Ileal lesions of Crohn disease (CD) patients are abnormally colonized by adherent-invasive Escherichia coli (AIEC) producing outer membrane vesicles (OMVs) that contribute to the bacterial invasion process. In addition, endoplasmic stress was recently reported to have a key role in CD patients after the discovery, in CD patients, of several single nucleotide polymorphisms within gene encoding key component of the ER stress response and of increased expression of ER-localised stress response proteins. We recently demonstrated that the ER-stress response chaperone Gp96 is strongly expressed on the apical surface of ileal epithelial cells in CD patients and acts as a host cell receptor for OMVs, promoting AIEC invasion. In this addendum, we provide a synopsis on current data concerning AIEC virulence, summarize our recent findings and also discuss, in more detail, unresolved issues and the potential implications of our findings.