Alcoholic liver disease is known to develop primarily as a result of alcohol abuse. However, evidence has recently been found that the disease is associated with certain microorganisms, which can be combated with the use of specific bacteriophages.

C. Llorente et al. (2017) found in mouse experiments that the development of alcoholic liver disease may be associated with a member of the gut microbiome known as Enterococcus faecalis . Various strains of E. faecalis are ancient companions of humans, having inhabited the intestines of many animal species for millions of years. However, in humans, their numbers are normally low (<0.1% of all bacteria in stool samples), and their numbers increase sharply after antibiotic use. Furthermore, in weakened patients, E. faecalis can cause infectious diseases of the blood, heart, brain, and teeth.

The authors of a new study* analyzed the microbial composition of human stool samples and identified E. faecalis in nearly 80% of patients with alcoholic liver disease. Moreover, the latter had 3,000 times more E. faecalis than patients without this diagnosis. This does not prove that E. faecalis causes disease. However, 30% of the detected E. faecalis strains carried the gene encoding the toxin cytolysin (cytolytic strains), and the presence of cytolysin in stool correlated with mortality in patients with alcoholic hepatitis: 89% of people with cytolysin in their stool died within 180 days of hospitalization, compared to 3.8% of people without cytolysin in their stool.

In the next step, the authors investigated the link between E. faecalis and alcoholic liver disease in mice. The animals were divided into two groups: one was infected with cytolytic strains of E. faecalis, the other with standard strains. Within each group, there were animals fed alcohol as part of their diet, and animals that did not. Only mice infected with cytolysin-producing E. faecalis and simultaneously fed alcohol developed liver damage.

To study the mechanisms of disease development, the authors isolated liver cells from animals and found that their death in response to cytolysin was dose-dependent. This response was independent of the presence of alcohol in the animals' diet. This may indicate that liver cell damage in alcoholic liver disease is not caused by direct alcohol exposure, but rather by alcohol increasing intestinal permeability to cytolytic E. faecalis , which, when released into the liver, causes the disease.

Given the limited treatment options for alcoholic hepatitis, the authors attempted to rid patients of cytolytic E. faecalis using bacteriophages. Bacterial viruses act specifically and attack only certain strains or species of bacteria, leaving beneficial members of the microbiota unaffected during the treatment of infections in humans and animals. The scientists isolated several phage strains that attacked cytolytic E. faecalis and tested them in mice infected with the microflora of people with alcoholic liver disease and fed alcohol. Animals receiving phages specific to cytolytic E. faecalis suffered less liver damage than control animals receiving phages specific to other bacteria found in animals.

Read also: Bacteriophages in the treatment of autoimmune liver diseases

Further research is needed to determine whether phages are effective in people with alcoholic liver disease.

The authors demonstrated that phages can be used, firstly, to identify bacteria that cause a particular disease, and secondly, to treat these ailments. Attempts to use bacteriophages to influence the composition of the intestinal microbiota hold great promise . Given the abundant evidence that components of the intestinal microbiome can influence the pathogenesis of a wide range of diseases, such as neurological ones, bacteriophages may well find application in the treatment of non-infectious diseases.

*Duan Y, Llorente C, Lang S et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature, 2019, 575: 451-453. doi:10.1038/d41586-019-03417-3