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Intestinal neutral ceramidase exacerbates MASH pathogenesis.

Ting Wang1,2, Liang Chen1, Chao Lei1

  • 1Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, Kentucky, USA.

Egastroenterology
|July 6, 2026
PubMed
Summary
This summary is machine-generated.

Intestinal neutral ceramidase drives metabolic dysfunction-associated steatohepatitis (MASH) by altering gut microbiota and reducing fucosylation. Inhibiting this enzyme may offer a new therapeutic strategy for MASH.

Keywords:
CeramidasesDiet, food, and nutritionGastrointestinal microbiomeMetabolic diseasesNon-alcoholic fatty liver disease

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Area of Science:

  • Gastroenterology
  • Hepatology
  • Microbiology

Background:

  • Metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe form, MASH, are influenced by genetics, gut microbiota, and barrier integrity.
  • Ceramidases and ceramides are implicated in MASH, but the specific role of intestinal neutral ceramidase is not fully understood.

Purpose of the Study:

  • To investigate the role of intestinal neutral ceramidase in the development of MASH.
  • To elucidate the mechanisms by which neutral ceramidase influences the gut microbiota, metabolite profiles, and host signaling pathways in MASH.

Main Methods:

  • Utilized murine models with specific gene deletions in intestinal epithelial cells (IECs) for neutral ceramidase (Asah2ΔIEC) or aryl hydrocarbon receptor (AhRΔIEC).
  • Administered Western Diet (WD) or a hydrogenated vegetable oil, sucrose, palmitate, and cholesterol (HSPC) diet to induce or accelerate MASH.
  • Performed fecal microbiota transplantation in germ-free mice to assess microbial contributions.

Main Results:

  • Induction of neutral ceramidase in MASH reshaped the gut microbiota and increased 2-hydroxyhippuric acid (2-HHA) production.
  • 2-HHA was identified as an inhibitor of AhR signaling, which normally promotes intestinal fucosylation.
  • Elevated 2-HHA suppressed AhR activity, reduced fucosylation, and contributed to MASH and airway inflammation. Conversely, deleting neutral ceramidase protected against MASH by restoring AhR signaling and fucosylation.

Conclusions:

  • Intestinal neutral ceramidase is a key driver of MASH via a microbiota-2-HHA-AhR axis that impairs intestinal fucosylation and barrier function.
  • Targeting intestinal neutral ceramidase presents a potential therapeutic strategy for MASH.