Compound Tested for Alcoholic Liver Disease

The most prevalent forms of ALD are fatty liver, alcoholic hepatitis and cirrhosis. Corticosteroids are the only treatment option for alcoholic hepatitis, or chronic inflammation of the liver, despite little evidence of long-term efficacy and considerable adverse side effects.

Investigators at Cedars-Sinai and the University of California, San Diego (UCSD), found that a synthetic compound given orally protected the liver against injury in an animal model for alcoholic hepatitis. The study was recently published in the Proceedings of the National Academy of Sciences. Ekihiro Seki, MD, PhD of Cedars-Sinai and Dennis A. Carson, MD, of UCSD are co-senior authors of the paper.

"Interleukin-22 (IL-22) is a beneficial cytokine that can help protect the body against invading pathogens, repair damage caused by intestinal or liver disease and potentially prevent the development of ALD," said Seki, professor of Medicine and Biomedical Sciences.

"But supplying recombinant IL-22 proteins for disease therapy can be quite expensive. We wanted to find out if a smaller, synthetic molecule that would be cheaper to manufacture — 1Z1—could be an alternative strategy," he said.

In the study, injury, fatty liver, and inflammation were induced in an alcoholic hepatitis mouse model. This resulted in a reduction of intestinal toll-like receptor 7 (TLR7)—a protein known to help prevent liver fibrosis and play a role in protecting it against harmful bacteria. Those mice were then given oral 1Z1, a synthetic TLR7 ligand.

"We found that ingestion of 1Z1, relying on IL-22 induction in the intestine, protected against alcohol-induced fatty liver and liver injury," said Seki.

The intestines and the gut microbiome play a key role in that ALD protection.

Alcohol consumption damages the lining of the intestines, allowing bacteria to escape and migrate to the liver where the microbes can do significant damage to the vital organ.

"In the animal study, we found that 1Z1 improved TLR7 activity in the intestines of the mice, ameliorating epithelial damage which prevented gut bacteria from migrating to the liver and doing harm. It also had the effect of boosting the levels of beneficial microbes in the gut microbiome," said Seki.

Another advantage of 1Z1, especially over corticosteroid therapy for liver disease, is that it did not cause systemic side effects in the mice.

Further clinical study is needed to confirm this treatment strategy, said Seki, but the need for new therapies for patients with alcoholic hepatitis is overdue. More than 16 million adults in the U.S. are characterized as heavy drinkers by the Department of Health and Human Services. Hospitals around the country are blaming the current COVID-19 pandemic for an alarming increase in the number of alcohol-related admissions for liver diseases such as alcoholic hepatitis.

"We are absolutely seeing a rise in ALD related to excessive use of alcohol. It is impacting younger people hardest —those under age 40," said Vinay Sundaram, MD, associate professor of Medicine and director of Hepatology Outcomes Research at Cedars-Sinai.

"Treatment options have remained largely unchanged since the 1970’s. Meanwhile, nearly 40% of patients who develop severe disease die within six months. The identification of a better molecular target is critical to the development of effective therapies for alcohol-associated liver disease," said Seki.

Funding: Research reported in this publication was supported by the National Institutes of Health under award numbers R01AA027036, R21AA025841 and P01CA233452.