Invasive Bacteria Cause Crohn's Disease

Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn's disease. A Darfeuille-Michaud, C Neut, N Barnich, E Lederman, P Di Martino, P Desreumaux, L Gambiez, B Joly, A Cortot, JF Colombel. Gastroenterology 1998 Dec;115(6):1405-1413. 20 resected chronic ileal lesions, 19 neoterminal ileum from patients with (n = 19) and without (n = 11) endoscopic recurrence, and 13 controls. "None of the strains harbored any of the virulence factor-encoding genes of E. coli involved in acute enteric diseases. However, mannose-resistant adhesion to differentiated Caco-2 cells was found for 84.6% and 78.9% of the E. coli strains isolated from chronic and early recurrent lesions, respectively, compared with 33% of controls (P < 0.02). In addition, 21.8% of the strains induced a cytolytic effect by synthesis of an alpha-hemolysin."

Darfeuille-Michaud - Gastroenterology 1998 abstract / PubMed

Invasive ability of an Escherichia coli strain isolated from the ileal mucosa of a patient with Crohn's disease. J Boudeau, AL Glasser, E Masseret, B Joly, A Darfeuille-Michaud. Infect Immun 1999 Sep;67(9):4499-4509. "E. coli LF82 was able to efficiently invade HEp-2 cells. Its invasive level was not significantly different from that of EIEC and EPEC strains (P > 0.5) but significantly higher than that of ETEC (P < 0.03), EHEC (P < 0. 005), EAggEC (P < 0.004) and DAEC (P < 0.02) strains. Strain LF82 also demonstrated efficient ability to invade intestinal epithelial cultured Caco-2, Intestine-407, and HCT-8 cells. Electron microscopy examination of infected HEp-2 cells revealed the presence of numerous intracellular bacteria located in vacuoles or free in the host cell cytoplasm. In addition, the interaction of strain LF82 with epithelial cells was associated with the elongation of microvillar extensions that extruded from the host cell membranes and engulfed the bacteria. This internalization mechanism strongly resembles Salmonella- or Shigella-induced macropinocytosis."

Boudeau - Infect Immun 1999 full article / PubMed Central
Boudeau / Infect Immun 1999 full article

Identification of a novel bacterial sequence associated with Crohn's disease. CL Sutton, J Kim, A Yamane, H Dalwadi, B Wei, C Landers, SR Targan, J Braun. Gastroenterology 2000 Jul;119(1):23-31. "[S]pecimens from 212 patients showed that I2 DNA was present in many CD colonic lesions (43%), but was infrequent in other colonic specimens (9% of ulcerative colitis lesions and 5% of non-inflammatory bowel disease diseases; P<0.0001)." In 150 individuals, 54% of patients with Crohn's disease, 10% with ulcerative colitis, 19% with other inflammatory enteric diseases, and 4% of normals showed immunoglobulin A seroreactivity to an I2 fusion protein (P<0.001 to 0.00001).

Sutton - Gastroenterology 2000 abstract / PubMed

Association of antibody responses to microbial antigens and complications of small bowel Crohn's disease. WS Mow, EA Vasiliauskas, YC Lin, PR Fleshner, KA Papadakis, KD Taylor, CJ Landers, MT Abreu-Martin, JI Rotter, H Yang, SR Targan. Gastroenterology 2004 Feb;126(2):414-424. 303 patients. "When the presence and magnitude of antibody responses were considered, 90% of patients with small bowel disease who required surgery had high levels of I2, Escherichia coli outer membrane porin C, and oligomannan antibodies, compared with only 18.2% with low-titer responses (P < 0.001)."

Mow - Gastroenterology 2004 abstract / PubMed

Enhanced Escherichia coli adherence and invasion in Crohn's disease and colon cancer. HM Martin, BJ Campbell, CA Hart, C Mpofu, M Nayar, R Singh, H Englyst, HF Williams, JM Rhodes. Gastroenterology 2004 Jul;127(1):80-93. Biopsy samples from 14 CD patients, 21 UC patients, and 24 controls, and from 21 colon cancers. "Mucosa-associated and intramucosal bacteria were cultured more commonly in Crohn's disease (79%, P = 0.03; and 71%, P < 0.01, respectively), but not ulcerative colitis (38% and 48%), than in noninflamed controls (42% and 29%) and were commonly cultured from colon cancers (71% and 57%). Mucosa-associated E. coli, which accounted for 53% of isolates, were more common in Crohn's disease (6/14; 43%) than in noninflamed controls (4/24, 17%), as also were intramucosal E. coli: Crohn's disease, 29%; controls, 9%."

Martin - Gastroenterology 2004 abstract / PubMed

High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn's disease. A Darfeuille-Michaud, J Boudeau, P Bulois, C Neut, AL Glasser, N Barnich, MA Bringer, A Swidsinski, L Beaugerie, JF Colombel. Gastroenterology 2004 Aug;127(2):412-421. Ileal specimens of 63 patients with CD and 16 controls without inflammatory bowel disease (IBD), and with colonic specimens of 27 patients with CD, 8 patients with UC, and 102 controls. "In ileal specimens, AIEC strains were found in 21.7% of CD chronic lesions vs. in 6.2% of controls. In neoterminal ileal specimens, AIEC strains were found in 36.4% of CD early lesions (P = 0.034 vs. controls) and 22.2% of healthy mucosa of CD patients. In colonic specimens, AIEC strains were found in 3.7% of CD patients, 0% of UC patients, and 1.9% of controls."

Darfeuille-Michaud - Gastroenterology 2004 abstract / PubMed

Elevated serum anti-I2 and anti-OmpW antibody levels in children with IBD. S Iltanen, L Tervo, T Halttunen, B Wei, J Braun, I Rantala, T Honkanen, M Kronenberg, H Cheroutre, O Turovskaya, V Autio, M Ashorn. Inflamm Bowel Dis 2006 May;12(5):389-394. 35 children (18 with Crohn's disease, 12 with ulcerative colitis, and 5 with indeterminate colitis); versus 43 children with no inflammation in the gut. "In CD, seroreactivity to I2 and OmpW was 50% (9 of 18) and 61% (11 of 18), respectively. Serum anti-I2 and anti-OmpW immunoglobulin A levels were significantly elevated in children with CD in comparison with the non-IBD group (P = 0.007 and P = 0.001, respectively). A combination of OmpW, I2, and anti-S cerevisiae tests identified 94% of CD patients, and a combination of OmpW, I2, and perinuclear anti-neutrophil cytoplasmic antibodies detected 83% of UC cases."

Iltanen - Inflamm Bowel Dis 2006 abstract / PubMed

CEACAM6 acts as a receptor for adherent-invasive E. coli, supporting ileal mucosa colonization in Crohn disease. N Barnich, FA Carvalho, AL Glasser, C Darcha, P Jantscheff, M Allez, H Peeters, G Bommelaer, P Desreumaux, JF Colombel, A Darfeuille-Michaud. J Clin Invest 2007 Jun;117(6):1566-1574. "Here, we show that CD-associated AIEC strains adhere to the brush border of primary ileal enterocytes isolated from CD patients but not controls without inflammatory bowel disease. AIEC adhesion is dependent on type 1 pili expression on the bacterial surface and on carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) expression on the apical surface of ileal epithelial cells. We report also that CEACAM6 acts as a receptor for AIEC adhesion and is abnormally expressed by ileal epithelial cells in CD patients. In addition, our in vitro studies show that there is increased CEACAM6 expression in cultured intestinal epithelial cells after IFN-gamma or TNF-alpha stimulation and after infection with AIEC bacteria, indicating that AIEC can promote its own colonization in CD patients."

Barnich - J Clin Invest 2007 full article / PubMed Central
Barnich / J Clin Invest 2007 full article

Culture independent analysis of ileal mucosa reveals a selective increase in invasive Escherichia coli of novel phylogeny relative to depletion of Clostridiales in Crohn's disease involving the ileum. M Baumgart, B Dogan, M Rishniw, G Weitzman, B Bosworth, R Yantiss, RH Orsi, M Wiedmann, P McDonough, SG Kim, D Berg, Y Schukken, E Scherl, KW Simpson. ISME J 2007 Sep;1(5):403-418. Patients with Crohn's disease of the ileum (13) and colon (8), and 7 healthy controls. "16S rDNA libraries of ileitis mucosa were enriched in sequences for Escherichia coli (P<0.001), but relatively depleted in a subset of Clostridiales (P<0.05). PCR of mucosal DNA was negative for Mycobacterium avium subspecies paratuberculosis, Shigella and Listeria. The number of E. coli in situ correlated with the severity of ileal disease (rho 0.621, P<0.001) and invasive E. coli was restricted to inflamed mucosa. E. coli strains isolated from the ileum were predominantly novel in phylogeny, displayed pathogen-like behavior in vitro and harbored chromosomal and episomal elements similar to those described in extraintestinal pathogenic E. coli and pathogenic Enterobacteriaceae."

Baumgart / ISME J 2007 full article

Invasive Escherichia coli are a feature of Crohn's disease. M Sasaki, SV Sitaraman, BA Babbin, P Gerner-Smidt, EM Ribot, N Garrett, JA Alpern, A Akyildiz, AL Theiss, A Nusrat, JM Klapproth. Lab Invest 2007 Oct;87(10):1042-1054. 15 patients with CD, 12 with UC, and 12 normal controls. "Of all invasive bacterial strains in CD 98.9% were identified as E. coli as opposed to 42.1% in UC and 2.1% in normal controls. Epithelial invasion in vitro was significantly higher for CD-associated E. coli (8.4%, +/-5.5 of initial inoculum (I/O)) in comparison to UC (2.5%, +/-0.4 I/O), but highest for strains from inflamed CD tissue (11.3%, +/-4.3 I/O). Both, CD and UC E. coli strains induced high mean TNF-alpha expression in macrophage cell lines (2604.8 pg/10(5) cells, +/-447.4; 2,402.6 pg/10(5) cells, +/-476.3, respectively), but concentrations were significantly higher for isolates from inflamed CD tissue (3071.3 pg/10(5) cells, +/-226.0). Invasive E. coli from IBD tissue induced similar concentrations of interleukin (IL)-8 in epithelial cell cultures, but strains from inflamed CD tissue induced significantly less epithelial IL-8 (674.1 pg/10(5) cells, +/-58.0 vs 920.5 pg/10(5) cells, +/-94.6). IBD-associated E. coli strains significantly decreased transepithelial resistance, induced disorganization of F-actin and displacement of ZO-1, and E-cadherin from the apical junctional complex (AJC)."

Sasaki / Lab Invest 2007 full article

Escherichia coli isolated from a Crohn's disease patient adheres, invades, and induces inflammatory responses in polarized intestinal epithelial cells.T Eaves-Pyles, CA Allen, J Taormina, A Swidsinski, CB Tutt, GE Jezek, M Islas-Islas, AG Torres. Int J Med Microbiol 2008 Jul;298(5-6):397-409. Of four strains of E. coli (LF82, O83:H1, 6604 and 6655) isolated from Crohn's Disease patients, "O83:H1 displayed the best characteristics of AIEC strains as compared to the prototype AIEC strain LF82, inducing cytokine secretion from IEC and promoting immune cell migration through IEC. Upon further analysis, E. coli O83:H1 did not harbor virulence genes present in known pathogenic intestinal organisms. Further characterization of E. coli O83:H1 virulence determinants showed that a non-flagellated O83:H1 strain significantly decreased the organism's ability to adhere to and invade both IEC and elicit IEC cytokine secretion compared to the wild type and complemented strains."

Eaves-Pyles - Int J Med Microbiol 2008 abstract / PubMed

Molecular diversity of Escherichia coli in the human gut: new ecological evidence supporting the role of adherent-invasive E. coli (AIEC) in Crohn's disease. M Martinez-Medina, X Aldeguer, M Lopez-Siles, F González-Huix, C López-Oliu, G Dahbi, JE Blanco, J Blanco, LJ Garcia-Gil, A Darfeuille-Michaud. Inflamm Bowel Dis 2009 Jun;15(6):872-882. "Approximately 100 E. coli colonies per biopsy from 20 CD patients (18 biopsies from colon and 23 from ileum) and 28 healthy controls (C) (25, colon; 27, ileum) were isolated... Mucosa-associated E. coli richness (E. coli subtypes/patient: C = 2.0 +/- 1.0; CD = 2.1 +/- 1.3) and diversity (Shannon Index: H'(C): 2.1 +/- 0.6; H'(CD): 2.5 +/- 0.8) were similar between CD and C, but higher E. coli counts were characteristic of CD patients (P = 0.010), particularly those with Crohn's ileitis (P = 0.001). Host-specific pulsotypes shared virulence features of ExPEC at similar frequencies between CD and C, except for iucD, which was more prevalent in E. coli from controls (C: 75%, CD: 40%, P = 0.027). In contrast, greater AIEC prevalence (% subjects with AIEC: CD = 51.9%; C = 16.7%; P = 0.003), abundance (% AIEC/E. coli: CD = 3.8 +/- 5.0%; C = 1.5 +/- 3.8%; P = 0.039), and richness (number of AIEC subtypes: CD = 0.8 +/- 1.4; C = 0.2 +/- 0.4; P = 0.015) of E. coli strains belonging to the AIEC pathovar was observed for CD patients. AIEC subtypes showed a high variability of seropathotypes and pulsotypes, although the B2 phylogroup was the most prevalent (AIEC: 64%, non-AIEC: 38%, P = 0.044)."

Martinez-Medina - Inflamm Bowel Dis 2009 abstract / PubMed

Crohn disease--associated adherent-invasive E. coli bacteria target mouse and human Peyer's patches via long polar fimbriae. B Chassaing, N Rolhion, A de Vallée, SY Salim, M Prorok-Hamon, C Neut, BJ Campbell, JD Söderholm, JP Hugot, JF Colombel, A Darfeuille-Michaud. J Clin Invest 2011 Mar;121(3):966-975. "We found that AIEC bacteria could interact with mouse and human PPs via long polar fimbriae (LPF). An LPF-negative AIEC mutant was highly impaired in its ability to interact with mouse and human PPs and to translocate across monolayers of M cells, specialized epithelial cells at the surface of PPs. The prevalence of AIEC strains harboring the lpf operon was markedly higher in CD patients compared with controls. In addition, increased numbers of AIEC, but not LPF-deficient AIEC, bacteria were found interacting with PPs from Nod2(-/-) mice compared with WT mice."

Chassaing - J Clin Invest 2011 full article / PubMed Central
Chassaing / J Clin Invest 2011 full article

Analysis of Escherichia coli isolated from patients affected by Crohn's disease. T Raso, S Crivellaro, MG Chirillo, P Pais, E Gaia, D Savoia. Curr Microbiol 2011 Aug;63(2):131-137. Seven E. coli strains from 14 biopsies from ileocolic ulcers of six patients with ulcerative colitis and eight with CD. "Five strains, exclusively isolated from CD patients, were found inside mucosal cells... Overall our pilot data suggest that five among eight strains isolated from CD patients belonged to the adherent-invasive E. coli (AIEC) group, and were invasive on Caco-2 cells and resistant to phagocytosis. These findings suggest that these bacteria could be considered target organisms whose elimination could reduce the intestinal inflammatory process and CD progression."

Raso - Curr Microbiol 2011 abstract / PubMed

Adherent-invasive Escherichia coli induce claudin-2 expression and barrier defect in CEABAC10 mice and Crohn's disease patients. J Denizot, A Sivignon, F Barreau, C Darcha, HF Chan, CP Stanners, P Hofman, A Darfeuille-Michaud, N Barnich. Inflamm Bowel Dis 2012 Feb;18(2):294-304. "Pore-forming tight junction protein claudin-2 is strongly expressed in the ileum of 51% patients in quiescent phase and in 49% of the patients with active CD. Infection of CEABAC10 transgenic mice expressing human CEACAMs with AIEC, but not with nonpathogenic E. coli, led to a significant 3.0-fold increase in intestinal permeability and to disruption of mucosal integrity in a type 1 pili-dependent mechanism. This is consistent with the claudin-2 abnormal expression at the plasma membrane of intestinal epithelial cells observed in AIEC-infected CEABAC10 mice. AIEC bacteria were able to translocate through CEABAC10 intestinal mucosa."

Denizot - Inflamm Bowel Dis 2012 abstract / PubMed

The many faces of Crohn’s Disease: Latest concepts in etiology. J Campbell, TJ Borody, S Leis. Open Journal of Internal Medicine 2012 Jun;2(2):107-115. "Here, we present an overview of the infectious pathogens in the CD Syndrome and propose that they are not 'mimickers' of the disease but actual causes of CD in subsets of patients." Mycobacterium avium ss paratuberculosis, Mycobacterium tuberculosis, Yersinia spp, Entamoeba histolytica, Adherent-Invasive Escherichia coli, and Campylobacter concisus are reviewed. "The list of documented pathogens capable of causing 'Crohn’s Disease' is extensive and one can no longer dismiss them as 'mere 'mimickers' or 'innocent by-standers' in the disease. Given the sheer number of infections capable of reproducing the hallmark clinical, colonoscopic and histological features of CD, it appears unlikely that a separate mechanism of an 'aberrant reaction' to our own normal colonic flora is at play. It is most likely that currently unidentifiable pathogens are responsible for the remaining subset of CDS cases."

Campbell / OJIM 2012 full article landing

Point Mutations in FimH Adhesin of Crohn's Disease-Associated Adherent-Invasive Escherichia coli Enhance Intestinal Inflammatory Response. N Dreux, J Denizot, M Martinez-Medina, A Mellmann, M Billig, D Kisiela, S Chattopadhyay, E Sokurenko, C Neut, C Gower-Rousseau, JF Colombel, R Bonnet, A Darfeuille-Michaud, N Barnich. PLoS Pathog 2013 Jan;9(1):e1003141. "The fimH genes of 45 AIEC and 47 non-AIEC strains were sequenced. The phylogenetic tree based on fimH DNA sequences indicated that AIEC strains predominantly express FimH with amino acid mutations of a recent evolutionary origin - a typical signature of pathoadaptive changes of bacterial pathogens. Point mutations in FimH, some of a unique AIEC-associated nature, confer AIEC bacteria a significantly higher ability to adhere to CEACAM-expressing T84 intestinal epithelial cells. Moreover, in the LF82 strain, the replacement of fimH(LF82) (expressing FimH with an AIEC-associated mutation) with fimH(K12) (expressing FimH of commensal E. coli K12) decreased the ability of bacteria to persist and to induce severe colitis and gut inflammation in infected CEABAC10 transgenic mice expressing human CEACAM receptors."

Dreux - PLoS Pathog 2013 full article / PubMed Central
Dreux / PLoS Pathog 2013 full article

Adherent-invasive Escherichia coli blocks interferon-γ-induced signal transducer and activator of transcription (STAT)-1 in human intestinal epithelial cells. JC Ossa, NK Ho, E Wine, N Leung, SD Gray-Owen, PM Sherman. Cell Microbiol 2013 Mar;15(3):446-457. "Our data show that live AIEC with active protein synthesis machinery is able to prevent IFNγ-mediated STAT1 phosphorylation, and that a secreted factor may be involved. We conclude that the suppression of epithelial cell STAT1 signal transduction by AIEC strains isolated from patients with Crohn disease represents a novel mechanism by which the pathogen evades host immune responses to the infection."

Ossa - Cell Microbiol 2013 abstract / PubMed

Pfit Is a Structurally Novel Crohn's Disease-Associated Superantigen. L Liu, H Chen, MB Brecher, Z Li, B Wei, B Nandi, J Zhang, H Ling, G Winslow, J Braun, H Li. PLoS Pathog 2013;9(12):e1003837. "In this study, we describe structural and functional studies of the CD-associated superantigen pfiT. We show that pfiT can stimulate the activation of both mouse splenocytes and human peripheral blood mononuclear cells (PBMCs). We show that pfiT specifically and directly interacts with class II MHC HLA-DR, and to a lesser extent HLA-DP or HLA-DQ, and show that pfiT shares an overlapping binding site on HLA-DR1 with other superantigens. Crystal structure of pfiT at high resolution revealed that pfiT belongs to the bacterial transcription factor family of tetracycline repressor (TetR). The distinct structure of pfiT relative to other SAgs suggests that it represents a novel family of SAg."

Liu / PLoS Pathog 2013 full article

Host Defense Peptide Resistance Contributes to Colonization and Maximal Intestinal Pathology by Crohn's Disease-Associated Adherent-Invasive Escherichia coli. JB McPhee, CL Small, SA Reid-Yu, JR Brannon, H Le Moual, BK Coombes. Infect Immun 2014 Aug;82(8):3383-3393. "We identified a plasmid-encoded genomic island (called PI-6) in AIEC strain NRG857c that confers high-level resistance to α-helical cationic peptides and α- and β-defensins. Deletion of PI-6 sensitized strain NRG857c to these host defense molecules, reduced its competitive fitness in a mouse model of infection, and attenuated its ability to induce cecal pathology. This phenotype is due to two genes in PI-6, arlA, which encodes a Mig-14 family protein implicated in defensin resistance, and arlC, an OmpT family outer membrane protease."

Small - Infect Immun 2014 abstract / PubMed

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cast 07-18-14