Animal research finds investigational drug disrupts MASH by targeting gut-liver axis

Animal studies have found that a new investigational compound was able to reverse metabolic dysfunction-associated steatohepatitis (MASH) by disrupting a disease pathway that links the gut and liver, according to research published recently in The Journal of Clinical Investigation.

MASH is a serious liver disease that causes the liver to swell and can lead to cirrhosis, liver cancer and liver failure. It is linked to Type 2 diabetes and other metabolic conditions such as obesity and affects about 7% of the global population. MASH is primarily treated with medications, lifestyle, and the management of metabolic conditions. Medications given to patients include Wegovy (semaglutide), a GLP-1 medication that was approved for MASH in August 2025, and Rezdiffra (resmetirom), which was granted an accelerated approval in April 2025 specifically for MASH.

The potential drug, DT-109, was developed at the University of Michigan Medical School and aims to treat MASH by improving gut health. Researchers, led by Eugene Chen, M.D., Ph.D., senior author of the study and Frederick G. L. Huetwell Professor of cardiovascular medicine, had determined that the bacterium Clostridium perfringens, which produces ammonia in the gut, is a driver of MASH.

Elevated ammonia levels erode the digestive tract’s inner lining and weaken the intestinal barrier, which leads to harmful toxins being able to reach the liver. Damage to the intestinal barrier triggers immune responses, such as a hyperactivation of CD8+ T cells.

DT-109 primarily acts in the gastrointestinal tract, researchers found. Chen and his team found that in mice and nonhuman primates, DT-109 was able to decrease Clostridium perfringens and ammonia production. Clostridium perfringensis a Gram-positive bacteria that can lead to gastrointestinal infections ranging from diarrhea to necrotizing enterocolitis, which is inflammation of the digestive tract.

In nonhuman primates DT-109 reduced liver inflammation and the severity of MASH. “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,” Chen said in a news release.

Previous studies the University of Michigan research team has conducted found that DT-1-9 accelerates fatty acid degradation and reshapes microbial bile acid metabolism.

“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 also found that DT-109 limited the formation of atherosclerosis plaques and stopped vascular calcification in nonhuman primates, which researchers said suggests could mean that DT-109 could be a potential treatment for cardiovascular disease.