Antibacterial hyaluronic acid hydrogel with sustained release of larazotide as effective colitis treatment

Abstract

Gut barrier loss exacerbated gut microbiota dysbiosis by permitting pathogenic blooms, while gut microbiota dysbiosis caused the development of gut mucosal wounds by reducing mucus and breaking down epithelial tight junction. Current therapies combating colitis often fail to address both gut barrier dysfunction and microbial imbalance. Herein, inspired by natural gut mucus, a dual-crosslinked hydrogel (HSMP-LA) composed of thiol/maleimide-modified hyaluronic acid together with co-loading of antimicrobial ε-polylysine (ε-PL) and larazotide acetate (LA) had been developed as an injectable artificial gut mucus to simultaneously restore barrier integrity and modulate gut microbiota. HSMP-LA exhibited robust muco-adhesion, the prolonged retention, and sustained-release profile of LA, effectively shielding the epithelium from luminal pathogens and toxins. Besides, HSMP-LA showed the broad-spectrum antimicrobial activity, while its sustained-release LA selectively inhibited zonulin-mediated tight junction disruption via combating MLCK/p-MLC signals, restoring epithelial integrity in LPS-injured Caco-2 cells. In DSS-induced colitis mice, HSMP-LA significantly reduced disease activity, suppressed pro-inflammatory cytokines and upregulated anti-inflammatory IL-10. It repaired tight junctions (ZO-1, occluding and claudin-5), restored mucus production (MUC2), and rebalanced gut microbiota. HSMP-LA hydrogel might offer a synergistic strategy to combat colitis via halting the vicious dysbiosis-mucus-epithelial barrier disorders cycle.

Keywords: Colitis; Gut barrier; Microbiota balance; Mucus-inspired hydrogel; Zonulin.