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November 26, 2019
Targeting gut bacteria to treat alcoholic hepatitis
At a Glance
- A therapy targeting bacteria that make a specific toxin lessened alcohol-associated liver disease in a mouse study.
- The approach warrants further study as a possible treatment for alcoholic hepatitis.
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 National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute of General Medical Sciences (NIGMS), and National 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.
- Fungi in the Gut Linked to Alcoholic Liver Disease
- Study Shows Increase in Problem Drinking
- The Healthy Human Microbiome
- Liver Disease
- Alcohol's Effects on Health
References: Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Duan Y, Llorente C, Lang S, Brandl K, Chu H, Jiang L, White RC, Clarke TH, Nguyen K, Torralba M, Shao Y, Liu J, Hernandez-Morales A, Lessor L, Rahman IR, Miyamoto Y, Ly M, Gao B, Sun W, Kiesel R, Hutmacher F, Lee S, Ventura-Cots M, Bosques-Padilla F, Verna EC, Abraldes JG, Brown RS Jr, Vargas V, Altamirano J, Caballería J, Shawcross DL, Ho SB, Louvet A, Lucey MR, Mathurin P, Garcia-Tsao G, Bataller R, Tu XM, Eckmann L, van der Donk WA, Young R, Lawley TD, Stärkel P, Pride D, Fouts DE, Schnabl B. Nature. 2019 Nov 13. doi: 10.1038/s41586-019-1742-x. PMID: 31723265.
Funding: NIH’s National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institute of General Medical Sciences (NIGMS), and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); American Association for the Study of Liver Diseases; Southern California Research Center for Alcoholic Liver and Pancreatic Disease and Cirrhosis; Wellcome Trust; Biocodex Microbiota Foundation; U.S. Department of Veterans Affairs.