The impact of the microbiota on the pathogenesis of IBD: Lessons from mouse infection models

Nature Reviews Microbiology

Volumn 8, Issue 8, 2010, Pages 564-577

  Nell, Sandra ^a   Suerbaum, Sebastian ^a   Josenhans, Christine ^a  

^a HANNOVER MEDICAL SCHOOL   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

IMMUNOGLOBULIN A; IMMUNOGLOBULIN G; IMMUNOGLOBULIN M; INTERLEUKIN 10; PROBIOTIC AGENT;

BACTERIAL COLONIZATION; BACTERIAL VIRULENCE; BACTERIUM IDENTIFICATION; BACTEROIDES FRAGILIS; CAMPYLOBACTER JEJUNI; CD4+ CD25+ T LYMPHOCYTE; CITROBACTER RODENTIUM; CROHN DISEASE; DIGESTIVE SYSTEM INFLAMMATION; ESCHERICHIA COLI; HELICOBACTER CINAEDI; HELICOBACTER HEPATICUS; LACTOBACILLUS ACIDOPHILUS; LACTOBACILLUS BREVIS; LACTOBACILLUS CASEI; LACTOBACILLUS PLANTARUM; LACTOBACILLUS RHAMNOSUS; MICROFLORA; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; SALMONELLA ENTERICA; STOMACH PROTECTION; ULCERATIVE COLITIS;

ANIMALS; BACTERIA; BACTERIAL PHYSIOLOGICAL PHENOMENA; DISEASE MODELS, ANIMAL; GASTROINTESTINAL TRACT; HUMANS; INFLAMMATORY BOWEL DISEASES; MICE;

BACTERIA (MICROORGANISMS);

EID: 77954758654     PISSN: 17401526     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrmicro2403     Document Type: Review

References (156)

1. Xavier, R. J. & Podolsky, D. K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427-434 (2007).
2. Gismera, C. S. & Aladren, B. S. Inflammatory bowel diseases: a disease (s) of modern times? Is incidence still increasing? World J. Gastroenterol. 14, 5491-5498 (2008).
3. Medzhitov, R. Recognition of microorganisms and activation of the immune response. Nature 449, 819-826 (2007).
4. Anderson, C. A. et al. Investigation of Crohn's disease risk loci in ulcerative colitis further defines their molecular relationship. Gastroenterology 136, 523-529 (2009).
5. Barrett, J. C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nature Genet. 40, 955-962 (2008).
6. Cho, J. H. The genetics and immunopathogenesis of inflammatory bowel disease. Nature Rev. Immunol. 8, 458-466 (2008).
7. Gaya, D. R., Russell, R. K., Nimmo, E. R. & Satsangi, J. New genes in inflammatory bowel disease: lessons for complex diseases? Lancet 367, 1271-1284 (2006).
8. Honda, K. & Takeda, K. Regulatory mechanisms of immune responses to intestinal bacteria. Mucosal Immunol. 2, 187-196 (2009).
9. Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 11 8, 229-241 (2004).
10. Coombes, J. L., Robinson, N. J., Maloy, K. J., Uhlig, H. H. & Powrie, F. Regulatory T cells and intestinal homeostasis. Immunol. Rev. 204, 184-194 (2005).
11. Bäckhed, F., Ley, R. E., Sonnenburg, J. L., Peterson, D. A. & Gordon, J. I. Host-bacterial mutualism in the human intestine. Science 307, 1915-1920 (2005).
12. Salzman, N. H. et al. Analysis of 16S libraries of mouse gastrointestinal microflora reveals a large new group of mouse intestinal bacteria. Microbiology 148, 3651-3660 (2002).
13. Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59-65 (2010).
14. Frank, D. N. & Pace, N. R. Gastrointestinal microbiology enters the metagenomics era. Curr. Opin. Gastroenterol. 24, 4-10 (2008).
15. Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070-11075 (2005).
16. Frank, D. N. et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl Acad. Sci. USA 104, 13780-13785 (2007).
17. Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635-1638 (2005).
18. Zoetendal, E. G., Rajilic-Stojanovic, M. & de Vos, W. M. High-throughput diversity and functionality analysis of the gastrointestinal tract microbiota. Gut 57, 1605-1615 (2008).
19. Hildebrandt, M. A. et al. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology 137, 1716-1724 (2009).
20. Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022-1023 (2006).
21. Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480-484 (2009).
22. Gophna, U., Sommerfeld, K., Gophna, S., Doolittle, W. F. & Veldhuyzen van Zanten, S. J. Differences between tissue-associated intestinal microfloras of patients with Crohn's disease and ulcerative colitis. J. Clin. Microbiol. 44, 4136-4141 (2006).
23. Bibiloni, R., Mangold, M., Madsen, K. L., Fedorak, R. N. & Tannock, G. W. The bacteriology of biopsies differs between newly diagnosed, untreated, Crohn's disease and ulcerative colitis patients. J. Med. Microbiol. 55, 1141-1149 (2006).
24. Kassinen, A. et al. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology 133, 24-33 (2007).
25. Othman, M., Aguero, R. & Lin, H. C. Alterations in intestinal microbial flora and human disease. Curr. Opin. Gastroenterol. 24, 11-16 (2008).
26. Manichanh, C. et al. Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach. Gut 55, 205-211 (2006).
27. Sokol, H. et al. Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm. Bowel Dis. 15, 1183-1189 (2009).
28. Hoffmann, C. et al. Community-wide response of the gut microbiota to enteropathogenic Citrobacter rodentium infection revealed by deep sequencing. Infect. Immun. 77, 4668-4678 (2009).
29. Lupp, C. et al. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2, 119-129 (2007).
30. Stecher, B. et al. Salmonella enterica serovar Typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol. 5, 2177-2189 (2007).
31. Heimesaat, M. M. et al. Shift towards pro-inflammatory intestinal bacteria aggravates acute murine colitis via Toll-like receptors 2 and 4. PLoS ONE 2, e662 (2007).
32. Petersen, A. M. et al. A phylogenetic group of Escherichia coli associated with active left-sided inflammatory bowel disease. BMC Microbiol. 9, 171 (2009).
33. Packey, C. D. & Sartor, R. B. Commensal bacteria, traditional and opportunistic pathogens, dysbiosis and bacterial killing in inflammatory bowel diseases. Curr. Opin. Infect. Dis. 22, 292-301 (2009).
34. Chow, J. & Mazmanian, S. K. A pathobiont of the microbiota balances host colonization and intestinal inflammation. Cell Host Microbe 7, 265-276 (2010).
35. Eckmann, L. Animal models of inflammatory bowel disease: lessons from enteric infections. Ann. N. Y. Acad. Sci. 1072, 28-38 (2006).
36. Uhlig, H. H. & Powrie, F. Mouse models of intestinal inflammation as tools to understand the pathogenesis of inflammatory bowel disease. Eur. J. Immunol. 39, 2021-2026 (2009).
37. Elson, C. O. et al. Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota. Immunol. Rev. 206, 260-276 (2005).
38. Pizarro, T. T., Arseneau, K. O., Bamias, G. & Cominelli, F. Mouse models for the study of Crohn's disease. Trends Mol. Med. 9, 218-222 (2003).
39. Sellon, R. K. et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect. Immun. 66, 5224-5231 (1998).
40. Mundy, R., MacDonald, T. T., Dougan, G., Frankel, G. & Wiles, S. Citrobacter rodentium of mice and man. Cell. Microbiol. 7, 1697-1706 (2005).
41. Borenshtein, D., McBee, M. E. & Schauer, D. B. Utility of the Citrobacter rodentium infection model in laboratory mice. Curr. Opin. Gastroenterol. 24, 32-37 (2008).
42. Savkovic, S. D., Villanueva, J., Turner, J. R., Matkowskyj, K. A. & Hecht, G. Mouse model of enteropathogenic Escherichia coli infection. Infect. Immun. 73, 1161-1170 (2005).
43. + T cells in immunity to infection by the attaching and effacing pathogen Citrobacter rodentium. Infect. Immun. 71, 5077-5086 (2003).
44. Wiles, S. et al. Organ. specificity, colonization and clearance dynamics in vivo following oral challenges with the murine pathogen Citrobacter rodentium. Cell. Microbiol. 6, 963-972 (2004).
45. Maaser, C. et al. Clearance of Citrobacter rodentium requires B cells but not secretory immunoglobulin A (IgA) or IgM antibodies. Infect. Immun. 72, 3315-3324 (2004).
46. Dennis, A. et al. The p50 subunit of NF-κB is critical for in vivo clearance of the noninvasive enteric pathogen Citrobacter rodentium. Infect. Immun. 76, 4978-4988 (2008).
47. Gibson, D. L. et al. Toll-like receptor 2 plays a critical role in maintaining mucosal integrity during Citrobacter rodentium-induced colitis. Cell. Microbiol. 10, 388-403 (2008).
48. Lebeis, S. L., Bommarius, B., Parkos, C. A., Sherman, M. A. & Kalman, D. TLR signaling mediated by MyD88 is required for a protective innate immune response by neutrophils to Citrobacter rodentium. J. Immunol. 179, 566-577 (2007).
49. Bry, L. & Brenner, M. B. Critical role of T cell-dependent serum antibody, but not the gut-associated lymphoid tissue, for surviving acute mucosal infection with Citrobacter rodentium, an attaching and effacing pathogen. J. Immunol. 172, 433-441 (2004).
50. Guttman, J. A., Samji, F. N., Li, Y., Vogl, A. W. & Finlay, B. B. Evidence that tight junctions are disrupted due to intimate bacterial contact and not inflammation during attaching and effacing pathogen infection in vivo. Infect. Immun. 74, 6075-6084 (2006).
51. Haraga, A., Ohlson, M. B. & Miller, S. I. Salmonellae interplay with host cells. Nature Rev. Microbiol. 6, 53-66 (2008).
52. Grassl, G. A. & Finlay, B. B. Pathogenesis of enteric Salmonella infections. Curr. Opin. Gastroenterol. 24, 22-26 (2008).
53. Halle, S. et al. Solitary intestinal lymphoid tissue provides a productive port of entry for Salmonella enterica serovar Typhimurium. Infect. Immun. 75, 1577-1585 (2007).
54. Niess, J. H. et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307, 254-258 (2005).
55. Vazquez-Torres, A. et al. Extraintestinal dissemination of Salmonella by CD18-expressing phagocytes. Nature 401, 804-808 (1999).
56. Stecher, B. et al. Comparison of Salmonella enterica serovar Typhimurium colitis in germfree mice and mice pretreated with streptomycin. Infect. Immun. 73, 3228-3241 (2005).
57. Barthel, M. et al. Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host. Infect. Immun. 71, 2839-2858 (2003).
58. Coombes, B. K. et al. Analysis of the contribution of Salmonella pathogenicity islands 1 and 2 to enteric disease progression using a novel bovine ileal loop model and a murine model of infectious enterocolitis. Infect. Immun. 73, 7161-7169 (2005).
59. Hapfelmeier, S. & Hardt, W. D. A mouse model for S. Typhimurium-induced enterocolitis. Trends Microbiol. 13, 497-503 (2005).
60. Hapfelmeier, S. et al. The Salmonella pathogenicity island (SPI)-2 and SPI-1 type III secretion systems allow Salmonella serovar Typhimurium to trigger colitis via MyD88-dependent and MyD88-independent mechanisms. J. Immunol. 174, 1675-1685 (2005).
61. + lamina propria cells. Nature Immunol. 7, 868-874 (2006).
62. Gazouli, M. et al. Role of functional polymorphisms of NRAMP1 gene for the development of Crohn's disease. Inflamm. Bowel Dis. 14, 1323-1330 (2008).
63. Valdez, Y. et al. Nramp1 drives an accelerated inflammatory response during Salmonella-induced colitis in mice. Cell. Microbiol. 11, 351-362 (2009).
64. +/+ mice. Infect. Immun. 74, 5047-5057 (2006).
65. Rieder, F. & Fiocchi, C. Intestinal fibrosis in IBD-a dynamic, multifactorial process. Nature Rev. Gastroenterol. Hepatol. 6, 228-235 (2009).
66. Grassl, G. A., Valdez, Y., Bergstrom, K. S., Vallance, B. A. & Finlay, B. B. Chronic enteric Salmonella infection in mice leads to severe and persistent intestinal fibrosis. Gastroenterology 134, 768-780 (2008).
67. Sartor, R. B. Mechanisms of disease: pathogenesis of Crohn's disease and ulcerative colitis. Nature Clin. Pract. Gastroenterol. Hepatol. 3, 390-407 (2006).
68. Sears, C. L. Enterotoxigenic Bacteroides fragilis: a rogue among symbiotes. Clin. Microbiol. Rev. 22, 349-369 (2009).
69. Sears, C. L. et al. Association of enterotoxigenic Bacteroides fragilis infection with inflammatory diarrhea. Clin. Infect. Dis. 47, 797-803 (2008).
70. Sack, R. B. et al. Enterotoxigenic Bacteroides fragilis: epidemiologic studies of its role as a human diarrhoeal pathogen. J. Diarrhoeal Dis. Res. 10, 4-9 (1992).
71. Prindiville, T. P. et al. Bacteroides fragilis enterotoxin gene sequences in patients with inflammatory bowel disease. Emerg. Infect. Dis. 6, 171-174 (2000).
72. Toprak, N. U. et al. A possible role of Bacteroides fragilis enterotoxin in the aetiology of colorectal cancer. Clin. Microbiol. Infect. 12, 782-786 (2006).
73. Wu, S. et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nature Med. 15, 1016-1022 (2009).
74. Wu, S. et al. The Bacteroides fragilis toxin binds to a specific intestinal epithelial cell receptor. Infect. Immun. 74, 5382-5390 (2006).
75. Wu, S., Rhee, K. J., Zhang, M., Franco, A. & Sears, C. L. Bacteroides fragilis toxin stimulates intestinal epithelial cell shedding and g-secretase-dependent E-cadherin cleavage. J. Cell Sci. 120, 1944-1952 (2007).
76. Wu, S., Morin, P. J., Maouyo, D. & Sears, C. L. Bacteroides fragilis enterotoxin induces c-Myc expression and cellular proliferation. Gastroenterology 124, 392-400 (2003).
77. Rhee, K. J. et al. Induction of persistent colitis by a human commensal, enterotoxigenic Bacteroides fragilis, in wild-type C57BL/6 mice. Infect. Immun. 77, 1708-1718 (2009).
78. D'Inca, R. et al. Increased intestinal permeability and NOD2 variants in familial and sporadic Crohn's disease. Aliment. Pharmacol. Ther. 23, 1455-1461 (2006).
79. Buhner, S. et al. Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation? Gut 55, 342-347 (2006).
80. Garcia Rodriguez, L. A., Ruigomez, A. & Panes, J. Acute gastroenteritis is followed by an increased risk of inflammatory bowel disease. Gastroenterology 130, 1588-1594 (2006).
81. Gradel, K. O. et al. Increased short-and long-term risk of inflammatory bowel disease after Salmonella or Campylobacter gastroenteritis. Gastroenterology 137, 495-501 (2009).
82. Man, S. M. et al. Campylobacter concisus and other Campylobacter species in children with newly diagnosed Crohn's disease. Inflamm. Bowel Dis. 16, 1008-1016 (2010).
83. Mansfield, L. S. et al. C57BL/6 and congenic interleukin-10-deficient mice can serve as models of Campylobacter jejuni colonization and enteritis. Infect. Immun. 75, 1099-1115 (2007).
84. Kalischuk, L. D., Inglis, G. D. & Buret, A. G. Campylobacter jejuni induces transcellular translocation of commensal bacteria via lipid rafts. Gut Pathog. 1, 2 (2009).
85. Fox, J. G. et al. Gastroenteritis in NF-κB-deficient mice is produced with wild-type Camplyobacter jejuni but not with C. jejuni lacking cytolethal distending toxin despite persistent colonization with both strains. Infect. Immun. 72, 1116-1125 (2004).
86. Fox, J. G. The non-H pylori helicobacters: their expanding role in gastrointestinal and systemic diseases. Gut 50, 273-283 (2002).
87. On, S. L., Hynes, S. & Wadstrom, T. Extragastric Helicobacter species. Helicobacter 7, (Suppl. 1) 63-67 (2002).
88. Solnick, J. V. & Schauer, D. B. Emergence of diverse Helicobacter species in the pathogenesis of gastric and enterohepatic diseases. Clin. Microbiol. Rev. 14, 59-97 (2001).
89. Suerbaum, S. et al. The complete genome sequence of the carcinogenic bacterium Helicobacter hepaticus. Proc. Natl Acad. Sci. USA 100, 7901-7906 (2003).
90. Fox, J. G. et al. Helicobacter hepaticus sp. nov., a microaerophilic bacterium isolated from livers and intestinal mucosal scrapings from mice. J. Clin. Microbiol. 32, 1238-1245 (1994).
91. Ward, J. M. et al. Inflammatory large bowel disease in immunodeficient mice naturally infected with Helicobacter hepaticus. Lab. Anim. Sci. 46, 15-20 (1996).
92. Taylor, N. S., Xu, S., Nambiar, P., Dewhirst, F. E. & Fox, J. G. Enterohepatic Helicobacter species are prevalent in mice from commercial and academic institutions in Asia, Europe, and North America. J. Clin. Microbiol. 45, 2166-2172 (2007).
93. Kullberg, M. C. et al. 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. 66, 5157-5166 (1998).
94. Cahill, R. J. et al. Inflammatory bowel disease: an immunity-mediated condition triggered by bacterial infection with Helicobacter hepaticus. Infect. Immun. 65, 3126-3131 (1997).
95. Chin, E. Y., Dangler, C. A., Fox, J. G. & Schauer, D. B. Helicobacter hepaticus infection triggers inflammatory bowel disease in T cell receptor alphabeta mutant mice. Comp. Med. 50, 586-594 (2000).
96. Burich, A. et al. Helicobacter-induced inflammatory bowel disease in IL-10-and T cell-deficient mice. Am. J. Physiol. Gastrointest. Liver Physiol. 281, G764-G778 (2001).
97. -/- mice results in colitis that progresses to dysplasia. Am. J. Pathol. 166, 1793-1806 (2005).
98. tm1Cgn mice. Microbes Infect. 10, 726-733 (2008).
99. Dieleman, L. A. et al. Helicobacter hepaticus does not induce or potentiate colitis in interleukin-10-deficient mice. Infect. Immun. 68, 5107-5113 (2000).
100. Whary, M. T. et al. Chronic active hepatitis induced by Helicobacter hepaticus in the A/JCr mouse is associated with a Th1 cell-mediated immune response. Infect. Immun. 66, 3142-3148 (1998).
101. Kullberg, M. C. et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J. Exp. Med. 203, 2485-2494 (2006).
102. Engle, S. J. et al. Elimination of colon cancer in germ-free transforming growth factor beta 1-deficient mice. Cancer Res. 62, 6362-6366 (2002).
103. + regulatory lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice. Cancer Res. 63, 6042-6050 (2003).
104. + T cell clone specific for a bacterial epitope. Proc. Natl Acad. Sci. USA 100, 15830-15835 (2003).
105. Buonocore, S. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371-1375 (2010).
106. Young, V. B. et al. In vitro and in vivo characterization of Helicobacter hepaticus cytolethal distending toxin mutants. Infect. Immun. 72, 2521-2527 (2004).
107. Sterzenbach, T. et al. Inhibitory effect of enterohepatic Helicobacter hepaticus on innate immune responses of mouse intestinal epithelial cells. Infect. Immun. 75, 2717-2728 (2007).
108. Fox, J. G. et al. Helicobacter bilis sp. nov., a novel Helicobacter species isolated from bile, livers, and intestines of aged, inbred mice. J. Clin. Microbiol. 33, 445-454 (1995).
109. -/-) mice. Am. J. Pathol. 160, 739-751 (2002).
110. Shen, Z. et al. Cytolethal distending toxin promotes Helicobacter cinaedi-associated typhlocolitis in interleukin-10-deficient mice. Infect. Immun. 77, 2508-2516 (2009).
111. Jergens, A. E. et al. Helicobacter bilis triggers persistent immune reactivity to antigens derived from the commensal bacteria in gnotobiotic C3H/HeN mice. Gut 56, 934-940 (2007).
112. Dubinsky, M. C. et al. Increased immune reactivity predicts aggressive complicating Crohn's disease in children. Clin. Gastroenterol. Hepatol. 6, 1105-1111 (2008).
113. Niess, J. H., Leithauser, F., Adler, G. & Reimann, J. Commensal gut flora drives the expansion of proinflammatory CD4 T cells in the colonic lamina propria under normal and inflammatory conditions. J. Immunol. 180, 559-568 (2008).
114. -/- mice with 2 nonpathogenic commensal bacteria induces aggressive pancolitis. Inflamm. Bowel Dis. 13, 1457-1466 (2007).
115. + memory T cells residing outside the intestine participate in the perpetuation of chronic colitis. J. Immunol. 183, 5059-5068 (2009).
116. -/-;NF-κB(EGFP) mice reveal the critical role of TLR/NF-κB signaling in commensal bacteria-induced colitis. J. Immunol. 178, 6522-6532 (2007).
117. Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253-261 (1993).
118. Balish, E. & Warner, T. Enterococcus faecalis induces inflammatory bowel disease in interleukin-10 knockout mice. Am. J. Pathol. 160, 2253-2257 (2002).
119. Stecher, B. et al. Like will to like: abundances of closely related species can predict susceptibility to intestinal colonization by pathogenic and commensal bacteria. PLoS Pathog. 6, e1000711 (2010).
120. Garrett, W. S. et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131, 33-45 (2007).
121. Prisciandaro, L., Geier, M., Butler, R., Cummins, A. & Howarth, G. Probiotics and their derivatives as treatments for inflammatory bowel disease. Inflamm. Bowel Dis. 15, 1906-1914 (2009).
122. Behm, B. W. & Bickston, S. J. Tumor necrosis factor-α antibody for maintenance of remission in Crohn's disease. Cochrane Database Syst. Rev. CD006893 (2008).
123. Damaskos, D. & Kolios, G. Probiotics and prebiotics in inflammatory bowel disease: microflora 'on the scope'. Br. J. Clin. Pharmacol. 65, 453-467 (2008).
124. Isaacs, K. & Herfarth, H. Role of probiotic therapy in IBD. Inflamm. Bowel Dis. 14, 1597-1605 (2008).
125. Llopis, M. et al. Lactobacillus casei downregulates commensals' inflammatory signals in Crohn's disease mucosa. Inflamm. Bowel Dis. 15, 275-283 (2009).
126. Sherman, P. M., Ossa, J. C. & Johnson-Henry, K. Unraveling mechanisms of action of probiotics. Nutr. Clin. Pract. 24, 10-14 (2009).
127. Lee, H. S. et al. Lactic acid bacteria inhibit proinflammatory cytokine expression and bacterial glycosaminoglycan degradation activity in dextran sulfate sodium-induced colitic mice. Int. Immunopharmacol. 8, 574-580 (2008).
128. Chen, C. C., Louie, S., Shi, H. N. & Walker, W. A. Preinoculation with the probiotic Lactobacillus acidophilus early in life effectively inhibits murine Citrobacter rodentium colitis. Pediatr. Res. 58, 1185-1191 (2005).
129. Chen, C. C., Chiu, C. H., Lin, T. Y., Shi, H. N. & Walker, W. A. Effect of probiotics Lactobacillus acidophilus on Citrobacter rodentium colitis: the role of dendritic cells. Pediatr. Res. 65, 169-175 (2009).
130. Johnson-Henry, K. C. et al. Amelioration of the effects of Citrobacter rodentium infection in mice by pretreatment with probiotics. J. Infect. Dis. 191, 2106-2117 (2005).
131. Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485-498 (2009).
132. Gaboriau-Routhiau, V. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677-689 (2009).
133. Waidmann, M. et al. Bacteroides vulgatus protects against Escherichia coli-induced colitis in gnotobiotic interleukin-2-deficient mice. Gastroenterology 125, 162-177 (2003).
134. Guslandi, M., Giollo, P. & Testoni, P. A. A pilot trial of Saccharomyces boulardii in ulcerative colitis. Eur. J. Gastroenterol. Hepatol. 15, 697-698 (2003).
135. Wu, X. et al. Saccharomyces boulardii ameliorates Citrobacter rodentium-induced colitis through actions on bacterial virulence factors. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G295-G306 (2008).
136. Dalmasso, G. et al. Saccharomyces boulardii inhibits inflammatory bowel disease by trapping T cells in mesenteric lymph nodes. Gastroenterology 131, 1812-1825 (2006).
137. Mazmanian, S. K., Round, J. L. & Kasper, D. L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620-625 (2008).
138. Feller, M. et al. Mycobacterium avium subspecies paratuberculosis and Crohn's disease: a systematic review and meta-analysis. Lancet Infect. Dis. 7, 607-613 (2007).
139. Snydman, D. R. The safety of probiotics. Clin. Infect. Dis. 46, (Suppl. 2) S104-S111 (2008).
140. Cannon, J. P., Lee, T. A., Bolanos, J. T. & Danziger, L. H. Pathogenic relevance of Lactobacillus: a retrospective review of over 200 cases. Eur. J. Clin. Microbiol. Infect. Dis. 24, 31-40 (2005).
141. Magalhaes, J. G., Tattoli, I. & Girardin, S. E. The intestinal epithelial barrier: how to distinguish between the microbial flora and pathogens. Semin. Immunol. 19, 106-115 (2007).
142. Glocker, E. O. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361, 2033-2045 (2009).
143. Kobayashi, K. S. et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307, 731-734 (2005).
144. Alex, P. et al. Distinct cytokine patterns identified from multiplex profiles of murine DSS and TNBS-induced colitis. Inflamm. Bowel Dis. 15, 341-352 (2009).
145. Kitajima, S., Morimoto, M., Sagara, E., Shimizu, C. & Ikeda, Y. Dextran sodium sulfate-induced colitis in germ-free IQI/Jic mice. Exp. Anim. 50, 387-395 (2001).
146. Beckwith, J., Cong, Y., Sundberg, J. P., Elson, C. O. & Leiter, E. H. Cdcs1, a major colitogenic locus in mice, regulates innate and adaptive immune response to enteric bacterial antigens. Gastroenterology 129, 1473-1484 (2005).
147. Klapproth, J. M. et al. Citrobacter rodentium lifA/efa1 is essential for colonic colonization and crypt cell hyperplasia in vivo. Infect. Immun. 73, 1441-1451 (2005).
148. Deng, W., Vallance, B. A., Li, Y., Puente, J. L. & Finlay, B. B. Citrobacter rodentium translocated intimin receptor (Tir) is an essential virulence factor needed for actin condensation, intestinal colonization and colonic hyperplasia in mice. Mol. Microbiol. 48, 95-115 (2003).
149. Newman, J. V., Zabel, B. A., Jha, S. S. & Schauer, D. B. Citrobacter rodentium espB is necessary for signal transduction and for infection of laboratory mice. Infect. Immun. 67, 6019-6025 (1999).
150. Hardwidge, P. R. et al. Modulation of host cytoskeleton function by the enteropathogenic Escherichia coli and Citrobacter rodentium effector protein EspG. Infect. Immun. 73, 2586-2594 (2005).
151. Coulthurst, S. J. et al. Quorum sensing has an unexpected role in virulence in the model pathogen Citrobacter rodentium. EMBO Rep. 8, 698-703 (2007).
152. Hapfelmeier, S. et al. Role of the Salmonella pathogenicity island 1 effector proteins SipA, SopB, SopE, and SopE2 in Salmonella enterica subspecies 1 serovar Typhimurium colitis in streptomycin-pretreated mice. Infect. Immun. 72, 795-809 (2004).
153. Stecher, B. et al. Flagella and chemotaxis are required for efficient induction of Salmonella enterica serovar Typhimurium colitis in streptomycin-pretreated mice. Infect. Immun. 72, 4138-4150 (2004).
154. Nakano, V., Gomes, D. A., Arantes, R. M., Nicoli, J. R. & Avila-Campos, M. J. Evaluation of the pathogenicity of the Bacteroides fragilis toxin gene subtypes in gnotobiotic mice. Curr. Microbiol. 53, 113-117 (2006).
155. Ge, Z. et al. Cytolethal distending toxin is essential for Helicobacter hepaticus colonization in outbred Swiss Webster mice. Infect. Immun. 73, 3559-3567 (2005).
156. Pratt, J. S., Sachen, K. L., Wood, H. D., Eaton, K. A. & Young, V. B. Modulation of host immune responses by the cytolethal distending toxin of Helicobacter hepaticus. Infect. Immun. 74, 4496-4504 (2006).