years. These beneficial E. faecalis strains keep the gut flora in balance by, among other things, consuming nutrients in the intestine that would otherwise be used by harmful bacteria. Phage therapy that specifically wipes out one type of bacteria, such as E. faecium, can therefore also kill beneficial variants. This can have dangerous consequences.

When you eradicate a specific bacterium in the intestines, other microorganisms have room to grow

Russia and Georgia have been researching phages for decades and these are one of the few countries that offer phage therapy. Researchers outside Russia and Georgia who ordered bottles of phages from them encountered a problem: the phages were not effective outside of Russia. The average Russian person has a different composition of gut bacteria than, for example, Dutch people. Factors such as diet and environment influence the composition of the gut flora. In that case, phages have too much specificity. They are only suitable for the local population.

Bacteria contain an immune system to defend themselfes against phages

Reactions

Newton already said it: every action has an equal and opposite reaction. This also applies to modifications of the gut flora. You could say that intestines are “full” with microorganisms. When you practically eradicate a specific bacterium in the intestines, other microorganisms have room to grow, shifting the balance of the gut flora. Such a shift can have consequences for the immune system in the intestines.

Another problem is that bacteria build up resistance to phages; they have an immune system to defend themselfes against phages, their natural enemy. This immune system, called CRISPR / Cas, collects small pieces of DNA from phages and stores them in its system. That helps the bacteria recognize and kill an attacking phage. The uptake and storage of foreign DNA is thus essential in this CRISPR / Cas immune system. The bacterium causing liver disease: E. faecalis, happen to be masters of DNA uptake. If we attack these gut bacteria with phages, there is more pressure on the bacteria to archive the DNA of their attacker. They will then build up resistance to that phage, rendering the treatment useless. This same problem could arise for other bacteria we want to treat.

For the time being, phage therapy doesn’t seem to be feasable. So I won’t be stirring in my poop again any time soon to determine which bacteria need to go.

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