Mechanisms of multi-organ damage in Wilson disease from the gut-liver-brain axis perspective: copper metabolism, gut microbiota, and metabolite communication

mutations, leading to pathological copper deposition in the liver, brain, and cornea. Although the gut-liver-brain axis plays a role, direct copper accumulation in multiple organs remains the primary cause of tissue damage. Recent years have seen growing attention to the gut microbiota in WD pathogenesis. Copper imbalance remodels gut microbiota composition and function, while dysbiosis, in turn, affects copper absorption and excretion, forming a vicious cycle that exacerbates multi-organ damage. Copper-induced intestinal barrier disruption, lipopolysaccharide translocation, and systemic inflammation are key links connecting local copper accumulation to systemic injury. This review summarizes the genetic basis of WD, mechanisms of copper toxicity, gut microbiota alterations, and their roles in liver injury and neurodegeneration. It highlights microbiota-derived metabolites-short-chain fatty acids, tryptophan metabolites, bile acids, sulfur-containing amino acids, and branched-chain amino acids-in inter-organ communication. The bidirectional interaction between WD therapies (chelators, zinc salts, dietary interventions) and the gut microbiota is analyzed, along with microbiota-based personalized therapies. However, most current evidence derives from animal models or small cross-sectional studies; large-scale longitudinal human data are critically lacking. A deeper understanding of the gut-liver-brain axis in WD may reveal novel biomarkers and therapeutic targets.