An experimental drug developed at Michigan Medicine has shown the ability to reverse severe fatty liver disease in animal studies by restoring gut health. The findings, published in The Journal of Clinical Investigation, suggest that targeting the connection between the gut and liver could offer a promising new approach for treating metabolic dysfunction-associated steatohepatitis (MASH).
MASH is a serious form of fatty liver disease that affects about 7% of people worldwide. It can progress to cirrhosis, liver cancer, and liver failure, yet effective treatment options remain limited.
The investigational compound, known as DT-109, is a glycine-based tripeptide. Researchers found that it reversed MASH in animal models by interrupting a harmful biological process linking the gut and liver.
“We see clear evidence that DT-109 protects the gut epithelial barrier, reducing the systemic influx of harmful microbial products that are thought to contribute to MASH development and progression,” 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 to the gastrointestinal system and has great potential as a treatment for MASH.”
How Gut Bacteria Can Drive Liver Disease
Earlier studies from Chen’s laboratory had already shown that DT-109 could improve MASH in animals. The new research explains how the compound produces those benefits.
The team first identified a major contributor to the disease: an overgrowth of the bacterium Clostridium perfringens, which generates ammonia inside the gut.
High ammonia levels damage the lining of the digestive tract, weakening 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, the researchers found that DT-109 disrupted this chain of events, helping restore the health of both the gut and the liver.
DT-109 Restores the Gut Barrier
In both mice and nonhuman primates, DT-109 reduced Clostridium perfringens levels and lowered ammonia production in the intestines. As a result, the intestinal barrier became stronger, limiting the movement of harmful substances from the gut into the body.
The results were especially encouraging in nonhuman 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 with liver protection by restoring gut barrier integrity and limiting the 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 U-M Medical School.
“We also found that DT-109 primarily acts in the gastrointestinal tract, but its reach stretches much further.”
Potential Benefits Beyond MASH
The 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 nonhuman primates, suggesting it could also become a treatment for cardiovascular disease.
Because breakdown of the intestinal barrier has also been linked to several digestive disorders, the team believes 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 move DT-109 into clinical trials and evaluate its safety and effectiveness in people.
“This study presents novel evidence about the pathogenesis of MASH and provides excitement about a therapeutic avenue to explore for a condition that remains difficult to treat,” said Elliot Tapper, M.D., Academic Director of Hepatology at Michigan Medicine.
“What patients with MASH need is a safe and effective therapy capable of improving their liver and heart health — of course we are excited about these developments.”
Additional authors include Yang Zhao, Ph.D., Ying Zhao M.S., and Yanhong Guo, MD., Ph.D., all of the University of Michigan. Additional co-authors are listed in the published study.
Funding and Disclosures
Ying Zhao, Oren Rom, Jifeng Zhang, and Y. Eugene Chen are inventors on the patent application (Tripeptides and treatment of metabolic, cardiovascular, and inflammatory disorders).
Chen is also an inventor of DT-109. The University of Michigan has patented the compound and licensed it to Diapin Therapeutics. Chen and the university hold an ownership interest in the company. Diapin Therapeutics supplied DT-109 for the study and is continuing to develop the compound.
The study protocol involving humans, all amendments and the informed consent form were reviewed and approved by the Institutional Review Boards at 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 performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.