Gut-liver metabolic and enterohormonal remodeling drives progression from metabolic dysfunction-associated steatotic liver disease to steatohepatitis.

BACKGROUND

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic liver disease that can progress to metabolic dysfunction-associated steatohepatitis (MASH), a more severe form characterized by inflammation, hepatocyte injury, and fibrosis. Although the gut-liver axis is implicated in disease progression, stage-specific changes in gut-derived metabolites, lipids, and enteroendocrine signaling remain unclear. This study investigated metabolic, lipidomic, and enteroendocrine alterations during MASLD-to-MASH progression.

METHODS

Male C57BL/6NTac mice were fed a modified Amylin liver NASH high-fat diet for 16 weeks to induce MASLD or 29 weeks to induce MASH, age-matched chow-fed mice served as controls. Liver, colon, and stool underwent untargeted metabolomics and lipidomics. Plasma hormones and cytokines were measured by multiplex assay and ELISA. Histology, immunofluorescence, disease-signature enrichment, cross-species network analysis, and organoid differentiation assays were used to assess tissue pathology and signaling pathways.

RESULTS

The high-fat diet produced histologically confirmed MASLD and MASH at 16 and 29 weeks, respectively. Cholic acid was elevated across liver, colon, and stool in both stages. MASLD was associated with increased circulating glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and peptide YY, which correlated with colonic cholic acid as well as increased colonic TGR5 expression, whereas these changes were absent in MASH. MASH showed broader metabolic and lipid remodeling, elevated tumor necrosis factor and interleukin-6, impaired enteroendocrine differentiation markers, and increased hepatic serotonin colocalized with fibronectin.

CONCLUSIONS

MASLD-to-MASH progression involves stage-specific gut-liver metabolic remodeling, loss of enteroendocrine responsiveness, and hepatic serotonergic-fibrotic signaling.