New drug reverses severe fatty liver disease by repairing the gut

An experimental drug developed at Michigan Medicine has reversed a serious form of fatty liver disease in animal studies by targeting an unexpected source of liver damage: 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. Findings published in The Journal of Clinical Investigation indicate 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 global population, characterized by excess fat accumulation in the liver, leading to inflammation and cellular damage. If untreated, it can progress to cirrhosis, liver cancer, and liver failure. Despite recent improvements in treatment options, 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 contribute to MASH development and progression,” said Eugene Chen, M.D., Ph.D., senior author of the study. “This compound shows benefits to the gastrointestinal system and has great potential as a treatment for MASH.”

Understanding the Link Between Gut Health and Liver Damage

Chen’s team previously demonstrated that DT-109, a glycine-based tripeptide, could improve MASH in animal studies. However, the exact mechanism behind its protective effects was unclear.

The latest research reveals that excessive growth of Clostridium perfringens, a bacterium producing ammonia in the intestines, contributes to MASH. Elevated ammonia levels can damage the gut’s protective lining, allowing toxins to enter the bloodstream and reach the liver, provoking inflammation and immune responses that worsen liver damage.

One response involves the excessive activation of CD8+ T cells, which can exacerbate inflammation associated with MASH. This highlights how liver disease can be influenced by events in the digestive system.

DT-109’s Mechanism of Action

Researchers found 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, DT-109 reduced levels of Clostridium perfringens and lowered ammonia production, strengthening the intestinal lining and limiting harmful microbial substances from damaging the liver.

The results were particularly promising in nonhuman primates, whose liver biology resembles that of humans. In these animals, DT-109 reduced liver inflammation and 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,” said Jifeng Zhang, Ph.D., co-author of the study.

Broader Implications of DT-109

The gut-liver axis refers to the biological relationship between the digestive tract and the liver. By targeting this connection, DT-109 may address processes driving liver inflammation rather than focusing solely on existing damage.

Researchers believe DT-109’s ability to protect the intestinal barrier could also be beneficial for conditions involving inflammation and metabolic dysfunction. Previous studies indicated that DT-109 can reduce atherosclerotic plaques and prevent vascular calcification, suggesting potential applications in treating both liver and cardiovascular conditions.

Additionally, researchers are exploring whether DT-109 could help individuals with inflammatory bowel disease (IBD), as strengthening the intestinal barrier may benefit various gastrointestinal disorders.

Next Steps for DT-109

Despite promising results, DT-109 remains experimental. Further evaluation is necessary to determine its safety and effectiveness in humans. The next research phase will aim to advance the compound toward clinical trials.

“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.

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 related to DT-109. The University of Michigan holds the patent and has licensed it to Diapin Therapeutics, which supplied DT-109 for the research.

 

Source: ScienceDaily