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 Clinical Investigation JournalThis approach successfully reversed metabolic dysfunction-associated steatohepatitis (MASH) in animal models, providing a promising new strategy to treat a disease that remains difficult to manage.

MASH affects approximately 7% of the world’s population. This is a serious form of fatty liver disease in which excess fat builds up in the liver, causing inflammation and cell damage. Over time, the disease can progress to cirrhosis, which leads to 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 intestinal epithelial barrier, thereby reducing the systemic influx of harmful microbial products thought to contribute to the development and progression of MASH,” said Eugene Chen, MD, Ph.D., senior author of the study and the Frederick GL Huetwell Professor of Cardiovascular Medicine at the University of Michigan School of Medicine.

“This compound has benefits for the gastrointestinal system and shows great potential as a treatment for MASH.”

How Harmful Gut Bacteria Can Cause Liver Damage

Chen’s research team previously demonstrated that DT-109, a glycine-based tripeptide, could improve MASH in animal studies. A tripeptide is a small molecule made up of 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 trigger a chain reaction that damages the liver and how DT-109 can interrupt this process.

Before examining the effects of the drug, scientists confirmed an important factor in MASH: excessive growth of Clostridium perfringensa bacteria that produces ammonia in the intestines.

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

However, as the barrier weakens, toxins and other products generated by gut microbes can move to the liver. Once there, they can cause inflammation and activate immune defenses in ways that worsen liver damage.

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

The findings help explain why liver-centered disease can be strongly influenced by events 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 strengthening the intestine’s protective barrier.

In mice and non-human primates, the compound reduced levels of Clostridium perfringens and decreased production of ammonia in the intestines. These changes helped strengthen the intestinal lining, limiting the movement of harmful microbial substances through the body and reducing their potential to damage the liver.

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

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

“DT-109 links microbiota modulation to liver protection by restoring intestinal barrier integrity and limiting systemic translocation of ammonia and other pro-inflammatory microbial products into the gut-liver axis,” said Jifeng Zhang, Ph.D., co-author and research professor of cardiovascular medicine at the UM School of Medicine.

“We also found that DT-109 works primarily in the gastrointestinal tract, but its reach extends 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 link, DT-109 could offer a way to treat some of the processes that cause liver inflammation rather than focusing exclusively on the 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 atherosclerotic plaque formation and prevent vascular calcification in non-human primates.

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

These results suggest that DT-109 may eventually have applications in the treatment of liver and cardiovascular diseases, an important possibility because metabolic disorders often affect multiple organs.

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

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

A promising treatment that still requires human trials

Despite 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 produce similar benefits safely and effectively in humans.

The next phase of research will involve further evaluation of the compound, with the aim of advancing it to clinical trials. These studies will be essential to determine its safety, appropriate use, and potential effectiveness in patients.

“This study presents new evidence on the pathogenesis of MASH and generates excitement about a therapeutic avenue to explore for a disease that remains difficult to treat,” said Elliot Tapper, MD, academic director of hepatology at Michigan Medicine.

“What MASH patients need is a safe and effective treatment that can improve their liver and heart health – of course, we are excited about these developments.”

The discovery highlights an important change in the way scientists approach fatty liver disease. By tackling harmful gut bacteria and restoring the intestinal barrier, researchers may be able to protect the liver with a treatment that works primarily outside the organ itself.

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

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 the inventor of the DT-109. The University of Michigan holds the patent for the compound and has licensed it to Diapin Therapeutics. Chen and the university both have a stake in Diapin, which provided the DT-109 for research and continues its development.

The human study protocol, all modifications, and the informed consent form received approval from the institutional review boards of the participating sites. These include the First Affiliated Hospital of Xi’an Jiaotong University (approval number:

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.