Microbial Influences in Inflammatory Bowel Diseases

Gastroenterology - Tập 134 - Trang 577-594 - 2008
R. Balfour Sartor1
1Department of Medicine, and Department of Microbiology and Immunology, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Tài liệu tham khảo

Eckburg, 2007, The role of microbes in Crohn’s disease, Clin Infect Dis, 44, 256, 10.1086/510385 Strober, 2007, The fundamental basis of inflammatory bowel disease, J Clin Invest, 117, 514, 10.1172/JCI30587 Sartor, 2006, Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis, Nat Clin Pract Gastroenterol Hepatol, 3, 390, 10.1038/ncpgasthep0528 Xavier, 2007, Unravelling the pathogenesis of inflammatory bowel disease, Nature, 448, 427, 10.1038/nature06005 Sartor, 2007, CCFA microbial-host interactions workshop: highlights and key observations, Inflamm Bowel Dis, 13, 600, 10.1002/ibd.20114 Eckburg, 2005, Diversity of the human intestinal microbial flora, Science, 308, 1635, 10.1126/science.1110591 Gill, 2006, Metagenomic analysis of the human distal gut microbiome, Science, 312, 1355, 10.1126/science.1124234 Turnbaugh, 2006, An obesity-associated gut microbiome with increased capacity for energy harvest, Nature, 444, 1027, 10.1038/nature05414 Frank, 2007, Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases, Proc Natl Acad Sci U S A, 104, 13780, 10.1073/pnas.0706625104 Ley, 2006, Ecological and evolutionary forces shaping microbial diversity in the human intestine, Cell, 124, 837, 10.1016/j.cell.2006.02.017 Hooper, 2001, Commensal host-bacterial relationships in the gut, Science, 292, 1115, 10.1126/science.1058709 Clavel, 2007, Bacteria- and host-derived mechanisms to control intestinal epithelial cell homeostasis: implications for chronic inflammation, Inflamm Bowel Dis, 13, 1153, 10.1002/ibd.20174 Ley, 2006, Microbial ecology: human gut microbes associated with obesity, Nature, 444, 1022, 10.1038/4441022a Pumbwe, 2007, Bile salts enhance bacterial co-aggregation, bacterial-intestinal epithelial cell adhesion, biofilm formation and antimicrobial resistance of Bacteroides fragilis, Microb Pathog, 43, 78, 10.1016/j.micpath.2007.04.002 Strober, 2006, Signalling pathways and molecular interactions of NOD1 and NOD2, Nat Rev Immunol, 6, 9, 10.1038/nri1747 Fukata, 2006, Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: role in proliferation and apoptosis in the intestine, Gastroenterology, 131, 862, 10.1053/j.gastro.2006.06.017 Neish, 2000, Prokaryotic regulation of epithelial responses by inhibition of IκB-α ubiquitination, Science, 289, 1560, 10.1126/science.289.5484.1560 Ruiz, 2006, IL-10 gene-deficient mice lack TGF-β/Smad-mediated TLR2 degradation and fail to inhibit proinflammatory gene expression in intestinal epithelial cells under conditions of chronic inflammation, Ann N Y Acad Sci, 1072, 389, 10.1196/annals.1326.023 Kagnoff, 1997, Epithelial cells as sensors for microbial infection, J Clin Invest, 100, 6, 10.1172/JCI119522 Haller, 2003, Transforming growth factor-β 1 inhibits non-pathogenic gram-negative bacteria-induced NF-κB recruitment to the interleukin-6 gene promoter in intestinal epithelial cells through modulation of histone acetylation, J Biol Chem, 278, 23851, 10.1074/jbc.M300075200 Karrasch, 2007, Gnotobiotic IL-10-/- NF-κBEGFP mice reveal the critical role of TLR/NF-κB signaling in commensal bacteria-induced colitis, J Immunol, 178, 6522, 10.4049/jimmunol.178.10.6522 Kitajima, 2001, Dextran sodium sulfate-induced colitis in germ-free IQI/Jic mice, Exp Anim, 50, 387, 10.1538/expanim.50.387 Lee, 2006, Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells, Nat Cell Biol, 8, 1327, 10.1038/ncb1500 Fukata, 2005, Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis, Am J Physiol Gastrointest Liver Physiol, 288, G1055, 10.1152/ajpgi.00328.2004 Rakoff-Nahoum, 2004, Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis, Cell, 118, 229, 10.1016/j.cell.2004.07.002 Ohkawara, 2005, Macrophage migration inhibitory factor contributes to the development of acute dextran sulphate sodium-induced colitis in Toll-like receptor 4 knockout mice, Clin Exp Immunol, 141, 412, 10.1111/j.1365-2249.2005.02877.x Heimesaat, 2007, Shift towards pro-inflammatory intestinal bacteria aggravates acute murine colitis via Toll-like receptors 2 and 4, PLos One, 2, e662, 10.1371/journal.pone.0000662 Nenci, 2007, Epithelial NEMO links innate immunity to chronic intestinal inflammation, Nature, 446, 557, 10.1038/nature05698 Egan, 2004, IκB-kinase β-dependent NF-κB activation provides radioprotection to the intestinal epithelium, Proc Natl Acad Sci U S A, 101, 2452, 10.1073/pnas.0306734101 Katakura, 2005, Toll-like receptor 9-induced type I IFN protects mice from experimental colitis, J Clin Invest, 115, 695, 10.1172/JCI22996 Zaph, 2007, Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis, Nature, 446, 552, 10.1038/nature05590 Shibolet, 2007, TLRs in the Gut, Am J Physiol Gastrointest Liver Physiol, 292, G1469, 10.1152/ajpgi.00531.2006 Zeng, 2006, Flagellin/TLR5 responses in epithelia reveal intertwined activation of inflammatory and apoptotic pathways, Am J Physiol Gastrointest Liver Physiol, 290, G96, 10.1152/ajpgi.00273.2005 Kelly, 2004, Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-γ and RelA, Nat Immunol, 5, 104, 10.1038/ni1018 Hooper, 2001, Molecular analysis of commensal host-microbial relationships in the intestine, Science, 291, 881, 10.1126/science.291.5505.881 Wehkamp, 2005, Reduced Paneth cell α-defensins in ileal Crohn’s disease, Proc Natl Acad Sci U S A, 102, 18129, 10.1073/pnas.0505256102 Kobayashi, 2005, Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract, Science, 307, 731, 10.1126/science.1104911 Lala, 2003, Crohn’s disease and the NOD2 gene: a role for paneth cells, Gastroenterology, 125, 47, 10.1016/S0016-5085(03)00661-9 Vora, 2004, Beta-defensin-2 expression is regulated by TLR signaling in intestinal epithelial cells, J Immunol, 173, 5398, 10.4049/jimmunol.173.9.5398 Lebeis, 2007, TLR signaling mediated by MyD88 is required for a protective innate immune response by neutrophils to Citrobacter rodentium, J Immunol, 179, 566, 10.4049/jimmunol.179.1.566 Karrasch, 2006, Wound-induced p38MAPK-dependent histone H3 phosphorylation correlates with increased COX-2 expression in enterocytes, J Cell Physiol, 207, 809, 10.1002/jcp.20626 Cebra, 1999, Influences of microbiota on intestinal immune system development, Am J Clin Nutr, 69, S1046, 10.1093/ajcn/69.5.1046s Smythies, 2005, Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity, J Clin Invest, 115, 66, 10.1172/JCI200519229 Hoentjen, 2005, STAT3 regulates NF-{κ}B recruitment to the IL-12p40 promoter in dendritic cells, Blood, 105, 689, 10.1182/blood-2004-04-1309 Becker, 2003, Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells, J Clin Invest, 112, 693, 10.1172/JCI200317464 Wannemuehler, 1982, Lipopolysaccharide (LPS) regulation of the immune response: LPS converts germfree mice to sensitivity to oral tolerance induction, J Immunol, 129, 959, 10.4049/jimmunol.129.3.959 Walton, 2006, T cell-mediated oral tolerance is intact in germ-free mice, Clin Exp Immunol, 143, 503, 10.1111/j.1365-2249.2006.03019.x Cong, 2002, Bacterial-reactive T regulatory cells inhibit pathogenic immune responses to the enteric flora, J Immunol, 169, 6112, 10.4049/jimmunol.169.11.6112 Macpherson, 1996, Mucosal antibodies in inflammatory bowel disease are directed against intestinal bacteria, Gut, 38, 365, 10.1136/gut.38.3.365 Barreau, 2007, CARD15/NOD2 is required for Peyer’s patches homeostasis in mice, PLos One, 2, e523, 10.1371/journal.pone.0000523 Watanabe, 2004, NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses, Nat Immunol, 5, 800, 10.1038/ni1092 van Beelen, 2007, Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells, Immunity, 27, 660, 10.1016/j.immuni.2007.08.013 Bibiloni, 2006, The bacteriology of biopsies differs between newly diagnosed, untreated, Crohn’s disease and ulcerative colitis patients, J Med Microbiol, 55, 1141, 10.1099/jmm.0.46498-0 Barnich, 2007, Adherent-invasive Escherichia coli and Crohn’s disease, Curr Opin Gastroenterol, 23, 16, 10.1097/MOG.0b013e3280105a38 Swidsinski, 2002, Mucosal flora in inflammatory bowel disease, Gastroenterology, 122, 44, 10.1053/gast.2002.30294 Cartun, 1993, An immunocytochemical search for infectious agents in Crohn’s disease, Mod Pathol, 6, 212 Liu, 1995, Immunocytochemical evidence of Listeria, Escherichia coli, and Streptococcus antigens in Crohn’s disease, Gastroenterology, 108, 1396, 10.1016/0016-5085(95)90687-8 Ryan, 2004, Bacterial DNA within granulomas of patients with Crohn’s disease—detection by laser capture microdissection and PCR, Am J Gastroenterol, 99, 1539, 10.1111/j.1572-0241.2004.40103.x D’Haens, 1998, Early lesions of recurrent Crohn’s disease caused by infusion of intestinal contents in excluded ileum, Gastroenterology, 114, 262, 10.1016/S0016-5085(98)70476-7 Rutgeerts, 1995, Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection, Gastroenterology, 108, 1617, 10.1016/0016-5085(95)90121-3 Rutgeerts, 2005, Ornidazole for prophylaxis of postoperative Crohn’s disease recurrence: a randomized, double-blind, placebo-controlled trial, Gastroenterology, 128, 856, 10.1053/j.gastro.2005.01.010 Darfeuille-Michaud, 1998, Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn’s disease, Gastroenterology, 115, 1405, 10.1016/S0016-5085(98)70019-8 Hugot, 2001, Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease, Nature, 411, 599, 10.1038/35079107 Ogura, 2001, A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease, Nature, 411, 603, 10.1038/35079114 Pierik, 2006, Toll-like receptor-1, -2, and -6 polymorphisms influence disease extension in inflammatory bowel diseases, Inflamm Bowel Dis, 12, 1, 10.1097/01.MIB.0000195389.11645.ab Hampe, 2007, A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn’s disease in ATG16L1, Nat Genet, 39, 207, 10.1038/ng1954 Rioux, 2007, Genome-wide association study identifies new susceptibility loci for Crohn’s disease and implicates autophagy in disease pathogenesis, Nat Genet, 39, 596, 10.1038/ng2032 Korzenik, 2007, Is Crohn’s disease due to defective immunity?, Gut, 56, 2, 10.1136/gut.2006.095588 Mow, 2004, High-level serum antibodies to bacterial antigens are associated with antibiotic-induced clinical remission in Crohn’s disease: a pilot study, Dig Dis Sci, 49, 1280, 10.1023/B:DDAS.0000037824.66186.e2 Duchmann, 1995, Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD), Clin Exp Immunol, 102, 448, 10.1111/j.1365-2249.1995.tb03836.x Targan, 2005, Antibodies to CBir1 flagellin define a unique response that is associated independently with complicated Crohn’s disease, Gastroenterology, 128, 2020, 10.1053/j.gastro.2005.03.046 Dubinsky, 2006, Serum immune responses predict rapid disease progression among children with Crohn’s disease: immune responses predict disease progression, Am J Gastroenterol, 101, 360, 10.1111/j.1572-0241.2006.00456.x Seibold, 1998, pANCA represents a cross-reactivity to enteric bacterial antigens, J Clin Immunol, 18, 153, 10.1023/A:1023203118100 Israeli, 2005, Anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic antibodies as predictors of inflammatory bowel disease, Gut, 54, 1232, 10.1136/gut.2004.060228 Spivak, 2006, Antibodies to I2 predict clinical response to fecal diversion in Crohn’s disease, Inflamm Bowel Dis, 12, 1122, 10.1097/01.mib.0000235833.47423.d7 Mei, 2006, Familial expression of anti-Escherichia coli outer membrane porin C in relatives of patients with Crohn’s disease, Gastroenterology, 130, 1078, 10.1053/j.gastro.2006.02.013 Papadakis, 2007, Anti-flagellin (CBir1) phenotypic and genetic Crohn’s disease associations, Inflamm Bowel Dis, 13, 524, 10.1002/ibd.20106 Devlin, 2007, NOD2 variants and antibody response to microbial antigens in Crohn’s disease patients and their unaffected relatives, Gastroenterology, 132, 576, 10.1053/j.gastro.2006.11.013 Hansen, 2007, Insights from animal models, 19 Sellon, 1998, Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice, Infect Immun, 66, 5224, 10.1128/IAI.66.11.5224-5231.1998 Rath, 1996, Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human β2 microglobulin transgenic rats, J Clin Invest, 98, 945, 10.1172/JCI118878 Veltkamp, 2001, Continuous stimulation by normal luminal bacteria is essential for the development and perpetuation of colitis in Tg(ε26) mice, Gastroenterology, 120, 900, 10.1053/gast.2001.22547 Taurog, 1994, The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats, J Exp Med, 180, 2359, 10.1084/jem.180.6.2359 Schultz, 1999, IL-2-deficient mice raised under germfree conditions develop delayed mild focal intestinal inflammation, Am J Physiol, 276, G1461 Bamias, 2007, Commensal bacteria exacerbate intestinal inflammation but are not essential for the development of murine ileitis, J Immunol, 178, 1809, 10.4049/jimmunol.178.3.1809 Sartor, 1985, Granulomatous enterocolitis induced in rats by purified bacterial cell wall fragments, Gastroenterology, 89, 587, 10.1016/0016-5085(85)90455-X Mourelle, 1998, Stimulation of transforming growth factor β1 by enteric bacteria in the pathogenesis of rat intestinal fibrosis, Gastroenterology, 114, 519, 10.1016/S0016-5085(98)70535-9 Sartor, 1988, Systemic uptake and intestinal inflammatory effects of luminal bacterial cell wall polymers in rats with acute colonic injury, Infect Immun, 56, 2101, 10.1128/IAI.56.8.2101-2108.1988 Dieleman, 1994, Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice, Gastroenterology, 107, 1643, 10.1016/0016-5085(94)90803-6 Kim, 2005, Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria, Gastroenterology, 128, 891, 10.1053/j.gastro.2005.02.009 Lodes, 2004, Bacterial flagellin is a dominant antigen in Crohn’s disease, J Clin Invest, 113, 1296, 10.1172/JCI200420295 Rath, 1999, Differential induction of colitis and gastritis in HLA-B27 transgenic rats selectively colonized with Bacteroides vulgatus and Escherichia coli, Infect Immun, 67, 2969, 10.1128/IAI.67.6.2969-2974.1999 Kim, 2005, Different host genetic backgrounds determine disease phenotypes induced by selective bacterial colonization, Gastroenterology, 128, A512 Kim, 2007, Dual association of gnotobiotic IL-10-/- mice with two nonpathogenic commensal bacteria induces aggressive pancolitis, Inflamm Bowel Dis, 13, 1457, 10.1002/ibd.20246 Hale, 2005, Piroxicam treatment of IL-10-deficient mice enhances colonic epithelial apoptosis and mucosal exposure to intestinal bacteria, Inflamm Bowel Dis, 11, 1060, 10.1097/01.MIB.0000187582.90423.bc Yamada, 1993, Mechanisms of acute and chronic intestinal inflammation induced by indomethacin, Inflammation, 17, 641, 10.1007/BF00920471 Gardiner, 1993, Colonic bacteria and bacterial translocation in experimental colitis, Br J Surg, 80, 512, 10.1002/bjs.1800800436 Hobson, 1988, Enterohepatic circulation of bacterial chemotactic peptide in rats with experimental colitis, Gastroenterology, 94, 1006, 10.1016/0016-5085(88)90560-4 Sartor, 2004, Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics and prebiotics, Gastroenterology, 126, 1620, 10.1053/j.gastro.2004.03.024 Sheil, 2007, Probiotic effects on inflammatory bowel disease, J Nutr, 137, S819, 10.1093/jn/137.3.819S Rath, 2001, Different subsets of enteric bacteria induce and perpetuate experimental colitis in rats and mice, Infect Immun, 69, 2277, 10.1128/IAI.69.4.2277-2285.2001 Hoentjen, 2003, Antibiotics with a selective aerobic or anaerobic spectrum have different therapeutic activities in various regions of the colon in interleukin-10 gene deficient mice, Gut, 52, 1721, 10.1136/gut.52.12.1721 Chiodini, 1989, Crohn’s disease and the mycobacterioses: a review and comparison of two disease entities, Clin Microbiol Rev, 2, 90, 10.1128/CMR.2.1.90 Sartor, 2005, Does Mycobacterium avium subspecies paratuberculosis cause Crohn’s disease?, Gut, 54, 896, 10.1136/gut.2004.055889 Chiodini, 1984, Possible role of mycobacteria in inflammatory bowel disease, Dig Dis Sci, 29, 1073, 10.1007/BF01317078 Behr, 2006, Mycobacteria in Crohn’s disease: a persistent hypothesis, Inflamm Bowel Dis, 12, 1000, 10.1097/01.mib.0000228183.70197.dd Autschbach, 2005, High prevalence of Mycobacterium avium subsp. paratuberculosis IS900 DNA in gut tissues from individuals with Crohn’s disease, Gut, 54, 944, 10.1136/gut.2004.045526 Millar, 1996, IS900 PCR to detect Mycobacterium paratuberculosis in retail supplies of whole pasteurized cows’ milk in England and Wales, Appl Environ Microbiol, 62, 3446, 10.1128/AEM.62.9.3446-3452.1996 Mishina, 1996, On the etiology of Crohn’s disease, Proc Natl Acad Sci U S A, 93, 9816, 10.1073/pnas.93.18.9816 Naser, 2000, Isolation of Mycobacterium avium subsp paratuberculosis from breast milk of Crohn’s disease patients, Am J Gastroenterol, 95, 1094, 10.1111/j.1572-0241.2000.01954.x Abubakar, 2007, A case-control study of drinking water and dairy products in Crohn’s disease—further investigation of the possible role of Mycobacterium avium paratuberculosis, Am J Epidemiol, 165, 776, 10.1093/aje/kwk067 Rumsey, 2006, Inhibition of phagosome maturation and survival of Mycobacterium avium subspecies paratuberculosis in polymorphonuclear leukocytes from Crohn’s disease patients, Med Sci Monit, 12, BR130 Bernstein, 2007, Testing the interaction between NOD-2 status and serological response to Mycobacterium paratuberculosis in cases of inflammatory bowel disease, J Clin Microbiol, 45, 968, 10.1128/JCM.02062-06 Sechi, 2005, Mycobacterium avium subsp. paratuberculosis, genetic susceptibility to Crohn’s disease, and Sardinians: the way ahead, J Clin Microbiol, 43, 5275, 10.1128/JCM.43.10.5275-5277.2005 Baumgart, 2007, 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, 1, 403, 10.1038/ismej.2007.52 Sechi, 2006, Relationship between Crohn’s disease, infection with Mycobacterium avium subspecies paratuberculosis and SLC11A1 gene polymorphisms in Sardinian patients, World J Gastroenterol, 12, 7161, 10.3748/wjg.v12.i44.7161 Gui, 1997, Two-year-outcomes analysis of Crohn’s disease treated with rifabutin and macrolide antibiotics, J Antimicrob Chemother, 39, 393, 10.1093/jac/39.3.393 Selby, 2007, Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn’s disease, Gastroenterology, 132, 2313, 10.1053/j.gastro.2007.03.031 Neut, 2002, Changes in the bacterial flora of the neoterminal ileum after ileocolonic resection for Crohn’s disease, Am J Gastroenterol, 97, 939, 10.1111/j.1572-0241.2002.05613.x Darfeuille-Michaud, 2004, High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease, Gastroenterology, 127, 412, 10.1053/j.gastro.2004.04.061 Glasser, 2001, Adherent invasive Escherichia coli strains from patients with Crohn’s disease survive and replicate within macrophages without inducing host cell death, Infect Immun, 69, 5529, 10.1128/IAI.69.9.5529-5537.2001 Nuding, 2007, Reduced mucosal antimicrobial activity in Crohn’s disease of the colon, Gut, 56, 1240, 10.1136/gut.2006.118646 Barnich, 2007, CEACAM6 acts as a receptor for adherent-invasive E coli, supporting ileal mucosa colonization in Crohn’s disease, J Clin Invest, 117, 1566, 10.1172/JCI30504 Rolhion, 2005, 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, 187, 2286, 10.1128/JB.187.7.2286-2296.2005 Boudeau, 2001, 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, 39, 1272, 10.1111/j.1365-2958.2001.02315.x Rolhion, 2007, 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, 63, 1684, 10.1111/j.1365-2958.2007.05638.x Simpson, 2006, Adherent and invasive Escherichia coli is associated with granulomatous colitis in boxer dogs, Infect Immun, 74, 4778, 10.1128/IAI.00067-06 Kotlowski, 2007, High prevalence of Escherichia coli belonging to the B2+D phylogenetic group in inflammatory bowel disease, Gut, 56, 669, 10.1136/gut.2006.099796 Issa, 2007, Impact of Clostridium difficile on inflammatory bowel disease, Clin Gastroenterol Hepatol, 5, 345, 10.1016/j.cgh.2006.12.028 Kim, 2007, Inflammation and apoptosis in Clostridium difficile enteritis is mediated by PGE(2) up-regulation of Fas ligand, Gastroenterology, 133, 875, 10.1053/j.gastro.2007.06.063 Rabizadeh, 2007, Enterotoxigenic Bacteroides fragilis: a potential instigator of colitis, Inflamm Bowel Dis, 13, 1475, 10.1002/ibd.20265 Yang, 2005, Rhinosinusitis derived Staphylococcal enterotoxin B possibly associates with pathogenesis of ulcerative colitis, BMC Gastroenterol, 5, 28, 10.1186/1471-230X-5-28 Huycke, 2002, Enterococcus faecalis produces extracellular superoxide and hydrogen peroxide that damages colonic epithelial cell DNA, Carcinogenesis, 23, 529, 10.1093/carcin/23.3.529 Nallapareddy, 2007, Endocarditis and biofilm-associated pili of Enterococcus faecalis, J Clin Invest, 116, 2799, 10.1172/JCI29021 Gophna, 2006, Differences between tissue-associated intestinal microfloras of patients with Crohn’s disease and ulcerative colitis, J Clin Microbiol, 44, 4136, 10.1128/JCM.01004-06 Manichanh, 2006, Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach, Gut, 55, 205, 10.1136/gut.2005.073817 Iwaya, 2006, Change in the bacterial flora of pouchitis, Hepatogastroenterology, 53, 55 Conte, 2006, Gut-associated bacterial microbiota in paediatric patients with inflammatory bowel disease, Gut, 55, 1760, 10.1136/gut.2005.078824 Martinez-medina, 2006, 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, 12, 1136, 10.1097/01.mib.0000235828.09305.0c Swidsinski, 2005, Spatial organization and composition of the mucosal flora in patients with inflammatory bowel disease, J Clin Microbiol, 43, 3380, 10.1128/JCM.43.7.3380-3389.2005 Kleessen, 2002, Mucosal and invading bacteria in patients with inflammatory bowel disease compared with controls, Scand J Gastroenterol, 37, 1034, 10.1080/003655202320378220 Sasaki, 2007, Invasive Escherichia coli are a feature of Crohn’s disease, Lab Invest, 10.1038/labinvest.3700661 Sokol, 2007, Molecular comparison of dominant microbiota associated with injured versus healthy mucosa in ulcerative colitis, Gut, 56, 152, 10.1136/gut.2006.109686 Swidsinski, 2005, Spatial organization of bacterial flora in normal and inflamed intestine: a fluorescence in situ hybridization study in mice, World J Gastroenterol, 11, 1131, 10.3748/wjg.v11.i8.1131 Tsang, 2004, Selective expansion of colitogenic commensal bacterial species in SPF IL-10-/- mice, Gastroenterology, 126, A291 Lupp, 2007, Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae, Cell Host Microbe, 2, 119, 10.1016/j.chom.2007.06.010 Bibiloni, 2005, Analysis of the large bowel microbiota of colitic mice using PCR/DGGE, Lett Appl Microbiol, 41, 45, 10.1111/j.1472-765X.2005.01720.x Scanlan, 2006, Culture-independent analyses of temporal variation of the dominant fecal microbiota and targeted bacterial subgroups in Crohn’s disease, J Clin Microbiol, 44, 3980, 10.1128/JCM.00312-06 Scupham, 2006, Abundant and diverse fungal microbiota in the murine intestine, Appl Environ Microbiol, 72, 793, 10.1128/AEM.72.1.793-801.2006 Standaert-Vitse, 2006, Candida albicans is an immunogen for anti-Saccharomyces cerevisiae antibody markers of Crohn’s disease, Gastroenterology, 130, 1764, 10.1053/j.gastro.2006.02.009 Marchesi, 2007, Rapid and noninvasive metabonomic characterization of inflammatory bowel disease, J Proteome Res, 6, 546, 10.1021/pr060470d Smith, 2005, A characterization of anaerobic colonization and associated mucosal adaptations in the undiseased ileal pouch, Colorectal Dis, 7, 563, 10.1111/j.1463-1318.2005.00833.x Roediger, 1993, Reducing sulfur compounds of the colon impair colonocyte nutrition: implications for ulcerative colitis, Gastroenterology, 104, 802, 10.1016/0016-5085(93)91016-B Schmidt, 2005, Expression of interleukin-12-related cytokine transcripts in inflammatory bowel disease: elevated interleukin-23p19 and interleukin-27p28 in Crohn’s disease but not in ulcerative colitis, Inflamm Bowel Dis, 11, 16, 10.1097/00054725-200501000-00003 Hollander, 1986, Increased intestinal permeability in patients with Crohn’s disease and their relatives, Ann Intern Med, 105, 883, 10.7326/0003-4819-105-6-883 Hilsden, 1996, Intestinal permeability changes in response to acetylsalicylic acid in relatives of patients with Crohn’s disease, Gastroenterology, 110, 1395, 10.1053/gast.1996.v110.pm8613043 Zeissig, 2007, 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, 56, 61, 10.1136/gut.2006.094375 Heller, 2005, Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution, Gastroenterology, 129, 550, 10.1016/j.gastro.2005.05.002 Madsen, 1999, Interleukin-10 gene-deficient mice develop a primary intestinal permeability defect in response to enteric microflora, Inflamm Bowel Dis, 5, 262, 10.1097/00054725-199911000-00004 Olson, 2006, The primary defect in experimental ileitis originates from a nonhematopoietic source, J Exp Med, 203, 541, 10.1084/jem.20050407 Panwala, 1998, A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis, J Immunol, 161, 5733, 10.4049/jimmunol.161.10.5733 Hermiston, 1995, Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin, Science, 270, 1203, 10.1126/science.270.5239.1203 Ho, 2005, Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis, Gastroenterology, 128, 288, 10.1053/j.gastro.2004.11.019 Rioux, 2001, Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn’s disease, Nat Genet, 29, 223, 10.1038/ng1001-223 van der Sluis, 2006, Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection, Gastroenterology, 131, 117, 10.1053/j.gastro.2006.04.020 Mashimo, 1996, Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor, Science, 274, 262, 10.1126/science.274.5285.262 Fellermann, 2006, A chromosome 8 gene-cluster polymorphism with low human β-defensin 2 gene copy number predisposes to Crohn’s disease of the colon, Am J Hum Genet, 79, 439, 10.1086/505915 Hisamatsu, 2003, CARD15/NOD2 functions as an anti-bacterial factor in human intestinal epithelial cells, Gastroenterology, 124, 993, 10.1053/gast.2003.50153 Wehkamp, 2007, The Paneth cell {α}-defensin deficiency of ileal Crohn’s disease is linked to Wnt/Tcf-4, J Immunol, 179, 3109, 10.4049/jimmunol.179.5.3109 Xu, 2007, Toll-like receptor 4 is a sensor for autophagy associated with innate immunity, Immunity, 27, 135, 10.1016/j.immuni.2007.05.022 Marks, 2006, Defective acute inflammation in Crohn’s disease: a clinical investigation, Lancet, 367, 668, 10.1016/S0140-6736(06)68265-2 Griga, 2005, Association between the promoter polymorphism T/C at position −159 of the CD14 gene and anti-inflammatory therapy in patients with inflammatory bowel disease, Eur J Med Res, 10, 183 Schreiter, 2005, Glycoprotein (gp) 96 expression: induced during differentiation of intestinal macrophages but impaired in Crohn’s disease, Gut, 54, 935, 10.1136/gut.2004.053116 Mow, 2004, Association of antibody responses to microbial antigens and complications of small bowel Crohn’s disease, Gastroenterology, 126, 414, 10.1053/j.gastro.2003.11.015 Kraus, 2004, Failure to induce oral tolerance to a soluble protein in patients with inflammatory bowel disease, Gastroenterology, 126, 1771, 10.1053/j.gastro.2004.03.076 Lamhonwah, 2005, Epitope shared by functional variant of organic cation/carnitine transporter, OCTN1, Campylobacter jejuni and Mycobacterium paratuberculosis may underlie susceptibility to Crohn’s disease at 5q31, Biochem Biophys Res Commun, 337, 1165, 10.1016/j.bbrc.2005.09.170 Rahbar, 2006, Detection of cytotoxic CD13-specific autoantibodies in sera from patients with ulcerative colitis and Crohn’s disease, J Autoimmun, 26, 155, 10.1016/j.jaut.2006.02.003 Ebringer, 2007, A possible link between Crohn’s disease and ankylosing spondylitis via Klebsiella infections, Clin Rheumatol, 26, 289, 10.1007/s10067-006-0391-2 Polymeros, 2006, Does cross-reactivity between Mycobacterium avium paratuberculosis and human intestinal antigens characterize Crohn’s disease?, Gastroenterology, 131, 85, 10.1053/j.gastro.2006.04.021 Keighley, 1982, Incidence and microbiology of abdominal and pelvic abscess in Crohn’s disease, Gastroenterology, 83, 1271, 10.1016/S0016-5085(82)80139-X O’Boyle, 1998, Microbiology of bacterial translocation in humans, Gut, 42, 29, 10.1136/gut.42.1.29 Ambrose, 1984, Incidence of pathogenic bacteria from mesenteric lymph nodes and ileal serosa during Crohn’s disease surgery, Br J Surg, 71, 623, 10.1002/bjs.1800710821 Alves, 2007, Risk factors for intra-abdominal septic complications after a first ileocecal resection for Crohn’s disease: a multivariate analysis in 161 consecutive patients, Dis Colon Rectum, 50, 331, 10.1007/s10350-006-0782-0 Colombel, 2004, Early postoperative complications are not increased in patients with Crohn’s disease treated perioperatively with infliximab or immunosuppressive therapy, Am J Gastroenterol, 99, 878, 10.1111/j.1572-0241.2004.04148.x Sands, 2006, Maintenance infliximab does not result in increased abscess development in fistulizing Crohn’s disease: results from the ACCENT II study, Aliment Pharmacol Ther, 23, 1127, 10.1111/j.1365-2036.2006.02878.x Colombel, 2004, The safety profile of infliximab in clinical practice in patients with Crohn’s disease: the Mayo Clinic experience in 500 patients, Gastroenterology, 12, 19, 10.1053/j.gastro.2003.10.047 Siegel, 2006, Risks and benefits of infliximab for the treatment of Crohn’s disease, Clin Gastroenterol Hepatol, 4, 1017, 10.1016/j.cgh.2006.05.020 Toruner, 2006, Risk factors for opportunistic infections in inflammatory bowel diseases: a case-control study, Gastroenterology, 130, A71 Kane, 2007, Higher incidence of abnormal PAP smears in women with inflammatory bowel disease, Am J Gastroenterol Van Assche, 2005, Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease, N Engl J Med, 353, 362, 10.1056/NEJMoa051586 Rodemann, 2007, Incidence of Clostridium difficile infection in inflammatory bowel disease, Clin Gastroenterol Hepatol, 5, 339, 10.1016/j.cgh.2006.12.027 Shen, 2006, Clostridium difficile-associated pouchitis, Dig Dis Sci, 51, 2361, 10.1007/s10620-006-9172-7 Matsuoka, 2007, Cytomegalovirus is frequently reactivated and disappears without antiviral agents in ulcerative colitis patients, Am J Gastroenterol, 102, 331, 10.1111/j.1572-0241.2006.00989.x Kojima, 2006, Cytomegalovirus infection in ulcerative colitis, Scand J Gastroenterol, 41, 706, 10.1080/00365520500408584 Hedin, 2007, Evidence for the use of probiotics and prebiotics in inflammatory bowel disease: a review of clinical trials, Proc Nutr Soc, 66, 307, 10.1017/S0029665107005563 Floch, 2006, Recommendations for probiotic use, J Clin Gastroenterol, 40, 275, 10.1097/00004836-200603000-00022 Rolfe, 2006, Probiotics for maintenance of remission in Crohn’s disease, Cochrane Database Syst Rev, 10.1002/14651858.CD004826.pub2 Lal, 2006, Antibiotic therapy for Crohn’s disease: a review, Can J Gastroenterol, 20, 651, 10.1155/2006/250490 Rioux, 2006, Probiotics in the treatment of inflammatory bowel disease, J Clin Gastroenterol, 40, 260, 10.1097/00004836-200603000-00019 Ohkusa, 2005, Effectiveness of antibiotic combination therapy in patients with active ulcerative colitis: a randomized, controlled pilot trial with long-term follow-up, Scand J Gastroenterol, 40, 1334, 10.1080/00365520510023648 Steidler, 2000, Treatment of murine colitis by Lactococcus lactis secreting interleukin-10, Science, 289, 1352, 10.1126/science.289.5483.1352 Han, 2006, Improvement of an experimental colitis in rats by lactic acid bacteria producing superoxide dismutase, Inflamm Bowel Dis, 12, 1044, 10.1097/01.mib.0000235101.09231.9e Carroll, 2007, The anti-inflammatory properties of Lactobacillus gasseri expressing manganese superoxide dismutase (MnSOD) using the interleukin 10-deficient mouse model of colitis, Am J Physiol Gastrointest Liver Physiol, 293, G729, 10.1152/ajpgi.00132.2007 Braat, 2006, A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn’s disease, Clin Gastroenterol Hepatol, 4, 754, 10.1016/j.cgh.2006.03.028 Targan, 2005, Defects in mucosal immunity leading to ulcerative colitis, Immunol Rev, 206, 296, 10.1111/j.0105-2896.2005.00286.x Gionchetti, 2000, Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial, Gastroenterology, 119, 305, 10.1053/gast.2000.9370 Kruis, 2004, Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine, Gut, 53, 1617, 10.1136/gut.2003.037747 Kuhn, 1993, Interleukin-10-deficient mice develop chronic enterocolitis, Cell, 75, 263, 10.1016/0092-8674(93)80068-P Cong, 1998, CD4+ T cells reactive to enteric bacterial antigens in spontaneously colitic C3H/HeJBir mice: increased T helper cell type 1 response and ability to transfer disease, J Exp Med, 187, 855, 10.1084/jem.187.6.855 Liu, 2007, APC regulate TH1/TH17-mediated colitis in IL-10 deficient mice, Gastroenterology, 132, A33 Izcue, 2006, Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation, Immunol Rev, 212, 256, 10.1111/j.0105-2896.2006.00423.x Beckwith, 2005, Cdcs1, a major colitogenic locus in mice, regulates innate and adaptive immune response to enteric bacterial antigens, Gastroenterology, 129, 1473, 10.1053/j.gastro.2005.07.057 Kontoyiannis, 1999, Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies, Immunity, 10, 387, 10.1016/S1074-7613(00)80038-2