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World J Gastroenterol. Sep 14, 2014; 20(34): 12102-12117
Published online Sep 14, 2014. doi: 10.3748/wjg.v20.i34.12102
Infectious etiopathogenesis of Crohn’s disease
Jessica Carrière, Arlette Darfeuille-Michaud, Hang Thi Thu Nguyen, Clermont Université, M2iSH, UMR 1071 Inserm/University of Auvergne, 63001 Clermont-Ferrand, France
Jessica Carrière, Arlette Darfeuille-Michaud, Hang Thi Thu Nguyen, INRA USC 2018, 63000 Clermont-Ferrand, France
Arlette Darfeuille-Michaud, Centre Hospitalier Universitaire, 63000 Clermont-Ferrand, France
Author contributions: Carrière J and Nguyen HTT wrote the manuscript. Darfeuille-Michaud A reviewed and edited the manuscript.
Supported by Ministère de la Recherche et de la Technologie, Inserm (UMR1071), INRA (USC-2018); Grants from the Association François Aupetit (to Darfeuille-Michaud A); and the European Union FP7 People Marie Curie International Incoming Fellowship (to Nguyen HTT)
Correspondence to: Hang Thi Thu Nguyen, PhD, Clermont Université, M2iSH, UMR 1071 Inserm/University of Auvergne, 28 Place Henri Dunant, 63001 Clermont-Ferrand, France. hang.nguyen@udamail.fr
Telephone: +33-4-73178372 Fax: +33-4-73178371
Received: February 26, 2014
Revised: April 18, 2014
Accepted: May 25, 2014
Published online: September 14, 2014

Abstract

Important advances during the last decade have been made in understanding the complex etiopathogenesis of Crohn’s disease (CD). While many gaps in our knowledge still exist, it has been suggested that the etiology of CD is multifactorial including genetic, environmental and infectious factors. The most widely accepted theory states that CD is caused by an aggressive immune response to infectious agents in genetically predisposed individuals. The rise of genome-wide association studies allowed the identification of loci and genetic variants in several components of host innate and adaptive immune responses to microorganisms in the gut, highlighting an implication of intestinal microbiota in CD etiology. Moreover, numerous independent studies reported a dysbiosis, i.e., a modification of intestinal microbiota composition, with an imbalance between the abundance of beneficial and harmful bacteria. Although microorganisms including viruses, yeasts, fungi and bacteria have been postulated as potential CD pathogens, based on epidemiological, clinicopathological, genetic and experimental evidence, their precise role in this disease is not clearly defined. This review summarizes the current knowledge of the infectious agents associated with an increased risk of developing CD. Therapeutic approaches to modulate the intestinal dysbiosis and to target the putative CD-associated pathogens, as well as their potential mechanisms of action are also discussed.

Key Words: Crohn’s disease, Intestinal microbiota, Dysbiosis, Adherent-invasive Escherichia coli, Probiotics, Antibiotics, Fecal microbiota transplantation

Core tip: Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract of which the etiopathogenesis is not fully understood. Increasing evidence has shown that the etiology of CD is multifactorial involving genetic, environmental and infectious factors. A dysbiosis with an increase in the abundance of putative pathogenic bacteria and a decrease in that of potentially beneficial bacteria has been observed in CD patients, revealing the involvement of intestinal microbiota in such disease. This review aims to summarize the current knowledge of the infectious etiology of CD and to discuss therapeutic approaches to modulate intestinal dysbiosis and to target CD-associated pathogens.



INTRODUCTION

The etiopathogenesis of Crohn’s disease (CD), a type of inflammatory bowel diseases (IBD), is complex and consists, according to clinical and epidemiological studies, of three interacting elements: environmental factors, genetic susceptibility and infectious agents. While many gaps in our knowledge still exist, the most widely accepted theory holds that the disorder is caused by an aggressive immune response to microorganisms of the intestinal microbiota in genetically predisposed individuals.

The early identification of nucleotide-binding oligomerization domain-containing protein 2 (NOD2), an intracellular sensor of pathogen/microbe-associated molecular patterns, as a susceptibility gene for CD[1,2] has highlighted the role of innate immunity in the disease. This has been substantiated by genome-wide association studies (GWAS) with the identification of genetic association between CD susceptibility and variants in genes involved in autophagy, ATG16L1 (autophagy-related 16-like 1) and IRGM (Immune-Related GTPase M)[3-6]. To date, 70 independent loci or genetic variants linked to various components of innate and adaptive immunity have been identified by GWAS as CD susceptibility factors[4-12]. Arguments in favor of the involvement of environmental factors in CD etiology, which are based on the observation of the irregular distribution of CD cases worldwide, have been raised. Since the appearance of IBD in the middle of the 20th century, the CD incidence and prevalence have shown a continually growing profile in industrialized countries or “Western” countries, such as North Europe and North America, suggesting an involvement of lifestyle[13]. Another epidemiological study also showed that “Western” diet, rich in fat and sugar and poor in fibers, is associated with an increased risk of developing CD[14]. This is recently reported that active smoking is associated with an increased risk of developing CD and that smoking cessation leads to a reduced progression of the disease comparatively to patients who still smoke[15]. Other environmental factors, such as antibiotic use, social status, microbial exposure early in life and during life have been also associated with CD[16]. Whether these factors, along with genetic susceptibility, lead directly to CD, or whether they allow the conditions needed for infectious agents to thrive, is not clear.

Numerous epidemiological studies, clinicopathological data, genetic and experimental evidence increasingly support an implication of microrganisms in CD pathogenesis. Three non-mutually exclusive theories are currently explored to explain the infectious etiology of CD: (1) a “dysbiosis”, i.e. a modification of intestinal microbiota composition with an imbalance between beneficial and harmful bacteria; (2) an excessive bacterial translocation caused by a disrupted intestinal barrier function and defective immune responses; and (3) persistence of a pathogen. This review summarizes our current knowledge of various organisms that have been postulated as infectious agents in CD, and discusses how this may be relevant to the pathogenesis of CD and the new therapeutic approaches.

INTESTINAL MICROBIOTA AND CD
Human intestinal microbiota

The human gastrointestinal (GI) tract contains 1014 microorganisms of more than 500-1000 different species, forming intestinal microbiota[17]. The density of intestinal microbiota varies along the GI tract, going from 102 colony forming units (CFU) per gram in stomach to 1012 CFU per gram in colon[18].

The intestinal microbial composition can vary greatly between individuals, and an epidemiological study comparing the fecal microbiota between African and European children showed that its composition is determined in part by hygiene, geography and diet[19]. Higher similarity in fecal bacterial species was reported within twins than in genetically unrelated couples sharing environment and dietary habits[20]. The gut microbiota composition of siblings also showed increased similarity compared to that of spouses, who were living in the same environment and had similar eating habits[21].

Given the complexity of the human intestinal microbiota, the characterization of its composition using conventional culture methods and morphological and biochemical-based traditional techniques is limited. Development of new biomolecular techniques, using high-throughput sequencing, allows circumventing these difficulties. Two approaches are currently available. The first is based on sequencing of the 16S ribosomal RNA coding gene (16S rDNA), which is conserved between all phylogenetic bacterial groups[22]. The second one, namely the metagenomic approach, is based on a complete sequencing of bacterial genome. The evolution of high-throughput technologies with next-generation sequencing allows producing thousands or millions of sequences at once, reducing drastically the costs and facilitating access to full metagenomic sequencing. Dominant bacterial populations in the human intestinal microbiota (> 90%) belong to two phyla: the Firmicutes and the Bacteroidetes; the remainders belong to rarer phyla such as Proteobacteria (containing genuses such as Escherichia and Helicobacter) and Actinobacteria as well as viruses, protists, and fungi[23-26]. Interestingly, mucosa-associated microbiota is different from the fecal microbiota[27]. The composition of the fecal microbiota may temporally vary following exposure to different types of foods, medications, or physical environments, and also from changes in transit time, as microbial composition in the lumen varies from caecum to rectum[24].

Intestinal dysbiosis and CD

An imbalance of the intestinal microbiota, i.e. a modification of its composition, with decreased complexity of commensal bacterial profiles and higher numbers of mucosa-associated bacteria, has been reported in CD patients.

Using a 16S rDNA-based profiling technique, Ott and colleagues showed that the diversity of mucosa-associated microbiota in specimens from patients with active CD undergoing surgery was markedly reduced compared with mucosal specimens from control individuals without inflammation[28]. Metagenomic studies have shown a decrease in the abundance of several species of the Firmicutes and the Bacteroidetes phyla in CD patients compared with control subjects[29-32]. The decrease in the abundance of Bacteroidetes could contribute to inflammation since some bacteria belonging to this phyla such as Bacteroides fragilis have been shown to exhibit protective effects in a mouse model of colitis induced by Helicobacter hepaticus, a murine commensal bacterium with pathogenic properties[33]. Among Firmicutes, a decrease of the amount of Faecalibacterium prausnitzii (F. prausnitzii) has been observed in CD patients compared with control subjects[34]. In mouse models of intestinal inflammation, administration of F. prausnitzii resulted in anti-inflammatory effects[34]. Therefore, the decreased abundance of F. prausnitzii could contribute to intestinal inflammation in CD. It has been consistently reported that CD patients have relatively increased amount of Enterobacteriaceae, particularly Escherichia coli (E. coli) species, compared with control subjects, with a more pronounced difference was observed for mucosa-associated microbiota than fecal samples[35-43]. An increase in the abundance of some mucolytic bacteria, such as Ruminococcus gnavus and Ruminococcus torques, in CD patients was also observed[44].

ROLE OF BACTERIA IN THE PATHOGENESIS OF CD

The intestinal mucosal surface is in a continuous contact with the intestinal microbiota. Given the enormous numbers of enteric bacteria and the persistent threat of opportunistic invasion, it is crucial that the host maintains homeostasis at the luminal surface of the intestinal-microbial interface. This is mediated by a perfect integrity of the intestinal barrier and a functional immunotolerance to the intestinal microbiota and luminal antigens.

Excessive bacterial translocation caused by intestinal epithelial barrier dysfunction

The intestinal barrier allows the absorption of water, ions and nutrients without leaving the microorganisms to penetrate across the mucosal surface. The first line of defence between the intestinal lumen and inner milieu, the physical barrier, is made up of a layer of columnar epithelial cells. More than 80% of these cells are enterocytes, and the rest are enteroendocrine, goblet, and Paneth cells[45]. Epithelial cells are connected via the intercellular junctional complexes including tight junctions, adherent junctions, desmosomes and gap junctions[46].

Many studies have shown an increased intestinal permeability in CD patients during active phases and a decreased permeability in remission phases[47-51]. Electron microscopy analyses of biopsies from CD patients in active phases revealed a reduced number of tight junctions compared with control subjects[52]. A deregulation of tight junction proteins has been reported in CD patients, with an up-regulation of claudin-2 and a down-regulation of claudin-5 and 8[52]. The alteration of intestinal permeability observed during active phases of CD could explain the chronic inflammation, given the probably resulting transit of bacteria and other luminal antigens through the mucosa, which are able to activate the sub-mucosal innate immune system.

The intestinal epithelial surface is covered by a mucus layer that prevents the contact between the epithelial layer and microorganisms and the diffusion of unwanted substances, as well as protects the physical barrier from sheer stress. The main component of the mucus layer is mucins secreted by goblet cells, which are heavily glycosylated proteins[53]. The outer loose mucus layer contains a limited number of intestinal microbes; whereas the inner adherent mucus layer contains very few microbes, forming a protected zone adjacent to the epithelial surface[54]. It is likely that the antimicrobial proteins, which are secreted by epithelial cells and are retained in the mucus layer, contribute to the maintenance of low bacterial numbers in the inner mucus layer[55]. These “bodyguards” are members of several distinct protein families such as defensins, cathelicidins, and C-type lectins, and they promote bacterial killing by targeting the integrity of bacterial cell walls[56]. Mice lacking the mucin MUC2 are unable to maintain this relative “bacteria-free” zone and suffer from intestinal inflammation[54]. It has been shown that mucin gene expression, mucus composition and secretion are altered by intestinal microbiota and host-derived inflammatory mediators[53].

Dysfunction of immunotolerance and innate immune response to bacteria

Maintenance of immunotolerance and innate immune responses, which allows the control of inflammatory responses in intestinal epithelium, is mediated by several mechanisms: (1) secretion of IgA; (2) bacterial clearance via the production of antimicrobial peptides; or (3) a functional autophagic process. Changes in these processes have been observed in CD, which could contribute to abnormal immune responses.

Defective secretory IgA production in CD: The IgA immunoglobulins are secreted by B lymphocytes localized in the intestinal lamina propria[57]. The secretory IgA is transcytosed across the epithelium and retained in the mucus layer, where it acts to entrap the luminal antigens and bacteria. Bacteria present in the lumen or penetrating the intestinal epithelium are detected by dendritic cells that will alert B cells in the Peyer’s patches, which will, in turn, produce IgA specific for intestinal bacteria[57]. Mice that lack activation-induced cytidine deaminase (AID), which results in defective IgA production in the intestine, exhibit an expansion of mucosa-associated bacteria such as segmented filamentous bacteria (SFB)[58]. This suggests that secreted IgA also regulates the composition and density of bacterial communities[58]. In IBD patients, a serologic shift from an IgA-dominant to an IgG-dominant response in the intestine, which may act as another local defense line, has been reported[59]. IgG is likely to have an inflammatory effect because in response to flagellin, a common bacterial antigen, the neonatal receptor for IgG FcRn, expressed in hematopoietic cells, promotes inflammation in the presence of anti-flagellin IgG in mice[60].

Defective bacterial killing through secretion of antimicrobial peptides: The intestinal epithelia secrete antimicrobial molecules whose function is to kill commensal or pathogenic bacteria. Among these molecules are peptides named defensins. Most defensins function by binding to the microbial cell membrane, and, once embedded, forming pore-like membrane defects that allow efflux of essential ions and nutrients[61,62]. Two classes of defensins have been described in human, α and β-defensins. The α-defensin peptides are mainly secreted by Paneth cells and neutrophils, while β-defensins are more generally secreted by epithelial cells[61]. The biosynthesis of defensins is triggered by the activation of receptors involved in recognition of extracellular and intracellular bacterial components like Toll-like receptors (TLR) and NOD receptors, respectively, leading to a rapid killing of bacteria in contact with the intestinal epithelium[63]. Changes in intestinal microbiota were observed in mice that express the human α-defensin 5 and also in mice that do not produce functional α-defensins[64], suggesting that defensins also regulate the composition and density of bacterial communities. A decrease in α-defensin expression in Paneth cells has been reported in patients with ileal CD, particularly those carrying mutations in NOD2 gene[65], indicating the link between infectious etiology and host genetic susceptibility. Reduced expression of β-defensins has been observed in patients with colonic CD[65]. Other antimicrobial proteins including lysozyme and RegIIIγ are secreted by Paneth cells upon exposure to bacteria or bacterial antigens[66], thereby contributing to host defense against mucosal penetration of both symbiotic and pathogenic bacteria. Mice with a genetic ablation of Paneth cells exhibit increased translocation of bacteria into the host tissues, indicating that Paneth cells contribute to maintaining luminal compartmentalization of intestinal bacteria[67]. The abnormal synthesis of antimicrobial proteins in CD patients could result in increased intestinal barrier permeability to bacteria that could consequently lead to chronic inflammation.

Defective bacterial clearance by autophagy: Autophagy is a homeostatic process that involves degradation of dysfunctional cellular components through the lysosomal machinery. The newly discovered specialized role of autophagy expands autophagic functions as an immune defense mechanism against intracellular pathogens (also referred to as xenophagy)[67,68]. GWAS have revealed CD-associated risk variants in several autophagy genes, such as ATG16L1, IRGM, ULK1 (Unc-51 like autophagy activating kinase 1), PTPN2 (protein tyrosine phosphatase nonreceptor type 2) and LRRK2 (leucine-rich repeat kinase 2)[68]. This raised autophagy as one of the most attractive molecular pathways in the field of CD. Further efforts have been made to investigate a functional implication of autophagy in CD pathogenesis[68,69]. A link between autophagy and the innate immune receptor NOD2 has been established, the latter recruits and interacts with ATG16L1 at site of bacterial entry in the plasma membrane[70-72]. These studies have also shown that in epithelial cells, macrophages and dendritic cells, one of the ATG16L1 or NOD2 risk variants could result in impaired intracellular pathogenic bacterial clearance owing to a defect in xenophagy response. CD patients homozygous for the ATG16L1 risk allele exhibited structural aberrances in Paneth cells similar to those observed in mice with hypomorphic ATG16L1 expression, i.e. decreased granule number and lack of lysosomes in the ileal mucus layer[73]. This indicates that defects in intestinal barrier function in CD could involve dysfunction of Paneth cells related to ATG16L1 mutation. Interestingly, the CD-associated c.313C>T polymorphism located within the IRGM mRNA region results in loss of binding of microRNA-196[74]. This consequently leads to aberrance of regulation of IRGM expression by microRNA-196 and defects in autophagy-mediated control of intracellular replication of the CD-associated adherent-invasive E. coli[74]. Together, these studies suggest that a defect in the autophagy machinery in CD patients could lead to an uncontrolled bacterial proliferation inside host cells and consequently cause chronic inflammation.

INFECTIOUS AGENTS AND CD

Numerous epidemiological, clinicopathological, genetic and experimental evidence has suggested an intervention of infectious agents in CD etiology. Firstly, the preferential location of the lesions in CD are situated in the terminal ileum and colon[75], where the largest population of bacteria is found[18]. Secondly, the use of antibiotics in CD treatment has been proven to be sometimes effective[76]. Thirdly, higher numbers of mucosa-associated and internalized bacteria in biopsies from CD patients compared to control subjects was also reported[37]. These observations, together with the identification of CD-associated polymorphisms in genes encoding innate immune receptors involved in the recognition of bacterial components or proteins participating in the clearance of pathogenic bacteria by autophagy highly support the hypothesis of an involvement of infectious agents in CD etiology. Those who have been suspected to modify the risk of developing CD include viruses, eukaryotes and bacteria.

Implication of virus in CD

Investigations of viral agents in CD patients have been accomplished with the use of PCR and RT-PCR, and allowed to identify the Epstein Barr virus (EBV) in 15% of patients[77]. No enterovirus has been detected in the gut of CD patients[77]. Interestingly, Cadwell et al[78] showed that the abnormalities of Paneth cells in hypomorphic ATG16L1HM mice are dependent on a contact with a particular murine norovirus strain CR6, since mice raised in a germ-free condition or mice infected with a non-persistent norovirus strain exhibited normal Paneth cell morphology. In humans, several clinical studies have shown that norovirus infection can aggravate IBD symptoms[79,80]. Although there is no direct evidence showing that viral infection could be a causative factor of CD, the study by Cadwell et al[78] suggests that the combination of host genetic susceptibility and the presence of viral factors could lead to CD occurrence.

Bacteriophages are other viral agents that have been suspected to play a role in CD pathogenesis. Indeed, it has been shown that bacteriophages may result in dysbiosis by triggering a destabilization of microbial communities[81]. A study analyzing the bacteriophage population in CD patients reported that each patient is colonized by one dominant phage family[82]. In addition, the amount of bacteriophages is significantly increased in CD patients compared with control subjects, and is decreased in ulcerated areas compared with non-ulcerated areas[82].

Implication of yeast in CD: Candida albicans

In 2006, the presence of anti-Saccharomyces cerevisiae antibodies (ASCA), involved in the recognition of a mannose residue on the surface of the non-pathogenic yeast Saccharomyces cerevisiae[83], was shown in the serum of 39%-70% of CD patients vs 0%-5% of control subjects[84]. A study proposed that the fungal pathogen Candida albicans could act as an intestinal pathogen by triggering the production of ASCA, given that it expresses the ASCA epitope on many surface molecules[85]. The presence of ASCA in CD patients could reflect a decrease of immunotolerance towards specific antigens of this endogenous yeast. It has been observed that CD patients and their unaffected relatives display a greater colonization of the gastrointestinal tract by Candida albicans with respective values of 44 and 38% than the general population with 22%[86]. In addition, Candida albicans colonizes and aggravates gut inflammation in mice[87]. Although its role in CD etiopathogenesis has not yet been elucidated, the hypothesis of an involvement of Candida albicans needs to be taken into consideration.

Implication of pathogenic bacteria in CD

Mycobacterium avium subspecies paratuberculosis:Mycobacterium avium subspecies paratuberculosis (MAP) is the causative agent of the Johne’s disease, a chronic granulomatous ileitis most common in ruminants, but can also affect many other species including primates. Given that this pathology shares some facets with CD, MAP could be an agent implicated in the complex etiology of CD[88,89]. Research groups aiming to identify MAP in CD patients by isolation methods or by amplification of specific DNA sequences have reported contradictory results; while some show the presence of this bacterium in the blood and intestinal biopsies from CD patients[90-94], some do not[95-98]. Furthermore, serologic analyses have highlighted the presence of antibodies against MAP in 90% of CD patients[99]. Administration of antibiotics with strong activity against mycobacteria has resulted in remission in approximately 66%-75% of patients with active CD as reported by three independent studies[100-102]. Although these antibiotics are also active against other bacterial groups and their effect needs to be confirmed, these studies highlight the potential role of MAP in CD etiology.

Yersinia: Yersiniosis, an infectious disease caused by the psychotrophic bacterium Yersinia, displays the common facets of CD, including the presence of granulomas and ulcerations along the epithelium[103]. Another study has shown the penetration of Yersinia enterocolitica across the epithelium via Peyer’s patches[104]. A Yersinia enterocolitica oral infection induces the secretion of pro-inflammatory cytokines in mice[105]. The presence of Yersinia enterocolitica and Yersinia pseudotuberculosis strains in the gut of CD patients has been shown[106,107]. It was also reported that two cases of patients displaying terminal ileitis involving Yersinia paratuberculosis were diagnosed with CD thereafter[108,109]. These observations support the hypothesis of the involvement of Yersinia in CD pathogenesis, but further studies are required to determine their precise role.

Listeria: Numerous studies have been conducted to investigate the role of Listeria in CD etiology[110,111]. Immunohistochemical[112] and molecular[111,113] analyses have shown the presence of Listeria monocytogenes in CD lesions. Listeria monocytogenes has been shown to disrupt and cross the intestinal barrier by entering nonphagocytic cells, escaping from the internalization vacuole, allowing bacteria to move in the cell and to spread from cell to cell[114]. A study reported that NOD2-deficient mice display an increased susceptibility to oral infection by Listeria monocytogenes, with a down-regulation of genes coding cryptids, the murine homologs to human α-defensins, in Paneth cells[115]. These elements are in favor of the hypothesis that Listeria is involved in CD etiology, but additional studies are required to ascertain its causative role.

Helicobacter: Bacteria belonging to the Helicobacter family have been suspected to play a role in CD pathogenesis. An association between the Helicobacter pylori strain and the human gastric mucosal system was highlighted since Helicobacter pylori provokes mucosal ulcerations[116]. Numerous species of Helicobacter have been identified in the human gut[117,118], suggesting that they can cause pathology by colonizing the intestinal mucosa. In vivo studies have shown that Helicobacter hepaticus, a benign murine commensal bacterium closed to the human Helicobacter pylori strain, was able to induce considerable intestinal inflammation in immunocompromised mouse models [mice deficient in T-cell receptor alpha, T-cell receptor beta or interleukine (IL)-10] by triggering similar immune responses to those observed in CD[119,120]. These experimental data suggest that Helicobacter could initiate disease in individuals being genetically susceptible to CD.

E. COLI AND CD

The involvement of E. coli in CD etiopathogenesis has been argued for long time. According to serologic studies, the antibodies raised against the outer membrane porin C of E. coli (anti-OmpC) have been found in 37%-55% of CD patients[121,122]. Numerous studies have shown the presence of E. coli-specific antigens in biopsies from CD patients, particularly in the ulcer areas, along the fissures and within the granulomas and lamina propria[37,112,123,124]. These reports are in accordance with numerous independent studies showing increased abundance of E. coli in the mucosa-associated microbiota of CD patients with dysbiosis compared with control subjects[37-43]. Specifically, we have shown that E. coli abnormally colonize acute and chronic ileal lesions of CD patients comparatively to control subjects[35,36].

Pathogenic traits of CD-associated E. coli

Adhesion and invasion of epithelial cells: Phenotypic characterization of the E. coli strains isolated from CD patients has evidenced their capacity to adhere to eukaryotic cells in vitro. It has been shown that 53%-62% of CD patients carry E. coli strains that display adhesion properties to buccal cells vs only 5%-6% of control subjects[125,126]. Another study reported that 84.6% of CD patients and 78.9% of patients with disease recurrence carry E. coli strains capable of adhering to human intestinal epithelial Caco-2 cells, vs only 33.3% of control individuals[35]. Finally, several independent studies have shown the presence of E. coli strains internalized in the intestinal mucosa of CD patients and their capacity to invade intestinal epithelial cells (IECs)[36,39,41,42,127]. Our group has more particularly studied the E. coli reference strain LF82, isolated from a chronic ileal lesion of a CD patient[35,36], and shown that LF82 is able to adhere to and to invade IECs[128].

Survival and proliferation in host cells: Increasing evidence has shown the capability of the CD-associated E. coli strains to invade, survive and replicate in IECs and macrophages. The first study showed by electron microscopy that the E. coli strain LF82 can trigger, in the same way as other enteropathogens such as Shigella, the lysis of endocytic vacuoles to be released in the cytoplasm, where the environment is more favorable for bacterial replication[129]. It has been later reported that CD-associated E. coli are able to survive and replicate in macrophages without inducing cell death[130,131]. The mechanism underlying these pathogenic properties of CD-associated E. coli has been then investigated. Given the association of polymorphisms in autophagy genes ATG16L1 and IRGM with an increased risk of developing CD, it has been proposed that defects in autophagic process could allow the CD-associated E. coli to survive and replicate within host cells. Our group has shown that the E. coli strain LF82 replicates more importantly in autophagy-deficient murine fibroblasts than in wild-type fibroblasts, and in human epithelial cells and macrophages with siRNA-mediated ATG16L1 expression silencing[132]. Increased intracellular replication of the LF82 strain was also observed in human cells expressing the ATG16L1 risk variant[132]. As discussed earlier, the CD-associated C313T mutation in IRGM gene results in loss of tight regulation of IRGM protein and therefore autophagy, leading to an increased persistence of the LF82 bacteria in host cells[74]. These studies suggest that impaired capacity of autophagy to handle and clear bacteria could be a mechanism underlying the increased risk of CD patients via increased numbers of pro-inflammatory bacteria.

Disruption of the intestinal barrier function: Several pathogenic bacteria are capable of disrupting the intestinal barrier to cross the mucosal surface by modulating expression and/or organization of proteins involved in establishment and maintenance of epithelial cell junctions. It has been shown that the CD-associated E. coli strains induce disorganization of F-actin and displacement of ZO-1 and E-cadherin from the apical junctional complex in human intestinal Caco-2 cell monolayer, leading to a drop in the trans-epithelial resistance and consequently increased epithelial permeability[127]. Likewise, the LF82 strain induces a redistribution of ZO-1 in Madin-Darby canine kidney-1 cell monolayer, causing a severe disruption of the epithelial barrier[133]. These data suggest that the CD-associated E. coli could play a causative role in CD etiopathogenesis by inducing disruption of intestinal barrier function.

Inducing pro-inflammatory cytokine/chemokine production: Several in vitro and in vivo studies have reported that the CD-associated E. coli can induce pro-inflammatory responses in host cells. Infection of macrophages with the LF82 strain induces the secretion of high level of TNF-α[127,130], and this is essential for the intramacrophagic replication of the bacteria[130]. This indicates that the CD-associated E. coli could induce production of TNF-α to create an amplification loop of replication and of inflammation. Increased production of IL-8 in LF82-infected IECs has been also reported[127,134,135]. In a transgenic CEABAC10 mouse model expressing human Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), the CD-associated E. coli strain LF82 can induce a severe colitis accompanied with an increase in production of the pro-inflammatory cytokines IL-1β, IL-6, and IL-17 and a decrease in that of the anti-inflammatory cytokine IL-10[136]. These in vitro and in vivo data support the hypothesis of the involvement of CD-associated E. coli in the etiopathogenesis of this chronic inflammatory disease.

Adherent-invasive E. coli: A new pathovar

Pathovar definition: Analysis of virulence factors and clinical manifestations engendered by different E. coli strains has allowed distinguishing six pathovars: enterotoxinogenic E. coli, enterohemorragic E. coli, enteroaggregative E. coli, diffusely adherent E. coli, enteropathogenic E. coli and enteroinvasive E. coli (EIEC)[137]. CD-associated E. coli strains share some virulence features with already established E. coli pathovars such as the ability to induce macrophage cell death, but the factors involved in the adhesion and invasion properties of the known pathovars are not present in the CD-associated E. coli strains[35,129]. Thus, a new pathovar was defined to classify these strains, and called adherent-invasive E. coli (AIEC)[129]. The criteria of this pathovar group include abilities to adhere to and to invade IECs, to survive and replicate in large vacuoles within macrophages without inducing cell death, and to induce secretion of high levels of the pro-inflammatory cytokine TNF-α by infected macrophages. The ability to trigger increased intestinal permeability also constitutes one of the pathogenic characteristics of AIEC[127]. Finally, AIEC have been shown to form biofilm and to induce granulomas formation in vitro[138-140]. The E. coli LF82 strain displays all of these characteristics, and is therefore considered as the AIEC reference strain.

AIEC prevalence in CD patients: Evidence has shown a high prevalence of ileal mucosa-associated AIEC in CD, since AIEC have been identified in the neoterminal ileum of 36.4%-51.9% of CD patients vs only 6.2%-16.7% of controls[36,141]. Comparative genomic analyses of AIEC strains isolated from different patients have shown that only one specific strain was not found in all of the patients, nevertheless, some genotypes of particular strains seem to be more frequently associated with ileal lesions of CD[40,142].

Virulence factors of AIEC: Genetic determinants of virulence of the AIEC reference strain LF82 are not known and are not similar to those of other invasive E. coli strains. Thus, they have been searched by random mutagenesis (insertion of the transposon Tn5phoA) and by comparison of the genome of LF82 with that of other pathogens[143,144]. These studies have permitted the identification of the lipoprotein NlpI which appears to be involved in adhesion and invasion capacities of LF82, since the insertion of the Tn5phoA transposon in the NlpI-encoding gene leads to a loss of invasion capacity of LF82 and the LF82-ΔnlpI isogenic mutant showed a decreased adhesion and invasion capacity in Intestine-407 epithelial cells[145]. Likewise, the analysis of the Tn5phoA insertion mutant library and the construction of isogenic mutants led to the identification of flagella and the membrane proteins YfgL, OmpC and OmpA as factors involved in adhesion and invasion properties of the reference strain LF82[146-149]. Another study showed that type 1 pili are a crucial virulence factor that allows AIEC to adhere to IECs via the receptor CEACAM6[150]. They are composed of a major subunit with repetition of FimA protein, minor subunits FimG and FimF, and one adhesin called FimH present at the end of the pilus[151]. Our group recently showed that point mutations in FimH confer AIEC bacteria a higher ability to adhere to CEACAM6-expressing human IECs[152]. The replacement of FimH-coding gene having an AIEC-associated mutation in the LF82 strain by a gene coding FimH of the commensal non-pathogenic E. coli K12 MG1655 strain decreased the ability of the bacteria to colonize the gut and to induce intestinal inflammation in CEABAC10 transgenic mice[152]. This suggests that selection of amino acid mutations in FimH is a mechanism of AIEC virulence evolution, which could increase the risk of CD development in a genetically susceptible host. Recently, we have identified long polar fimbriae (LPF) as a key factor for AIEC to target microfold cells (or M cells) on the surface of Peyer’s patches, and that the prevalence of the AIEC strains harboring the lpf operon was markedly higher in CD patients compared with controls[153]. This operon has also been identified in other enteropathogenic bacteria such as Salmonella Typhimurium and been shown to be involved in specific adherence of the bacteria to M cells on Peyer’s patches[154]. Interestingly, bile salts, of which the composition has been reported to be modified in CD patients[155], induce LPF expression favoring the colonization of the epithelium by AIEC[156]. These data could explain the presence of early lesions in the Peyer’s patches of CD patients.

THERAPEUTIC APPROACHES TARGETING INFECTIOUS AGENTS TO TREAT CD

Current CD treatment strategies aim to control inflammation, relieve symptoms and correct nutritional deficiencies. The treatment depends on the location and severity of disease, complications and response to previous treatment. At this time, treatment can help control the disease, but there is no cure. Established therapies for CD include anti-inflammatory agents [e.g., aminosalicylates (5-ASA), omega 3 fatty acids], immunosuppressive drugs (e.g., corticosteroids, azathioprine and 6-mercaptopurine) and antibiotics. An increasing number of novel and alternative therapeutic approaches are in progress[157]. New biologic therapies include the targeting of pro-inflammatory cytokines, enhancement or infusion of anti-inflammatory cytokines, blocking intravascular adhesion molecules, and modifying T-cell functions[157]. Given the increasing evidence supporting the infectious etiology of CD, therapeutic approaches to manipulate gut microbiota have been attempted by using antibiotics, probiotics, prebiotics and possibly defensins. Although these approaches are widely used, their benefits are variable and certainly not permanent. One important reason for this is the fact that the etiology of CD is complex and multifactorial, and does not include only infectious factors. Therefore, manipulation of the gut microbiota is beneficial, but, on its own, is insufficient to cure the disease.

Antibiotics

The beneficial effect of broad-spectrum antibiotics in the treatment of a moderate form of CD has been reported, although it lacked a large-scale clinical trial[158]. A controlled clinical trial conducted in American and Canadian centers reported that metronidazole, an antibiotic active against strictly anaerobic bacteria, is more effective in CD patients than a placebo at both a low dose (10 mg/kg per day) and a high dose (20 mg/kg per day)[159]. A therapy based on ciprofloxacin has been shown to be effective in CD treatment and is also effective in combination with conventional treatments in patients with resistant CD[160,161]. Combination of ciprofloxacin and metronidazole has been tested in treatment of acute phase of the disease and appeared to be effective[162]. Numerous clinical trials have been performed to test the potential benefit of antibiotics during different clinical manifestations of CD. Papi and colleagues showed that administration of antibiotics (metronidazole and ornidazole) is effective in preventing post-operative recurrence of CD, which is inevitable since the surgery is not curative[163]. The efficiency of antibiotics in the treatment of perianal fistulas, a complication of CD, was tested, but did not allow obtaining extended closure of fistulas[164]. The authors of this study suggest the use of antibiotics as a second-line therapy for fistula healing following the use of anti-TNF-α antibodies, which are known to be effective. Pre-operative administration of antibiotics seems to reduce the risk of surgery[165]. Although antibiotic treatment is effective in some cases, it has some side effects including non-specific effects against microbiota, the possibility of inducing an antibiotic resistance and the risk of Clostridium difficile superinfection. Those antibiotics have been therefore recommended as a second-line treatment for CD.

Probiotics

Given that intestinal dysbiosis has been postulated to cause CD in genetically predisposed individuals, therapeutic strategies based on the use of probiotics have been developed to modulate the imbalance of intestinal microbiota observed in CD patients.

Potential action mechanisms of probiotics include competitive interactions with enteropathogens, production of antimicrobial metabolites, influences on the epithelium, and immune modulation[166]. The use of the probiotic yeast strain Saccharomyces boulardii has been shown to be effective in prevention and treatment of antibiotic-associated and Clostridium difficile infection-associated diarrhea, as well as traveler’s diarrhea[167]. Several probiotic strains have been tested in CD treatment. Treatment of CD patients with the probiotic E. coli strain Nissle 1917 leads to a remission more rapidly than untreated patients, without affecting the number of patients entering remission[168]. One study, although involving only a few subjects, 32 patients, reported the maintenance of remission in CD patients treated with the probiotic strain Saccharomyces boulardii comparatively to patients treated with mesalamine[169], of which the effect in maintaining remission has been raised[170,171]. However, a recent randomized, placebo-controlled trial reported no significant effect of the yeast Saccharomyces boulardii in preventing relapse following a medically-induced remission[172]. Clinical trials have been carried out to evaluate the potential efficacy of the probiotic strain Lactobacillus GG in the prevention of post-operative recurrence in CD patients[173] and on the average time of relapse after a medically induced remission period[174]. The first reported contradictory effects with rates of clinical and endoscopic recurrence of 16.6% and 60%, respectively, in the Lactobacillus-treated group vs 10.5% and 35.3% in the placebo group. The second showed a shorter average time of relapse of 9.8 mo in patients treated with the probiotic vs 11 mo in the placebo group. Another strain of Lactobacillus, Lactobacillus johnsonii, was tested in CD patients during two double-blind trials, and both reported no significant effect of this strain in preventing clinical recurrence of the disease following a surgically-induced remission in probiotic-treated patients comparatively to the placebo group[175,176]. Although probiotics may be the most physiologic and non-toxic way to prevent and treat CD, it may be transient and has a limited and debatable usefulness at present.

Fecal microbiota transplantation

Given the potential role played by intestinal microbiota in CD pathogenesis, another therapeutic approach has been considered for CD treatment: fecal microbiota transplantation. The transfer of fecal microbiota from a healthy individual to the gut of a patient, enabling the re-establishment of a normal microbial community, has been shown to be effective in the treatment of ulcerative colitis[177], another form of IBD, or infection with Clostridium difficile[178]. Clostridium difficile infection has become a major public health problem, occurring after antibiotic treatment or ingestion of spores in the environment. In patients with a recalcitrant infection, fecal microbiota transplantation has been shown to be effective, with an efficiency rate of 90%[179,180]. Only few case reports and case series of fecal microbiota transplantation for the management of CD have been published. The first case was a 31-year-old man diagnosed with terminal ileal CD who remained symptom-free for 4 mo after the transplantation[181]. Among the other cases reported, the use of fecal microbiota transplants leads to CD resolution, i.e. to a complete cessation of symptoms or to the absence of active disease confirmed by endoscopic and histologic analyses, but in most cases, it does not[182]. A recent study reported the effectiveness of fecal microbiota transplantation in a case of severe fistulizing CD with a sustained clinical remission for more than 9 mo after the treatment[183]. Fecal microbiota transplants have also been used to manage Clostridium difficile infections in CD patients, and it appears to be effective in most of patients with a reduction or a complete resolution of the infection-associated diarrhea[182]. More clinical trials with better standardized protocols are required to confirm the beneficial effect of fecal microbiota transplantation in treatment of this complex disease.

CONCLUSION

Since the first description of CD in 1932, numerous research groups worldwide have attempted to unravel the complex and multifactorial etiology of the disease to develop a curative therapy. In addition to the identification of genetic and environmental risk factors in CD, increasing lines of evidence have supported a role for infectious agents in CD etiopathogenesis. These include the disruption of the intestinal barrier function associated with excessive bacterial translocation, an intestinal dysbiosis, defects in the secretion of IgA entrapping antigens and bacteria in the intestinal lumen and inefficacity of autophagy-mediated clearance of intracellular bacteria. These defects, which have been reported in CD patients, can lead to the emergence of infectious agents (viruses, eukaryotes or bacteria) that could induce chronic inflammatory characteristic of CD. Advances in the knowledge of infectious etiology of CD enable to develop different therapies based on the clearance of CD-associated pathogens, the modification of the imbalanced intestinal microbiota and re-establishment of a “healthy” microbiota with the use of antibiotics, probiotics and fecal microbiota transplantation. However, these therapies on their own are insufficient to provide a cure for CD. Therefore, successful CD therapies are likely to require multiple pathway-integrated treatments depending on the stage of the disease and each patient subset.

Footnotes

P- Reviewer: Castro FJ, Sadik R S- Editor: Nan J L- Editor: A E- Editor: Ma S

References
1.  Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001;411:599-603.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3986]  [Cited by in F6Publishing: 3811]  [Article Influence: 165.7]  [Reference Citation Analysis (0)]
2.  Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001;411:603-606.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3555]  [Cited by in F6Publishing: 3393]  [Article Influence: 147.5]  [Reference Citation Analysis (0)]
3.  Brest P, Corcelle EA, Cesaro A, Chargui A, Belaïd A, Klionsky DJ, Vouret-Craviari V, Hebuterne X, Hofman P, Mograbi B. Autophagy and Crohn’s disease: at the crossroads of infection, inflammation, immunity, and cancer. Curr Mol Med. 2010;10:486-502.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 52]  [Cited by in F6Publishing: 57]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
4.  Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, Albrecht M, Mayr G, De La Vega FM, Briggs J. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39:207-211.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1387]  [Cited by in F6Publishing: 1402]  [Article Influence: 77.9]  [Reference Citation Analysis (0)]
5.  Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA, Roberts RG, Nimmo ER, Cummings FR, Soars D. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nat Genet. 2007;39:830-832.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 870]  [Cited by in F6Publishing: 867]  [Article Influence: 51.0]  [Reference Citation Analysis (0)]
6.  Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447:661-678.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7131]  [Cited by in F6Publishing: 6955]  [Article Influence: 409.1]  [Reference Citation Analysis (0)]
7.  Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD, Brant SR, Silverberg MS, Taylor KD, Barmada MM. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40:955-962.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2041]  [Cited by in F6Publishing: 1980]  [Article Influence: 123.8]  [Reference Citation Analysis (0)]
8.  Cho JH, Brant SR. Recent insights into the genetics of inflammatory bowel disease. Gastroenterology. 2011;140:1704-1712.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 291]  [Cited by in F6Publishing: 293]  [Article Influence: 22.5]  [Reference Citation Analysis (0)]
9.  Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, Lees CW, Balschun T, Lee J, Roberts R. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42:1118-1125.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1894]  [Cited by in F6Publishing: 1912]  [Article Influence: 136.6]  [Reference Citation Analysis (0)]
10.  Kenny EE, Pe’er I, Karban A, Ozelius L, Mitchell AA, Ng SM, Erazo M, Ostrer H, Abraham C, Abreu MT. A genome-wide scan of Ashkenazi Jewish Crohn’s disease suggests novel susceptibility loci. PLoS Genet. 2012;8:e1002559.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 113]  [Cited by in F6Publishing: 126]  [Article Influence: 10.5]  [Reference Citation Analysis (0)]
11.  Lees CW, Barrett JC, Parkes M, Satsangi J. New IBD genetics: common pathways with other diseases. Gut. 2011;60:1739-1753.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 406]  [Cited by in F6Publishing: 420]  [Article Influence: 32.3]  [Reference Citation Analysis (1)]
12.  Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, Green T, Kuballa P, Barmada MM, Datta LW. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet. 2007;39:596-604.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1392]  [Cited by in F6Publishing: 1347]  [Article Influence: 79.2]  [Reference Citation Analysis (0)]
13.  Loftus EV. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology. 2004;126:1504-1517.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2085]  [Cited by in F6Publishing: 2046]  [Article Influence: 102.3]  [Reference Citation Analysis (1)]
14.  Chapman-Kiddell CA, Davies PS, Gillen L, Radford-Smith GL. Role of diet in the development of inflammatory bowel disease. Inflamm Bowel Dis. 2010;16:137-151.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 160]  [Cited by in F6Publishing: 162]  [Article Influence: 11.6]  [Reference Citation Analysis (0)]
15.  Parkes GC, Whelan K, Lindsay JO. Smoking in inflammatory bowel disease: Impact on disease course and insights into the aetiology of its effect. J Crohns Colitis. 2014;8:717-725.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 160]  [Cited by in F6Publishing: 157]  [Article Influence: 15.7]  [Reference Citation Analysis (0)]
16.  Frolkis A, Dieleman LA, Barkema HW, Panaccione R, Ghosh S, Fedorak RN, Madsen K, Kaplan GG. Environment and the inflammatory bowel diseases. Can J Gastroenterol. 2013;27:e18-e24.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Gill SR, Pop M, Deboy RT, Eckburg PB, Turnbaugh PJ, Samuel BS, Gordon JI, Relman DA, Fraser-Liggett CM, Nelson KE. Metagenomic analysis of the human distal gut microbiome. Science. 2006;312:1355-1359.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3104]  [Cited by in F6Publishing: 2983]  [Article Influence: 165.7]  [Reference Citation Analysis (0)]
18.  Sartor RB. Microbial influences in inflammatory bowel diseases. Gastroenterology. 2008;134:577-594.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1339]  [Cited by in F6Publishing: 1307]  [Article Influence: 81.7]  [Reference Citation Analysis (0)]
19.  De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S, Collini S, Pieraccini G, Lionetti P. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci USA. 2010;107:14691-14696.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3584]  [Cited by in F6Publishing: 3690]  [Article Influence: 263.6]  [Reference Citation Analysis (0)]
20.  Guarner F. The intestinal flora in inflammatory bowel disease: normal or abnormal? Curr Opin Gastroenterol. 2005;21:414-418.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Zoetendal E, Akkermans A, Akkermans-van Vliet W, de Visser J, de Vos W. The host genotype affects the bacterial community in the human gastronintestinal tract. Microb Ecol Health Dis. 2001;13:129-134.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 330]  [Cited by in F6Publishing: 164]  [Article Influence: 10.9]  [Reference Citation Analysis (0)]
22.  Fraher MH, O’Toole PW, Quigley EM. Techniques used to characterize the gut microbiota: a guide for the clinician. Nat Rev Gastroenterol Hepatol. 2012;9:312-322.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 226]  [Cited by in F6Publishing: 218]  [Article Influence: 18.2]  [Reference Citation Analysis (0)]
23.  Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, Fernandes GR, Tap J, Bruls T, Batto JM. Enterotypes of the human gut microbiome. Nature. 2011;473:174-180.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4310]  [Cited by in F6Publishing: 4445]  [Article Influence: 341.9]  [Reference Citation Analysis (0)]
24.  Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA. Diversity of the human intestinal microbial flora. Science. 2005;308:1635-1638.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5700]  [Cited by in F6Publishing: 5230]  [Article Influence: 275.3]  [Reference Citation Analysis (2)]
25.  Ley RE, Hamady M, Lozupone C, Turnbaugh PJ, Ramey RR, Bircher JS, Schlegel ML, Tucker TA, Schrenzel MD, Knight R. Evolution of mammals and their gut microbes. Science. 2008;320:1647-1651.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2433]  [Cited by in F6Publishing: 2349]  [Article Influence: 146.8]  [Reference Citation Analysis (0)]
26.  Peterson DA, Frank DN, Pace NR, Gordon JI. Metagenomic approaches for defining the pathogenesis of inflammatory bowel diseases. Cell Host Microbe. 2008;3:417-427.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 348]  [Cited by in F6Publishing: 368]  [Article Influence: 23.0]  [Reference Citation Analysis (0)]
27.  Lepage P, Seksik P, Sutren M, de la Cochetière MF, Jian R, Marteau P, Doré J. Biodiversity of the mucosa-associated microbiota is stable along the distal digestive tract in healthy individuals and patients with IBD. Inflamm Bowel Dis. 2005;11:473-480.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 200]  [Cited by in F6Publishing: 189]  [Article Influence: 9.9]  [Reference Citation Analysis (0)]
28.  Ott SJ, Musfeldt M, Wenderoth DF, Hampe J, Brant O, Fölsch UR, Timmis KN, Schreiber S. Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease. Gut. 2004;53:685-693.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 875]  [Cited by in F6Publishing: 872]  [Article Influence: 43.6]  [Reference Citation Analysis (0)]
29.  Mondot S, Kang S, Furet JP, Aguirre de Carcer D, McSweeney C, Morrison M, Marteau P, Doré J, Leclerc M. Highlighting new phylogenetic specificities of Crohn’s disease microbiota. Inflamm Bowel Dis. 2011;17:185-192.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 195]  [Cited by in F6Publishing: 200]  [Article Influence: 15.4]  [Reference Citation Analysis (0)]
30.  Sokol H, Lay C, Seksik P, Tannock GW. Analysis of bacterial bowel communities of IBD patients: what has it revealed? Inflamm Bowel Dis. 2008;14:858-867.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 160]  [Cited by in F6Publishing: 156]  [Article Influence: 9.8]  [Reference Citation Analysis (0)]
31.  Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci USA. 2007;104:13780-13785.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3075]  [Cited by in F6Publishing: 3154]  [Article Influence: 185.5]  [Reference Citation Analysis (1)]
32.  Martinez-Medina M, Aldeguer X, Gonzalez-Huix F, Acero D, Garcia-Gil LJ. Abnormal microbiota composition in the ileocolonic mucosa of Crohn’s disease patients as revealed by polymerase chain reaction-denaturing gradient gel electrophoresis. Inflamm Bowel Dis. 2006;12:1136-1145.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 193]  [Cited by in F6Publishing: 190]  [Article Influence: 10.6]  [Reference Citation Analysis (0)]
33.  Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature. 2008;453:620-625.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1625]  [Cited by in F6Publishing: 1633]  [Article Influence: 102.1]  [Reference Citation Analysis (0)]
34.  Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermúdez-Humarán LG, Gratadoux JJ, Blugeon S, Bridonneau C, Furet JP, Corthier G. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA. 2008;105:16731-16736.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2747]  [Cited by in F6Publishing: 2881]  [Article Influence: 180.1]  [Reference Citation Analysis (0)]
35.  Darfeuille-Michaud A, Neut C, Barnich N, Lederman E, Di Martino P, Desreumaux P, Gambiez L, Joly B, Cortot A, Colombel JF. Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn’s disease. Gastroenterology. 1998;115:1405-1413.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 609]  [Cited by in F6Publishing: 605]  [Article Influence: 23.3]  [Reference Citation Analysis (0)]
36.  Darfeuille-Michaud A, Boudeau J, Bulois P, Neut C, Glasser AL, Barnich N, Bringer MA, Swidsinski A, Beaugerie L, Colombel JF. High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology. 2004;127:412-421.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1075]  [Cited by in F6Publishing: 1054]  [Article Influence: 52.7]  [Reference Citation Analysis (0)]
37.  Swidsinski A, Ladhoff A, Pernthaler A, Swidsinski S, Loening-Baucke V, Ortner M, Weber J, Hoffmann U, Schreiber S, Dietel M. Mucosal flora in inflammatory bowel disease. Gastroenterology. 2002;122:44-54.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 977]  [Cited by in F6Publishing: 1015]  [Article Influence: 46.1]  [Reference Citation Analysis (0)]
38.  Neut C, Bulois P, Desreumaux P, Membré JM, Lederman E, Gambiez L, Cortot A, Quandalle P, van Kruiningen H, Colombel JF. Changes in the bacterial flora of the neoterminal ileum after ileocolonic resection for Crohn’s disease. Am J Gastroenterol. 2002;97:939-946.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 186]  [Cited by in F6Publishing: 204]  [Article Influence: 9.3]  [Reference Citation Analysis (0)]
39.  Martin HM, Campbell BJ, Hart CA, Mpofu C, Nayar M, Singh R, Englyst H, Williams HF, Rhodes JM. Enhanced Escherichia coli adherence and invasion in Crohn’s disease and colon cancer. Gastroenterology. 2004;127:80-93.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 508]  [Cited by in F6Publishing: 518]  [Article Influence: 25.9]  [Reference Citation Analysis (0)]
40.  Baumgart M, Dogan B, Rishniw M, Weitzman G, Bosworth B, Yantiss R, Orsi RH, Wiedmann M, McDonough P, Kim SG. 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. ISME J. 2007;1:403-418.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 456]  [Cited by in F6Publishing: 456]  [Article Influence: 26.8]  [Reference Citation Analysis (0)]
41.  Kotlowski R, Bernstein CN, Sepehri S, Krause DO. High prevalence of Escherichia coli belonging to the B2+D phylogenetic group in inflammatory bowel disease. Gut. 2007;56:669-675.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 306]  [Cited by in F6Publishing: 317]  [Article Influence: 18.6]  [Reference Citation Analysis (0)]
42.  Conte MP, Schippa S, Zamboni I, Penta M, Chiarini F, Seganti L, Osborn J, Falconieri P, Borrelli O, Cucchiara S. Gut-associated bacterial microbiota in paediatric patients with inflammatory bowel disease. Gut. 2006;55:1760-1767.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 266]  [Cited by in F6Publishing: 266]  [Article Influence: 14.8]  [Reference Citation Analysis (0)]
43.  Mylonaki M, Rayment NB, Rampton DS, Hudspith BN, Brostoff J. Molecular characterization of rectal mucosa-associated bacterial flora in inflammatory bowel disease. Inflamm Bowel Dis. 2005;11:481-487.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 189]  [Cited by in F6Publishing: 168]  [Article Influence: 8.8]  [Reference Citation Analysis (0)]
44.  Png CW, Lindén SK, Gilshenan KS, Zoetendal EG, McSweeney CS, Sly LI, McGuckin MA, Florin TH. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol. 2010;105:2420-2428.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 863]  [Cited by in F6Publishing: 909]  [Article Influence: 64.9]  [Reference Citation Analysis (0)]
45.  van der Flier LG, Clevers H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol. 2009;71:241-260.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1156]  [Cited by in F6Publishing: 1188]  [Article Influence: 79.2]  [Reference Citation Analysis (0)]
46.  FARQUHAR MG, PALADE GE. Junctional complexes in various epithelia. J Cell Biol. 1963;17:375-412.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2475]  [Cited by in F6Publishing: 2652]  [Article Influence: 102.0]  [Reference Citation Analysis (0)]
47.  Adenis A, Colombel JF, Lecouffe P, Wallaert B, Hecquet B, Marchandise X, Cortot A. Increased pulmonary and intestinal permeability in Crohn’s disease. Gut. 1992;33:678-682.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 50]  [Cited by in F6Publishing: 46]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
48.  Benjamin J, Makharia GK, Ahuja V, Kalaivani M, Joshi YK. Intestinal permeability and its association with the patient and disease characteristics in Crohn’s disease. World J Gastroenterol. 2008;14:1399-1405.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 42]  [Cited by in F6Publishing: 42]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
49.  Jenkins RT, Jones DB, Goodacre RL, Collins SM, Coates G, Hunt RH, Bienenstock J. Reversibility of increased intestinal permeability to 51Cr-EDTA in patients with gastrointestinal inflammatory diseases. Am J Gastroenterol. 1987;82:1159-1164.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Jenkins RT, Ramage JK, Jones DB, Collins SM, Goodacre RL, Hunt RH. Small bowel and colonic permeability to 51Cr-EDTA in patients with active inflammatory bowel disease. Clin Invest Med. 1988;11:151-155.  [PubMed]  [DOI]  [Cited in This Article: ]
51.  Sanderson IR, Boulton P, Menzies I, Walker-Smith JA. Improvement of abnormal lactulose/rhamnose permeability in active Crohn’s disease of the small bowel by an elemental diet. Gut. 1987;28:1073-1076.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 133]  [Cited by in F6Publishing: 132]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
52.  Zeissig S, Bürgel N, Günzel D, Richter J, Mankertz J, Wahnschaffe U, Kroesen AJ, Zeitz M, Fromm M, Schulzke JD. Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn‘s disease. Gut. 2007;56:61-72.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 931]  [Cited by in F6Publishing: 879]  [Article Influence: 51.7]  [Reference Citation Analysis (0)]
53.  Deplancke B, Gaskins HR. Microbial modulation of innate defense: goblet cells and the intestinal mucus layer. Am J Clin Nutr. 2001;73:1131S-1141S.  [PubMed]  [DOI]  [Cited in This Article: ]
54.  Johansson ME, Phillipson M, Petersson J, Velcich A, Holm L, Hansson GC. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci USA. 2008;105:15064-15069.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1326]  [Cited by in F6Publishing: 1381]  [Article Influence: 86.3]  [Reference Citation Analysis (1)]
55.  Meyer-Hoffert U, Hornef MW, Henriques-Normark B, Axelsson LG, Midtvedt T, Pütsep K, Andersson M. Secreted enteric antimicrobial activity localises to the mucus surface layer. Gut. 2008;57:764-771.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 209]  [Cited by in F6Publishing: 204]  [Article Influence: 12.8]  [Reference Citation Analysis (0)]
56.  Mukherjee S, Vaishnava S, Hooper LV. Multi-layered regulation of intestinal antimicrobial defense. Cell Mol Life Sci. 2008;65:3019-3027.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 103]  [Cited by in F6Publishing: 101]  [Article Influence: 6.3]  [Reference Citation Analysis (0)]
57.  Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012;336:1268-1273.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3003]  [Cited by in F6Publishing: 2726]  [Article Influence: 227.2]  [Reference Citation Analysis (0)]
58.  Suzuki K, Meek B, Doi Y, Muramatsu M, Chiba T, Honjo T, Fagarasan S. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. Proc Natl Acad Sci USA. 2004;101:1981-1986.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 521]  [Cited by in F6Publishing: 519]  [Article Influence: 26.0]  [Reference Citation Analysis (0)]
59.  Brandtzaeg P, Carlsen HS, Halstensen TS. The B-cell system in inflammatory bowel disease. Adv Exp Med Biol. 2006;579:149-167.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 95]  [Cited by in F6Publishing: 93]  [Article Influence: 5.2]  [Reference Citation Analysis (0)]
60.  Kobayashi K, Qiao SW, Yoshida M, Baker K, Lencer WI, Blumberg RS. An FcRn-dependent role for anti-flagellin immunoglobulin G in pathogenesis of colitis in mice. Gastroenterology. 2009;137:1746-56.e1.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 71]  [Cited by in F6Publishing: 76]  [Article Influence: 5.1]  [Reference Citation Analysis (0)]
61.  Jarczak J, Kościuczuk EM, Lisowski P, Strzałkowska N, Jóźwik A, Horbańczuk J, Krzyżewski J, Zwierzchowski L, Bagnicka E. Defensins: natural component of human innate immunity. Hum Immunol. 2013;74:1069-1079.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 137]  [Cited by in F6Publishing: 119]  [Article Influence: 10.8]  [Reference Citation Analysis (0)]
62.  Kagan BL, Selsted ME, Ganz T, Lehrer RI. Antimicrobial defensin peptides form voltage-dependent ion-permeable channels in planar lipid bilayer membranes. Proc Natl Acad Sci USA. 1990;87:210-214.  [PubMed]  [DOI]  [Cited in This Article: ]
63.  Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol. 2010;28:573-621.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1352]  [Cited by in F6Publishing: 1440]  [Article Influence: 102.9]  [Reference Citation Analysis (0)]
64.  Salzman NH, Hung K, Haribhai D, Chu H, Karlsson-Sjöberg J, Amir E, Teggatz P, Barman M, Hayward M, Eastwood D. Enteric defensins are essential regulators of intestinal microbial ecology. Nat Immunol. 2010;11:76-83.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 835]  [Cited by in F6Publishing: 857]  [Article Influence: 57.1]  [Reference Citation Analysis (0)]
65.  Wehkamp J, Fellermann K, Stange EF. Human defensins in Crohn‘s disease. Chem Immunol Allergy. 2005;86:42-54.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 30]  [Cited by in F6Publishing: 33]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
66.  Ayabe T, Satchell DP, Wilson CL, Parks WC, Selsted ME, Ouellette AJ. Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol. 2000;1:113-118.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 776]  [Cited by in F6Publishing: 737]  [Article Influence: 30.7]  [Reference Citation Analysis (0)]
67.  Vaishnava S, Behrendt CL, Ismail AS, Eckmann L, Hooper LV. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc Natl Acad Sci USA. 2008;105:20858-20863.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 715]  [Cited by in F6Publishing: 717]  [Article Influence: 44.8]  [Reference Citation Analysis (0)]
68.  Nguyen HT, Lapaquette P, Bringer MA, Darfeuille-Michaud A. Autophagy and Crohn’s disease. J Innate Immun. 2013;5:434-443.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 51]  [Cited by in F6Publishing: 63]  [Article Influence: 5.7]  [Reference Citation Analysis (0)]
69.  Stappenbeck TS, Rioux JD, Mizoguchi A, Saitoh T, Huett A, Darfeuille-Michaud A, Wileman T, Mizushima N, Carding S, Akira S. Crohn disease: a current perspective on genetics, autophagy and immunity. Autophagy. 2011;7:355-374.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 50]  [Reference Citation Analysis (0)]
70.  Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, Ferguson DJ, Campbell BJ, Jewell D, Simmons A. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med. 2010;16:90-97.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 760]  [Cited by in F6Publishing: 766]  [Article Influence: 51.1]  [Reference Citation Analysis (0)]
71.  Homer CR, Richmond AL, Rebert NA, Achkar JP, McDonald C. ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway implicated in Crohn’s disease pathogenesis. Gastroenterology. 2010;139:1630-141, 1630-141.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 284]  [Cited by in F6Publishing: 274]  [Article Influence: 19.6]  [Reference Citation Analysis (0)]
72.  Travassos LH, Carneiro LA, Ramjeet M, Hussey S, Kim YG, Magalhães JG, Yuan L, Soares F, Chea E, Le Bourhis L. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol. 2010;11:55-62.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 916]  [Cited by in F6Publishing: 967]  [Article Influence: 64.5]  [Reference Citation Analysis (0)]
73.  Cadwell K, Liu JY, Brown SL, Miyoshi H, Loh J, Lennerz JK, Kishi C, Kc W, Carrero JA, Hunt S. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature. 2008;456:259-263.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1084]  [Cited by in F6Publishing: 1169]  [Article Influence: 73.1]  [Reference Citation Analysis (0)]
74.  Brest P, Lapaquette P, Souidi M, Lebrigand K, Cesaro A, Vouret-Craviari V, Mari B, Barbry P, Mosnier JF, Hébuterne X. A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn’s disease. Nat Genet. 2011;43:242-245.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 428]  [Cited by in F6Publishing: 445]  [Article Influence: 34.2]  [Reference Citation Analysis (0)]
75.  Dorn SD, Abad JF, Panagopoulos G, Korelitz BI. Clinical characteristics of familial versus sporadic Crohn‘s disease using the Vienna Classification. Inflamm Bowel Dis. 2004;10:201-206.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 19]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
76.  Khan KJ, Ullman TA, Ford AC, Abreu MT, Abadir A, Marshall JK, Talley NJ, Moayyedi P. Antibiotic therapy in inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol. 2011;106:661-673.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 386]  [Cited by in F6Publishing: 366]  [Article Influence: 28.2]  [Reference Citation Analysis (0)]
77.  Van Kruiningen HJ, Poulin M, Garmendia AE, Desreumaux P, Colombel JF, De Hertogh G, Geboes K, Vermeire S, Tsongalis GJ. Search for evidence of recurring or persistent viruses in Crohn’s disease. APMIS. 2007;115:962-968.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 20]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
78.  Cadwell K, Patel KK, Maloney NS, Liu TC, Ng AC, Storer CE, Head RD, Xavier R, Stappenbeck TS, Virgin HW. Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell. 2010;141:1135-1145.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 688]  [Cited by in F6Publishing: 677]  [Article Influence: 48.4]  [Reference Citation Analysis (0)]
79.  Khan RR, Lawson AD, Minnich LL, Martin K, Nasir A, Emmett MK, Welch CA, Udall JN. Gastrointestinal norovirus infection associated with exacerbation of inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2009;48:328-333.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 71]  [Cited by in F6Publishing: 70]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
80.  Gebhard RL, Greenberg HB, Singh N, Henry P, Sharp HL, Kaplan L, Kapikian AZ. Acute viral enteritis and exacerbations of inflammatory bowel disease. Gastroenterology. 1982;83:1207-1209.  [PubMed]  [DOI]  [Cited in This Article: ]
81.  Riley PA. Bacteriophages in autoimmune disease and other inflammatory conditions. Med Hypotheses. 2004;62:493-498.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 13]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
82.  Lepage P, Colombet J, Marteau P, Sime-Ngando T, Doré J, Leclerc M. Dysbiosis in inflammatory bowel disease: a role for bacteriophages? Gut. 2008;57:424-425.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 168]  [Cited by in F6Publishing: 167]  [Article Influence: 10.4]  [Reference Citation Analysis (0)]
83.  Sendid B, Colombel JF, Jacquinot PM, Faille C, Fruit J, Cortot A, Lucidarme D, Camus D, Poulain D. Specific antibody response to oligomannosidic epitopes in Crohn’s disease. Clin Diagn Lab Immunol. 1996;3:219-226.  [PubMed]  [DOI]  [Cited in This Article: ]
84.  Bossuyt X. Serologic markers in inflammatory bowel disease. Clin Chem. 2006;52:171-181.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 134]  [Cited by in F6Publishing: 151]  [Article Influence: 7.9]  [Reference Citation Analysis (0)]
85.  Standaert-Vitse A, Jouault T, Vandewalle P, Mille C, Seddik M, Sendid B, Mallet JM, Colombel JF, Poulain D. Candida albicans is an immunogen for anti-Saccharomyces cerevisiae antibody markers of Crohn’s disease. Gastroenterology. 2006;130:1764-1775.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 155]  [Cited by in F6Publishing: 164]  [Article Influence: 9.1]  [Reference Citation Analysis (0)]
86.  Standaert-Vitse A, Sendid B, Joossens M, François N, Vandewalle-El Khoury P, Branche J, Van Kruiningen H, Jouault T, Rutgeerts P, Gower-Rousseau C. Candida albicans colonization and ASCA in familial Crohn’s disease. Am J Gastroenterol. 2009;104:1745-1753.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 138]  [Cited by in F6Publishing: 152]  [Article Influence: 10.1]  [Reference Citation Analysis (0)]
87.  Sonoyama K, Miki A, Sugita R, Goto H, Nakata M, Yamaguchi N. Gut colonization by Candida albicans aggravates inflammation in the gut and extra-gut tissues in mice. Med Mycol. 2011;49:237-247.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 26]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
88.  Chiodini RJ. Crohn’s disease and the mycobacterioses: a review and comparison of two disease entities. Clin Microbiol Rev. 1989;2:90-117.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 250]  [Cited by in F6Publishing: 258]  [Article Influence: 7.4]  [Reference Citation Analysis (0)]
89.  Greenstein RJ. Is Crohn’s disease caused by a mycobacterium? Comparisons with leprosy, tuberculosis, and Johne’s disease. Lancet Infect Dis. 2003;3:507-514.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 242]  [Cited by in F6Publishing: 249]  [Article Influence: 11.9]  [Reference Citation Analysis (0)]
90.  Autschbach F, Eisold S, Hinz U, Zinser S, Linnebacher M, Giese T, Löffler T, Büchler MW, Schmidt J. High prevalence of Mycobacterium avium subspecies paratuberculosis IS900 DNA in gut tissues from individuals with Crohn’s disease. Gut. 2005;54:944-949.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 128]  [Cited by in F6Publishing: 121]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
91.  Romero C, Hamdi A, Valentine JF, Naser SA. Evaluation of surgical tissue from patients with Crohn’s disease for the presence of Mycobacterium avium subspecies paratuberculosis DNA by in situ hybridization and nested polymerase chain reaction. Inflamm Bowel Dis. 2005;11:116-125.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 50]  [Cited by in F6Publishing: 45]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
92.  Sechi LA, Scanu AM, Molicotti P, Cannas S, Mura M, Dettori G, Fadda G, Zanetti S. Detection and Isolation of Mycobacterium avium subspecies paratuberculosis from intestinal mucosal biopsies of patients with and without Crohn’s disease in Sardinia. Am J Gastroenterol. 2005;100:1529-1536.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 155]  [Cited by in F6Publishing: 163]  [Article Influence: 8.6]  [Reference Citation Analysis (0)]
93.  Naser SA, Ghobrial G, Romero C, Valentine JF. Culture of Mycobacterium avium subspecies paratuberculosis from the blood of patients with Crohn’s disease. Lancet. 2004;364:1039-1044.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 440]  [Cited by in F6Publishing: 418]  [Article Influence: 20.9]  [Reference Citation Analysis (0)]
94.  Ryan P, Bennett MW, Aarons S, Lee G, Collins JK, O’Sullivan GC, O’Connell J, Shanahan F. PCR detection of Mycobacterium paratuberculosis in Crohn’s disease granulomas isolated by laser capture microdissection. Gut. 2002;51:665-670.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 94]  [Cited by in F6Publishing: 98]  [Article Influence: 4.5]  [Reference Citation Analysis (0)]
95.  Parrish NM, Radcliff RP, Brey BJ, Anderson JL, Clark DL, Koziczkowski JJ, Ko CG, Goldberg ND, Brinker DA, Carlson RA. Absence of mycobacterium avium subsp. paratuberculosis in Crohn’s patients. Inflamm Bowel Dis. 2009;15:558-565.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 25]  [Cited by in F6Publishing: 24]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
96.  Freeman H, Noble M. Lack of evidence for Mycobacterium avium subspecies paratuberculosis in Crohn’s disease. Inflamm Bowel Dis. 2005;11:782-783.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 13]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
97.  Shanahan F, O’Mahony J. The mycobacteria story in Crohn’s disease. Am J Gastroenterol. 2005;100:1537-1538.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 46]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
98.  Ellingson JL, Cheville JC, Brees D, Miller JM, Cheville NF. Absence of Mycobacterium avium subspecies paratuberculosis components from Crohn’s disease intestinal biopsy tissues. Clin Med Res. 2003;1:217-226.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 40]  [Cited by in F6Publishing: 43]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
99.  Naser SA, Hulten K, Shafran I, Graham DY, El-Zaatari FA. Specific seroreactivity of Crohn‘s disease patients against p35 and p36 antigens of M. avium subsp. paratuberculosis. Vet Microbiol. 2000;77:497-504.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 58]  [Cited by in F6Publishing: 61]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
100.  Borody TJ, Bilkey S, Wettstein AR, Leis S, Pang G, Tye S. Anti-mycobacterial therapy in Crohn’s disease heals mucosa with longitudinal scars. Dig Liver Dis. 2007;39:438-444.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 37]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
101.  Borody TJ, Leis S, Warren EF, Surace R. Treatment of severe Crohn’s disease using antimycobacterial triple therapy--approaching a cure? Dig Liver Dis. 2002;34:29-38.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 76]  [Cited by in F6Publishing: 78]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
102.  Gui GP, Thomas PR, Tizard ML, Lake J, Sanderson JD, Hermon-Taylor J. Two-year-outcomes analysis of Crohn’s disease treated with rifabutin and macrolide antibiotics. J Antimicrob Chemother. 1997;39:393-400.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 104]  [Cited by in F6Publishing: 97]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
103.  Lamps LW, Madhusudhan KT, Greenson JK, Pierce RH, Massoll NA, Chiles MC, Dean PJ, Scott MA. The role of Yersinia enterocolitica and Yersinia pseudotuberculosis in granulomatous appendicitis: a histologic and molecular study. Am J Surg Pathol. 2001;25:508-515.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 101]  [Cited by in F6Publishing: 71]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
104.  Grützkau A, Hanski C, Hahn H, Riecken EO. Involvement of M cells in the bacterial invasion of Peyer‘s patches: a common mechanism shared by Yersinia enterocolitica and other enteroinvasive bacteria. Gut. 1990;31:1011-1015.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 208]  [Cited by in F6Publishing: 219]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
105.  Handley SA, Dube PH, Revell PA, Miller VL. Characterization of oral Yersinia enterocolitica infection in three different strains of inbred mice. Infect Immun. 2004;72:1645-1656.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 42]  [Cited by in F6Publishing: 42]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
106.  Lamps LW, Madhusudhan KT, Havens JM, Greenson JK, Bronner MP, Chiles MC, Dean PJ, Scott MA. Pathogenic Yersinia DNA is detected in bowel and mesenteric lymph nodes from patients with Crohn’s disease. Am J Surg Pathol. 2003;27:220-227.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 87]  [Cited by in F6Publishing: 89]  [Article Influence: 4.2]  [Reference Citation Analysis (0)]
107.  Kallinowski F, Wassmer A, Hofmann MA, Harmsen D, Heesemann J, Karch H, Herfarth C, Buhr HJ. Prevalence of enteropathogenic bacteria in surgically treated chronic inflammatory bowel disease. Hepatogastroenterology. 1998;45:1552-1558.  [PubMed]  [DOI]  [Cited in This Article: ]
108.  Zippi M, Colaiacomo MC, Marcheggiano A, Pica R, Paoluzi P, Iaiani G, Caprilli R, Maccioni F. Mesenteric adenitis caused by Yersinia pseudotubercolosis in a patient subsequently diagnosed with Crohn’s disease of the terminal ileum. World J Gastroenterol. 2006;12:3933-3935.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 11]  [Cited by in F6Publishing: 9]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
109.  Homewood R, Gibbons CP, Richards D, Lewis A, Duane PD, Griffiths AP. Ileitis due to Yersinia pseudotuberculosis in Crohn’s disease. J Infect. 2003;47:328-332.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 12]  [Article Influence: 0.6]  [Reference Citation Analysis (0)]
110.  Huijsdens XW, Linskens RK, Taspinar H, Meuwissen SG, Vandenbroucke-Grauls CM, Savelkoul PH. Listeria monocytogenes and inflammatory bowel disease: detection of Listeria species in intestinal mucosal biopsies by real-time PCR. Scand J Gastroenterol. 2003;38:332-333.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 16]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
111.  Chen W, Li D, Paulus B, Wilson I, Chadwick VS. Detection of Listeria monocytogenes by polymerase chain reaction in intestinal mucosal biopsies from patients with inflammatory bowel disease and controls. J Gastroenterol Hepatol. 2000;15:1145-1150.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 45]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
112.  Liu Y, van Kruiningen HJ, West AB, Cartun RW, Cortot A, Colombel JF. Immunocytochemical evidence of Listeria, Escherichia coli, and Streptococcus antigens in Crohn’s disease. Gastroenterology. 1995;108:1396-1404.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 220]  [Cited by in F6Publishing: 237]  [Article Influence: 8.2]  [Reference Citation Analysis (0)]
113.  Chiba M, Fukushima T, Inoue S, Horie Y, Iizuka M, Masamune O. Listeria monocytogenes in Crohn’s disease. Scand J Gastroenterol. 1998;33:430-434.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 24]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
114.  Cossart P. Illuminating the landscape of host-pathogen interactions with the bacterium Listeria monocytogenes. Proc Natl Acad Sci USA. 2011;108:19484-19491.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 246]  [Cited by in F6Publishing: 251]  [Article Influence: 19.3]  [Reference Citation Analysis (0)]
115.  Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nuñez G, Flavell RA. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science. 2005;307:731-734.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1334]  [Cited by in F6Publishing: 1302]  [Article Influence: 68.5]  [Reference Citation Analysis (2)]
116.  Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet. 1984;1:1311-1315.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3302]  [Cited by in F6Publishing: 3112]  [Article Influence: 77.8]  [Reference Citation Analysis (0)]
117.  Fox JG. The non-H pylori helicobacters: their expanding role in gastrointestinal and systemic diseases. Gut. 2002;50:273-283.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 211]  [Cited by in F6Publishing: 220]  [Article Influence: 10.0]  [Reference Citation Analysis (0)]
118.  Solnick JV, Schauer DB. Emergence of diverse Helicobacter species in the pathogenesis of gastric and enterohepatic diseases. Clin Microbiol Rev. 2001;14:59-97.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 273]  [Cited by in F6Publishing: 280]  [Article Influence: 12.2]  [Reference Citation Analysis (0)]
119.  Chin EY, Dangler CA, Fox JG, Schauer DB. Helicobacter hepaticus infection triggers inflammatory bowel disease in T cell receptor alphabeta mutant mice. Comp Med. 2000;50:586-594.  [PubMed]  [DOI]  [Cited in This Article: ]
120.  Kullberg MC, Ward JM, Gorelick PL, Caspar P, Hieny S, Cheever A, Jankovic D, Sher A. Helicobacter hepaticus triggers colitis in specific-pathogen-free interleukin-10 (IL-10)-deficient mice through an IL-12- and gamma interferon-dependent mechanism. Infect Immun. 1998;66:5157-5166.  [PubMed]  [DOI]  [Cited in This Article: ]
121.  Mei L, Targan SR, Landers CJ, Dutridge D, Ippoliti A, Vasiliauskas EA, Papadakis KA, Fleshner PR, Rotter JI, Yang H. Familial expression of anti-Escherichia coli outer membrane porin C in relatives of patients with Crohn’s disease. Gastroenterology. 2006;130:1078-1085.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 63]  [Cited by in F6Publishing: 64]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
122.  Landers CJ, Cohavy O, Misra R, Yang H, Lin YC, Braun J, Targan SR. Selected loss of tolerance evidenced by Crohn’s disease-associated immune responses to auto- and microbial antigens. Gastroenterology. 2002;123:689-699.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 324]  [Cited by in F6Publishing: 330]  [Article Influence: 15.0]  [Reference Citation Analysis (0)]
123.  Fujita H, Eishi Y, Ishige I, Saitoh K, Takizawa T, Arima T, Koike M. Quantitative analysis of bacterial DNA from Mycobacteria spp., Bacteroides vulgatus, and Escherichia coli in tissue samples from patients with inflammatory bowel diseases. J Gastroenterol. 2002;37:509-516.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 54]  [Cited by in F6Publishing: 57]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
124.  Cartun RW, Van Kruiningen HJ, Pedersen CA, Berman MM. An immunocytochemical search for infectious agents in Crohn’s disease. Mod Pathol. 1993;6:212-219.  [PubMed]  [DOI]  [Cited in This Article: ]
125.  Giaffer MH, Holdsworth CD, Duerden BI. Virulence properties of Escherichia coli strains isolated from patients with inflammatory bowel disease. Gut. 1992;33:646-650.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 79]  [Cited by in F6Publishing: 80]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
126.  Burke DA, Axon AT. Adhesive Escherichia coli in inflammatory bowel disease and infective diarrhoea. BMJ. 1988;297:102-104.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 97]  [Cited by in F6Publishing: 95]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
127.  Sasaki M, Sitaraman SV, Babbin BA, Gerner-Smidt P, Ribot EM, Garrett N, Alpern JA, Akyildiz A, Theiss AL, Nusrat A. Invasive Escherichia coli are a feature of Crohn’s disease. Lab Invest. 2007;87:1042-1054.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 171]  [Cited by in F6Publishing: 182]  [Article Influence: 10.7]  [Reference Citation Analysis (0)]
128.  Chassaing B, Darfeuille-Michaud A. The commensal microbiota and enteropathogens in the pathogenesis of inflammatory bowel diseases. Gastroenterology. 2011;140:1720-1728.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 326]  [Cited by in F6Publishing: 338]  [Article Influence: 26.0]  [Reference Citation Analysis (0)]
129.  Boudeau J, Glasser AL, Masseret E, Joly B, Darfeuille-Michaud A. Invasive ability of an Escherichia coli strain isolated from the ileal mucosa of a patient with Crohn’s disease. Infect Immun. 1999;67:4499-4509.  [PubMed]  [DOI]  [Cited in This Article: ]
130.  Bringer MA, Billard E, Glasser AL, Colombel JF, Darfeuille-Michaud A. Replication of Crohn’s disease-associated AIEC within macrophages is dependent on TNF-α secretion. Lab Invest. 2012;92:411-419.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 46]  [Article Influence: 3.8]  [Reference Citation Analysis (0)]
131.  Glasser AL, Boudeau J, Barnich N, Perruchot MH, Colombel JF, Darfeuille-Michaud A. Adherent invasive Escherichia coli strains from patients with Crohn’s disease survive and replicate within macrophages without inducing host cell death. Infect Immun. 2001;69:5529-5537.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 328]  [Cited by in F6Publishing: 323]  [Article Influence: 14.0]  [Reference Citation Analysis (0)]
132.  Lapaquette P, Glasser AL, Huett A, Xavier RJ, Darfeuille-Michaud A. Crohn’s disease-associated adherent-invasive E. coli are selectively favoured by impaired autophagy to replicate intracellularly. Cell Microbiol. 2010;12:99-113.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 227]  [Cited by in F6Publishing: 251]  [Article Influence: 16.7]  [Reference Citation Analysis (0)]
133.  Wine E, Ossa JC, Gray-Owen SD, Sherman PM. Adherent-invasive Escherichia coli, strain LF82 disrupts apical junctional complexes in polarized epithelia. BMC Microbiol. 2009;9:180.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 50]  [Cited by in F6Publishing: 49]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
134.  Vazeille E, Bringer MA, Gardarin A, Chambon C, Becker-Pauly C, Pender SL, Jakob C, Müller S, Lottaz D, Darfeuille-Michaud A. Role of meprins to protect ileal mucosa of Crohn’s disease patients from colonization by adherent-invasive E. coli. PLoS One. 2011;6:e21199.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 34]  [Cited by in F6Publishing: 37]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
135.  Nguyen HT, Dalmasso G, Müller S, Carrière J, Seibold F, Darfeuille-Michaud A. Crohn’s disease-associated adherent invasive Escherichia coli modulate levels of microRNAs in intestinal epithelial cells to reduce autophagy. Gastroenterology. 2014;146:508-519.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 168]  [Cited by in F6Publishing: 175]  [Article Influence: 17.5]  [Reference Citation Analysis (0)]
136.  Carvalho FA, Barnich N, Sivignon A, Darcha C, Chan CH, Stanners CP, Darfeuille-Michaud A. Crohn’s disease adherent-invasive Escherichia coli colonize and induce strong gut inflammation in transgenic mice expressing human CEACAM. J Exp Med. 2009;206:2179-2189.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 214]  [Cited by in F6Publishing: 225]  [Article Influence: 15.0]  [Reference Citation Analysis (0)]
137.  Clements A, Young JC, Constantinou N, Frankel G. Infection strategies of enteric pathogenic Escherichia coli. Gut Microbes. 2012;3:71-87.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 227]  [Cited by in F6Publishing: 177]  [Article Influence: 14.8]  [Reference Citation Analysis (0)]
138.  Chassaing B, Darfeuille-Michaud A. The σE pathway is involved in biofilm formation by Crohn’s disease-associated adherent-invasive Escherichia coli. J Bacteriol. 2013;195:76-84.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 26]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
139.  Martinez-Medina M, Naves P, Blanco J, Aldeguer X, Blanco JE, Blanco M, Ponte C, Soriano F, Darfeuille-Michaud A, Garcia-Gil LJ. Biofilm formation as a novel phenotypic feature of adherent-invasive Escherichia coli (AIEC). BMC Microbiol. 2009;9:202.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 67]  [Cited by in F6Publishing: 71]  [Article Influence: 4.7]  [Reference Citation Analysis (0)]
140.  Meconi S, Vercellone A, Levillain F, Payré B, Al Saati T, Capilla F, Desreumaux P, Darfeuille-Michaud A, Altare F. Adherent-invasive Escherichia coli isolated from Crohn’s disease patients induce granulomas in vitro. Cell Microbiol. 2007;9:1252-1261.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 86]  [Cited by in F6Publishing: 97]  [Article Influence: 5.7]  [Reference Citation Analysis (0)]
141.  Martinez-Medina M, Aldeguer X, Lopez-Siles M, González-Huix F, López-Oliu C, Dahbi G, Blanco JE, Blanco J, Garcia-Gil LJ, Darfeuille-Michaud A. 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. Inflamm Bowel Dis. 2009;15:872-882.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 272]  [Cited by in F6Publishing: 255]  [Article Influence: 17.0]  [Reference Citation Analysis (0)]
142.  Masseret E, Boudeau J, Colombel JF, Neut C, Desreumaux P, Joly B, Cortot A, Darfeuille-Michaud A. Genetically related Escherichia coli strains associated with Crohn’s disease. Gut. 2001;48:320-325.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 77]  [Cited by in F6Publishing: 83]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
143.  Boudeau J, Barnich N, Darfeuille-Michaud A. Type 1 pili-mediated adherence of Escherichia coli strain LF82 isolated from Crohn’s disease is involved in bacterial invasion of intestinal epithelial cells. Mol Microbiol. 2001;39:1272-1284.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 164]  [Cited by in F6Publishing: 166]  [Article Influence: 7.2]  [Reference Citation Analysis (0)]
144.  Miquel S, Peyretaillade E, Claret L, de Vallée A, Dossat C, Vacherie B, Zineb el H, Segurens B, Barbe V, Sauvanet P. Complete genome sequence of Crohn’s disease-associated adherent-invasive E. coli strain LF82. PLoS One. 2010;5:pii e12714.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 129]  [Cited by in F6Publishing: 126]  [Article Influence: 9.0]  [Reference Citation Analysis (0)]
145.  Barnich N, Bringer MA, Claret L, Darfeuille-Michaud A. Involvement of lipoprotein NlpI in the virulence of adherent invasive Escherichia coli strain LF82 isolated from a patient with Crohn’s disease. Infect Immun. 2004;72:2484-2493.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 46]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
146.  Rolhion N, Barnich N, Claret L, Darfeuille-Michaud A. Strong decrease in invasive ability and outer membrane vesicle release in Crohn’s disease-associated adherent-invasive Escherichia coli strain LF82 with the yfgL gene deleted. J Bacteriol. 2005;187:2286-2296.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 80]  [Cited by in F6Publishing: 82]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
147.  Rolhion N, Carvalho FA, Darfeuille-Michaud A. OmpC and the sigma(E) regulatory pathway are involved in adhesion and invasion of the Crohn’s disease-associated Escherichia coli strain LF82. Mol Microbiol. 2007;63:1684-1700.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 91]  [Cited by in F6Publishing: 101]  [Article Influence: 5.9]  [Reference Citation Analysis (0)]
148.  Rolhion N, Barnich N, Bringer MA, Glasser AL, Ranc J, Hébuterne X, Hofman P, Darfeuille-Michaud A. Abnormally expressed ER stress response chaperone Gp96 in CD favours adherent-invasive Escherichia coli invasion. Gut. 2010;59:1355-1362.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 82]  [Cited by in F6Publishing: 92]  [Article Influence: 6.6]  [Reference Citation Analysis (0)]
149.  Barnich N, Boudeau J, Claret L, Darfeuille-Michaud A. Regulatory and functional co-operation of flagella and type 1 pili in adhesive and invasive abilities of AIEC strain LF82 isolated from a patient with Crohn’s disease. Mol Microbiol. 2003;48:781-794.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 109]  [Cited by in F6Publishing: 104]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
150.  Barnich N, Carvalho FA, Glasser AL, Darcha C, Jantscheff P, Allez M, Peeters H, Bommelaer G, Desreumaux P, Colombel JF. CEACAM6 acts as a receptor for adherent-invasive E. coli, supporting ileal mucosa colonization in Crohn disease. J Clin Invest. 2007;117:1566-1574.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 389]  [Cited by in F6Publishing: 401]  [Article Influence: 23.6]  [Reference Citation Analysis (0)]
151.  Capitani G, Eidam O, Glockshuber R, Grütter MG. Structural and functional insights into the assembly of type 1 pili from Escherichia coli. Microbes Infect. 2006;8:2284-2290.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 47]  [Cited by in F6Publishing: 47]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
152.  Dreux N, Denizot J, Martinez-Medina M, Mellmann A, Billig M, Kisiela D, Chattopadhyay S, Sokurenko E, Neut C, Gower-Rousseau C. Point mutations in FimH adhesin of Crohn’s disease-associated adherent-invasive Escherichia coli enhance intestinal inflammatory response. PLoS Pathog. 2013;9:e1003141.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 112]  [Cited by in F6Publishing: 114]  [Article Influence: 10.4]  [Reference Citation Analysis (0)]
153.  Chassaing B, Rolhion N, de Vallée A, Salim SY, Prorok-Hamon M, Neut C, Campbell BJ, Söderholm JD, Hugot JP, Colombel JF. Crohn disease--associated adherent-invasive E. coli bacteria target mouse and human Peyer’s patches via long polar fimbriae. J Clin Invest. 2011;121:966-975.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 181]  [Cited by in F6Publishing: 189]  [Article Influence: 14.5]  [Reference Citation Analysis (0)]
154.  Bäumler AJ, Tsolis RM, Heffron F. The lpf fimbrial operon mediates adhesion of Salmonella typhimurium to murine Peyer’s patches. Proc Natl Acad Sci USA. 1996;93:279-283.  [PubMed]  [DOI]  [Cited in This Article: ]
155.  Lapidus A, Akerlund JE, Einarsson C. Gallbladder bile composition in patients with Crohn ‘s disease. World J Gastroenterol. 2006;12:70-74.  [PubMed]  [DOI]  [Cited in This Article: ]
156.  Chassaing B, Etienne-Mesmin L, Bonnet R, Darfeuille-Michaud A. Bile salts induce long polar fimbriae expression favouring Crohn’s disease-associated adherent-invasive Escherichia coli interaction with Peyer’s patches. Environ Microbiol. 2013;15:355-371.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 40]  [Cited by in F6Publishing: 43]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
157.  Bandzar S, Gupta S, Platt MO. Crohn’s disease: a review of treatment options and current research. Cell Immunol. 2013;286:45-52.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 46]  [Cited by in F6Publishing: 51]  [Article Influence: 4.6]  [Reference Citation Analysis (0)]
158.  Gionchetti P, Rizzello F, Lammers KM, Morselli C, Sollazzi L, Davies S, Tambasco R, Calabrese C, Campieri M. Antibiotics and probiotics in treatment of inflammatory bowel disease. World J Gastroenterol. 2006;12:3306-3313.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 73]  [Cited by in F6Publishing: 61]  [Article Influence: 3.4]  [Reference Citation Analysis (1)]
159.  Sutherland L, Singleton J, Sessions J, Hanauer S, Krawitt E, Rankin G, Summers R, Mekhjian H, Greenberger N, Kelly M. Double blind, placebo controlled trial of metronidazole in Crohn’s disease. Gut. 1991;32:1071-1075.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 370]  [Cited by in F6Publishing: 379]  [Article Influence: 11.5]  [Reference Citation Analysis (0)]
160.  Arnold GL, Beaves MR, Pryjdun VO, Mook WJ. Preliminary study of ciprofloxacin in active Crohn’s disease. Inflamm Bowel Dis. 2002;8:10-15.  [PubMed]  [DOI]  [Cited in This Article: ]
161.  Colombel JF, Lémann M, Cassagnou M, Bouhnik Y, Duclos B, Dupas JL, Notteghem B, Mary JY. A controlled trial comparing ciprofloxacin with mesalazine for the treatment of active Crohn’s disease. Groupe d’Etudes Thérapeutiques des Affections Inflammatoires Digestives (GETAID). Am J Gastroenterol. 1999;94:674-678.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 179]  [Cited by in F6Publishing: 183]  [Article Influence: 7.3]  [Reference Citation Analysis (0)]
162.  Prantera C, Zannoni F, Scribano ML, Berto E, Andreoli A, Kohn A, Luzi C. An antibiotic regimen for the treatment of active Crohn’s disease: a randomized, controlled clinical trial of metronidazole plus ciprofloxacin. Am J Gastroenterol. 1996;91:328-332.  [PubMed]  [DOI]  [Cited in This Article: ]
163.  Papi C, Fasci Spurio F, Margagnoni G, Aratari A. Randomized controlled trials in prevention of postsurgical recurrence in Crohn’s disease. Rev Recent Clin Trials. 2012;7:307-313.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 2]  [Article Influence: 0.2]  [Reference Citation Analysis (0)]
164.  Renna S, Orlando A, Cottone M. Randomized controlled trials in perianal Crohn’s disease. Rev Recent Clin Trials. 2012;7:297-302.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 4]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
165.  Iesalnieks I, Dederichs F, Kilger A, Schlitt HJ, Agha A. [Postoperative morbidity after bowel resections in patients with Crohn’s disease: risk, management strategies, prevention]. Z Gastroenterol. 2012;50:595-600.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 9]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
166.  Veerappan GR, Betteridge J, Young PE. Probiotics for the treatment of inflammatory bowel disease. Curr Gastroenterol Rep. 2012;14:324-333.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 73]  [Cited by in F6Publishing: 61]  [Article Influence: 5.1]  [Reference Citation Analysis (0)]
167.  Girardin M, Seidman EG. Indications for the use of probiotics in gastrointestinal diseases. Dig Dis. 2011;29:574-587.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 40]  [Cited by in F6Publishing: 44]  [Article Influence: 3.4]  [Reference Citation Analysis (1)]
168.  Malchow HA. Crohn’s disease and Escherichia coli. A new approach in therapy to maintain remission of colonic Crohn’s disease? J Clin Gastroenterol. 1997;25:653-658.  [PubMed]  [DOI]  [Cited in This Article: ]
169.  Guslandi M, Mezzi G, Sorghi M, Testoni PA. Saccharomyces boulardii in maintenance treatment of Crohn‘s disease. Dig Dis Sci. 2000;45:1462-1464.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 485]  [Cited by in F6Publishing: 386]  [Article Influence: 16.1]  [Reference Citation Analysis (0)]
170.  de Franchis R, Omodei P, Ranzi T, Brignola C, Rocca R, Prada A, Pera A, Vecchi M, Del Piano M, Ferrara A. Controlled trial of oral 5-aminosalicylic acid for the prevention of early relapse in Crohn’s disease. Aliment Pharmacol Ther. 1997;11:845-852.  [PubMed]  [DOI]  [Cited in This Article: ]
171.  Prantera C, Pallone F, Brunetti G, Cottone M, Miglioli M. Oral 5-aminosalicylic acid (Asacol) in the maintenance treatment of Crohn’s disease. The Italian IBD Study Group. Gastroenterology. 1992;103:363-368.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 1]  [Article Influence: 0.0]  [Reference Citation Analysis (0)]
172.  Bourreille A, Cadiot G, Le Dreau G, Laharie D, Beaugerie L, Dupas JL, Marteau P, Rampal P, Moyse D, Saleh A. Saccharomyces boulardii does not prevent relapse of Crohn’s disease. Clin Gastroenterol Hepatol. 2013;11:982-987.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 120]  [Cited by in F6Publishing: 121]  [Article Influence: 11.0]  [Reference Citation Analysis (0)]
173.  Prantera C, Scribano ML, Falasco G, Andreoli A, Luzi C. Ineffectiveness of probiotics in preventing recurrence after curative resection for Crohn’s disease: a randomised controlled trial with Lactobacillus GG. Gut. 2002;51:405-409.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 419]  [Cited by in F6Publishing: 419]  [Article Influence: 19.0]  [Reference Citation Analysis (0)]
174.  Bousvaros A, Guandalini S, Baldassano RN, Botelho C, Evans J, Ferry GD, Goldin B, Hartigan L, Kugathasan S, Levy J. A randomized, double-blind trial of Lactobacillus GG versus placebo in addition to standard maintenance therapy for children with Crohn’s disease. Inflamm Bowel Dis. 2005;11:833-839.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 259]  [Cited by in F6Publishing: 229]  [Article Influence: 12.1]  [Reference Citation Analysis (0)]
175.  Van Gossum A, Dewit O, Louis E, de Hertogh G, Baert F, Fontaine F, DeVos M, Enslen M, Paintin M, Franchimont D. Multicenter randomized-controlled clinical trial of probiotics (Lactobacillus johnsonii, LA1) on early endoscopic recurrence of Crohn’s disease after lleo-caecal resection. Inflamm Bowel Dis. 2007;13:135-142.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 206]  [Cited by in F6Publishing: 181]  [Article Influence: 10.6]  [Reference Citation Analysis (0)]
176.  Marteau P, Lémann M, Seksik P, Laharie D, Colombel JF, Bouhnik Y, Cadiot G, Soulé JC, Bourreille A, Metman E. Ineffectiveness of Lactobacillus johnsonii LA1 for prophylaxis of postoperative recurrence in Crohn’s disease: a randomised, double blind, placebo controlled GETAID trial. Gut. 2006;55:842-847.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 289]  [Cited by in F6Publishing: 263]  [Article Influence: 14.6]  [Reference Citation Analysis (0)]
177.  Damman CJ, Miller SI, Surawicz CM, Zisman TL. The microbiome and inflammatory bowel disease: is there a therapeutic role for fecal microbiota transplantation? Am J Gastroenterol. 2012;107:1452-1459.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 147]  [Cited by in F6Publishing: 151]  [Article Influence: 12.6]  [Reference Citation Analysis (0)]
178.  Karadsheh Z, Sule S. Fecal transplantation for the treatment of recurrent clostridium difficile infection. N Am J Med Sci. 2013;5:339-343.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 17]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
179.  Bakken JS, Borody T, Brandt LJ, Brill JV, Demarco DC, Franzos MA, Kelly C, Khoruts A, Louie T, Martinelli LP. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol. 2011;9:1044-1049.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 650]  [Cited by in F6Publishing: 641]  [Article Influence: 49.3]  [Reference Citation Analysis (0)]
180.  Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin Infect Dis. 2011;53:994-1002.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 721]  [Cited by in F6Publishing: 692]  [Article Influence: 57.7]  [Reference Citation Analysis (0)]
181.  Borody TJ, George L, Andrews P, Brandl S, Noonan S, Cole P, Hyland L, Morgan A, Maysey J, Moore-Jones D. Bowel-flora alteration: a potential cure for inflammatory bowel disease and irritable bowel syndrome? Med J Aust. 1989;150:604.  [PubMed]  [DOI]  [Cited in This Article: ]
182.  Anderson JL, Edney RJ, Whelan K. Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease. Aliment Pharmacol Ther. 2012;36:503-516.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 224]  [Cited by in F6Publishing: 226]  [Article Influence: 18.8]  [Reference Citation Analysis (0)]
183.  Zhang FM, Wang HG, Wang M, Cui BT, Fan ZN, Ji GZ. Fecal microbiota transplantation for severe enterocolonic fistulizing Crohn‘s disease. World J Gastroenterol. 2013;19:7213-7216.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 87]  [Cited by in F6Publishing: 85]  [Article Influence: 7.7]  [Reference Citation Analysis (1)]