Prebiotic augmented nanozyme-armored probiotics reprogramme the gut microenvironment for synchronous treatment of colitis and sepsis via antioxidant defense.

INTRODUCTION: Ulcerative colitis (UC) is characterised by intestinal barrier disruption, gut microbiota dysbiosis, and reactive oxygen species (ROS) overexpression. Its prolonged pathological process leads to intestinal leakage accompanied by translocation of pathogens and endotoxins, thereby accelerating the triggering of sepsis.

OBJECTIVES: This study aimed to construct a multifunctional probiotic delivery platform (LK@BCCR-FP) consisting of Lactobacillus kefiranofaciens (LK) loaded with boronic acid chitosan-modified nanozyme (BCCR) core and Fu brick tea polysaccharide (FBTP) prebiotic shell to synergistically exert ROS scavenging and microbiota regulation for synchronous treatment of UC and sepsis. The dual-location intervention mechanism of LK@BCCR-FP was investigated from the perspective of anti-inflammatory tissue repair and cascade metabolic modulation.

METHODS: LK@BCCR-FP was successfully constructed through natural product self-assembly and click chemistry methods. The key role of apoptosis pathway in intestinal barrier repair was revealed through Western blot and immunofluorescence. The remodeling of intestinal homeostasis by LK@BCCR-FP was evaluated by combining functional metabolomics and microbiomics.

RESULTS: LK@BCCR-FP provided enhanced protection and nutritional substrates for probiotics and nanozymes, and promoted their colonization in damaged colonic regions by targeting inflamed mucosa to achieve UC targeted therapy. Unlike conventional antimicrobial nanozymes, BCCR can exert sustained biocatalysis in the inflammatory microenvironment and maintain probiotic viability, ensuring that LK@BCCR-FP remodels intestinal homeostasis through gut microbiota-mediated metabolic regulation. In DSS-induced UC murine model, LK@BCCR-FP stimulated the Nrf2-related pathway to alleviate oxidative stress, suppressed the growth of pathogenic bacteria and boosted the abundance of beneficial bacteria, recovered intestinal barrier integrity by inhibiting the p53/C-caspase-3 apoptosis pathway and reduced lipopolysaccharide translocation. In addition, LK@BCCR-FP exhibited potent UC prophylactic and therapeutic efficacy, further downregulated cascade inflammatory mediators in serum metabolites, and alleviated extraintestinal organ damage in LPS-induced sepsis mice.

CONCLUSION: Metabolically augmented LK@BCCR-FP in this study combining antioxidant and apoptosis gene-regulation provides a promising therapeutic strategy for UC and sepsis.