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The identification of mutations in the nucleotide oligomerization domain 2-encoding gene in patients with Crohn's disease suggests a link between the innate immune response to invasive bacteria and the development of Crohn's disease. Herein, we review reports concerning the association of pathogenic Escherichia coli with the intestinal mucosa of Crohn's disease patients.Adherent-invasive E. coli were isolated from ileal biopsies of 36.4% of patients with ileal Crohn's disease. Adherent-invasive E. coli colonize the intestinal mucosa by adhering to intestinal epithelial cells. They are also true invasive pathogens, able to invade intestinal epithelial cells and to replicate intracellularly. Adherent-invasive E. coli strains replicate extensively into macrophages inducing the secretion of very large amounts of tumor necrosis factor-α. Similar pathogenic E. coli strains were recently associated with granulomatous colitis of Boxer dogs. Interestingly, high levels of E. coli outer membrane protein C antibodies are present in 37–55% of Crohn's disease patients and reactivity to outer membrane protein C is associated with increased severity of Crohn's disease.As the infection cycle of adherent-invasive E. coli could depend upon the ability of these pathogenic bacteria to colonize the gastrointestinal tract of genetically predisposed Crohn's disease patients, antibiotics which could eradicate the bacteria, or probiotics which could substitute them in the gastrointestinal tract, could be of therapeutic value in ileal Crohn's disease.