Engineering <i>Escherichia coli</i> Nissle 1917 Carrying PD1 Agonists Resolves Intestinal Inflammation via Local Immune Modulation
Meng‐Yuan Hu, Tingting Li, Mengmeng Xu, Anqi Dong, Chonghai Zhang, Lei Wang, Wenhao Shen, Yang He, Kai Yang, Lin Hu
Abstract
Immunological imbalance is a key factor in the progression of intestinal inflammation, yet effective treatments remain elusive. Using a radiation-induced intestinal injury model, we investigated the causes of inflammation at the single-cell level and identified abnormal T-cell activation as a major contributor. To address this, we targeted the PD1 signaling pathway to suppress T-cell activation and evaluated the anti-inflammatory and intestinal repair effects of the PD1 agonist displaying probiotic Escherichia coli Nissle 1917 (EcN MP1-M ) in two mouse models. Encapsulated in Eudragit L100-55 for pH-dependent release, EcN MP1-M and its bacterial outer membrane vesicles (OMVs) expressed PD1 agonists, which inhibited excessive immune activation and reduced inflammatory cytokines. EcN MP1-M promoted the expression of proteins that maintain intestinal epithelial barrier integrity, improving gut function and immune responses in colitis mice. Furthermore, 16S rDNA microbiome sequencing revealed that EcN MP1-M enhanced intestinal microbiota diversity, increased beneficial bacteria, and reduced harmful bacteria. This study proposes a localized EcN-based immunosuppressive therapy for radiation-induced enteritis and inflammatory bowel disease with promising potential for clinical applications.