Cellular membrane protein MipA from <i>E.coli</i> Nissle 1917 protects against <i>Salmonella</i> infection

Intestinal microbiota resists pathogenic bacterial infections through colonization resistance, largely attributed to direct microbial competition. However, whether commensals can provide colonization resistance by remodeling the host epithelial niche remains underexplored. Here, by combining in vivo mouse models and a gut-on-chip model, this study demonstrates that the resistance of commensal E. coli Nissle 1917 (EcN) against Salmonella Typhimurium (STm) infection is strictly dependent on EcN pre-colonization. Mechanistically, the EcN outer membrane protein MipA was identified as a key factor that induces the upregulation of integrin-linked kinase (ILK), thereby reinforcing tight junction integrity and restricting Salmonella infection. Engineering a non-protective strain to express MipA was sufficient to confer resistance against Salmonella infection. This work reveals an epithelial defense mechanism triggered by a specific probiotic protein, with implications for developing preventive strategies against enteric infections.