Intestinal Epithelial Cell-derived Osteopontin Protects Against Metabolic Dysfunction-associated Steatohepatitis by...

Area of Science:

• Gastroenterology and Hepatology
• Immunology
• Microbiome Research

Background:

• The gut-liver axis is crucial in metabolic dysfunction-associated steatohepatitis (MASH).
• Osteopontin (OPN) is linked to chronic liver disease, but its role in intestinal epithelial cells (IECs) during MASH is unknown.

Purpose of the Study:

• To investigate the expression and function of OPN in IECs during MASH progression.
• To elucidate the mechanisms by which IEC-derived OPN influences MASH development.

Main Methods:

• Evaluated intestinal OPN expression in MASH patients.
• Generated and studied mice with altered OPN expression in IECs (Spp1^{KI IEC} and Spp1^ΔIEC) fed a diet inducing MASH.
• Analyzed hepatic inflammation, IEC morphology, apoptosis, epithelial turnover, intestinal permeability, gut microbiome composition, and bile acid profiles.

Main Results:

• IEC OPN expression decreased with MASH progression.
• Loss of IEC OPN exacerbated MASH, leading to increased hepatic inflammation, disrupted IECs, elevated apoptosis, reduced cell turnover, and heightened intestinal permeability.
• IEC-specific OPN deficiency altered bile acid metabolism and gut microbiome composition, promoting MASH progression.

Conclusions:

• IEC-derived OPN is protective against MASH.
• OPN modulates MASH by regulating bile acid composition and shaping the gut microbiome.