Integrated multiomics analysis reveals metabolic and microbiome alterations in Wilson disease

Wilson disease (WD) is a rare autosomal recessive disorder caused by mutations in ATP7B, which encodes a copper transporter. Abnormal ATP7B function leads to copper deposition, mainly in the liver and brain, resulting in hepatic, neurological, and psychiatric impairments. Metabolic alterations have been reported in patients with WD and in murine WD models. We performed a multiomics study in an in-depth phenotyped and multi-center cohort to establish gut microbiota perturbations and metabolic dysfunctions in WD. Metabolomics helped distinguish changes in the tricarboxylic acid cycle, amino acid metabolism, and dyslipidemia in patients with WD. Metataxonomics allowed the detection of attenuated pivotal bacterial species. Independent WD cohorts and in vitro assays validated the lipid metabolism alterations and loss of Akkermansia muciniphila. Our results indicate a profound metabolic dysfunction in patients with WD beyond ATP7B-linked copper toxicity. Pharmacological treatment appears detrimental for beneficial species, aggravating organ cross-talk in the gut-liver axis.