An experimental drug developed at Michigan Medicine has shown in animal studies the ability to reverse severe fatty liver disease by restoring gut health. The survey results are clinical research journalsuggest that targeting the connection between the intestine and liver may provide a promising new approach for the treatment of metabolic dysfunction-associated steatohepatitis (MASH).
MASH is a severe 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 compound under investigation, known as DT-109, is a glycine-based tripeptide. Researchers have found that they reverse MASH in animal models by disrupting a harmful biological process that connects the intestines and liver.
“We see clear evidence that DT-109 protects the intestinal epithelial barrier and reduces the systemic influx of harmful microbial products that are thought to contribute to the development and progression of MASH,” said Eugene Chen, M.D., senior author of the study and Frederick GL Hutwell 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 cause liver disease
Previous research in Cheng’s lab had already shown that DT-109 could improve MASH in animals. New research explains how this compound produces such benefits.
The research team first identified the main cause of the disease. It’s an overgrowth of bacteria. Clostridium perfringensAmmonia is produced in the intestines.
High ammonia levels damage the lining of the digestive tract and weaken the intestinal barrier. When the protective barrier is compromised, harmful microbial products can enter the bloodstream and reach the liver, triggering inflammatory immune responses such as overactivation of CD8+ T cells.
Through a series of experiments, researchers discovered that DT-109 can help disrupt this chain of events and restore the health of both the intestines and liver.
DT-109 Restores the intestinal barrier
In both mice and non-human primates, DT-109 was reduced Clostridium perfringens lowers levels and reduces ammonia production in the intestines. As a result, the intestinal barrier becomes stronger and the movement of harmful substances from the intestines into the body is restricted.
The results were particularly promising in non-human primates, whose liver biology and gut microbiota closely resemble those of humans. In these animals, DT-109 reduced liver inflammation and significantly improved the severity of MASH.
“DT-109 couples microbiota regulation and liver protection by restoring the integrity of the intestinal barrier and limiting the systemic translocation of ammonia and other pro-inflammatory microbial products within the gut-liver axis,” said co-author Jifeng Zhang, Ph.D., research professor of cardiovascular medicine at the U-M School of Medicine.
“We also found that DT-109 primarily acts in the gastrointestinal tract, but its range is broader.”
Potential benefits beyond MASH
Researchers believe DT-109 may have uses beyond treating fatty liver disease.
Previous studies have shown that the compound reduces atherosclerotic plaque formation and prevents calcification of blood vessels in non-human primates, suggesting it could also be a treatment for cardiovascular disease.
Because disruption of the intestinal barrier has also been linked to several gastrointestinal diseases, the research team believes DT-109 could eventually be investigated 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 efficacy in humans.
“This study provides new evidence about the pathogenesis of MASH and provides excitement about treatments exploring a condition that remains difficult to treat,” said Elliott Tapper, MD, academic director of hepatology at the University of Michigan School of Medicine.
“What MASH patients need are safe and effective treatments that can improve liver and heart health. Of course, we are excited about these developments.”
Additional authors include Yang Zhao, PhD, Ying Zhao, MS, and Yanhong Guo, MD, of the University of Michigan. Additional co-authors are listed in the published study.
Funding and disclosure
Ying Zhao, Oren Rom, Jifeng Zhang, and Y. Eugene Chen are the inventors of this patent application. (Tripeptides and the treatment of metabolic diseases, cardiovascular diseases, and inflammatory diseases).
Mr. Chen is also the inventor of the DT-109. The University of Michigan patented the compound and licensed it to Diapin Therapeutics. Mr. Chen and the university retain ownership of the company. Diapin Therapeutics supplied DT-109 for this study and continues to develop this compound.
The human subject study protocol, all amendments and informed consent forms were reviewed and approved by the institutional review boards of each institution, including the First Affiliated Hospital of Xi’an Jiaotong University (approval number: XJTU1AF2023LSK330), 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: UW20-700). 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). This study was conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
