ABSTRACT: Background: Alcoholic liver disease (ALD) is a prevalent chronic liver disorder worldwide. Chronic alcohol exposure not only damages the liver but also disrupts metabolic and elemental homeostasis in multiple organs. However, its systemic effects remain incompletely understood. This study used an integrated metabolomics–ionomics approach based on the chronic-plus-binge ethanol feeding (NIAAA) model to investigate multi-organ metabolic and ionic alterations induced by chronic alcohol exposure. Methods: An ALD mouse model was established using the NIAAA protocol. Liver, spleen, kidney, lung, stomach, serum, cerebral cortex, and hippocampus samples were analyzed by gas chromatography–mass spectrometry (GC–MS) and inductively coupled plasma mass spectrometry (ICP–MS). Differential metabolites, altered elements, and affected pathways were identified through statistical, pathway enrichment, and correlation analyses. Results: Chronic alcohol exposure induced oxidative stress, evidenced by increased malondialdehyde (MDA) and decreased reduced glutathione (GSH). A total of 48 differential metabolites were identified across eight tissues, involving 16 significantly altered pathways, including linoleic acid metabolism, amino acid metabolism, one-carbon metabolism, primary bile acid biosynthesis, galactose metabolism, and butanoate metabolism. Ionomic analysis revealed widespread elemental dyshomeostasis, particularly in the liver, cerebral cortex, and stomach, with significant alterations in Na, Mg, Fe, Cu, Zn, and Se. Extensive correlations were observed among elements and between elements and metabolites. Conclusions: Chronic alcohol exposure causes multi-organ metabolic disturbances and elemental dyshomeostasis, providing new insights into ALD pathogenesis and potential targets for diagnosis and treatment.
