Multidimensional intestinal barrier repair strategies for alleviating inflammatory bowel disease and gut-liver axis-associated metabolic liver disease.

Abstract

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation driven by intestinal barrier disruption, immune dysregulation, and microbiota imbalance. Barrier dysfunction not only aggravates intestinal inflammation but also promotes metabolic liver diseases, such as non-alcoholic steatohepatitis (NASH), through the gut-liver axis. However, current IBD therapies mainly target intestinal oxidative stress and inflammation, with limited efficacy, while NASH treatments focus on the liver, and interventions targeting the gut-liver axis remain limited. Here, we developed a synergistic quadruple intestinal barrier repair system, termed PGaA Gel, based on an inulin hydrogel loaded with gallium-based mesoporous polydopamine nanoparticles (MPDA-Ga) and L-alanyl-l-glutamine (ALG). PGaA Gel was designed to simultaneously restore the physical, chemical, immune, and microbial barriers of the intestine. MPDA-Ga effectively scavenged reactive oxygen species and inhibited pathogenic bacteria, while ALG promoted epithelial regeneration and mucin production. In addition, inulin enhanced intestinal retention and acted as a prebiotic to produce short-chain fatty acids, thereby reinforcing immune tolerance. In mouse models, PGaA Gel exhibited superior efficacy in restoring multidimensional intestinal barrier integrity and significantly alleviated IBD symptoms compared with single-component treatments. Importantly, PGaA Gel also repaired intestinal barrier dysfunction associated with NASH, reduced lipopolysaccharide translocation via the gut-liver axis, and mitigated hepatic inflammation and lipid accumulation. These findings highlight comprehensive intestinal barrier repair as an effective therapeutic strategy for IBD and gut-liver axis-related liver diseases.