Drug candidate treats severe fatty liver disease by protecting the gut in animal models

Researchers discovered that a potential drug developed at Michigan Medicine treats severe fatty liver disease by improving gut health, according to a study published in The Journal of Clinical Investigation.  

The glycine-based tripeptide, DT-109, reversed metabolic dysfunction-associated steatohepatitis (MASH) in animal models by disrupting a disease-driving pathway that links the gut and liver.

MASH affects roughly 7% of the global population and can lead to cirrhosis, liver cancer and liver failure. Treatment options remain limited despite recent therapeutic advances.

“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.”

While previous animal studies from Chen’s team showed DT-109 could serve as a treatment for MASH, the researchers now understand the mechanism behind its therapeutic effects.

Before testing their compound, Chen’s team first confirmed a key driver of MASH: proliferation of the bacterium Clostridium perfringens, which produces ammonia in the gut. 

Elevated ammonia levels erode the digestive tract’s inner lining and weaken the intestinal barrier, allowing harmful toxins to reach the liver and trigger inflammatory immune responses, such as a hyperactivation of CD8+ T cells.

Through a series of experiments, Chen’s team found that DT-109 interrupted this process to restore the integrity of both the gut and liver.

The compound diminished Clostridium perfringens and intestinal ammonia production in mice and nonhuman primates, strengthening the intestinal barrier.

In nonhuman primates, whose livers and gut microbiota more closely resemble those of humans, DT-109 reduced liver inflammation and 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.”

Researchers say the findings suggest DT-109's benefits may extend beyond MASH.

DT-109 has been shown to limit the formation of atherosclerosis plaques and stop vascular calcification in nonhuman primates, positioning it as a potential treatment for cardiovascular disease.

Because intestinal barrier dysfunction is implicated in several gastrointestinal disorders, the team also believes DT-109 could eventually have applications in conditions such as inflammatory bowel disease (IBD).

Future studies will focus on further evaluating DT-109 to advance the compound toward clinical trials to assess its safety and effectiveness in humans.

“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: Yang Zhao, Ph.D., Ying Zhao M.S., Yanhong Guo, MD., Ph.D., all of University of Michigan. See remaining authors online.

Funding/disclosures: Ying Zhao, Oren Rom, Jifeng Zhang, and Y. Eugene Chen are inventors of the patent application (Tripeptides and treatment of metabolic, cardiovascular, and inflammatory disorders).

Chen is an inventor of the compound DT-109. The University of Michigan has patented it and licensed it to Diapin Therapeutics. Chen and the university have an ownership interest in Diapin. Diapin provided DT-109 for this study. The company is further developing 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.

Paper cited: “Metabolic dysfunction–associated steatohepatitis exacerbated by Clostridium perfringens–derived ammonia is attenuated by tripeptide DT-109,” The Journal of Clinical Investigation. DOI: 10.1172/JCI200522