Small proteins known as microcins that are secreted from commensal intestinal bacteria exhibit antibacterial properties in vitro. Sassone-Corsi et al. now show in mouse colitis models, that inoculation with a probiotic microcin-secreting Escherichia coli strain (EcN) outcompetes and limits gut colonization with commensal E. coli, Salmonella enterica serovar Typhimurium (STm) and adherent invasive E. coli (frequently isolated from patients with Crohn disease), in contrast to a mutant EcN unable to secrete microcins. EcN inoculation also reduced STm colonization, inflammation and weight loss in mice with an active STm infection.