The fundamental basis of inflammatory bowel disease

Strober, Warren; Fuss, Ivan J.; Mannon, Peter J.

doi:10.1172/jci30587

Cited by 1,205 publications

(961 citation statements)

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“…A role for E. coli has been demonstrated in Crohn's disease (CD), an inflammatory bowel disease that occurs in individuals with a genetic predisposition to environmental or infectious triggers that cause an abnormal immune response (10)(11)(12)(13). 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).…”

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confidence: 99%

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

et al. 2015

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“…The role of the commensal bacteria in Crohn's disease and ulcerative colitis is currently being studied intensively (11,269,270). Some studies have implicated E. coli and B. vulgatus in the development of this disease.…”

Section: Infections In Adultsmentioning

confidence: 99%

“…High titers of antisera to a 26-kDa antigen on the surface of B. vulgatus was found in patients with Crohn's disease (10), but the association of these bacteria with the disease process remains somewhat unclear (95). In a very recent report, two hypotheses of the nature of the bacterial role in IBD (including ulcerative colitis and Crohn's disease) are discussed (270). One theory attributes an excessive immunologic response to normal microflora to a malfunction in the immune system.…”

Section: Infections In Adultsmentioning

confidence: 99%

Bacteroides: the Good, the Bad, and the Nitty-Gritty

2007

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SUMMARY Summary: Bacteroides species are significant clinical pathogens and are found in most anaerobic infections, with an associated mortality of more than 19%. The bacteria maintain a complex and generally beneficial relationship with the host when retained in the gut, but when they escape this environment they can cause significant pathology, including bacteremia and abscess formation in multiple body sites. Genomic and proteomic analyses have vastly added to our understanding of the manner in which Bacteroides species adapt to, and thrive in, the human gut. A few examples are (i) complex systems to sense and adapt to nutrient availability, (ii) multiple pump systems to expel toxic substances, and (iii) the ability to influence the host immune system so that it controls other (competing) pathogens. B. fragilis, which accounts for only 0.5% of the human colonic flora, is the most commonly isolated anaerobic pathogen due, in part, to its potent virulence factors. Species of the genus Bacteroides have the most antibiotic resistance mechanisms and the highest resistance rates of all anaerobic pathogens. Clinically, Bacteroides species have exhibited increasing resistance to many antibiotics, including cefoxitin, clindamycin, metronidazole, carbapenems, and fluoroquinolones (e.g., gatifloxacin, levofloxacin, and moxifloxacin).

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“…Changes in the normal bacterial flora and or the decreased incidence of intestinal parasites including worm infections are cited as the basis for the hygiene hypothesis in IBD (Khan et al 2002;Strober et al 2007;Koloski et al 2008). Experimental evidence shows that gastrointestinal worm infections can suppress IBD in experimental animals and humans (Khan et al 2002;Strober et al 2007;Koloski et al 2008). In addition, approaches that aim to alter the types of bacteria in the gastrointestinal track including the use of probiotics to replace the existing bacteria with "good" bacteria have been successful in some circumstances (Rolfe et al 2006).…”

Section: Vitamin D and The Hygiene Hypothesismentioning

confidence: 99%

The paradoxical effects of vitamin D on type 1 mediated immunity

Cantorna

Bruce

2008

Molecular Aspects of Medicine

123

115

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Low vitamin D status is associated with an increased risk of Th1 mediated autoimmune diseases like inflammatory bowel disease. 1,25(OH) 2 D 3 treatments have been shown to suppress Th1 mediated immunity and protect animals from experimental autoimmunity. Th1 mediated immunity is important for clearance of a number of different infectious diseases. For tuberculosis 1,25(OH) 2 D 3 treatment is associated with decreased Th1 mediated immunity but increased bactericidal activity. Systemic candidiasis is unaffected by 1,25(OH) 2 D 3 treatment. The seemingly paradoxical effects of 1,25(OH) 2 D 3 and vitamin D on Th1 mediated autoimmunity versus infectious immunity point to a broad array of vitamin D targets in the immune system. The interplay of these vitamin D targets and their impact on the host-immune response then dictate the outcome.

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The fundamental basis of inflammatory bowel disease

Abstract: Nonstandard abbreviations used: CARD15, caspase recruitment domain protein 15;ECOVA, E. coli-expressing OVA peptide; HD5, human α-defensin 5; IBD, inflammatory bowel disease; MDP, muramyl dipeptide; NOD2, nucleotide-binding oligomerization domain containing 2; PGN, peptidoglycan.

Cited by 1,205 publications

References 85 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

Bacteroides: the Good, the Bad, and the Nitty-Gritty

The paradoxical effects of vitamin D on type 1 mediated immunity

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