Hydrogel-Based Therapeutic Strategies for Post-Cholecystectomy NAFLD: Targeting Bile Acid Signaling, Gut Microbiota, Inflammation, and Hepatic Fibrosis

Post-cholecystectomy non-alcoholic fatty liver disease (NAFLD), now encompassed within metabolic dysfunction-associated steatotic liver disease (MASLD), is increasingly linked to persistent disruption of bile acid kinetics and gut-liver axis signaling after gallbladder removal. Continuous bile delivery to the intestine reshapes the bile acid pool, perturbs FXR-FGF19/TGR5 pathways, remodels gut microbiota, and compromises epithelial barrier integrity, collectively promoting portal endotoxemia, chronic hepatic inflammation, and fibrogenic remodeling. Hydrogel-based biomaterials offer a mechanistically aligned therapeutic platform for this setting because they enable localized, sustained, and stimuli-responsive interventions at intestinal or hepatic sites. Functional hydrogels can sequester excess bile acids, protect and deliver probiotics/prebiotics/postbiotics, reinforce mucosal barrier function, and provide controlled release of anti-inflammatory or antifibrotic agents with reduced systemic exposure. In this review, we map emerging hydrogel strategies relevant to post-cholecystectomy NAFLD across four pathogenic nodes, bile acid dysregulation, dysbiosis, inflammation, and fibrosis, and highlight design principles (polymer chemistry, charge/hydrophobicity balance, mucoadhesion, and pH/redox/enzyme responsiveness) that enable targeted modulation of the gut-liver axis. Finally, we identify key translational gaps, including the lack of post-cholecystectomy-specific experimental models and standardized outcome measures integrating bile acid profiling, microbiome readouts, and hepatic histology. Hydrogel technologies represent a promising route toward localized and multimodal therapy in metabolic liver disease, warranting focused preclinical validation and clinical development.