Experimental Drug DT-109 Reverses Severe Fatty Liver Disease by Repairing Gut Health

An experimental drug, DT-109, developed at Michigan Medicine, has successfully reversed a severe form of fatty liver disease in animal studies by targeting the gut. The compound 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 reversed metabolic dysfunction-associated steatohepatitis (MASH) in animal models, offering a new strategy for a difficult-to-manage disease.

MASH, affecting approximately 7% of the global population, is a serious fatty liver condition where excess fat causes inflammation and cellular damage, potentially progressing to cirrhosis, liver cancer, and liver failure. 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, stated, "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." He added that the compound shows benefits to the gastrointestinal system and has "great potential as a treatment for MASH."

Chen's research team previously showed that DT-109, a glycine-based tripeptide, could improve MASH in animals. The latest research explains its protective effects by revealing how changes in gut bacteria trigger liver damage and how DT-109 interrupts this process. Scientists confirmed excessive growth of Clostridium perfringens, a bacterium producing ammonia in the intestines, contributes to MASH. Elevated ammonia levels can damage the gut's protective inner lining, allowing toxins and microbial products to travel to the liver, causing inflammation and activating immune defenses, including overactive CD8+ T cells, which worsen liver damage.

DT-109 disrupts this cycle by improving the intestinal environment. In both mice and nonhuman primates, the compound reduced Clostridium perfringens levels and lowered intestinal ammonia production. These changes strengthened the intestinal lining, limiting harmful microbial substances from entering the bloodstream and reducing their liver-damaging potential. Results in nonhuman primates were particularly encouraging due to their closer resemblance to human liver biology and gut microbial communities. In these animals, DT-109 reduced liver inflammation and lessened MASH severity.

Jifeng Zhang, Ph.D., co-author and research professor of cardiovascular medicine at U-M Medical School, noted, "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." He added that while DT-109 primarily acts in the gastrointestinal tract, its reach extends much further, suggesting it could address inflammation drivers rather than just existing damage. Researchers believe DT-109’s ability to protect the intestinal barrier could also benefit other inflammatory and metabolic conditions, including reducing atherosclerotic plaques and preventing vascular calcification, as shown in previous nonhuman primate research.

What to watch: Further clinical trials for DT-109 and its potential application in other inflammatory conditions.

Editor's note: The draft clearly explains the mechanism of DT-109, the role of gut health, and the findings regarding MASH in animal models.