Phage therapy: viruses as medicine

Healthy state

Bacteriophages Bacteriophages Viruses that only infect bacteria. In the gut there are probably about as many phages as bacteria, perhaps more, and they help determine which bacteria prevail. More in the chapter “Bacteriophages: the hunters in the gut”, or phages for short, are viruses that infect only bacteria. They were discovered a little over a hundred years ago and were soon used against dysentery and other infections. In Georgia and Poland there are still research institutes and clinics that use phages as treatment. In the West they were forgotten once penicillin and its successors became cheap, easy to produce and broadly effective.

This is how a phage kills: it recognises a specific structure on the surface of its victim, the receptor, like a key fitting a lock. That is why a phage often fits only certain strains of a bacterial species, not whole genera. It injects its genetic material into the cell, which then builds hundreds of new phages and finally bursts. For therapy, almost only such “lytic” phages are used, which always kill. Phages that instead insert themselves into the bacterial genome and sleep there are unsuitable because they can pass on genes.

Two properties set phages apart from antibiotics. First, they multiply where their target sits: as long as the germ is there, new phages are made, and when it is gone, they disappear too. Second, many phages carry enzymes that can drill through the slime and protective coat of a biofilm Biofilm A community of microbes that sticks to a surface and embeds itself in a self-made protective coat, such as dental plaque. More in the chapter “Biofilms in the gut and “biofilm busters”” (a firm layer of bacteria in which germs are hard for antibiotics to reach). Because they attack at a different point than antibiotics, they also work against germs that are insensitive to antibiotics. Human cells do not have the matching receptors, which is why phages are considered well tolerated.

In the body, however, phages face obstacles. In the blood, the spleen and liver filter them out quickly, and with longer use antibodies can slow them down. Anyone swallowing phages exposes them to stomach acid, which inactivates many, so protection or buffering may be needed. Today phages are mainly used for severe, stubborn infections when antibiotics have failed, for example on joint prostheses, in the lungs in cystic fibrosis, in the urinary tract or in the diabetic foot. Usually they are given in addition to antibiotics, not instead of them.

Disrupted state: causes and effects

Interest is returning because antibiotics are losing their effect: more and more germs are resistant to many or all common drugs, and new antibiotics are rare. Phages are one possible addition. But they are not a miracle cure, and the reasons lie in the biology of phages themselves.

First, bacteria also become resistant to phages, often quickly, for example by changing the receptor. That is why mixtures of several phages are used, or phages whose receptor matters to the bacterium. If it loses it, it harms itself, for instance by becoming less dangerous or more sensitive to an antibiotic again. Such effects have been seen in the lab and in individual treatments, but not as a reliable rule. Second, phages fit only certain strains: before treatment, the patient’s germ is tested in the lab against various phages. This needs collections (“phage banks”), expertise and time.

The evidence is thinner than reports of spectacular cures suggest. A systematic review from 2022 evaluated 16 trials with a total of 378 treated people: all 13 trials from after 2000 considered the treatment safe. But efficacy was shown in only 2 of 7 modern trials that examined it. The authors see the cause more in planning and delivery (wrong phage, wrong site, wrong timing, too few phages at the infection) than in phages failing to kill. In addition, case reports are more likely to be published when things went well.

Practical hurdles come on top. Phages are alive and change, which fits poorly with classic approval procedures, especially when they are chosen anew for each person. Preparations must be very clean, because leftovers of the bacteria in which they were grown (endotoxins Endotoxin (LPS) A component of the outer coat of certain bacteria. When it reaches the blood, it triggers inflammatory responses. More in the chapter “The gut barrier”) can cause fever, and their genome must be decoded so that no toxin or resistance genes are hidden in them. Countries regulate whether and how phages may be used very differently.

For the gut, development is still at an early stage. It is conceivable to reduce individual unwanted germs, for example resistant gut germs in severely ill people, while sparing the rest of the microbiota. So far this rests mainly on lab and animal experiments and small studies. With C. difficile Clostridioides difficile A bacterium that can spread after antibiotics and cause severe diarrhoea with its toxins. More in the chapter “After antibiotics: C. difficile and faecal transplants” it is difficult because many of its phages belong to the “sleeping” kind. For complaints such as bloating or irritable bowel without a proven infection, phage therapy has not been studied and is not intended.