An experimental drug developed at Michigan Medicine has reversed a severe form of fatty liver disease in animal studies by acting on the gut rather than directly on the liver. The compound, DT-109, is a glycine-based tripeptide, and the findings were published in The Journal of Clinical Investigation. The research shows that restoring gut health can block harmful substances from reaching the liver, offering a new strategy for treating metabolic dysfunction-associated steatohepatitis (MASH).
The study identified a chain reaction that contributes to MASH: excessive growth of the gut bacterium Clostridium perfringens raises ammonia levels, which damages the intestinal lining. That damage allows microbial toxins to travel to the liver, where they drive inflammation and overactivate CD8+ T cells. DT-109 interrupted this cycle by reducing the bacterium and ammonia production, reinforcing the gut barrier, and limiting the movement of pro-inflammatory microbial products into the body. In both mice and nonhuman primates, the drug reduced liver inflammation and lessened MASH severity.
MASH affects about 7% of the world's population and can progress to cirrhosis, liver cancer, and liver failure. Senior author Eugene Chen said the evidence shows DT-109 protects the gut epithelial barrier and has great potential as a treatment for MASH. Co-author Jifeng Zhang noted that the drug acts primarily in the gastrointestinal tract, but its reach extends much further. The researchers also believe the compound's ability to protect the intestinal barrier could make it useful against other conditions involving inflammation and metabolic dysfunction, including cardiovascular disease.