Intestinal enzyme links microbial metabolism to MASH progression

Using mice with intestinal epithelial cell-specific deletion of Asah2, the gene encoding neutral ceramidase, Wang and colleagues showed that loss of this enzyme protected animals from diet-induced MASH. Notably, this protection was not mainly explained by reduced steatosis. Instead, Asah2-deficient mice displayed less liver fibrosis, lower inflammatory injury, improved gut barrier integrity and reduced lipopolysaccharide translocation. These findings support the concept that MASH progression can be driven by intestinal inflammatory signals even when hepatic fat accumulation is not substantially altered.

An accompanying editorial by Cristina Llorente highlights the broader significance of these findings. The commentary emphasizes that epithelial fucosylation is not merely a surface modification, but a functional regulator of microbial ecology and epithelial homeostasis. It also notes that 2-HHA is best interpreted as a host–microbe co-metabolite rather than a purely microbial product. Importantly, the editorial cautions that fucosylation may be context-dependent: it can support barrier protection in one setting, yet have different effects depending on diet, microbial composition, substrate availability and host signalling status.

The study also extends beyond the liver. Both intestinal neutral ceramidase and epithelial AhR influenced lung inflammation, supporting a gut–liver–lung axis in metabolic disease. This suggests that intestinal barrier dysfunction and microbial metabolites may contribute to systemic immune activation, not only hepatic injury.

Source:

First Hospital of Jilin University

Journal references:

1. Wang T, Chen L,Lei C, et al. Intestinal neutral ceramidase exacerbates MASH pathogenesis. eGastroenterology 2026;4:e100417. doi:10.1136/egastro-2026-100417
2. Llorente C. Intestinal neutral ceramidase, microbial metabolites and epithelial fucosylation in MASH. eGastroenterology 2026;4:e100458. doi:10.1136/egastro-2026-100458