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Targeting gut bacteria to treat alcoholic hepatitis

In this false-color micrograph, a bacteriophage (orange) attaches to the membrane of a bacterial cell (blue). UC San Diego

Alcoholic hepatitis is a life-threatening form of alcohol-associated liver disease (AALD) caused by heavy drinking over time. It involves liver inflammation, jaundice (a yellow appearance), and ultimately liver failure. There are few treatments available for alcoholic hepatitis. Liver transplantation is the only cure. In severe cases, more than half of patients die within 60 days of a diagnosis.

Previous research has shown that microbes living in the gut can influence AALD. People with the disease have significant changes in their gut microbes. Scientists have also been able to induce liver injury in mice by transferring fecal bacteria from people with alcoholic hepatitis. But the link between AALD and gut bacteria isn’t well understood.

A research team led by Dr. Bernd Schnabl at the University of California, San Diego, explored how gut microbes contribute to alcoholic hepatitis. The study was funded by NIH’s �����鶹��Ƶ Institute on Alcohol Abuse and Alcoholism (NIAAA), �����鶹��Ƶ Institute of General Medical Sciences (NIGMS), and �����鶹��Ƶ Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Findings were published in Nature on November 13, 2019.

The team first analyzed bacteria in fecal samples from patients with alcohol use disorder and alcoholic hepatitis. The samples from people with alcoholic hepatitis contained 2,700-fold more Enterococcus faecalis—a common gut bacterium—than samples from otherwise healthy drinkers. E. faecalis was found in about 80% of the people with alcoholic hepatitis. However, the amount of E. faecalis wasn’t linked to the severity of the disease.

The researchers detected cytolysin in fecal samples from 30% of the people with alcoholic hepatitis. Cytolysin is a cell-destroying toxin secreted by specific E. faecalis strains. Upon further study, the team found that people carrying toxin-producing strains of E. faecalis had more severe alcoholic hepatitis and greater risk of death. Among those with cytolysin-positive E. faecalis, 89% died within 180 days of admission, compared with only 3.8% of people with cytolysin-negative E. faecalis.

The researchers then studied mice that had been transplanted with feces from people with alcoholic hepatitis. They confirmed that transplantation of feces with cytolysin-positive E. faecalis caused more severe liver disease in mice than feces without it.

The team next investigated the therapeutic potential of bacteriophages (or phages)—viruses that destroy bacteria. Traditional antibiotics kill many types of bacteria. The team identified four phages in sewage water (a rich source of bacteriophages) that specifically target cytolytic E. faecalis.

Using mice engineered to model AALD, the scientists transplanted stool from cytolysin-positive alcoholic hepatitis patients. The mice were then treated with phages targeting the cytolytic E. faecalis strains. The mice treated with these phages had less liver injury and inflammation compared to controls. This therapy also significantly reduced levels of cytolysin in the liver.

These findings suggest that cytolytic E. faecalis causes more severe alcoholic hepatitis. Bacteriophages might be used to specifically target these bacteria to treat AALD.

“A prospective clinical trial is required to validate the human relevance of our findings and to test whether this new therapeutic approach is effective for patients with alcoholic hepatitis,” Schnabl says.