SAN DIEGO—Bacteriophages (phages) are viruses that infect and destroy bacteria by replicating inside of the bacteria. According to Scitable by Nature Education, bacteriophages “are composed of a nucleic acid molecule that is surrounded by a protein structure. A bacteriophage attaches itself to a susceptible bacterium and infects the host cell. Following infection, the bacteriophage hijacks the bacterium's cellular machinery to prevent it from producing bacterial components and instead forces the cell to produce viral components. Eventually, new bacteriophages assemble and burst out of the bacterium in a process called lysis.” Phages were once considered as a treatment for bacterial infections in the past, and as antibiotic resistance increases, they are making something of a comeback.
But some of the most recent news for phages isn't about their potential in bacterial infections, but instead in alcoholic liver disease.
Bacteria aren't typically the first thing that comes to mind regarding alcoholic liver disease, but there is a connection. Dr. Bernd Schnabl, senior author of a recent study out of the University of California San Diego School of Medicine, and his team previously found that alcohol diminishes the natural antibiotics found in the gut microbiome, which was found to make mice more prone to bacterial growth in the liver and to worsen alcohol-induced liver disease. In a previous paper for which Schnabl was an author (“Role of the intestinal microbiome in liver fibrosis development and new treatment strategies,” published in July 2019 in Translational Research), it was reported that “The liver and intestinal microbiome are linked by the portal vein and have bidirectional interactions. Changes in the intestinal microbiome contribute to the pathogenesis and progression of liver diseases including ALD [alcohol-associated liver disease], NAFLD [non-alcoholic fatty liver disease], viral hepatitis and cholestatic disorders, based on studies in patients and animal models. Intestinal microbial dysbiosis has been associated with liver cirrhosis and its complications.”
Schnabl is also a professor of medicine and gastroenterology at the UC San Diego School of Medicine and director of the National Institutes of Health-funded San Diego Digestive Diseases Research Center.
For this most recent work, published in Nature by Schnabl, colleagues and a global team of collaborators, the focus was on a specific type of bacteria: cytolysin-producing Enterococcus faecalis. Cytolysin is a toxin that damages liver cells, and alcoholic hepatitis patients tend to have more cytolysin-producing E. faecalis in their gut microbiome than healthy individuals, with increased levels correlating to increased disease severity. Upon study, it was found that in individuals with alcoholic liver disease, more than 5 percent of their fecal bacteria were Enterococcus, while healthy individuals had almost none. Roughly 80 percent of alcoholic hepatitis patients were found to have E. faecalis present in their fecal bacteria colonies, with 30 percent positive for cytolysin.
This points to the potential of E. faecalis as a biomarker for disease severity, as the team discovered that almost 90 percent of alcoholic hepatitis patients with cytolysin-positive E. faecalis died within six months of hospital admission, versus roughly 4 percent of cytolysin-negative patients.
To further confirm the impact of cytolysin, the researchers implanted feces from cytolysin-positive and cytolysin-negative patients with alcoholic hepatitis into mice, and found that the cytolysin-positive samples led to the development of more severe liver disease and worse survival rates than seen in the mice with cytolysin-negative samples.
“Based on this finding, we believe detection of the cytolysin-gene in feces from patients with alcoholic hepatitis could be a very good biomarker for liver disease severity and risk of death,” Schnabl stated. “One day, we might be able to select patients for tailored therapies based on their cytolysin status.”
Taking their work a step further, the team isolated four phages from sewage water that are proven to specifically target cytolysin-producing E. faecalis. When the phages were administered to mice, E. faecalis was eliminated—as was alcohol-induced liver disease.
The results are encouraging, though the authors note that further work is needed: “A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.”
Currently, roughly three-fourths of patients with severe alcoholic hepatitis die within 90 days of diagnosis. According to the U.S. Centers for Disease Control and Prevention, approximately 22,246 people died from alcoholic liver disease in 2017 in the U.S. alone, and the numbers seem to be rising every year. Corticosteroids are the most common treatment for this disease, but effectiveness is limited, and liver transplantation is the only cure. Given the high demand for liver transplants and the limited supply, an alternative is greatly needed.