An experimental drug developed at Michigan Medicine has demonstrated the ability to reverse severe fatty liver disease in animal studies by restoring intestinal health. The findings, published in The journal of clinical researchsuggest that targeting the connection between the gut and the liver could offer a promising new approach for the treatment of metabolic dysfunction-associated steatohepatitis (MASH).
MASH is a severe form of fatty liver disease that affects approximately 7% of people worldwide. It can progress to cirrhosis, liver cancer, and liver failure, but effective treatment options remain limited.
The investigational compound, known as DT-109, is a glycine-based tripeptide. The researchers found that it reversed MASH in animal models by disrupting a harmful biological process that links the intestine and liver.
“We see clear evidence that DT-109 protects the intestinal epithelial barrier, reducing the systemic influx of harmful microbial products that are thought to contribute to the development and progression of MASH,” said Eugene Chen, M.D., Ph.D., senior author of the study and Frederick G.L. Huetwell Professor of Cardiovascular Medicine at the University of Michigan Medical School.
“This compound shows benefits for the gastrointestinal system and has great potential as a treatment for MASH.”
How gut bacteria can cause liver disease
Previous studies from Chen’s lab had already shown that DT-109 could improve MASH in animals. The new research explains how the compound produces those benefits.
The team identified for the first time a major contributor to the disease: an overgrowth of the bacteria. Clostridium perfringenswhich generates ammonia within the intestine.
High levels of ammonia damage the lining of the digestive tract and weaken the intestinal barrier. Once that protective barrier is compromised, harmful microbial products can enter the bloodstream, reach the liver, and trigger inflammatory immune responses, including excessive activation of CD8+ T cells.
Through a series of experiments, researchers discovered that DT-109 interrupted this chain of events, helping to restore the health of both the intestine and the liver.
DT-109 restores the intestinal barrier
In both mice and non-human primates, DT-109 reduced Clostridium perfringens levels and reduction of ammonia production in the intestines. As a result, the intestinal barrier became stronger, which limited the movement of harmful substances from the intestine to the body.
The results were especially encouraging in non-human primates, whose liver biology and gut microbiota more closely resemble those of humans. In these animals, DT-109 reduced liver inflammation and significantly improved the severity of MASH.
“DT-109 connects microbiota modulation to liver protection by restoring intestinal barrier integrity and limiting systemic translocation of ammonia and other pro-inflammatory microbial products within the gut-liver axis,” said Jifeng Zhang, Ph.D., co-author and research professor of cardiovascular medicine at the U-M School of Medicine.
“We also found that DT-109 acts primarily in the gastrointestinal tract, but its reach extends far beyond that.”
Potential benefits beyond MASH
Researchers believe DT-109 may have uses beyond treating fatty liver disease.
Previous studies have shown that the compound can reduce the formation of atherosclerosis plaques and prevent vascular calcification in non-human primates, suggesting that it could also become a treatment for cardiovascular diseases.
Because intestinal barrier breakdown has also been linked to several digestive disorders, the team believes that DT-109 could eventually be explored as a treatment for conditions such as inflammatory bowel disease (IBD).
Future research will focus on additional testing needed to bring DT-109 into clinical trials and evaluate its safety and effectiveness in people.
“This study presents novel evidence on the pathogenesis of MASH and provides excitement about a therapeutic avenue to explore for a condition that remains difficult to treat,” said Elliot Tapper, MD, academic director of hepatology at Michigan Medicine.
“What patients with MASH need is a safe and effective therapy capable of improving the health of their liver and heart; of course, we are excited about these advances.”
Additional authors include Yang Zhao, Ph.D., Ying Zhao MS, and Yanhong Guo, MD., Ph.D., all of the University of Michigan. Additional co-authors are listed in the published study.
Financing and disclosures
Ying Zhao, Oren Rom, Jifeng Zhang and Y. Eugene Chen are the inventors of the patent application. (Tripeptides and treatment of metabolic, cardiovascular and inflammatory disorders).
Chen is also the inventor of the DT-109. The University of Michigan patented the compound and licensed it to Diapin Therapeutics. Chen and the university have ownership stakes in the company. Diapin Therapeutics supplied DT-109 for the study and continues to develop the compound.
The human study protocol, all modifications, and the informed consent form were reviewed and approved by the Institutional Review Boards of each site, including the First Affiliated Hospital of Xi’an Jiaotong University (approval number: XJTU1AF2023LSK330) and the Institutional Review Board of Jinan University (approval number: 2016-017) and the University of Hong Kong/Hospital Authority Hong Kong West Cluster (approval number: UW 20-700). All experimental protocols involving non-human primates were approved by the Laboratory Animal Care Committee of Xi’an Jiaotong University (approval number: 20191278) and the Institutional Animal Care and Use Committee of Spring Biological Technology Development Co., Ltd. (approval number: 201901). The study was conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.