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Home > Research > Some examples > Crohn's disease: evidence for a key molecule that causes inflammation of the intestinal mucosa

Press Info item. 24/11/2009

Crohn's disease: evidence for a key molecule that causes inflammation of the intestinal mucosa

INRA researchers at Université Clermont 1, working in association with scientists from McGill University in Quebec, have recently published results of considerable importance to our understanding of the mechanism underlying Crohn's disease, a highly disabling inflammatory disease of the digestive tract for which no effective treatment is currently available. In affected patients, the intestinal mucosa is abnormally colonised by Escherichia coli bacteria. The research team has demonstrated the possible adhesion of these bacteria in the intestine of individuals at risk of developing Crohn's disease, thanks to the expression of a molecule in intestinal cells: the CEACAM6 receptor. The interaction between Escherichia coli and this receptor favours abnormal colonisation of the intestinal mucosa by these bacteria, inducing the chronic inflammation that is the principal symptom of the disease. Preventing the adhesion of these bacteria to the intestinal mucosa may thus constitutes a new direction for therapeutic strategy to prevent or treat Crohn's disease.
This study was published in the "Journal of Experimental Medicine" on September 28, 2009.

Crohn's disease (CD) is an inflammatory disease of the digestive tract that is particularly common in developed countries, with 750,000 patients in Europe and 550,000 in the USA. It is a chronic condition that comprises phases of activity (or "flare-ups") of varying intensity, alternating with more or less complete and prolonged periods of remission. Crohn's disease lesions are usually observed in the terminal portion of the small intestine (ileum), or in the large intestine (colon), or in both segments.

Many epidemiological, clinical and experimental arguments are in favour of an infective origin for Crohn's disease. Thus as early as 1998, the team of researchers led by Arlette Darfeuille-Michaud demonstrated that the intestine of CD patients was abnormally colonised by Escherichia coli bacteria. The Escherichia coli strains endowed with a capacity for adherence thus invade the intestinal epithelial cells of CD patients, and then proliferate.

The adhesion of bacteria to intestinal epithelial cells results from an interaction between fine bacterial filaments and a receptor - CEACAM6 – located on the intestinal cells. CEACAM6 is abnormally expressed in the ileum of 35% of CD patients, but is not expressed in subjects who do not present with chronic inflammatory disease of the digestive tract.

Based on these findings, the scientists suggested that in some Crohn's disease patients, strong expression of the CEACAM6 receptor in the ileum favoured an abnormally high level of intestinal colonisation by Escherichia coli bacteria. Their recent results thus verify this hypothesis. Using a mouse that expresses the human CEACAM6 receptor in the intestine, the scientists induced severe intestinal inflammation, with a high mortality rate when the animals were infected by these invasive bacteria. On the other hand, they did not observe these symptoms in mice not expressing the CEACAM6 receptor, nor in those expressing this receptor but infected by bacteria which did not synthesise filaments. The induced inflammation thus resulted from the binding of bacteria to the CEACAM6 receptor via the intermediary of filaments.

The results published here are of prime importance to enabling the development of specific therapies for Crohn's disease designed to block the interaction between bacteria and the intestinal mucosa, which may thus make it possible to prevent chronic intestinal inflammation in high-risk subjects.

Patients with a high risk of developing an ileal form of Crohn's disease express the CEACAM6 receptor. The adhesion of Escherichia coli bacteria to the intestinal mucosa triggers enhanced expression of the CEACAM6 receptor, thus leading to a colonisation loop. The invasive bacteria can cross the intestinal barrier and proliferate in a specific type of immune cell, the macrophages. Once they are in these cells, they induce a high level of synthesis of the pro-inflammatory molecules responsible for inflammation.