The role of intestine in metabolic dysregulation in murine Wilson disease

Wilson Disease is a genetic disease due to copper accumulation in the liver and in the brain. It is characterized by a varied phenotype and metabolic changes involving systemic and hepatic lipid metabolism, potentially affected by gut microbiome profiles. Previous evidence indicates a role for intestine ATP7B copper transporter in affecting lipid processing in the intestinal epithelial cells but the systemic effects of intestinal ATP7B defects are unknown.This is the first study exploring integrated microbiome and lipidomic profiles in animal models of Wilson disease and showing the first lipidomics analysis of a new animal model of altered copper metabolism characterized by tissue-specific ATP7B inactivation in the intestinal epithelial cells.Gut microbiome and lipidomic analyses revealed metabolic changes underlying the systemic manifestations of Wilson disease. Intestine-specific ATP7B deficit affected both intestine and systemic response to high-fat challenge. We conclude that Wilson disease is a systemic disease and organ-specific ATP7B variants can explain the varied phenotypic and metabolic presentations