Mucosal flora in inflammatory bowel disease

Swidsinski, Alexander; Ladhoff, Axel; Pernthaler, Annelie; Swidsinski, Sonja; Loening‐Baucke, Vera; Ortner, Maria-Anna; Weber, Jutta; Hoffmann, Uwe; Schreiber, Stefan; Dietel, Manfred; Lochs, Herbert

doi:10.1053/gast.2002.30294

Cited by 1,213 publications

(927 citation statements)

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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).…”

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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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“…Although washing colon biopsies removes residual fecal material and allows short-term cultures in the presence of antibiotics, it does not eliminate bacterial contamination. Furthermore, Swidsinski et al showed that IBD patients, particularly those with CD, have increased numbers of mucosally-associated bacteria that are not removed by washing (26). Thus, cytokine production during culture of colon biopsies may reflect stimulation that occurred in vivo or may be due to mucosallyadherent bacteria and their products that remain present at low levels within the cultures themselves.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, cytokine production during culture of colon biopsies may reflect stimulation that occurred in vivo or may be due to mucosallyadherent bacteria and their products that remain present at low levels within the cultures themselves. Any differences in mucosally-associated bacteria between biopsies obtained from normal and IBD patients would reflect differences that are also present in vivo (26).…”

Section: Discussionmentioning

confidence: 99%

Bromelain treatment decreases secretion of pro-inflammatory cytokines and chemokines by colon biopsies in vitro

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Calingaert

et al. 2008

Clinical Immunology

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Oral bromelain has been anecdotally reported to decrease inflammation in ulcerative colitis (UC). Proteolytically active bromelain is known to decrease expression of mRNAs encoding proinflammatory cytokines by human leukocytes in vitro. To assess the effect of bromelain on mucosal secretion of cytokines in inflammatory bowel disease (IBD), endoscopic colon biopsies from patients with UC, Crohn's disease (CD), and non-IBD controls were treated in vitro with bromelain or media, then cultured. Secretion of pro-inflammatory cytokines and chemokines was measured. Significant increases in granulocyte colony stimulating factor (G-CSF), interferon (IFN)-γ, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF) were detected in the media from actively inflamed areas in UC and CD as compared with non-inflamed IBD tissue and non-IBD controls. In vitro bromelain treatment decreased secretion of G-CSF, granulocyte-macrophage colony stimulating factor (GM-CSF), IFN-γ, CCL4/macrophage inhibitory protein (MIP)-1β, and TNF by inflamed tissue in IBD. Bromelain may be a novel therapy for IBD.

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“…This gene encodes a protein directly involved in the innate immune response to microbial antigens. This fact and evidence derived from animal models and clinical studies [11][12][13] suggest that an inappropriate innate response to normal constituents of the luminal microflora plays a crucial role in the development of these diseases.…”

Section: Introductionmentioning

confidence: 99%

Association of ATG16L1 and IRGM genes polymorphisms with inflammatory bowel disease: a meta-analysis approach

et al. 2009

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The aim of this study was to determine the role of the ATG16L1 (rs2241880) and IRGM (rs13361189 and rs4958847) genes polymorphism in Crohn's disease (CD) and ulcerative colitis (UC). Our study included 557 CD and 425 UC patients and 672 ethnically matched Spanish controls and a meta-analysis with the data published to date. The polymorphisms were genotyped using predesigned TaqMan single nucleotide polymorphism genotyping assays. There was a statistically significant difference in the distribution of the ATG16L1 rs2241880 G allele between CD patients and controls in the Spanish population: P ¼ 6.5 Â 10 À9 , odds ratio (OR) ¼ 1.62. Although no differences were observed between UC patients and controls in the Spanish cohort, a meta-analysis demonstrated that the ATG16L1 G allele increase significantly risk for UC (P ¼ 0.0003, pooled OR ¼ 1.08). In addition, our meta-analysis data showed that IRGM rs13361189 and rs4958847 polymorphisms were associated with CD (rs13361189 C allele P ¼ 1.07 Â 10 À19 , pooled OR ¼ 1.34; rs4958847 A allele P ¼ 2.78 Â 10 À17 , pooled OR ¼ 1.31) and UC (rs13361189 P ¼ 0.0069, pooled OR ¼ 1.16; rs4958847 P ¼ 0.014, pooled OR ¼ 1.13). In conclusion, our results confirm the ATG16L1 rs2241880 and IRGM rs13361189 and rs4958847 polymorphisms as important markers for CD susceptibility and indicate that these variants are also associated with UC.

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Mucosal flora in inflammatory bowel disease

Cited by 1,213 publications

References 29 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

Bromelain treatment decreases secretion of pro-inflammatory cytokines and chemokines by colon biopsies in vitro

Association of ATG16L1 and IRGM genes polymorphisms with inflammatory bowel disease: a meta-analysis approach

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