The gut-liver-kidney-brain axis in Wilson disease: copper speciation-flux and barrier-mediated organ crosstalk

Wilson disease (WD) has long been framed as a hepatocentric disorder of copper accumulation. That view is now giving way to a broader model centered on the gut–liver–kidney–brain axis. In WD, copper is not simply stored in tissues as an inert burden. It circulates in dynamic, bioactive pools—particularly relative exchangeable copper (REC)—that disrupt barrier structures, including the intestinal epithelium and blood–brain barrier, and spread toxicity through measurable biochemical mediators. Major pathogenic processes include copper-induced suppression of autophagy, disruption of FXR-regulated bile acid signaling, and direct injury to the intestinal barrier. Gut dysbiosis, supported by fecal microbiota transplantation (FMT) studies in ATP7B-deficient mice, further amplifies hepatic inflammation and favors copper retention. Renal tubular dysfunction and neurotoxicity appear to reflect copper species-dependent passage across biological barriers together with secondary metabolic disturbances, including the recently described pathway of cuproptosis. In the clinic, this shift has been accompanied by greater use of copper-species biomarkers such as ceruloplasmin oxidase activity and REC, along with advanced imaging approaches such as 64 Cu-PET/CT. Treatment is also moving beyond conventional chelation alone, with increasing attention to biliary copper excretion, epithelial barrier repair, and microbiome-directed interventions. Viewed in this way, the axis model helps explain the marked phenotypic heterogeneity of WD and offers a mechanistic basis for more precise interventions aimed at breaking pathogenic feedback loops across organs.