Most experimental treatments for metabolic dysfunction-associated steatohepatitis (MASH), the severe form of fatty liver disease that affects roughly 7% of the global population, target the liver directly, attempting to reduce fat accumulation, inflammation, or fibrosis. A new study from the University of Michigan and collaborators in China takes a fundamentally different approach: fix the gut, and the liver heals itself.
The study, published in the Journal of Clinical Investigation, describes DT-109, a glycine-based tripeptide (Gly-Gly-Leu) that targets the ammonia-producing bacterium Clostridium perfringens in the ileum. By reducing this bacterium’s ammonia production, the drug restores intestinal barrier integrity and blocks the immune cascade that drives liver inflammation.
The gut-liver axis in MASH
The researchers identified a specific chain of causation linking the gut microbiome to liver damage in MASH. The bacterium Clostridium perfringens becomes overgrown in the ileum of both human MASH patients and animal models. It uses a gene called NirA (nitrite reductase A) to produce high levels of ammonia. That ammonia erodes the intestinal epithelial lining, reducing protective mucins and tight junction proteins, allowing bacterial products to leak into the bloodstream.
Once in circulation, the ammonia reaches the liver, where it triggers the transcription factor FosB in CD8-positive T cells. This upregulates CCL5, a chemokine that drives a cytotoxic T-cell phenotype characterized by increased perforin and granzyme B production, directly inflaming and damaging liver tissue.
The causal chain was confirmed through multiple lines of evidence: NirA-knockout C. perfringens mutants produced less ammonia and less liver damage. Phage therapy targeting C. perfringens also reduced ammonia and MASH severity. Direct ammonia infusion caused gut barrier damage and liver inflammation. And depleting CD8 T cells or inhibiting CCL5 with the drug maraviroc abolished ammonia-induced liver injury.
DT-109 results
DT-109, administered orally, reduced C. perfringens abundance roughly ten-fold in mice and suppressed bacterial NirA-mediated ammonia production. This restored gut barrier integrity and attenuated CD8 T cell-driven liver inflammation.
In cynomolgus monkeys with diet-induced MASH, the results were similar: reduced C. perfringens, restored ileal mucosal integrity, lower plasma endotoxin levels, reduced liver CD8 T cell infiltration, and restored normal liver histology.
The drug’s pharmacokinetics are notable: DT-109 was detectable in the gut for up to 24 hours after oral administration but was not detected in plasma, meaning it acts locally in the intestine without systemic exposure.
Human data
The study included two human cohorts, one with 44 healthy controls and 67 MASH patients (measuring elevated serum CCL5 in MASH) and another with 6 healthy and 6 MASH patients (confirming CD8/CCL5/perforin-positive cells in liver biopsies). These were observational validation cohorts; DT-109 has not yet been administered to humans.
What’s next
The drug is being developed by Diapin Therapeutics, a University of Michigan spinout that holds exclusive license to the patents. The researchers state that additional testing is needed before moving DT-109 to clinical trials.
The study represents a conceptual shift in how MASH might be treated: rather than drugging the liver’s metabolic pathways, the approach targets the gut microbiome’s production of ammonia as the upstream driver of inflammation.
Sources
[1] Qu, P., Ding, S., Zhang, Y., et al. “Metabolic dysfunction-associated steatohepatitis exacerbated by Clostridium perfringens-derived ammonia is attenuated by tripeptide DT-109.” Journal of Clinical Investigation, Vol. 136(13), e200522 (2026). DOI: 10.1172/JCI200522
[2] ScienceDaily. “Experimental DT-109 reverses fatty liver by repairing the gut.” (2026). https://www.sciencedaily.com/releases/2026/07/260711010116.htm