Alcoholic liver disease includes a broad range of liver diseases, from simple steatosis (fatty liver) to end-stage liver disease, or cirrhosis (liver cell death). Liver cirrhosis is a leading cause of death worldwide, and alcohol abuse accounts for about half of these deaths. The need for a treatment for alcoholic liver disease is crucial.
Alcohol abuse can change the community of microorganisms, or microbiome, in the intestine. It encourages bacterial and fungal overgrowth, and can also cause a leaky gut barrier, which allows substances to enter the bloodstream. Studies have linked changes in intestinal fungal communities with other illnesses, but research related to alcoholic liver disease has primarily focused on bacteria.
A team led by Dr. Bernd Schnabl at the University of California, San Diego, and Dr. Derrick Fouts at the J. Craig Venter Institute set out to investigate fungal overgrowth in the intestines and determine its role in alcoholic liver disease. Their work was funded in part by NIH’s National Institutes of Alcohol Abuse and Alcoholism (NIAAA). The study appeared online on May 22, 2017, in the Journal of Clinical Investigation.
The researchers fed mice a liquid diet over the course of eight weeks with an escalating number of calories from alcohol (ethanol). Control mice received the same number of calories from isomaltose. The ethanol-containing diet caused liver damage along with a surge of intestinal fungal growth. It also increased fungal products in the animal’s blood. This is likely due both to the rise in fungal populations and leakage from the gut.
Fungal cell wall components are known to activate inflammatory elements of the immune system through a receptor called CLEC7A. The researchers examined this immune pathway in liver immune cells and found high levels of activity in ethanol-fed mice. Mice without CLEC7A, in contrast, were protected from ethanol-induced liver disease.
When the researchers treated mice with an antifungal drug called amphotericin B, it lessened the level of ethanol-associated liver disease. The drug reduced fungal overgrowth in the gut, lowered levels of fungal products in the bloodstream, and dampened the inflammatory response.
In a preliminary study, the researchers found that people who were alcohol-dependent had distinct differences in their intestinal fungi relative to healthy people. Blood samples revealed increased exposure and immune response to fungal products. This elevated immune response was linked to the likelihood of death in patients with alcoholic cirrhosis. A larger study, however, will be required to confirm these findings.
Taken together, these results illustrate the importance of alcohol-induced changes to intestinal fungi in alcoholic liver disease. They also suggest that antifungal agents like amphotericin B might be useful as a therapy. “Since it was so effective in mice, we are interested in testing amphotericin B in patients with alcohol-related liver disease—a population in urgent need of new therapeutics,” Schnabl says.