Immunometabolic crosstalk in gallstone disease: driving roles of bacterial infection, NETs and MMP activation

Gallstone disease (GSD) is a prevalent hepatobiliary disorder driven by complex interaction between metabolic imbalance, biliary dysfunction and chronic inflammation. While cholesterol supersaturation and impaired gallbladder motility are well established, the role of integrated immunometabolic mechanisms in gallstone formation remains unclear. This review focuses on the coordinated interplay between bacterial infection, neutrophil extracellular traps (NETs) and Matrix metalloproteinase (MMP) activation in the pathogenesis of GSD. Bacterial colonization of the biliary tract triggers inflammatory signalling pathways, leading to cytokine release, oxidative stress and activation of MMPs which disrupt extracellular matrix integrity and the protective mucin barrier. These changes promote cholesterol crystal nucleation and retention with the gallbladder. In the parallel NETs act as structural scaffolds that enhance crystal aggregation and stabilize gallstone growth. Bile acid toxicity and altered lipid metabolism further exacerbate epithelial injury and inflammatory responses, reinforcing a pro-lithogenic microenvironment. Overall, these interconnected processes highlight process highlight a unified immunometabolic framework underlying gallstone formation. Targeting key pathways such as NET formation, MMP activity and bile acid mediated toxicity emphasize key molecular pathways involved in GSD and highlight potential avenues for therapeutic intervention in GSD.