Document resource
Background Gut microbiota-targeted therapy represents a promising strategy for inflammatory bowel disease (IBD). However, oral probiotic therapy faces critical challenges in targeting inflamed intestinal regions and establishing colonization, owing to the harsh luminal environment in IBD, such as elevated reactive oxygen species (ROS). Metal-polyphenol networks (MPNs) exhibit high surface affinity and robust antioxidant properties, making them attractive candidates for probiotic surface engineering to enhance intestinal retention and therapeutic efficacy.Methods Lactobacillus plantarum was isolated from healthy donor feces and surface-engineered with iron-proanthocyanidin (Fe-PC). Surface modification of Fe-PC-coated L. plantarum (L. p@Fe-PC) was confirmed by transmission electron microscopy (TEM) and zeta potential, with antioxidant capacity assessed by electron paramagnetic resonance spectroscopy and acid resistance evaluated using simulated gastric fluid assays. Targeted colonization was assessed using an in vivo imaging system (IVIS) and quantitative PCR (qPCR). Multi-omics integration (metabolomics, single-cell RNA sequencing, and transcriptomics) identified key metabolic pathways and target cell populations, which were functionally validated through genetically modified mouse models and cellular assays.Results TEM and zeta potential confirmed Fe-PC surface adsorption. L. p@Fe-PC retained viability and growth capacity with enhanced ROS scavenging and acid resistance. IVIS imaging and qPCR demonstrated selective accumulation and enhanced colonization of L. p@Fe-PC in inflamed intestinal regions. In vivo, L. p@Fe-PC achieved comparable therapeutic efficacy to a higher dose of unmodified probiotics. Metabolomics and single-cell RNA sequencing identified macrophage Ido1 as the key target, a finding corroborated by genetically modified mouse models. Transcriptomics and western blotting further revealed that L. p@Fe-PC exerts anti-inflammatory effects via suppression of the macrophage Toll-like receptor 4 (TLR4)-ido1 signaling axis.Conclusions In summary, we developed an MPN surface-engineered probiotic ( L. p@Fe-PC) that overcomes the critical limitations of poor colonization and inadequate targeting in oral probiotic therapy for IBD. By enhancing intestinal retention and suppressing the macrophage TLR4-ido1 inflammatory axis, this strategy provides preclinical evidence supporting clinical translation of engineered probiotics in IBD.