Engineered probiotics remodel the intestinal epithelial barrier and enhance bacteriotherapy for inflammatory bowel diseases

Inflammatory bowel diseases (IBDs) are often associated with compromised epithelial barriers and dysregulated gut microbiota. In this study, we revealed the synergistic effect that zinc and indole-3-carbinol (I3C) have in restoring the epithelial barrier, and co-localized them on a ZI platform, which was further conjugated to the surface of Escherichia coli Nissle 1917 (EcN). The ZI@EcN formulation effectively delivered ZI to colon tissues and extended its retention in the intestines due to the colonic colonization effect of EcN, thereby promoting the sustained release of zinc and I3C for optimal synergistic effects on epithelial barrier remodeling. The restored epithelium acts as a protective barrier, preventing the infiltration of toxins and pathogens, which significantly reduces inflammation in colonic tissues. Additionally, EcN enriched the gut microbiome, increasing the abundance of beneficial bacteria while reducing that of pathogens, demonstrating its significant efficacy in gut microbiome regulation. In dextran sulfate sodium-induced mouse colitis models, ZI@EcN exhibited substantially improved prophylactic and therapeutic efficacy with favorable safety profiles, highlighting its potential for clinical applications. STATEMENT OF SIGNIFICANCE: This study highlighted the synergistic effects that zinc and indole-3-carbinol, both derived from dietary sources, have on restoring integrity of the intestinal epithelial barrier. A platform (ZI@EcN) was also developed for the targeted delivery and sustained release of zinc and indole-3-carbinol, specifically in colonic tissues, for colitis treatment. This platform not only restores the compromised intestinal epithelial barrier but also regulates the dysbiotic gut microbiota, promoting the recovery of a healthy intestinal microenvironment and showing promise in alleviating complex symptoms in a single formulation. Furthermore, the formulation demonstrated potent prophylactic and therapeutic efficacy against colitis, with favorable safety profiles, and a strong potential for clinical applications.

Colonic epithelial barrier remodeling; Gut microbiome regulation; Indole-3-carbinol; Inflammatory bowel disease; Probiotics; Zinc.