A mucin-integrated probiotic hydrogel microsphere for prophylactic gut modulation and Sepsis mitigation

Mucin-integrated ternary microspheres achieve robust gastro-protection and targeted intestinal co-delivery of E. coli Nissle 1917 and mucin glycoproteins. • Prophylactic gut modulation concurrently restores microbiome equilibrium, fortifies epithelial barrier integrity, and attenuates systemic hyperinflammation. • Preventive intervention significantly reduces bacterial translocation, mitigates end-organ damage, and improves survival in experimental sepsis. Sepsis remains a leading cause of mortality worldwide, in part because current treatment is typically initiated after systemic inflammation and organ injury are already established. This temporal limitation highlights the need for prophylactic strategies before sepsis fully develops. Growing evidence indicates that gut microbiota dysbiosis and intestinal barrier disruption are active drivers of sepsis pathogenesis, yet practical approaches to modulate the gut microenvironment prophylactically remain limited. Here, we reported a paradigm shift from conventional probiotic delivery to a microenvironment-centered strategy that enhances bacterial integration and mucosal defense. We developed a mucin-integrated probiotic microsphere system for the oral co-delivery of Escherichia coli Nissle 1917 (EcN) and mucin glycoproteins. This formulation combines a gastro-resistant alginate shell with a biocompatible HAMA/mucin hydrogel core, which not only protects bacteria during gastrointestinal transit but also mimics the natural mucosal niche to facilitate EcN retention and barrier reinforcement. In vivo , prophylactic administration of these microspheres enhanced intestinal barrier integrity, restored gut microbiota balance, and suppressed systemic inflammation, ultimately reducing bacterial translocation and attenuating organ injury. Our findings demonstrate that regulating the gut microbiota–barrier–immune axis represents a practical approach to sepsis prophylaxis.