Findings in mice show alcoholic hepatitis has a microbial component and could be tackled by specific phages

Alcoholic hepatitis is considered to be a severe form of alcohol-related liver disease with a high mortality rate in the first 1 to 6 months after diagnosis. The overgrowth of intestinal Enterococcus faecalis—a member of the healthy human gut microbiome that can flourish due to gastric acid suppression and after antibiotic treatment and which is involved in nosocomial infections—has been shown to exacerbate ethanol-induced liver disease in mice and humans.

Yi Duan from the University of California San Diego and colleagues have found in mice that specific phages targeting the gut-dwelling bacterium E. faecalis, might be used to treat patients with alcoholic hepatitis.

The authors observed the presence of E. faecalis in the fecal samples of about 80% of patients with alcoholic hepatitis. Indeed, patients with alcoholic hepatitis had about 2,700-fold more E. faecalis than controls. Moreover, faecal samples from 30% of patients were positive for the bacterial exotoxin cytolysin which is produced by E. faecalis.

The presence of cytolysin in stools was a predictor of mortality, as 89% of the patients with samples containing cytolysin died within 180 days of hospitalization, whereas patients with alcoholic hepatitis who did not have the toxin in their stool exhibited a mortality rate of 4%.

In a next step, Duan and colleagues found that mice colonized with cytolysin-producing E. faecalis from patients with alcoholic hepatitis developed liver damage when they were put on a high-alcohol diet, due to increased gut permeability that allowed the bacteria to translocate from the gut to the liver. On the other hand, animals on a high-alcohol diet and colonized with stools lacking cytolysin did not show signs of liver damage.

In parallel, in vitro tests using mice liver cells showed that liver cell damage in response to cytolysin exposure was dose-dependent, regardless of a high-alcohol diet. Then, the authors go on to suggest that alcohol may increase the permeability of the gut lining, allowing cytolysin to reach the animals’ liver and causing alcoholic hepatitis.

Current treatment options for alcoholic hepatitis are limited and the authors explored to what extent targeting E. faecalis with specific phages might help tackle the disease. Mice receiving fecal samples from patients with alcoholic hepatitis and treated with phages that specifically targeted cytolysin-producing E. faecalis did not develop liver disease when they were fed a high-alcohol diet.

Phages hold an advantage over antibiotics in that they are highly specific and leave beneficial gut bacteria unaffected. In the discussion, the authors highlight the useful role of phages for treating a disease such as alcoholic hepatitis that is not considered a classic infectious disease, but where a member of the gut microbiome has been identified as a culprit.

In conclusion, this study shows that a common gut microbiome bacterium might be involved in damage to liver cells relating to alcoholic hepatitis. The fact that specific phages targeting E. faecalis within the gut were successful in decreasing damage to liver cells opens up a new potential therapeutic avenue based on phages as antimicrobial therapies for conditions beyond the gut.

Keywords: Gut microbiota, Alcoholic hepatitis, Phages.

Reference:

Duan Y, Llorente C, Lang S, et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature. 2019; 575(7783):505-11. doi: 10.1038/s41586-019-1742-x.