Elsevier

Pathologie Biologie

Volume 61, Issue 5, October 2013, Pages e65-e69
Pathologie Biologie

Biological actuality
E. coli-mediated gut inflammation in genetically predisposed Crohn's disease patientsInflammation intestinale induite par des souches de E. coli chez des patients génétiquement prédisposés à développer une maladie de Crohn

https://doi.org/10.1016/j.patbio.2010.01.004Get rights and content

Abstract

Many advances have been made in the understanding of Crohn's disease (CD) pathogenesis over the last decade. In CD patients abnormal ileal bacterial colonization could be linked to inappropriate innate immune responses to invasive bacteria. Adherent and invasive Escherichia coli strains have been isolated from CD patients and are able to adhere to and to invade intestinal epithelial cells and to induce colitis in transgenic mice expressing the human CEACAM6 molecule. In this review, we report recent advances concerning the involvement of adherent-invasive E. coli in the aetiology of CD and analyze how they can initiate inflammation of the gut mucosa in individuals with genetic predisposition.

Résumé

Au cours de la dernière décennie, de nombreuses avancées ont permis de mieux comprendre la pathogenèse de la maladie de Crohn (MC). Chez les patients atteints de MC, la colonisation bactérienne anormale de la muqueuse iléale pourrait être la cause d’une réponse immunitaire innée inappropriée à des bactéries invasives. Des souches de Escherichia coli adhérentes et invasives ont été isolées chez des patients atteints de MC. Ces souches sont capables d’adhérer et d’envahir des cellules épithéliales intestinales et d’induire une colite chez des souris transgéniques exprimant le récepteur CEACAM6 humain. Dans cette revue, nous rapportons les avancées récentes relatives à l’implication des souches de E. coli adhérentes et invasives dans l’étiologie de la MC et analysons comment ces souches peuvent être à l’origine de l’inflammation de la muqueuse intestinale chez des individus génétiquement prédisposés.

Introduction

The pathogenic mechanisms of inflammatory bowel disease (IBD) have been studied intensely. It is increasingly clear that microbiota plays a major role in the pathogenesis of IBD. The abnormal inflammatory response observed in IBD requires interplay between host genetic factors and the intestinal microbiota [1], [2], [3]. The role of the microbiota in CD development is highlighted with the observations that:

  • •

    in CD patients after surgery, exposure of the terminal ileum to luminal contents is associated with increased inflammation, and diversion of the fecal stream is associated with improvement [4];

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    some CD patients improve upon antibiotic treatment [5], [6];

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    the severity of colitis in multiple animal models is decreased by the administration of antibiotics;

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    no sign of colitis is observed when those animals are in germ-free conditions (for a review [7]).

At least three not necessarily mutually exclusive theories can be proposed concerning the implication of bacteria in the etiopathogenesis of CD:

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    a persistent pathogen;

  • •

    an abnormally permeable mucosal barrier leading to excessive bacterial translocation;

  • •

    a breakdown in the balance between putative “protective” versus “harmful” intestinal bacteria (“dysbiosis”) that can promote inflammation.

Arguments in favour of the latter hypothesis are:

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    the low proportion of Faecalibacterium prausnitzii, i.e., bacteria with anti-inflammatory properties, on ileal Crohn mucosa [8], [9];

  • •

    the abnormal colonisation of the ileal mucosa by adherent-invasive Escherichia coli, bacteria able to initiate and perpetuate inflammation of the gut mucosa in CD susceptible patients.

Section snippets

Adherent-invasive E. coli in IBD patients

Increased numbers of mucosa-associated E. coli forming a biofilm on the surface of the gut mucosa are observed in patients with IBD [10], [11], [12], [13], [14], [15], [16]. In CD patients, E. coli abnormally colonize acute and chronic ileal lesions representing up to 100% of total aero-anaerobic flora [11]. Bacteria colonizing the gut mucosa have the ability to strongly adhere to intestinal epithelial cells (IEC) [11], [13]. They are also able to invade IEC by a mechanism involving

Carcinoembryonic antigen-related cell-adhesion molecule 6 (CEACAM6)-dependent colonization of the ileal mucosa by AIEC

Bacterial adhesion to IEC is the first step in the pathogenicity of many bacteria involved in infectious diseases of the gut. Adhesion enables bacteria to colonize the gut, thus limiting clearance from the intestine. AIEC strains were found to be highly associated with ileal mucosa in CD patients [22]. CD-associated AIEC adhere to the brush border of primary ileal enterocytes isolated from CD patients but not controls without IBD [28], suggesting that there are specific alterations of the ileal

Genetic predisposition in CD leading to the loss of intracellular bacterial clearance

CD is not a « hereditary » disease but many genetic predisposition factors have been recently discovered. Genome-wide association studies (GWAS) have identified more than 30 independent loci conclusively associated with CD [31], [32], [33], [34], [35]. In the innate immunity, the association of CD with polymorphisms in the two autophagy-related genes, ATG16L1 and IRGM, and in NOD2 (CARD15), implicates defects in the recognition and handling of intracellular bacteria in the immunopathogenesis of

Impaired barrier function in CD patients

Intestinal permeability is significantly increased in 36% of CD patients [55] and bacterial translocation of E. coli, Enterococcus spp., Clostridium perfringens has been observed in mesenteric nodes in 30% to 50% of CD patients versus 5% to 15% in healthy controls [56], [57]. Two different not necessarily mutually exclusive arguments can be proposed to explain increased intestinal permeability and bacterial translocation observed in CD:

  • •

    bacterial uptake via Peyer's Patches;

  • •

    bacterial

Conclusion

A lot of advances have been made in the understanding of CD pathogenesis over the last decade. CD is thought to result from inappropriate and continuous activation of the intestinal mucosal immune system due to a complex interaction of genetic, environmental, microbial and host immune factors. In CD patients with increased ileal expression of the CEACAM6 molecule, which acts as a receptor recognized by type 1 pilus bacterial adhesin, and with the identification of mutations in innate immune

Conflict of interest statement

None.

Acknowledgments

Research in the laboratory JE2526 is made possible by grants from Association F. Aupetit, institut de recherche des maladies de l’appareil digestif (IRMAD, laboratoire Astra, France), INRA (through USC 2018) and université d’Auvergne through JE2526.

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    NB and JD contributed equally to this work.

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