Science has shown that bacteria, viruses and other microbes that live in and on the human body – the microbiota – are essential in maintaining and restoring health. Researchers across UofL are investigating the roles of specific bacteria and their metabolites – the substances they produce – and how to employ them in improving health.

Two recent studies from researchers in UofL’s have shown that a specific type of bacteria shows significant benefits in the treatment of alcohol-associated liver disease and alcohol use disorder. The research reveals that both probiotics and the metabolites made by the bacteria have beneficial effects.

One study, a clinical trial in which patients took oral doses of the bacterium Lactobacillus rhamnosus GG (LGG), resulted in reduced alcohol use and liver injury in these patients. A related laboratory study in animal models showed that metabolites from LGG are a source of the benefits.

In the multi-center clinical trial, led by Craig McClain, professor of medicine and director of the Alcohol Research Center, LGG reduced liver injury and, just as importantly, reduced drinking in patients with early alcohol-associated liver disease. Study participants who were treated with LGG showed a significant reduction in liver injury after one month. Six months of LGG therapy was associated with a reduction of heavy drinking to social or abstinence levels.

“There are multiple lines of evidence from several groups showing that altering gut flora plays a role in alcohol consumption and alcohol use disorder treatment. We are pursuing this line of inquiry, but the study is early work,” McClain said. The study was  in April.

In preclinical research, lab studies led by Wenke Feng, professor in the UofL Department of Pharmacology and Toxicology, showed that the substances produced by LGG, its metabolites, are responsible for the beneficial effects to the gut and liver of alcohol-treated mice. That study, , was published in Hepatology in April.

“Our ongoing research aims to uncover mechanistic insights that could pave the way for new treatments for alcohol-associated disorders,” Feng said.

“Dr. Feng’s studies show that it is not the live bacteria that is required to obtain benefits, but instead substances that the bacteria make are the active, beneficial ingredients. Working with our metabolomics group, Dr. Xiang Zhang and colleagues, we have identified some of these active substances,” McClain said. Zhang is professor of chemistry and director of the UofL Center for Regulatory and Environmental Analytical Metabolomics.

“These exciting results suggest that probiotics may be a source of new therapies for alcohol-use disorder as well as alcohol-associated liver disease,” McClain said.

Alcohol use disorder (AUD) is a medical condition in which people have limited ability to stop or control their alcohol use. According to the 2021 National Survey on Drug Use and Health, AUD affected 29.5 million Americans over the age of 12 in the past year. Prolonged excessive alcohol use can result in high blood pressure, heart disease, stroke, liver disease and digestive problems, as well as cancer, mental health problems, weakened immune system and social problems.

For more information on alcohol use disorder, visit the .

The UofL Hepatobiology and Toxicology Center was created in 2016 with an $11.5 million grant from the NIH to support unique research focused on liver injury and disease and toxicology. The center supports leading-edge research conducted by junior investigators with mentorship from senior researchers, as well as pilot projects and core laboratory facilities that support research across the university. The researchers’ goal is reducing the impact of many types of liver illness through prevention and the development of therapies.

Kentucky leads the nation in increases in cirrhosis-related deaths and in liver cancer-related deaths. According to research published in , mortality due to cirrhosis has been increasing in the U.S. since 2009, with the greatest increase in deaths from cirrhosis in Kentucky. Non-alcoholic fatty liver diseases affect approximately 25% of adults and 10% of children in the U.S.

“This vital research at the University of Louisville advances the health of Kentuckians and people throughout the world,” said UofL President Neeli Bendapudi. “Through this center, UofL researchers will continue to expand their work to find ways to prevent and treat liver illnesses, many of which today have no FDA-approved treatment.”

Researchers at the focus on liver injury, nutrition and gut-liver interactions as well as interactions between the liver and environment, toxicants and drugs. Their ultimate goal is to contribute to the prevention and treatment of non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (a major cause of cirrhosis of the liver), alcoholic liver disease and liver cancer.

“This incredible cohort of researchers is discovering new ways to address the liver illnesses that afflict so many Kentuckians. I am thrilled that young researchers will continue to be supported with COBRE funding at UofL,” said Toni Ganzel, dean of the UofL School of Medicine.

In its first five years, four of the funded junior investigators in the UofL H&T Center received independent NIH research funding, making way for a new cohort of project researchers. The renewal of COBRE funding encourages a continuous supply of researchers in specialized areas of medicine and the search for new disease treatments.

“This unique thematic center is focused on liver injury, disease and toxicology. We evaluate critical barriers in our understanding of the development and progression of liver disease and we define potential therapeutic targets that could transform current practice,” said Craig McClain, associate vice president for health affairs and translational research and principal investigator for the UofL H&T Center. “This new phase will build on that success and extend and strengthen the scope of the program.”  

“To push past the limitations of existing therapeutics, you need COBRE infrastructure grants to establish cutting-edge biomedical research centers and capabilities,” said Joshua L. Hood, a project investigator in the UofL H&T Center. “The more of these capabilities we have, the more we can explore multidisciplinary frontiers in biomedical science to facilitate the development of new treatments for liver-related cancer and other diseases.”

Current projects supported by the center include:

• Yan Li, associate professor in the Department of Surgery, is investigating preventive strategies and possible mechanisms behind non-alcoholic steatohepatitis, a potential precursor of liver cancer.
• Joshua L. Hood, assistant professor in the Department of Pharmacology & Toxicology, is examining how very small membrane-bound compartments known as nanovesicles that are released by cancer cells influence immune function in liver cancer.
• Ming Song, assistant professor in the Department of Medicine, is studying the role of fructose consumption on the disruption of intestinal barrier function in non-alcoholic fatty liver disease.
• Smita Ghare, instructor in the Department of Medicine, is investigating how alcohol-induced changes in the liver contribute to liver inflammation and injury.

UofL has a legacy of liver research dating to the 1970s when faculty members began investigating a cluster of cases of hepatic angiosarcoma, a rare liver cancer caused by exposure to vinyl chloride in a polymer manufacturing facility in an area of West Louisville known as Rubbertown. UofL researchers worked with the community and industry to document and reduce the effects of toxicants on worker health. UofL still maintains a biorepository of blood and liver tissue specimens begun during that research that serves as a resource for investigators studying the effects of environmental exposures on the liver.

In addition to research, the center provides support for community health. During the epidemic of Hepatitis A and C in the last decade, center investigators helped create the Kentucky Hepatitis Academic Mentorship Program. This program helped to train more than 140 primary care providers in the diagnosis and treatment of Hepatitis C. Those diseases now are declining.