Intestinal fungi worsen alcoholic liver disease

May 22, 2017, University of California - San Diego
Alcohol-dependent patients at all stages of liver disease had dramatic overgrowths of one fungal type in particular -- Candida (shown here growing in a petri dish). Credit: UC San Diego Health

Liver cirrhosis is the 12th leading cause of mortality worldwide and approximately half of those deaths are due to alcohol abuse. Yet apart from alcohol abstinence, there are no specific treatments to reduce the severity of alcohol-associated liver disease. Researchers at University of California San Diego School of Medicine and J. Craig Venter Institute (JCVI) have linked intestinal fungi to increased risk of death for patients with alcohol-related liver disease. They also found that antifungal treatment protects mice from alcohol-related liver disease progression.

The study is published May 22 in the Journal of Clinical Investigation.

"Not only is this the first study to associate fungi and liver disease," said senior author Bernd Schnabl, MD, associate professor of gastroenterology at UC San Diego School of Medicine, "we might be able to to slow the progression of alcoholic liver disease by manipulating the balance of fungal species living in a patient's intestine."

Alcoholism is associated with bacterial overgrowth in the intestines, as well as a shift in the types of bacteria found there, but little was known about the role of intestinal fungi in alcoholic liver disease.

In this study, Schnabl and colleagues found that fungi flourished in the intestines of mice with chronic alcohol exposure. In turn, they noted, the fungal overgrowth exacerbated liver disease. Parts of the fungal cell wall, mainly a sugar called beta-glucan, moved through the mouse's intestinal wall into the surrounding body cavity and organs. Once relocated inside the liver, beta-glucan bound certain immune cells and triggered inflammation. Chronic inflammation kills and ultimately promotes alcoholic liver disease.

But the researchers were able to protect mice from alcohol-induced liver disease by treating them with the antifungal compound amphotericin B. Compared to untreated mice, mice with alcohol-related liver disease that received amphotericin B had lower levels of and fat accumulation. These outcomes were determined by measuring plasma levels of a called alanine aminotransferase (reduced by approximately 55 percent) and levels of liver triglycerides (reduced by approximately 21 percent).

In this study, the mice received a type of oral amphotericin B that is not absorbed into the bloodstream. The drug only acts locally in the intestine and thus did not cause systemic side effects. Because it has no effect on systemic fungal infections, oral amphotericin B is not FDA-approved for human use. Intravenous amphotericin B is FDA approved for the treatment of serious fungal infections and it can cause side effects such as stomach, bone, muscle or joint pain and shortness of breath.

"This work demonstrates that alcoholic liver disease is exacerbated not only by bacteria, but also by fungi. Therefore, therapeutic strategies that target both need to be translated into clinical practice," said co-author Derrick Fouts, PhD, professor of genomic medicine at JCVI. "This study suggests a greater role of fungi in modulating the human microbiome than previously appreciated."

The team also compared fungi in the stool of eight healthy people and 20 people with chronic alcohol abuse and various stages of liver disease. They found that the healthy people had a richer diversity of fungi living in their intestines, as compared to alcohol-dependent patients. Instead, alcohol-dependent patients at all stages of liver disease had dramatic overgrowths of one fungal type in particular—Candida, which includes the species that causes yeast infections.

In addition, Schnabl's team found a correlation between fungi and disease severity in a separate group of 27 patients with alcohol-related liver disease: The higher the exposure to fungi, as measured by a person's level of antibodies that recognize them, the higher the risk of death. Fourteen patients had high fungi levels and 13 were classified as low. After five years, 77 percent of the low-fungi group survived, compared to 36 percent of the high-fungi group.

Schnabl cautioned that this human study is just proof-of-concept in a relatively small number of patients. In addition, he said it might not be the changes in fungal populations that cause progression of . Rather, it could be the overgrowth of intestinal in combination with leaky intestinal walls—a known result of alcohol abuse—that trigger chronic inflammatory responses in the liver. Further studies are needed to determine if a single fungal species contributes to disease progression more than others.

"Since it was so effective in mice, we are interested in testing amphotericin B in patients with alcohol-related —a population in urgent need of new therapeutics," Schnabl said.

Explore further: Alcohol also damages the liver by allowing bacteria to infiltrate

More information: An-Ming Yang et al, Intestinal fungi contribute to development of alcoholic liver disease, Journal of Clinical Investigation (2017). DOI: 10.1172/JCI90562

Related Stories

Alcohol also damages the liver by allowing bacteria to infiltrate

February 10, 2016
Alcohol itself can directly damage liver cells. Now researchers at University of California, San Diego School of Medicine report evidence that alcohol is also harmful to the liver for a second reason—it allows gut bacteria ...

Worldwide lack of early referral of patients with alcoholic liver disease

April 20, 2017
Results from a worldwide analysis of over 3,000 patients highlights that there is significant disparity in the referral of patients with liver disease, and that those with alcoholic liver disease (ALD) are 12 times more likely ...

Enzyme treatment reduces alcohol-induced liver damage in mouse models

April 25, 2017
An intestinal enzyme previously shown to keep bacterial toxins from passing from the gastrointestinal system into the bloodstream may be able to prevent or reduce the liver damage caused by excess alcohol consumption. In ...

Predicting severe liver disease: Obesity, insulin, diabetes, cholesterol, alcohol

April 22, 2017
A study conducted in Finland, presented today, demonstrates that in the general population, central obesity, insulin resistance, diabetes, lipid abnormalities and high alcohol consumption were the strongest predictors of ...

Cholesterol drug shown to reduce inflammation, other factors in patients

March 24, 2017
Statin drugs are widely used to manage high cholesterol and reduce the risk of cardiovascular disease. But in a new review of more than 50 studies, researchers cite reductions in liver inflammation and improvements in other ...

Initial hospital contact for alcohol issues predicts cirrhosis

November 24, 2016
(HealthDay)—An initial hospital contact for alcohol problems is a significant predictor of alcoholic liver cirrhosis, particularly for patients 40 to 59 years and those diagnosed with harmful use or dependence, according ...

Recommended for you

A versatile vaccine that can protect mice from emerging tick-borne viruses

December 18, 2018
A group of researchers led by Michael Diamond of Washington University School of Medicine in St. Louis have developed a vaccine that is effective in mice against Powassan virus, an emerging tick-borne virus that can cause ...

How cholera bacteria make people so sick

December 18, 2018
The enormous adaptability of the cholera bacterium explains why it is able to claim so many victims. Professor Ariane Briegel from the Leiden Institute of Biology has now discovered that this adaptability is due to rapid ...

Green leafy vegetables may prevent liver steatosis

December 17, 2018
A larger portion of green leafy vegetables in the diet may reduce the risk of developing liver steatosis, or fatty liver. In a study published in PNAS researchers from Karolinska Institutet in Sweden show how a larger intake ...

Discovery of novel mechanisms that cause migraines

December 17, 2018
Researchers at CNRS, Université Côte d'Azur and Inserm have demonstrated a new mechanism related to the onset of migraine. They found how a mutation that causes dysfunction in a protein which inhibits neuronal electrical ...

RNA processing and antiviral immunity

December 14, 2018
The RIG-I like receptors (RLRs) are intracellular enzyme sentries that detect viral infection and initiate a first line of antiviral defense. The cellular molecules that activate RLRs in vivo are not clear.

Faster test for Ebola shows promising results in field trials

December 13, 2018
A team of researchers with members from the U.S., Senegal and Guinea, in cooperation with Becton, Dickinson and Company (BD), has developed a faster test for the Ebola virus than those currently in use. In their paper published ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.