A glycine-based experimental tripeptide developed at Michigan Medicine improved metabolic dysfunction–associated steatohepatitis (MASH) in mice and nonhuman primates, with researchers linking the benefit to reduced gut-derived ammonia and a stronger intestinal barrier, according to a study in The Journal of Clinical Investigation.
Researchers at Michigan Medicine report that an overgrowth of the gut bacterium Clostridium perfringens can increase ammonia levels in the intestine, which can erode the intestinal lining and weaken the gut barrier, allowing inflammatory microbial products to reach the liver and worsen MASH.
In a series of experiments in mice and nonhuman primates, the team found that DT-109—a glycine-based tripeptide—reduced C. perfringens levels and intestinal ammonia production while strengthening the intestinal barrier. In nonhuman primates, DT-109 was associated with reduced liver inflammation and lower overall disease severity.
“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,” said Eugene Chen, the study’s senior author and the Frederick G. L. Huetwell Professor of Cardiovascular Medicine at the University of Michigan Medical School.
The researchers said the findings may have implications beyond fatty liver disease because intestinal barrier dysfunction is implicated in multiple gastrointestinal disorders. They also pointed to prior preclinical work suggesting DT-109 may affect cardiovascular disease pathways, including studies reporting reductions in atherosclerosis and vascular calcification in nonhuman primates.
The work was published in The Journal of Clinical Investigation, and the researchers said additional studies are planned to further evaluate DT-109’s safety and effectiveness as the compound is advanced toward potential human clinical trials.
