Intestinal Fungi Contribute to Alcoholic Liver Disease

Chronic liver disease with cirrhosis is the 12th leading cause of death in the USA, and alcoholic liver disease accounts for approximately half of all cirrhosis deaths. Chronic alcohol consumption is associated with intestinal bacterial dysbiosis, yet little is known about the contribution of intestinal fungi, or mycobiota, to alcoholic liver disease.

Intestinal fungi may contribute to the development of alcoholic liver disease (ALD), which encompasses a broad range of liver diseases, from simple steatosis (fatty liver) to end-stage liver disease, or cirrhosis (liver cell death). Patients with cirrhosis are either frequently exposed to fungal products or develop fungal infections, with high mortality.

Scientists at the University of California, San Diego (La Jolla, CA, USA) and the J. Craig Venter Institute (Rockville, MD, USA) used both a mouse model and human samples of serum and feces in their study. They analyzed human serum samples data collected from 28 patients with alcoholic liver cirrhosis from July 1, 2010, through October 31, 2010. The human fecal samples were from eight healthy individuals without chronic disease (controls), 10 alcohol-dependent patients without evidence of progressive liver disease (non-progressive liver disease), six patients with alcoholic hepatitis (alcoholic hepatitis) and four patients with alcoholic liver cirrhosis (alcoholic cirrhosis). Primary human hepatocytes, Kupffer cells, and hepatic stellate cells were isolated and RNA extraction and quantitative reverse transcriptase polymerase chain reaction (PCR) were performed.

The scientists observed that alcohol-dependent patients displayed reduced intestinal fungal diversity and Candida overgrowth. Compared with healthy individuals and patients with non–alcohol-related cirrhosis, alcoholic cirrhosis patients had increased systemic exposure and immune response to mycobiota. Moreover, the levels of extraintestinal exposure and immune response correlated with mortality. There were concomitant decreases in Epicoccum, unclassified fungi, Galactomyces, and Debaryomyces.

The authors concluded that alcohol-associated fungal dysbiosis in humans is characterized by a large increase in Candida, which is susceptible to amphotericin B. The effects of this drug should be tested in patients with alcohol-related liver disease, who are in urgent need of new therapeutics. Manipulation of the intestinal mycobiome might be an effective strategy for attenuation of alcohol-related liver disease.

Bernd Schnabl, MD, an associate professor of gastroenterology and senior author of the study, said, “Not only is this the first study to associate fungi and liver disease, we might be able to slow the progression of alcoholic liver disease by manipulating the balance of fungal species living in a patient’s intestine.” The study was published on May 22, 2017, in the Journal of Clinical Investigation.

Related Links:
University of California, San Diego
J. Craig Venter Institute