New drug candidate treats severe fatty liver disease by improving gut health

The glycine-based tripeptide, DT-109, reversed metabolic dysfunction-associated steatohepatitis (MASH) in animal models by disrupting a disease-driving pathway that links the gut and liver.

MASH affects roughly 7% of the global population and can lead to cirrhosis, liver cancer and liver failure. Treatment options remain limited despite recent therapeutic advances.

"This compound shows benefits to the gastrointestinal system and has great potential as a treatment for MASH."

While previous animal studies from Chen's team showed DT-109 could serve as a treatment for MASH, the researchers now understand the mechanism behind its therapeutic effects.

Elevated ammonia levels erode the digestive tract's inner lining and weaken the intestinal barrier, allowing harmful toxins to reach the liver and trigger inflammatory immune responses, such as a hyperactivation of CD8+ T cells.

Through a series of experiments, Chen's team found that DT-109 interrupted this process to restore the integrity of both the gut and liver.

"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 say the findings suggest DT-109's benefits may extend beyond MASH.

Because intestinal barrier dysfunction is implicated in several gastrointestinal disorders, the team also believes DT-109 could eventually have applications in conditions such as inflammatory bowel disease (IBD).

Future studies will focus on further evaluating DT-109 to advance the compound toward clinical trials to assess its safety and effectiveness in humans.

"What patients with MASH need is a safe and effective therapy capable of improving their liver and heart health – of course we are excited about these developments."

Source:

Michigan Medicine - University of Michigan

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