For a heavy drinker whose liver has been destroyed by alcohol, an organ transplant is often the only realistic option. But because of donor liver shortages and rules that withhold them from people who have not shed their alcohol addiction, many go without. Tens of thousands die from alcoholic liver disease each year in the United States—and some go downhill much faster than others. Now, scientists have found a reason for this disparity: a toxin produced by some strains of a common gut bacterium. Working in mice, they have also tested a potential therapy, based on bacteria-destroying viruses found lurking in the sewer.
Why some drinkers with liver disease fare much worse than others "has always been a conundrum," says Jasmohan Bajaj, a gastroenterologist and liver specialist at Virginia Commonwealth University in Richmond. The bacterium Enterococcus faecalis offers an explanation, Bernd Schnabl, a gastroenterologist at the University of California, San Diego (UCSD), School of Medicine, and colleagues report this week in Nature. In fecal samples from patients with alcoholic liver disease, levels of it were 2700 times higher than in nondrinkers, although the mere quantity didn't correlate with a person's outcome. Instead, the researchers identified a cell-destroying toxin called cytolysin produced by select strains of E. faecalis as the likely reason that some patients with alcoholic liver disease had severe symptoms.
Fewer than 5% of healthy people carry the toxinmaking strains, but the group found them in 30% of the people hospitalized with alcoholic liver disease whom they tested. And those patients had a much higher mortality rate within 180 days of admission—89% of the cytolysin-positive patients died compared with only 3.8% of the other patients. "Cytolysin is a factor that really drives mortality and liver disease severity," Schnabl says.
He and colleagues don't know why the strains flourish in people with alcoholic liver disease. But the team confirmed their deadly influence by colonizing some mice with the toxin-producing bacteria and others with nontoxic strains, then dosing the animals with alcohol to damage their livers. Mice with the toxin-producing bacteria fared much worse than those without.
Next, the team sought a way to precisely remove the toxic E. faecalis to see whether the animals' symptoms improved. Traditional antibiotics kill broadly, so the group enlisted UCSD colleagues who study therapeutic uses of bacteriophages, or phages. These viruses kill specific bacteria, and researchers—many in Russia and Eastern Europe—have used them for decades to treat conditions such as dysentery and gangrene.
In the university's sewage plant—a ready-made buffet for organisms that live off fecal bacteria—the team found phages that targeted cytolytic E. faecalis. When mice that harbored the deadly bacteria were treated with the phages, they had less liver injury, less inflammation, and less cytolysin in their livers than animals treated with control phages. "We can reduce the disease but we could not completely get the mice with alcoholic liver disease back to a baseline," Schnabl says.
Bajaj calls the mouse studies "exquisitely done," adding that although the phage therapy is far from ready for use clinically, this work pushes research on alcoholic liver disease in "an encouraging direction."
The UCSD team is now working to create a library of phages isolated from different liver disease patients that are effective against cytolysin-positive E. faecalis strains. They plan to evaluate the phages for safety and then consider testing them in people with severe cases of the disease. Andrzej Górski, a phage expert at the Polish Academy of Sciences in Wrocław, applauds the plan. "Now is a good time for performing clinical trials" with phages, he says.