Adhering and invading E. Coli: Defining the link to Crohnʼs Disease

Although the exact cause of chronic inflammatory bowel diseases is not known, current evidence - obtained from both affected human subjects and experimental models - indicate an essential role for enteric luminal bacteria. Commensal E. coli do not typically bind to the mucosal epithelia, however E. coli isolated from the ileal mucosa of Crohn's patients frequently attach and penetrate into epithelial cells. These adherent and invasive E. coli (AIEC) strains are of a single ribotype profile. They are commonly isolated from the feces of Crohn's patients but are rarely seen in healthy controls or inflammatory comparison groups with infectious enteritidis or ulcerative colitis. In vitro studies by the group of Arlette Darfeuille-Michaud (2007 J Clin Invest. 117:1566-74) suggest that human carcinoembryonic antigen-related cellular adhesion molecule 6 (CEACAM6) is the host receptor for a variant type I fimbriae expressed by AIEC strains. In order to ascertain whether AIEC are virulent bacteria and establish a causal role for CEACAM6 expression in AIEC infection, we have performed orogastric challenge of transgenic mice expressing human CEACAMs. While CEACAM6 is not expressed by rodents, the CEABAC mouse lines express either normal (CEABAC2 mice) human levels of CEACAM3, CEACAM5, CEACAM6 and CEACAM7, or five times normal levels (CEABAC10 mice) of these receptors, the latter reflecting the over-expression of CEACAM6 found in Crohn's disease patients. While wild type mice resist AIEC strain LF82 infection, CEABAC2 mice tend to lose weight and then recover. Strikingly, CEABAC10 mice challenged with the LF82 strain rapidly lose weight and succumb. The generation of luciferase-expressing AIEC allowed us to establish that the rapid progression to death occurs because these bacteria are able to effectively penetrate the mucosal barrier in CEACAM-over-expressing mice, resulting in a systemic infection that allows bacterial recovery from the blood, lymph nodes liver and spleen. This finding is consistent with our in vitro studies demonstrating that AIEC strain LF82 disrupts the integrity of the polarized human epithelial cell barrier in vitro. Given that the CEABAC10 mice are more susceptible to infection than are the CEABAC2 mice, our results suggest that the bacteria possess a tropism for Crohns disease-inflamed tissues due to upregulation of CEACAM6 in the affected areas. Their subsequent penetration into the submucosa may then initiate a pathogenic inflammatory response.

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