More Evidence that Adds to the Growing Promise of Phage Therapy

As many of you know, I am particularly fascinated by the promise of using bacteriophages – viruses that infect bacteria – as an alternative to antibiotics.  As they are specific to only one kind of bacteria, they leave other species unharmed. Unlike “broad spectrum antibiotics,” which kill good as well as bad, these can be targeted to the pathogen only, leaving the probiotic species unharmed.

Thus, I am really fascinated by research (performed in a mouse model for the moment) recently conducted at the University of California San Diego, School of Medicine on using phage therapy to treat a classic bacterial infection:  alcoholic liver disease.[i]  Says the senior author of the paper:  “We not only linked a specific bacterial toxin to worse clinical outcomes in patients with alcoholic liver disease, we found a way to break that link by precisely editing gut microbiota with phages…”

Of course this research has broader implications, which I will come to in a bit.  But first, the research on alcoholic hepatitis…

The morbidity from severe alcoholic hepatitis is staggering: 75% of people with it die within 90 days of their diagnosis.  It is typically treated with steroids but these are highly ineffective for the most part.  Liver transplant is the only known cure, but the waiting list for a new liver is about 14,000 people, so most will die waiting, even if they manage to qualify.

While alcohol is a known toxin to the liver, what many don’t know – and I certainly did not – is that it also destroys “natural gut antibiotics” which leave mammals more prone to developing bacterial growth in the liver.

The researchers discovered that in alcoholic liver disease, a toxin (cytolysin) secreted by the bacteria, Enterococcus faecalis (usually found at low levels in healthy people but found at markedly higher levels in people with diseased livers), damages liver cells.  The more diseased the liver, the more E.faecalis the scientists found present. Their findings were so distinct, in fact, that they believe that measuring cytolsyin genes in the feces may be a clear indicator of the severity of the liver damage and the risk of death:

“Furthermore, people with the disease had almost 3,000 times more E. faecalis in their stool samples than did people who did not have alcoholic hepatitis. That isn’t concrete proof that the disease is caused by this bacterium. However, the authors’ data also show that the presence of cytolysin in stools correlates with mortality — 89% of the people whose faecal samples contained cytolysin died within 180 days of hospitalization, compared with only 3.8% of the people who had alcoholic hepatitis but whose stool samples lacked the toxin.”[ii]

Anyway, back to the super interesting part:  the researchers isolated 4 different phages that specifically target cytolysin-producing E. faecalis and when they treated the mice with these, they were able to completely eradicate the bacteria and cure the liver disease.  How insanely cool is that?

The broader implications of this kind of work:  scientists at UC San Diego have also successfully treated humans with other antibiotic resistant bacterial infections with phages, with emergency permission from the FDA.

The wheels of science turn slowly, unfortunately, much of the reason being the regulatory process.  Let’s hope this one gets approval soon.

“There is growing evidence that gut microbes can affect the function of certain cells in the brain, and studies are ongoing to determine whether such microbes have a role in human brain diseases. Perhaps phages could become part of the next generation of targeted antimicrobial therapies for diseases that are currently difficult to treat. Indeed, there might be many diseases that we currently don’t realize have a microbial component, and which could be tackled by phages.”ii

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[i] https://health.ucsd.edu/news/releases/Pages/2019-11-13-phage-therapy-promise-for-alcoholic-liver-disease.aspx

[ii] https://www.nature.com/articles/d41586-019-03417-3