Precision targeting of bacteria in a different way to antibiotics shows promise as a treatment for alcoholic liver disease, according to new research in mice.
They used a particular mixture of phages to selectively eliminate Enterococcus faecalis, a gut bacterium that releases a toxin that kills liver cells.
They found that people with alcoholic liver disease had more E. faecalis in their guts than people without this condition.
In addition, they saw that levels of the bacterium correlated with disease severity.
“We not only linked a specific bacterial toxin to worse clinical outcomes in [people] with alcoholic liver disease, we found a way to break that link by precisely editing gut microbiota with phages,” says senior study author Bernd Schnabl, a professor of medicine and gastroenterology at the University of California San Diego School of Medicine.
Alcoholic liver disease is a major global public health concern. In fact, it is the leading cause of death in people with liver conditions worldwide.
The cause of this disease is damage to the liver from drinking high amounts of alcohol. Disease severity can range from mild to life threatening.
Fatty liver, which can develop after a few days of heavy alcohol use, is the first stage of alcoholic liver disease.
Alcoholic hepatitis and other severe forms of alcoholic liver disease are on the rise in the United States. According to the Centers for Disease Control and Prevention (CDC), they were responsible for around 22,246 deaths in the U.S. in 2017.
Doctors usually treat alcoholic hepatitis with corticosteroids, but these drugs are not very effective. In fact, up to three-quarters of people with this severe form of alcoholic liver disease usually die within 3 months of receiving a diagnosis.
Currently, the only cure is to receive an early liver transplant. However, these operations are not widely available, and there is a long waiting list.
Previous studies have demonstrated that gut microbes can promote alcohol-induced liver disease in mice, but as the recent study authors explain, “little is known about the microbial factors that are responsible for this process.”
In the new study, the researchers identified cytolysin, which is a toxin that E. faecalis produces, as a cause of injury and cell death in the liver. They investigated this further in samples from people with alcoholic hepatitis.
They found that the vast majority of people with alcoholic hepatitis who tested positive for cytolysin died within 180 days of being admitted to the hospital. In contrast, of those who tested negative for cytolysin, only a small minority died within 180 days.
In the next stage of the study, the team demonstrated that treatment with bacteriophages could abolish alcohol-induced liver disease in mice.
They first isolated four bacteriophages that can target cytolysin-secreting E. faecalis bacteria.
When they treated mice with these phages, they eradicated the animals’ alcoholic-induced liver disease. Treatment using phages that target other strains of bacteria, or those that target E. faecalis that does not release cytolysin, had no such effect.
The team suggests that these findings also highlight the potential for using cytolysin as a predictor of alcoholic hepatitis.
The idea of using viruses that kill bacteria as a way to treat bacterial infections is not new. In fact, scientists were experimenting with phage therapy about 100 years ago, but they seemed to lose interest when antibiotics came along.
However, because of the rising problem of antibiotic resistance, researchers are looking again at phage therapy as an alternative approach to treating bacteria-related illness.
It is likely to be a while before phage therapy is ready as a treatment for alcoholic liver disease, however.
Much more research is necessary, particularly into safety; phages can trigger a strong immune response in people with this type of disease.
“This novel avenue of research now needs to be expanded to test the safety and effectiveness of phage therapy in human clinical trials in [people] with alcohol-related disease,” says study co-author Debbie L. Shawcross, a professor of hepatology and chronic liver failure at King’s College London in the United Kingdom.
“It is also likely that other forms of chronic liver disease associated with changes in the gut microbiome will also benefit from this novel approach, such as fatty liver disease.”
Prof. Debbie L. Shawcross