Intestinal phage therapy for antimicrobial resistance

But, as promising as faecal transplants might be for some people, they’re not a silver bullet for everyone with antimicrobial resistance. That means we need more treatment options in our arsenal, and there’s a strong sense that bacteriophages - viruses that exclusively attack bacterial cells - could be one of them. Tom Ireland is the author of The Good Virus: The Untold Story of Phages…

Tom - People have been studying the different bacterial communities in the gut for a long time, but there's actually another layer of microbe in the gut: the viruses that infect those bacteria. When we say viruses, we often think of bad viruses that make us ill, but actually the majority of viruses in our gut are viruses that infect bacteria. These are called bacteriophages or just phages for short. These can be really useful as a way to modulate and change those bacterial communities in our body. So if we have a particular bacteria that's causing a problem, we can then use a virus to kill that particular bacteria. This isn't actually a new idea, people have been using these viruses to kill off bacterial infections before we had antibiotics like penicillin. The idea has gone in and out of fashion over the years and it's just really starting to be taken seriously again because of the rise in antibiotic resistant bacteria that our antibiotics are just not effective on.

Chris - And is that the major advantage, then? You've got a way of fighting fire with fire. We're not giving drugs, we're not having to give other bacteria which might carry other risks, you're using something that's discreet for the bacteria and would be there anyway.

Tom - Yes. So we have trillions of these phages in our guts all the time. So having the right phages in our guts are important, just like having the right bacteria are important. The idea of using this so-called phage therapy is that we just give that immune system a boost and we make sure that the right phages, the right viruses, are in the intestines and they can kill the specific type of bacteria that we're looking to get rid of.

Chris - Would this mean then that, if someone has a particular class of antimicrobial resistance, would it be that we would have specific phages in a pot and if we knew someone carried those bacteria, we could administer these phages and they would go through them and hopefully wipe out the bad bacteria?

Tom - Yeah, that's the idea. There are so many different types of these viruses out there in the world that ideally you would have two or three different types of virus that can target that particular species. Bacteria can develop resistance to these viruses just like they can develop resistance to antibiotic drugs. But if you can hit them with two or three different phages, different viruses at the same time, then the likelihood that they can fight off all three of those viruses is absolutely tiny. But, it's taking a long time to get it into the hospitals and into clinical practice.

Chris - Is that just because we've got other alternatives that we regard as easier? Or is it just that people have found this a bit risky and they haven't invested hard enough in it, and it could be just a door waiting to be opened as it were?

Tom - Yeah, I think there's an element of we've just had antibiotics for so long, it's just the first thing that clinicians reach for when there's a bacterial infection. But using a virus in the human body as medicine, there is an inherent difficulty to that. When you think of something like dose, how much do you give when the medicine itself self replicates? If it works, it's going to replicate in the body. There's also all sorts of other complications to think of. You have to find exactly the right phage for the patient, which means doing some lab work for every patient. And there's a lack of a regulatory framework around this. So this is not something that doctors or drug regulators are used to using, so people don't know where to start. It's much more complicated than just giving someone an antibiotic and saying, take two of these a day for two weeks.

Chris - There are a number of other conditions as well, though, we call them non-communicable diseases, where your microbiome goes off kilter. Or, if you've taken certain classes of drugs, it can affect your microbiome and that can have knock-on effects for your health because, as people often say, your bowel bugs see your dinner before you do and, if you disrupt them, you do a lot of consequences for the rest of your body. So are there also grounds to consider using phage therapy to remould, refashion, to replenish, as it were, the normal makeup of a healthy microbiome in some people for other disease indications?

Tom - We're starting to hear people look at things like virus based probiotics. So instead of bacterial probiotics where you drink a drink that's got friendly bacteria in it and it seeds the colonisation of your guts with better bacteria, you could have the same thing but with viruses. So you drink some good viruses and that hopefully creates a healthier environment in your guts. There's also been some interesting work that combines faecal transplants with phage therapy. So if you've got a particularly nasty bacteria in your gut, you don't want your nice new poo to be recolonised by that bacteria, so you would combine a faecal transplant with phage therapy. So you get your new poo in your bowels and you have some phages so that any remnants of that bacteria that were causing the problem are wiped out by the phages. So there are lots of different ways that you can use phages potentially, not just diseases of the intestines and of the gut, but cardiovascular diseases, even neurological diseases, diabetes. It's a fascinating area and we know more about the bacteria in the gut and how that works, but we're only just starting to understand this additional layer.

Chris - Have we got a paucity of evidence at the moment then? Is it that we need to now start doing clinical trials? We know we can do this. We know it works in other situations outside the body or in animals, for example, but now we really do need to do some clinical trials and get some robust clinical data to really give clinicians the confidence that this is the way to go.

Tom - As I said, this isn't a particularly new idea; using viruses to kill bacterial infections. Getting good data from clinical trials has always been a problem. So, phage therapy can have really spectacular results on individual patients where you've matched the right phage to the bacteria that you want to get rid of, but if you have slightly different strains of bacteria among those different patients, it can mean that it works on some and doesn't work so well on others. The good news is, there's lots of good information that phages are very safe. There's been so many trials of phages over many years and very few of them ever report any side effects, and that's probably because we live with phages in and on us all the time. And there have also been studies using simulations of the human gut that show phages can be used to get rid of all sorts of drug resistant bacteria. It's just a case now of working out some regulations that allow for the unusual characteristics of a medicine based on a virus and designing some clinical trials that take these unique circumstances into account.