Molecular diversity of Escherichia coli in the human gut: New ecological evidence supporting the role of adherent-invasive E. coli (AIEC) in Crohnʼs disease

Martínez-Medina, Margarita; Aldeguer, Xavier; López-Siles, Mireia; González-Húix, Ferrán; López-Oliu, Carles; Dahbi, Ghizlane; Blanco, Jesús E.; Blanco, Jorge; Garcia‐Gil, L. J.; Darfeuille‐Michaud, Arlette

doi:10.1002/ibd.20860

Cited by 348 publications

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“…Most E. coli strains isolated from the ileal mucosa of CD patients are able to adhere to and invade intestinal epithelial cells (14)(15)(16) and belong to the pathogenic group of adherent invasive E. coli (AIEC) (17). AIEC is highly associated with the ileal mucosa in CD patients (14)(15)(16)(18)(19)(20)(21)(22)(23). CD-associated AIEC cells adhere to the brush border of primary ileal enterocytes isolated from CD patients but not to enterocytes isolated from controls without inflammatory bowel disease.…”

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Ribonucleotide Reductase NrdR as a Novel Regulator for Motility and Chemotaxis during Adherent-Invasive Escherichia coli Infection

et al. 2015

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A critical step in the life cycle of all organisms is the duplication of the genetic material during cell division. Ribonucleotide reductases (RNRs) are essential enzymes for this step because they control the de novo production of the deoxyribonucleotides required for DNA synthesis and repair. Enterobacteriaceae have three functional classes of RNRs (Ia, Ib, and III), which are transcribed from separate operons and encoded by the genes nrdAB, nrdHIEF, and nrdDG, respectively. Here, we investigated the role of RNRs in the virulence of adherent-invasive Escherichia coli (AIEC) isolated from Crohn's disease (CD) patients. Interestingly, the LF82 strain of AIEC harbors four different RNRs (two class Ia, one class Ib, and one class III). Although the E. coli RNR enzymes have been extensively characterized both biochemically and enzymatically, little is known about their roles during bacterial infection. We found that RNR expression was modified in AIEC LF82 bacteria during cell infection, suggesting that RNRs play an important role in AIEC virulence. Knockout of the nrdR and nrdD genes, which encode a transcriptional regulator of RNRs and class III anaerobic RNR, respectively, decreased AIEC LF82's ability to colonize the gut mucosa of transgenic mice that express human CEACAM6 (carcinoembryonic antigen-related cell adhesion molecule 6). Microarray experiments demonstrated that NrdR plays an indirect role in AIEC virulence by interfering with bacterial motility and chemotaxis. Thus, the development of drugs targeting RNR classes, in particular NrdR and NrdD, could be a promising new strategy to control gut colonization by AIEC bacteria in CD patients.R ibonucleotide reductase (RNR) is an essential enzyme in all living organisms. It catalyzes the reduction of ribonucleotides (nucleoside triphosphates [NTPs]) to their corresponding 2=-deoxyribonucleotides (deoxynucleoside triphosphates [dNTPs]) and therefore plays an essential role in DNA synthesis and repair. Three RNR classes (classes I, II, and III) exist; these classes exhibit different primary structures, subunit cofactor requirements, and quaternary three-dimensional (3D) structures, but they all are allosterically regulated and share similar catalytic mechanisms (1, 2). Class I RNRs are oxygendependent enzymes that occur in eubacteria, eukaryotes, and some viruses. This class comprises two main subgroups (Ia and Ib). Class Ia RNRs are encoded by an operon containing nrdA and nrdB genes. These genes encode the NrdA subunit, which is catalytically and allosterically regulated, and the NrdB subunit, which possesses radical-generating activity. Class Ib RNRs are encoded by an operon containing the nrdH, nrdI, nrdE, and nrdF genes, which encode the corresponding specific redoxin NrdH, the activating subunit NrdI, the catalytic subunit NrdE, and the radical-generating subunit NrdF. Class III RNRs are present in facultative anaerobic and strict anaerobic microorganisms and use S-adenosylmethionine and iron-sulfur clusters in the NrdG accessory protein to create a stab...

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Ribonucleotide Reductase NrdR as a Novel Regulator for Motility and Chemotaxis during Adherent-Invasive Escherichia coli Infection

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“…18 Increased levels of E. coli and AIEC strains have been repeatedly observed in ileal CD patients, suggesting a role for E. coli in disease pathogenesis. [19][20][21] In earlier work from our laboratory, we found that patients with ileal CD have a mucosal microbiome enriched for MDX metabolism, as compared to colonic CD patients and non-IBD controls. 22 Additionally, we demonstrated that MDX has a direct effect on multiple E. coli strains, including AIEC, to enhance cellular adhesion and biofilm formation, mimicking the dense biofilms observed in the gut of CD patients 21 (Fig.…”

Section: Maltodextrin (Mdx) Is a Common Food Additive That Alters Botmentioning

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Deregulation of intestinal anti-microbial defense by the dietary additive, maltodextrin

2015

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“…Indeed recent genomic studies have failed to identify any AIEC-specific genes that can adequately explain the ability of this group of E. coli to invade epithelial cells and replicate in macrophages (Clarke et al, 2011;Krause et al, 2011;Miquel et al, 2010;Nash et al, 2010;Vejborg et al, 2011;Zhang et al, 2015). Nonetheless epidemiological evidence does suggest that E. coli are enriched in the guts and macrophages of the lamina propria of CD patients compared to healthy controls (Conte et al, 2014;Darfeuille-Michaud et al, 2004;de Souza et al, 2012;Elliott et al, 2015;Martinez-Medina et al, 2009).…”

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Glycolysis and pyrimidine biosynthesis are required for replication of adherent–invasive Escherichia coli in macrophages

et al. 2016

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Adherent-invasive Escherichia coli (AIEC) have been implicated in the aetiology of Crohn's disease (CD), a chronic inflammatory bowel condition. It has been proposed that AIEC-infected macrophages produce high levels of pro-inflammatory cytokines thus contributing to the inflammation observed in CD. AIEC can replicate in macrophages and we wanted to determine if bacterial replication was linked to the high level of cytokine production associated with AIECinfected macrophages. Therefore, we undertook a genetic analysis of the metabolic requirements for AIEC replication in the macrophage and we show that AIEC replication in this niche is dependent on bacterial glycolysis. In addition, our analyses indicate that AIEC have access to a wide range of nutrients in the macrophage, although the levels of purines and pyrimidines do appear to be limiting. Finally, we show that the macrophage response to AIEC infection is indistinguishable from the response to the non-replicating glycolysis mutant (DpfkAB) and a nonpathogenic strain of E. coli, MG1655. Therefore, AIEC does not appear to subvert the normal macrophage response to E. coli during infection.

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Molecular diversity of Escherichia coli in the human gut: New ecological evidence supporting the role of adherent-invasive E. coli (AIEC) in Crohnʼs disease

Abstract: New data about ecological parameters of AIEC reinforces the implication of AIEC in CD.

Cited by 348 publications

References 48 publications

Ribonucleotide Reductase NrdR as a Novel Regulator for Motility and Chemotaxis during Adherent-Invasive Escherichia coli Infection

Ribonucleotide Reductase NrdR as a Novel Regulator for Motility and Chemotaxis during Adherent-Invasive Escherichia coli Infection

Deregulation of intestinal anti-microbial defense by the dietary additive, maltodextrin

Glycolysis and pyrimidine biosynthesis are required for replication of adherent–invasive Escherichia coli in macrophages

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