Adhesion‐Enhanced Engineered Probiotic for Prolonged Intestinal Retention and Calprotectin‐Responsive IBD Therapy

Abstract

ABSTRACT The clinical translation of engineered probiotics for inflammatory bowel disease (IBD) is hindered by limited intestinal retention and insufficient inflammation‐responsive precision. This study utilizes a surface display strategy to construct an adhesion‐enhanced Escherichia coli Nissle 1917 chassis. By presenting a truncated SpaC adhesin derived from Lactobacillus rhamnosus GG via the ice nucleation protein system, the engineered strain achieves enhanced mucosal anchoring and prolonged intestinal retention. To achieve an autonomous response, the probiotic platform integrates a calprotectin‐responsive ykgMO promoter to drive a CAT‐SOD‐GPx tripartite fusion system (TFS) and secretion of human trefoil factor 3 (TFF3). In the TFS, CAT and SOD mediate ROS scavenging, whereas GPx is proposed to serve as a non‐catalytic structural‐support component associated with improved folding and soluble expression. Combined with pH‐responsive Eudragit L100‐55 microencapsulation to ensure gastric survival, this programmable system effectively alleviates inflammation, restores epithelial barrier integrity, and reverses oxidative damage in both prophylactic and therapeutic murine colitis models. Furthermore, the platform remodels the gut microbiota by suppressing opportunistic pathobionts such as Escherichia‐Shigella while simultaneously promoting the resurgence of beneficial taxa, including Lachnospiraceae. Together, this biomarker‐responsive strategy offers a versatile and programmable framework for the precision management of IBD during acute flare‐ups.