A potential new treatment for one of the world's most widespread liver diseases has emerged from the University of Michigan, and its mechanism of action is surprising: rather than targeting the liver directly, the drug works by repairing the gut.
The compound, called DT-109, is a glycine-based tripeptide that reversed metabolic dysfunction-associated steatohepatitis (MASH) in animal models by disrupting a disease-driving pathway that links the gut and liver. The findings represent a fundamentally new approach to treating the condition.
The Silent Epidemic
MASH — formerly known as non-alcoholic steatohepatitis (NASH) — is a severe form of fatty liver disease that affects an estimated 5% of adults worldwide. It occurs when fat buildup in the liver triggers inflammation and cell damage, leading to scarring (fibrosis), cirrhosis, and eventually liver failure. It is also strongly linked to cardiovascular disease.
Despite its enormous prevalence, treatment options remain limited. The FDA approved the first MASH drug, Rezdiffra (resmetirom), only in 2024. DT-109 offers a potentially complementary or alternative approach.
The Gut-Liver Connection
DT-109 works by restoring the intestinal barrier — the lining that prevents toxins and bacteria from leaking from the gut into the bloodstream. In MASH, this barrier becomes compromised, allowing harmful molecules to reach the liver and trigger inflammation.
By strengthening the gut barrier, DT-109 prevents this cascade before it starts. In animal studies, the compound not only stopped disease progression but reversed existing fat accumulation and scarring.
From Discovery to Application
The research, led by Dr. Y. Eugene Chen and his team at Michigan Medicine, builds on years of work on the gut-liver axis. A 2023 study published in Cell Metabolism had already shown DT-109 could reverse fat buildup in the livers of mice and nonhuman primates. The new findings extend this work, showing the drug also reduces atherosclerosis — the artery-clogging condition that frequently accompanies fatty liver disease.
What's Next
The researchers are now preparing for human clinical trials. If successful, DT-109 could become one of the first treatments to address MASH through gut repair rather than direct liver intervention — a paradigm shift that could also prove relevant for other diseases driven by intestinal barrier breakdown.
