Ammonia in the crosshairs: microbial targets for metabolic dysfunction-associated steatohepatitis prevention.

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is increasingly linked to disruptions of the gut/liver axis, yet the microbial mechanisms driving disease progression remain incompletely defined. Here, Qu et al. have identified ileal microbial ammonia production by Clostridium perfringens as a mechanistic driver of epithelial barrier dysfunction and hepatic CD8+ T cell remodeling in MASH. In nonhuman primate and mouse models of MASH, the authors demonstrated that the glycine-based tripeptide DT-109 restored gut barrier integrity and attenuated FosB-mediated CCL5 expression in CD8+ T cells via inhibition of bacterial nitrite reductase A-mediated microbial ammonia production. These findings position microbial nitrogen metabolism as a tractable therapeutic target and highlight metabolite-focused microbiome interventions as a potential MASH intervention.