Novel Experimental Compound DT-109 Reverses Severe Fatty Liver Disease via Gut Microbiome Regulation

Researchers at Michigan Medicine have developed an experimental treatment, DT-109, which demonstrates potential to reverse severe fatty liver disease in animal models by targeting the gut-liver axis through microbiome modulation. Published in The Journal of Clinical Investigation, these findings suggest a groundbreaking strategy for addressing metabolic dysfunction-associated steatohepatitis (MASH), a progressive and often undertreated condition.

MASH affects approximately 7% of the global population and can advance to cirrhosis, liver cancer, or liver failure, with few effective therapies available. DT-109, a glycine-based tripeptide, interrupts a harmful biological pathway connecting gut health to liver function, offering hope for a new treatment paradigm.

“Our study provides compelling evidence that DT-109 strengthens the gut barrier, thereby reducing harmful microbial translocation into the bloodstream—a key driver of MASH progression,” explained Eugene Chen, M.D., Ph.D., senior author and Frederick G. L. Huetwell Professor of Cardiovascular Medicine at the University of Michigan Medical School. “This compound shows significant gastrointestinal benefits and is a strong candidate for MASH therapy.”**

How Gut Microbiota Drive Liver Pathology

Prior research identified the bacterium Clostridium perfringens as a critical factor in MASH development. It produces ammonia in the gut, damaging the intestinal lining and enabling microbial products to breach into circulation. These substances trigger inflammatory immune responses, including uncontrolled CD8+ T-cell activation in the liver.

The team demonstrated that DT-109 disrupts this chain reaction, restoring both gut and liver health in preclinical models through targeted barrier protection.

DT-109 Reinforces Intestinal Integrity

In mice and nonhuman primates—a model more akin to human physiology—DT-109 effectively reduced Clostridium perfringens colonization and cut intestinal ammonia levels. This fortified the gut barrier, preventing pathogen-derived molecules from entering systemic circulation. Nonhuman primates treated with DT-109 exhibited reduced liver inflammation and marked MASH severity improvements, underscoring translational potential.

“DT-109 bridges gut microbiota regulation and liver protection by blocking harmful microbial product infiltration via the gut-liver axis,” noted co-author Jifeng Zhang, Ph.D., research professor of cardiovascular medicine at U-M. “Though primarily active in the GI tract, its effects extend systemically.”**

Broader Therapeutic Potential Explored

Preclinical data reveal DT-109’s capacity to inhibit atherosclerosis plaque formation and vascular calcification in primates, suggesting cardiovascular applications. Its gut-barrier-strengthening properties also align with treating conditions like inflammatory bowel disease (IBD).

“This work redefines MASH pathogenesis and introduces a promising therapeutic avenue for an area of profound clinical need,” stated Elliot Tapper, M.D., Academic Director of Hepatology at Michigan Medicine. “Patients urgently require therapies that improve both liver and cardiovascular outcomes, and we’re optimistic about DT-109’s future.”**

The research team includes Yang Zhao, Ph.D., Ying Zhao, M.S., and Yanhong Guo, M.D., Ph.D., with additional contributors listed in the original publication.

Funding and Disclosures

D patent holders Ying Zhao, Oren Rom, Jifeng Zhang, and Y. Eugene Chen are involved in a patent covering tripeptides for metabolic and cardiovascular disorders. Chen and the University of Michigan own rights to DT-109, licensed to Diapin Therapeutics, which funds further development. All human/animal protocols underwent rigorous ethical approval, detailed in the original study.

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