Unravelling the role of bilirubin metabolism in gallstone formation: a genetic and metabolic perspective

Abstract Gallstone disease is a widespread health issue driven by genetic, metabolic, and environmental factors. Among its types, pigment stones, primarily composed of bilirubin, arise due to disruptions in bilirubin metabolism. Heme degradation produces biliverdin, which is reduced to unconjugated bilirubin and transported to the liver. There, UGT1A1 conjugates bilirubin, making it water-soluble for excretion into bile. However, genetic variations, impaired hepatic processing, altered enterohepatic recycling, and gut microbiota imbalances can lead to bilirubin supersaturation, increasing the risk of gallstone formation. Conditions like haemolysis, liver dysfunction, and chronic biliary infections further promote bilirubin precipitation and stone development. This review examines the molecular and genetic regulation of bilirubin metabolism, the role of gut microbiota in bile metabolism, and their contributions to gallstone pathogenesis. Recent advancements in therapeutic strategies, including bile composition modulation, microbiome interventions, and nanoparticle-based drug delivery, present promising approaches for gallstone prevention and treatment. Understanding these mechanisms is crucial for developing novel diagnostic and therapeutic solutions for gallstone-related disorders.