Biological actualityE. 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
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:
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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;
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an abnormally permeable mucosal barrier leading to excessive bacterial translocation;
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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];
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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:
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bacterial uptake via Peyer's Patches;
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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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Cited by (25)
Comparative genomics of a subset of Adherent/Invasive Escherichia coli strains isolated from individuals without inflammatory bowel disease
2020, GenomicsCitation Excerpt :It has been suggested that a complex interaction of environmental, immunological and genetic factors contribute to the immunopathology of CD. Several studies have demonstrated the association between CD and non-diarrheagenic Adherent/Invasive Escherichia coli (AIEC) strains, in which AIEC takes advantage of the inflammatory process and together with the rest of the host factors (as the patient's immune status, predisposition or dysbiosis), participates in the perpetuation of the disease [7–13]. However, an interesting observation is that AIEC strains have also been isolated from people without IBD [14]
Dysbiosis in intestinal inflammation: Cause or consequence
2016, International Journal of Medical MicrobiologyCitation Excerpt :Once dysbiosis is established, pathogens can rapidly outcompete commensals due to factors in their genomes (e.g. those encoding bacterial toxins, antimicrobial resistance, adhesion factors) that confer greater resistance to host defense mechanisms (e.g. antimicrobial peptides, reactive oxygen species and phagocyte killing), and better utilization of the gut nutrient environment (Raffatellu et al., 2009; Winter et al., 2010; Keeney and Finlay, 2011; Rivera-Chavez and Baumler, 2015). It has been shown that infectious bacteria, such as adherent-invasive Escherichia coli (AIEC) and Mycobacterium avium subsp. paratuberculosis, are frequently associated with the pathogenesis of inflammation in CD patients (Rhodes, 2007; Behr and Kapur, 2008; Barnich et al., 2013; Chassaing et al., 2014, 2015; Vazeille et al., 2016). This observation leads to the tempting speculation that transient infection with pathogens cause changes in the microbial environment of the susceptible host, and thereby triggers the development of chronic inflammation once the pathogen has been cleared.
Mannans and health, with a special focus on glucomannans
2013, Food Research InternationalCitation Excerpt :More recently, a study by Suzuki et al. (2010) has concluded that consuming hydrolysed konjac glucomannan can help prevent atopic diseases by suppressing IgE production in mice. Studies have indicated that certain carbohydrates can inhibit the binding of bacteria to the mucosa of the gut or bladder and hence reduce infections (Barnich, Denizot, & Darfeuilli-Michaud, 2010; Darfeuille-Michaud et al., 2004; King, Young, Nequin, & Carnevale, 2000; Klemm & Schembri, 2000; Martin et al., 2004; Rhodes, 2007; Schaeffer, Amundsen, & Jones, 1980). This binding is usually mediated by the bacterial fimbriae which are adhesive organelles that enable bacteria to target then bind to and colonise specific host tissues (Klemm & Schembri, 2000).
Influences of Intestinal Bacteria in Human Inflammatory Bowel Disease
2010, Infectious Disease Clinics of North AmericaCitation Excerpt :This possibility obviously adds credence to the theory of a microbial cause of IBD and genetically determined defects in the handling of invasive bacteria at the intestinal mucosa may be the link between IBD and AIEC. AIEC are harbored by healthy subjects, which suggests that AIEC are opportunistic pathogens that are capable of causing disease in susceptible hosts.67 IBD is a prevalent and serious chronic disease in which gut microbes very likely have a major role in cause and development.
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NB and JD contributed equally to this work.