Background/Objectives: Sepsis remains a leading cause of global mortality despite advances in critical care, largely because treatment is initiated only after systemic inflammation and organ damage are already established. Emerging evidence highlights gut microbiota dysbiosis and intestinal barrier impairment as critical drivers of sepsis pathogenesis, particularly in immunocompromised patients. We propose that early modulation of the gut microbiome represents a viable prophylactic strategy against sepsis.
Methods: In this study, we designed and fabricated an advanced probiotic delivery platform based on ternary hydrogel microspheres, designated EcN+Muc@SHM. These microspheres were constructed by first encapsulating E. coli Nissle 1917 (EcN) and mucin within a methacrylated hyaluronic acid (HAMA) core via a photopolymerization-coupled emulsification method. Subsequently, a protective alginate shell was coated onto the surface through ion polymerization to enhance stability and targeted delivery.
Results: In vitro assessments demonstrated the potent bioactivity of the hydrogel components, wherein HAMA and mucin synergistically promoted intestinal cell proliferation, mitigated lipopolysaccharide (LPS)-induced mucus secretion injury in HT29-MTX cells, and alleviated inflammatory responses and oxidative stress in macrophages. Critically, the integrated EcN+Muc@SHM microsphere structure conferred robust protection to the probiotic EcN payload against the harsh gastric environment, as validated both in vitro and in vivo. In a clinically relevant cecal ligation and puncture (CLP) mouse model, this advanced probiotic platform exhibited remarkable prophylactic and therapeutic efficacy. Administration of the microspheres significantly reduced bacterial translocation, resolved local inflammation, and alleviated intestinal injury. Fecal microbiome sequencing further elucidated the underlying mechanism, revealing that the treatment effectively corrected post-CLP dysbiosis, thereby restoring microbial homeostasis and promoting the recovery of a healthy gut flora.
Conclusions: Our findings underscore the potential of proactive, microbiome-targeted strategies to disrupt the vicious cycle of dysbiosis and inflammation, offering a promising avenue for sepsis prevention in high-risk populations.
