Carvalho, F. A. et al. Crohn's disease adherent-invasive Escherichia coli colonize and induce strong gut inflammation in transgenic mice expressing human CEACAM. J. Exp. Med. 206, 2179-2189

Université Clermont 1, Pathogénie Bactérienne Intestinale, JE2526, Unité Sous Contrat Institut National de la Recherche Agronomique 2018, Clermont-Ferrand F-63001, France.
Journal of Experimental Medicine (Impact Factor: 12.52). 10/2009; 206(10):2179-89. DOI: 10.1084/jem.20090741
Source: PubMed


Abnormal expression of CEACAM6 is observed at the apical surface of the ileal epithelium in Crohn's disease (CD) patients, and CD ileal lesions are colonized by pathogenic adherent-invasive Escherichia coli (AIEC). We investigated the ability of AIEC reference strain LF82 to colonize the intestinal mucosa and to induce inflammation in CEABAC10 transgenic mice expressing human CEACAMs. AIEC LF82 virulent bacteria, but not nonpathogenic E. coli K-12, were able to persist in the gut of CEABAC10 transgenic mice and to induce severe colitis with reduced survival rate, marked weight loss, increased rectal bleeding, presence of erosive lesions, mucosal inflammation, and increased proinflammatory cytokine expression. The colitis depended on type 1 pili expression by AIEC bacteria and on intestinal CEACAM expression because no sign of colitis was observed in transgenic mice infected with type 1 pili-negative LF82-Delta fimH isogenic mutant or in wild-type mice infected with AIEC LF82 bacteria. These findings strongly support the hypothesis that in CD patients having an abnormal intestinal expression of CEACAM6, AIEC bacteria via type 1 pili expression can colonize the intestinal mucosa and induce gut inflammation. Thus, targeting AIEC adhesion to gut mucosa represents a new strategy for clinicians to prevent and/or to treat ileal CD.

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Available from: Frederic Carvalho, Jun 16, 2015
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    • "Six categories of classic diarrheagenic E. coli (DEC) have been described (Kaper et al., 2004). Likewise, analysis of CD patient-derived tissue has identified bacteria named adherentinvasive E. coli (AIEC) (Hansen et al., 2010) as potential contributors to CD pathogenesis (Carvalho et al., 2009; Darfeuille-Michaud et al., 2004; Nash et al., 2010). Previous studies showed that 22–65% of CD patients harbour AIEC, compared to 6–9% in controls (Darfeuille- Michaud et al., 2004; Glasser et al., 2001; Sasaki et al., 2007). "
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    ABSTRACT: Crohn's disease (CD) is a multifactorial pathology associated with the presence of adherent-invasive Escherichia coli (AIEC) and NLRP3 polymorphic variants. The presence of intracellular E. coli in other intestinal pathologies (OIP) and the role of NLRP3-inflammasome in the immune response activated by these bacteria have not been investigated. In this study, we sought to characterize intracellular strains isolated from patients with CD, ulcerative colitis (UC) and OIP, and analyze NLRP3-inflammasome role in the immune response and bactericidal activity induced in macrophages exposed to invasive bacteria. For this, intracellular E. coli isolation from ileal biopsies, using gentamicin-protection assay, revealed a prevalence and CFU/biopsy of E. coli higher in biopsies from CD, UC and OIP patients than in controls. To characterization of bacterial isolates, pulsed-field gel electrophoresis (PFGE) patterns, virulence genes, serogroup and phylogenetic group were analyzed. We found out that bacteria isolated from a given patient were closely related and shared virulence factors; however, strains from different patients were genetically heterogeneous. AIEC characteristics in isolated strains, such as invasive and replicative properties, were assessed in epithelial cells and macrophages, respectively. Some strains from CD and UC demonstrated AIEC properties, but not strains from OIP. Furthermore, the role of NLRP3 in pro-inflammatory cytokines production and bacterial elimination was determined in macrophages. E. coli strains induced IL-1β through NLRP3-dependent mechanism; however, their elimination by macrophages was independent of NLRP3. Invasiveness of intracellular E. coli strains into the intestinal mucosa and IL-1β production may contribute to CD and UC pathogenesis.
    Full-text · Article · May 2014 · International journal of medical microbiology: IJMM
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    • "Numerous lines of evidence suggest that adherent-invasive E. coli (AIEC) subtypes may be pro-inflammatory in the context of chronic intestinal inflammatory conditions such as CD [22]. Specifically, the AIEC strains NC101 (murine origin) and LF82 (human CD origin) have both been shown to induce intestinal inflammation in genetically-engineered mice [23], [24]. Given the higher levels of E. coli observed in 129 mice, we hypothesized that ileal α-defensins isolated from 129 animals would have attenuated antimicrobial activity against E. coli, as compared to B6 mice. "
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    ABSTRACT: Increasing evidence supports the central role of Paneth cells in maintaining intestinal host-microbial homeostasis. However, the direct impact of host genotype on Paneth cell function remains unclear. Here, we characterize key differences in Paneth cell function and intestinal microbial composition in two widely utilized, genetically distinct mouse strains (C57BL/6 and 129/SvEv). In doing so, we demonstrate critical influences of host genotype on Paneth cell activity and the enteric microbiota. Paneth cell numbers were determined by flow cytometry. Antimicrobial peptide (AMP) expression was evaluated using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR), acid urea-polyacrylamide gel electrophoresis, and mass spectrometry. Effects of mouse background on microbial composition were assessed by reciprocal colonization of germ-free mice from both background strains, followed by compositional analysis of resultant gut bacterial communities using terminal restriction fragment length polymorphism analysis and 16 S qPCR. Our results revealed that 129/SvEv mice possessed fewer Paneth cells and a divergent AMP profile relative to C57BL/6 counterparts. Novel 129/SvEv á-defensin peptides were identified, including Defa2/18v, Defa11, Defa16, and Defa18. Host genotype profoundly affected the global profile of the intestinal microbiota, while both source and host factors were found to influence specific bacterial groups. Interestingly, ileal α-defensins from 129/SvEv mice displayed attenuated antimicrobial activity against pro-inflammatory E. coli strains, a bacterial species found to be expanded in these animals. This work establishes the important impact of host genotype on Paneth cell function and the composition of the intestinal microbiota. It further identifies specific AMP and microbial alterations in two commonly used inbred mouse strains that have varying susceptibilities to a variety of disorders, ranging from obesity to intestinal inflammation. This will be critical for future studies utilizing these murine backgrounds to study the effects of Paneth cells and the intestinal microbiota on host health and disease.
    Full-text · Article · Feb 2012 · PLoS ONE
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    • "Barnich et al. [7], revealed that the ileal epithelium in CD patients is highly mannosylated compared to that of the colon; possibly explaining previous reports of AIEC preference for the ileal compartment. The adhesion mechanism of AIEC strains involves interactions between type 1 fimbriae [8] [9], and mannosylated glycoreceptors, mainly carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), present on the apical side of ileal enterocytes [7] [9]. Adhesion mechanisms involved in AIEC interaction with colonic epithelium has not yet been described, however, the presence of pathogenic E. coli spp. in the colonic mucosa from CD is reported [5,10e12]. "
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    ABSTRACT: Adherent-invasive Escherichia coli (AIEC) are reported to inhabit the gut mucosa in Crohn's disease (CD), however, little is known about the importance of host factors for the interplay between AIEC and the human gut. To examine if differences in bacterial adhesion patterns are disease associated, the AIEC-prototype strain LF82 was evaluated for its ability to adhere to ileal and colonic biopsies from CD and healthy controls (HC). Moreover, the efficacy of the non-pathogenic E. coli Nissle 1917 (ECN) in averting LF82 adhesion to ileal mucosa was assessed. Similar numbers of LF82 adhered to biopsies from CD and HC. A significantly greater LF82 attachment to ileal versus colonic mucosa was found in HC (P < 0.01), however, not in CD. ECN did not reduce the adhesion of LF82 to ileal specimens in CD or HC. These results show that enhanced bacterial adhesion ability is unlikely to play any significant role in CD, thus implying that other host protective factors may be impaired in CD. Further, exclusion of LF82 attachment by ECN co-incubation does not appear to represent a relevant treatment regimen.
    Full-text · Article · Sep 2011 · Microbial Pathogenesis
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