Ileal lesions in Crohn's disease (CD) patients are colonized by pathogenic adherent-invasive Escherichia coli (AIEC) able to invade and to replicate within intestinal epithelial cells. Recent advances have highlighted the importance of the innate immune system and the critical relationship between the gut flora and the intestinal mucosa. Several combinations of genetic predisposing factors to CD have been described, with the most significant replicable associations including genes for intracellular receptor of bacterial cell walls (NOD2/CARD15), and for bacterial clearance and antigen processing through autophagy (ATG16L1 and IRGM). We recently reported that in IRGM and ATG16L1 deficient cells, intracellular AIEC LF82 bacteria have enhanced replication and that autophagy deficiency surprisingly did not interfere with the ability of intracellular bacteria to survive and/or replicate for any other E. coli strains tested, including nonpathogenic, environmental, commensal, or pathogenic strains involved in gastroenteritis. As autophagy is an innate defense mechanism acting as a cell-autonomous system for elimination of intracellular pathogens, these findings lead weight to the notion that intracellular bacteria including AIEC might play a role in CD pathogenesis.