Gut Microbiome and Hepatic Transcriptomic Determinants of HCC Development in Mice with Metabolic...

Area of Science:

• Hepatology
• Microbiome Research
• Cancer Biology

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing cause of hepatocellular carcinoma (HCC).
• Early detection of HCC in MASLD patients is challenging due to late-stage diagnosis.
• Predictive biomarkers are crucial for identifying individuals at high risk of developing HCC.

Purpose of the Study:

• To characterize the gut microbiome and hepatic transcriptome associated with HCC development.
• To investigate HCC development in female mice with hepatocyte-deletion of Pten (HepPten-/-) as a model for biomarker discovery.

Main Methods:

• Sequencing of stool 16S rRNA and hepatic RNA from HepPten-/- mice.
• Analysis of liver histology, microbiome composition, and gene expression.
• Validation of key associations in an independent cohort of mice.

Main Results:

• Microbiome composition changes strongly correlated with tumor number and inflammation.
• Specific bacterial taxa (e.g., Lachnospiraceae UCG) were enriched, while others (e.g., Palleniella intestinalis) were depleted in mice with higher tumor burden.
• Hepatic transcriptomic changes, including leukocyte extravasation and IL10RA pathways, correlated with tumor burden and fibrosis.
• Spp1-high epithelial cells and circulating CXCL13/SCF levels were associated with tumor burden.

Conclusions:

• Gut microbiome alterations contribute to liver carcinogenesis by promoting inflammation.
• Changes in hepatic gene expression and cell distribution influence tumor growth.
• Identified microbiome and molecular signatures offer potential for HCC prevention strategies and risk modeling biomarkers.