High-Resolution Exposomics and Metabolomics Reveals Specific Associations in Cholestatic Liver Diseases

Area of Science:

• Hepatology and Environmental Health
• Metabolomics and Exposomics Research

Background:

• Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are rare cholestatic liver diseases with poorly understood pathogeneses.
• The roles of environmental chemicals and metabolic alterations in PSC and PBC remain largely unstudied.

Purpose of the Study:

• To investigate potential pathogenic contributors to PSC and PBC using a comprehensive exposomics-metabolomics approach.
• To identify environmental chemicals and altered metabolic pathways associated with PSC and PBC.

Main Methods:

• Applied untargeted high-resolution mass spectrometry to analyze plasma exposome and metabolome.
• Conducted exposome-wide association studies (EWAS) and metabolome-wide association studies (MWAS).
• Performed EWAS × MWAS network analysis to link environmental agents with metabolic disruptions.

Main Results:

• EWAS identified associations between environmental chemicals (pesticides, pollutants, additives) and PSC/PBC.
• MWAS revealed significant alterations in amino acid, lipid, co-factor, nucleotide, mitochondrial, and microbial metabolic pathways, many shared between PSC and PBC.
• The 5-lipoxygenase pathway was implicated in disease pathogenesis.

Conclusions:

• Combined exposomics-metabolomics is a powerful approach for identifying pathogenic environmental agents and metabolic alterations in PSC and PBC.
• This study provides a foundation for developing novel diagnostic and therapeutic strategies for these rare liver diseases.