In addition to NOD2 mutations, recent genome-wide association studies have highlighted mutations in ATG16L1 and IRGM as being associated with Crohn’s disease risk. Given the intracellular location of NOD2 and the role of ATG16L1 and IRGM in autophagy, the presence of pathogenic invasive bacteria could be the link between innate immune response to these invasive bacteria and the development of inflammation. In Crohn’s disease patients, increased numbers of mucosa-associated Escherichia coli are observed, and Crohn’s disease-associated E coli, termed adherent–invasive E coli (AIEC), colonize the intestinal mucosa. These, too, are true invasive pathogens, able to invade intestinal epithelial cells and replicate intracellularly. They also survive and replicate extensively within macrophages without inducing host cell death, and their high replication rates induce the secretion of large amounts of tumor necrosis factor-α. AIEC bacteria, via type 1 pili expression, colonize the intestinal mucosa and induce gut inflammation in Crohn’s disease patients who have abnormal intestinal expression of carcinoembryonic antigen-related cell adhesion molecule 6, the receptor for AIEC type 1 pili. Functional autophagy plays a central role in restraining intracellular AIEC replication. Hence, AIEC infection in patients with polymorphisms in autophagy genes may have a significant impact on the outcome of intestinal inflammation. Inflamm Bowel Dis Monit 2010;10(3):77–83.