Scientists at Michigan Medicine have discovered that an experimental compound can reverse advanced fatty liver disease by healing damage to the digestive tract, according to research published in The Journal of Clinical Investigation. The findings offer a fresh therapeutic target for a condition that currently has few effective treatment options.
The drug, called DT-109, works by interrupting a harmful chain of events that connects gut bacteria to liver damage. In animal models, the compound restored intestinal health and eliminated signs of metabolic dysfunction-associated steatohepatitis, or MASH, a severe form of fatty liver disease that affects roughly 7 percent of the global population.
MASH can progress to cirrhosis, liver cancer, and organ failure. Yet treatment options remain limited, making new approaches urgent.
The discovery centers on an unexpected culprit: bacteria called Clostridium perfringens that overgrow in the guts of people and animals with MASH. These bacteria generate ammonia that damages the intestinal lining, weakening the barrier that normally prevents harmful substances from entering the bloodstream.
Once that barrier breaks down, microbial toxins slip into the circulation and trigger inflammatory reactions in the liver. The immune system becomes hyperactive, damaging liver tissue and accelerating disease. This gut-to-liver pathway had been suspected in earlier research, but the new study explains the precise mechanism and shows how to stop it.
"We see clear evidence that DT-109 protects the gut epithelial barrier, reducing the systemic influx of harmful microbial products," said Eugene Chen, the senior researcher and a cardiovascular medicine professor at the University of Michigan. "This compound shows benefits to the gastrointestinal system and has great potential as a treatment for MASH."
In both mice and nonhuman primates, DT-109 reduced Clostridium perfringens and lowered intestinal ammonia levels. The strengthened gut barrier then prevented those toxic microbial products from entering the bloodstream. Results were especially striking in nonhuman primates, whose liver biology and gut bacteria more closely resemble human physiology. The drug reduced liver inflammation and significantly improved MASH severity in these animals.
The compound operates as a glycine-based tripeptide, a small protein fragment that acts primarily within the gastrointestinal tract but produces effects throughout the body.
Beyond MASH, earlier studies suggest DT-109 could treat other conditions linked to gut barrier breakdown. The compound has shown promise in reducing atherosclerosis plaques and preventing vascular calcification in animal studies, hinting at potential cardiovascular applications. Researchers also believe it could eventually be tested for inflammatory bowel disease and other digestive disorders where intestinal barrier failure plays a role.
The next phase involves additional safety testing and preparation for human clinical trials. Researchers must confirm that the benefits seen in animals translate to people and that the drug poses no serious safety risks.
"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, 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."
Author Jessica Williams: "If DT-109 works in humans as cleanly as it does in animals, this could become the first drug to actually reverse the disease rather than just slow it down, which would be a major shift in how we treat fatty liver disease."
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