New drug reverses severe fatty liver disease by repairing the gut

The compound, known as DT-109, works by reducing harmful gut bacteria, protecting the intestinal lining, and preventing inflammatory substances from reaching the liver. According to findings published in The Journal of Clinical Investigation, this approach successfully reversed metabolic dysfunction-associated steatohepatitis (MASH) in animal models, offering a promising new strategy for treating a disease that remains difficult to manage.

MASH affects approximately 7% of the world’s population. It is a severe form of fatty liver disease in which excess fat accumulates in the liver, causing inflammation and cellular damage. Over time, the condition can progress to cirrhosis, which involves extensive liver scarring, as well as liver cancer and liver failure. Although treatment options have improved in recent years, effective therapies remain limited.

“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 Harmful Gut Bacteria Can Trigger Liver Damage

Chen’s research team had previously demonstrated that DT-109, a glycine-based tripeptide, could improve MASH in animal studies. A tripeptide is a small molecule made from three amino acids, which are the building blocks of proteins. What remained unclear was exactly how the compound produced its protective effects.

The latest research provides an explanation, revealing how changes in gut bacteria can set off a chain reaction that damages the liver and how DT-109 can interrupt that process.

Before examining the drug’s effects, the scientists confirmed an important contributor to MASH: excessive growth of Clostridium perfringens, a bacterium that produces ammonia inside the intestines.

When ammonia levels rise, they can damage the gut’s protective inner lining. Normally, this intestinal barrier helps prevent potentially harmful substances from escaping the digestive tract and entering the bloodstream.

As the barrier weakens, however, toxins and other products generated by gut microbes can travel to the liver. Once there, they can provoke inflammation and activate immune defenses in ways that worsen liver damage.

One response involves the excessive activation of CD8+ T cells, immune cells that normally help the body destroy infected or abnormal cells. When these cells become overactive, they can contribute to the inflammatory processes associated with MASH.

The findings help explain why a disease centered in the liver can be strongly influenced by events occurring elsewhere in the digestive system.

Experimental Drug Repairs the Gut and Protects the Liver

Through a series of experiments, researchers discovered that DT-109 disrupts this damaging cycle by improving the intestinal environment and reinforcing the gut’s protective barrier.

In both mice and nonhuman primates, the compound reduced levels of Clostridium perfringens and lowered ammonia production in the intestines. These changes helped strengthen the intestinal lining, limiting the movement of harmful microbial substances into the body and reducing their potential to damage the liver.

The results were particularly encouraging in nonhuman primates, whose liver biology and gut microbial communities more closely resemble those of humans than those of mice. In these animals, DT-109 reduced liver inflammation and lessened the severity of MASH.

Together, the findings show how targeting harmful processes in the gut can produce beneficial effects in the liver, even though the drug acts primarily within the gastrointestinal system.

“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.”

The gut-liver axis refers to the close biological relationship between the digestive tract and the liver. Substances absorbed from the intestines travel to the liver through the bloodstream, making liver health particularly sensitive to changes in gut bacteria and intestinal barrier function.

By targeting this connection, DT-109 may offer a way to address some of the processes driving liver inflammation rather than focusing exclusively on damage that has already occurred.

Potential Benefits Beyond Fatty Liver Disease

Researchers believe the compound’s ability to protect the intestinal barrier could make it useful against other conditions involving inflammation and metabolic dysfunction.

Previous research has shown that DT-109 can reduce the formation of atherosclerotic plaques and prevent vascular calcification in nonhuman primates.

Atherosclerotic plaques are deposits of fat and other substances that accumulate inside artery walls, potentially restricting blood flow and increasing the risk of cardiovascular problems. Vascular calcification occurs when calcium builds up in blood vessel walls, making them less flexible and contributing to cardiovascular disease.

These findings suggest that DT-109 could eventually have applications in treating both liver and cardiovascular conditions, an important possibility because metabolic disorders often affect multiple organs.

The researchers are also interested in whether the compound could help people with inflammatory bowel disease (IBD), a group of chronic conditions that includes Crohn’s disease and ulcerative colitis.

Because problems with the intestinal barrier are associated with several gastrointestinal disorders, a treatment that strengthens this barrier might have benefits beyond protecting the liver. However, additional research will be needed to determine whether DT-109 is effective against these conditions.

A Promising Treatment That Still Needs Human Trials

Despite the encouraging results, DT-109 remains an experimental treatment. Its ability to reverse MASH has been demonstrated in animal models, but researchers have not yet established whether it can safely and effectively produce similar benefits in humans.

The next phase of research will involve further evaluation of the compound, with the goal of advancing it toward clinical trials. Those studies will be essential for determining its safety, appropriate use, and potential effectiveness in patients.

“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.”

The discovery highlights an important shift in how scientists are approaching fatty liver disease. By addressing harmful gut bacteria and restoring the intestinal barrier, researchers may be able to protect the liver through a treatment that acts primarily outside the organ itself.

If future human studies confirm the benefits seen in animals, DT-109 could offer a new therapeutic option for patients with severe fatty liver disease while potentially addressing cardiovascular complications as well.

Funding and Disclosures

Ying Zhao, Oren Rom, Jifeng Zhang, and Y. Eugene Chen are listed as inventors on a patent application (Tripeptides and treatment of metabolic, cardiovascular, and inflammatory disorders).

Chen is also an inventor of DT-109. The University of Michigan holds the patent for the compound and has licensed it to Diapin Therapeutics. Both Chen and the university have an ownership interest in Diapin, which supplied DT-109 for the research and is continuing its development.

The human study protocol, all amendments, and the informed consent form received approval from the Institutional Review Boards at the participating sites. These included 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: UW 20-700).

All experimental procedures involving nonhuman 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.