Synergistic Genetic and Chemical Engineering of Probiotics for Enhanced Intestinal Microbiota Regulation and Ulcerative Colitis Treatment

Abstract Live bacterial therapeutics (LBT) hold significant promise for treating ulcerative colitis (UC) by utilizing engineered microorganisms to restore mucosal barrier function, modulate microbiota imbalances, and enhance immunity. However, challenges such as low bacterial survival under harsh gastrointestinal conditions, difficulties in achieving long‐term colonization, and unclear therapeutic targets limit their effectiveness. To address these issues, a novel approach is proposed that integrates genetic and chemical engineering for intestinal flora regulation in UC treatment. This strategy employs bacterial programmability and gene editing to produce bactericidal agents that dynamically modulate the intestinal microecology and utilize controlled chemical modifications to enhance bacterial resistance. Using Escherichia coli Nissle 1917 (EcN) as a model, a polyelectrolyte composite coating is developed that significantly increased bacterial survival in the gastrointestinal tract—40‐fold in the stomach and 74‐fold in the small intestine. Additionally, EcN::mcmA is engineered to overproduce iron‐carrier microcins (MccM) with a “Trojan horse” mechanism to target and disrupt pathogenic bacteria. In a dextran sulfate sodium (DSS)‐induced mouse UC model, EcN::mcmA@P/O treatment effectively reduced inflammation and improved intestinal flora regulation, presenting a promising and potentially safer long‐term solution for UC.