Chapter 13 : Role of Commensal Enteric Bacteria in Intestinal Inflammation: Lessons from Animal Models

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This chapter outlines evidence supporting the hypothesis that chronic immune-mediated intestinal inflammation in genetically susceptible hosts is a consequence of overly aggressive cell-mediated immune responses to a subset of commensal luminal bacteria. The most compelling evidence that normal luminal bacteria induce colitis is the fact that in at least 11 separate models of induced or spontaneous intestinal inflammation, no disease occurs in the absence of bacteria (germ free or sterile state). Recent results in several independent gnotobiotic models demonstrate that commensal enteric bacterial species differ in their capacity to induce chronic intestinal inflammation. Chronic intestinal inflammation is mediated by T lymphocytes, based on the absence of experimental colitis in T-cell-deficient hosts, induction of disease by transfer of CD T lymphocytes, and prevention and reversal of chronic inflammation by blockade of products of T cytokines. A key factor in the induction of chronic immune-mediated intestinal inflammation is the loss of tolerance to luminal bacterial antigens in genetically susceptible hosts. Many studies discussed in the chapter support the hypothesis that chronic intestinal inflammation is a consequence of an overly aggressive cell mediated immune response to a subset of the complex resident enteric bacterial population in genetically susceptible hosts. Results in animal models indicate that manipulation of the luminal microflora by antibiotics, probiotics, and prebiotics can treat established disease and prevent recurrent inflammation. These physiologic bacterial manipulations may have additive and perhaps synergistic activities with more widely used immunosuppressive therapies and emerging growth factor treatments.

Citation: Sartor R. 2003. Role of Commensal Enteric Bacteria in Intestinal Inflammation: Lessons from Animal Models, p 223-240. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch13
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1. Aderem, A.,, and R. J. Ulevitch. 2000. Toll-like receptors in the induction of the innate immune response. Nature 406: 782 787.
2. Albright, C.,, S. L. Tonkonogy,, and R. B. Sartor. 2002. Endogenous IL-10 inhibits APC stimulation of T lymphocyte responses to luminal bacteria. Gastroenterology 122: A270.
3.Ambrose N. S., M. Johnson, D. W. Burdon, and M. R. Keighley. 1984. Incidence of pathogenic bacteria from mesenteric lymph nodes and ileal serosa during Crohn’s disease surgery. Br. J. Surg. 71: 623625.
4. Aranda, R.,, B. C. Sydora,, P. L. McAllister,, S. W. Binder,, H. Y. Yang,, S. R. Targan,, and M. Kronenberg. 1997. Analysis of intestinal lymphocytes in mouse colitis mediated by transfer of CD4 +, CD45RB high T cells to SCID recipients. J. Immunol. 158: 3464 3473.
5. Asseman, C.,, S. Mauze,, M. W. Leach,, R. L. Coffman,, and F. Powrie. 1999. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med. 190: 995 1004.
6. Auer, I. O.,, A. Roder,, F. Wensinck,, J. P. van de Merwe,, and H. Schmidt. 1983. Selected bacterial antibodies in Crohn’s disease and ulcerative colitis. Scand. J. Gastroenterol. 18: 217 223.
7. Axelsson, L. G.,, T. Midtvedt,, and A. C. Bylund-Fellenius. 1996. The role of intestinal bacteria, bacterial translocation and endotoxin in dextran sodium sulphate-induced colitis in the mouse. Microb. Ecol. Health Dis. 9: 225 237.
8. Balish, E.,, and T. Warner. 2002. Enterococcus faecalis induces inflammatory bowel disease in interleukin-10 knockout mice. Am. J. Pathol. 160: 2253 2257.
9. Boivin, G. P.,, B. A. O’Toole,, I. E. Orsmby,, R. J. Diebold,, M. J. Eis,, T. Doetschman,, and A. B. Kier. 1995. Onset and progression of pathological lesions in transforming growth factor-beta-1-deficient mice. Am. J. Pathol. 146: 276 288.
10. Cender, C. J.,, D. Haller,, C. Walters,, and R. B. Sartor. 2002. VSL #3 alters cytokine production of unfractionated splenocytes upon stimulation with cecal bacterial lysate: immunomodulation by this probiotic combination. Gastroenterology 122: A145.
11. Cohavy, O.,, D. Bruckner,, L. K. Gordon,, R. Misra,, B. Wei,, M. E. Eggena,, S. R. Targan,, and J. Braun. 2000. Colonic bacteria express an ulcerative colitis pANCA-related protein epitope. Infect. Immun. 68: 1542 1548.
12. Cohavy, O.,, G. Harth,, M. Horwitz,, M. Eggena,, C. Landers,, C. Sutton,, S. R. Targan,, and J. Braun. 1999. Identification of a novel mycobacterial histone H1 homologue (HupB) as an antigenic target of pANCA monoclonal antibody and serum immunoglobulin A from patients with Crohn’s disease. Infect. Immun. 67: 6510 6517.
13. Cohn, S. M.,, S. Schloemann,, T. Tessner,, K. Seibert,, and W. F. Stenson. 1997. Crypt stem cell survival in the mouse intestinal epithelium is regulated by prostaglandins synthesized through cyclooxygenase-1. J. Clin. Invest. 99: 1367 1379.
14. Colombel, J. F.,, M. Lemann,, M. Cassagnou,, Y. Bouhnik,, B. Duclos,, J. L. Dupas,, B. Notteghem,, and J. Y. Mary. 1999. A controlled trial comparing ciprofloxacin with mesalazine for the treatment of active Crohn’s disease. Groupe d’Etudes Therapeutiques des Affections Inflammatoires Digestives (GETAID). Am. J. Gastroenterol. 94: 674 678.
15. Cong, Y.,, S. L. Brandwein,, R. P. McCabe,, A. Lazenby,, E. H. Birkenmeier,, J. P. Sundberg,, and C. O. Elson. 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: 855 864.
16. Cong, Y.,, C. T. Weaver,, A. Lazenby,, and C. O. Elson. 2000. Colitis induced by enteric bacterial antigen-specific CD4 + T cells requires CD40-CD40 ligand interactions for a sustained increase in mucosal IL-12. J. Immunol. 165: 2173 2182.
17. Cong, Y.,, C. T. Weaver,, A. Lazenby,, J. P. Sundberg,, and C. O. Elson. 2000. Tregulatory-1 (TR1) cells prevent colitis induced by enteric bacterial antigen-reactive pathogenic TH1 cells. Gastroenterology 118: A683.
18. Darfeuille-Michaud, A.,, C. Neut,, N. Barnich,, E. Lederman,, P. Di Martino,, P. Desreumaux,, L. Gambiez,, B. Joly,, A. Cortot,, and J. F. Colombel. 1998. Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn’s disease. Gastroenterology 115: 1405 1413.
19. Davidson, N. J.,, M. W. Leach,, M. M. Fort,, L. Thompson-Snipes,, R. Kuhn,, W. Muller,, D. J. Berg,, and D. M. Rennick. 1996. T helper cell 1-type CD4 + T cells, but not B cells, mediate colitis in interleukin 10-deficient mice. J. Exp. Med. 184: 241 251.
20. D’Haens, G. R.,, K. Geboes,, M. Peeters,, F. Baert,, F. Penninckx,, and P. Rutgeerts. 1998. Early lesions of recurrent Crohn’s disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology 114: 262 267.
21. Dianda, L.,, A. M. Hanby,, N. A. Wright,, A. Sebesteny,, A. C. Hayday,, and M. J. Owen. 1997. T cell receptor-alpha beta-deficient mice fail to develop colitis in the absence of a microbial environment. Am. J. Pathol. 150: 91 97.
22. Dieleman, L. A.,, A. Arends,, S. L. Tonkonogy,, M. S. Goerres,, D. W. Craft,, W. Grenther,, R. K. Sellon,, E. Balish,, and R. B. Sartor. 2000. Helicobacter hepaticus does not induce or potentiate colitis in interleukin-10-deficient mice. Infect. Immun. 68: 5107 5113.
23. Dieleman, L. A.,, M. Goerres,, A. Arends,, T. A. Springer,, and R. B. Sartor. 2000. Lactobacillus GG prevents recurrence of colitis in HLA B 27 transgenic rats after antibiotic treatment. Gastroenterology 118: A814.
24. Dieleman, L. A.,, F. Hoentjen,, C. Ehre,, B. A. Mann,, and D. Sprengers. 2001. Antibiotics with a selective aerobic and anaerobic spectrum have different therapeutic activities in various regions of the colon in IL-10 knockout mice. Gastroenterology 120: A687.
25. Dieleman, L. A.,, F. Hoentjen,, R. Williams,, C. Torrice,, R. B. Sartor,, and S. L. Tonkonogy. 2002. B cells from mesenteric lymph nodes of resistant rats produce more interleukin-10 than those from B27 transgenic rats following in vitro stimulation with cecal bacterial lysate. Gastroenterology 122: A261.
26. Duchmann, R.,, I. Kaiser,, E. Hermann,, W. Mayet,, K. Ewe,, and K. H. Meyer zum Buschenfelde. 1995. Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD). Clin. Exp. Immunol. 102: 448 455.
27. Duchmann, R.,, E. Marker-Hermann,, and K. H. Meyer zum Buschenfelde. 1996. Bacteria-specific T-cell clones are selective in their reactivity towards different enterobacteria or H. pylori and increased in inflammatory bowel disease. Scand. J. Immunol. 44: 71 79.
28. Duchmann, R.,, E. May,, M. Heike,, P. Knolle,, M. Neurath,, and K. H. Meyer zum Buschenfelde. 1999. T cell specificity and cross reactivity towards Enterobacteria, Bacteroides, Bifidobacterium, and antigens from resident intestinal flora in humans. Gut 44: 812 818.
29. Duchmann, R.,, E. Schmitt,, P. Knolle,, K. H. Meyer zum Buschenfelde,, and M. Neurath. 1996. Tolerance towards resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin-10 or antibodies to interleukin-12. Eur. J. Immunol. 26: 934 938.
30. Elson, C. O.,, Y. Cong,, S. Brandwein,, C. T. Weaver,, R. P. McCabe,, M. Mahler,, J. P. Sundberg,, and E. H. Leiter. 1998. Experimental models to study molecular mechanisms underlying intestinal inflammation. Ann. N.Y. Acad. Sci. 859: 85 95.
31. Fabia, R.,, A. Ar’Rajab,, M. L. Johansson,, R. Andersson,, R. Willen,, B. Jeppsson,, G. Molin,, and S. Bengmark. 1993. Impairment of bacterial flora in human ulcerative colitis and experimental colitis in the rat. Digestion 54: 248 255.
32. Fiocchi, C. 1998. Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 115: 182 205.
33. Furne, J. K.,, F. L. Suarez,, S. L. Ewing,, J. Springfield,, and M. D. Levitt. 2000. Binding of hydrogen sulfide by bismuth does not prevent dextran sulfate-induced colitis in rats. Dig. Dis. Sci. 45: 1439 1443.
34. Gaboriau-Routhiau, V.,, and M. C. Moreau. 1996. Gut flora allows recovery of oral tolerance to ovalbumin in mice after transient breakdown mediated by cholera toxin or Escherichia coli heat-labile enterotoxin. Pediatr. Res. 39: 625 629.
35. Gardiner, K. R.,, N. H. Anderson,, M. D. McCaigue,, P. J. Erwin,, M. I. Halliday,, and B. J. Rowlands. 1993. Adsorbents as antiendotoxin agents in experimental colitis. Gut 34: 51 55.
36. Gardiner, K. R.,, M. I. Halliday,, G. R. Barclay,, L. Milne,, D. Brown,, S. Stephens,, R. J. Maxwell,, and B. J. Rowlands. 1995. Significance of systemic endotoxaemia in inflammatory bowel disease. Gut 36: 897 901.
37. Gionchetti, P.,, F. Rizzello,, A. Venturi,, P. Brigidi,, D. Matteuzzi,, G. Bazzocchi,, G. Poggioli,, M. iglioli,, and M. Campieri. 2000. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology 119: 305 309.
38. Greenbloom, S. L.,, A. H. Steinhart,, and G. R. Greenberg. 1998. Combination ciprofloxacin and metronidazole for active Crohn’s disease. Can. J. Gastroenterol. 12: 53 56.
39. Haller, D.,, M. P. Russo,, R. B. Sartor,, and C. Jobin. 2002. IKKβ and phosphatidylinositol 3-kinase/Akt participate in non-pathogenic Gram-negative enteric bacteria-induced RelA phosphorylation and NFkB activation in both primary and intestinal epithelial cell lines. J. Biol. Chem. 277: 38168 38178.
40. Hammer, R. E.,, S. D. Maika,, J. A. Richardson,, J. P. Tang,, and J. D. Taurog. 1990. Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m: an animal model of HLA-B27-associated human disorders. Cell 63: 1099 1112.
41. Harper, P. H.,, E. C. Lee,, M. G. Kettlewell,, M. K. Bennett,, and D. P. Jewell. 1985. Role of the faecal stream in the maintenance of Crohn’s colitis. Gut 26: 279 284.
42. Harper, P. H.,, S. C. Truelove,, E. C. Lee,, M. G. Kettlewell,, and D. P. Jewell. 1983. Split ileostomy and ileocolostomy for Crohn’s disease of the colon and ulcerative colitis: a 20 year survey. Gut 24: 106 113.
43. Hermiston, M. L.,, and J. I. Gordon. 1995. Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin. Science 270: 1203 1207.
44. Hessle, C.,, B. Andersson,, and A. E. Wold. 2000. Gram-positive bacteria are potent inducers of monocytic interleukin-12 (IL-12) while gram-negative bacteria preferentially stimulate IL-10 production. Infect. Immun. 68: 3581 3586.
45. Hilsden, R. J.,, J. B. Meddings,, and L. R. Sutherland. 1996. Intestinal permeability changes in response to acetylsalicylic acid in relatives of patients with Crohn’s disease. Gastroenterology 110: 1395 1403.
46. Hollander, D.,, C. M. Vadheim,, E. Brettholz,, G. M. Petersen,, T. Delahunty,, and J. I. Rotter. 1986. Increased intestinal permeability in patients with Crohn’s disease and their relatives. A possible etiologic factor. Ann. Intern. Med. 105: 883 885.
47. Hooper, L. V.,, M. H. Wong,, A. Thelin,, L. Hansson,, P. G. Falk,, and J. I. Gordon. 2001. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291: 881 884.
48. Hugot, J. P.,, M. Chamaillard,, H. Zouali,, S. Lesage,, J. P. Cezard,, J. Belaiche,, and S. Almer. 2001. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411: 599 603.
49. Jiang, H. Q.,, N. Kushnir,, M. C. Thurnheer,, N. A. Bos,, and J. J. Cebra. 2002. Monoassociation of SCID mice with Helicobacter muridarum, but not four other enterics, provokes IBD upon receipt of T cells. Gastroenterology 122: 1346 1354.
50. Kim, S. C.,, S. L. Tonkonogy,, and R. B. Sartor. 2001. Role of endogenous IL-10 in down regulating proinflammatory cytokine expression. Gastroenterology 120: A183.
51. Kim, S. C.,, S. L. Tonkonogy,, E. Balish,, and R. B. Sartor. 2002. Bacterial antigen specific T cell activation precedes intestinal inflammation in E. faecalis monoassociated IL-10 deficient mice. Gastroenterology 122: A85.
52. Korzenik, J. R.,, and B. K. Dieckgraefe. 2000. Immunostimulation in Crohn’s disease: results of a pilot study of G-CSF (R-Methug-CSF) in mucosal and fistulizing Crohn’s disease. Gastroenterology 118: A874.
53. Korzenik, J. R.,, and B. K. Dieckgraefe. 2000. Is Crohn’s disease an immunodeficiency? A hypothesis suggesting possible early events in the pathogenesis of Crohn’s disease. Dig. Dis. Sci. 45: 1121 1129.
54. Kruis, W.,, E. Schutz,, P. Fric,, B. Fixa,, G. Judmaier,, and M. Stolte. 1997. Double-blind comparison of an oral Escherichia coli preparation and mesalazine in maintaining remission of ulcerative colitis. Aliment. Pharmacol. Ther. 11: 853 858.
55. Kuhn, R.,, J. Lohler,, D. Rennick,, K. Rajewsky,, and W. Muller. 1993. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75: 263 274.
56. Kulkarni, A. B.,, J. M. Ward,, L. Yaswen,, C. L. Mackall,, S. R. Bauer,, C. G. Huh,, R. E. Gress,, and S. Karlsson. 1995. Transforming growth factor-beta 1 null mice. An animal model for inflammatory disorders. Am. J. Pathol. 146: 264 275.
57. Kullberg, M. C.,, J. M. Ward,, P. Gorelick,, P. Caspar,, S. Hieny,, A. Cheever,, D. Jankovic,, and A. Sher. 1998. Helicobacter hepaticus triggers colitis in specific-pathogen-free interleukin-10 (IL-10)-deficient mice through an IL-12and gamma interferon-dependent mechanism. Infect. Immun. 66: 5157 5166.
58. Lichtman, S. N.,, J. Keku,, J. H. Schwab, andR. B. Sartor. 1991. Hepatic injury associated with small bowel bacterial overgrowth in rats is prevented by metronidazole and tetracycline. Gastroenterology 100: 513 519.
59. Lichtman, S. N.,, E. E. Okoruwa,, J. Keku,, J. H. Schwab,, and R. B. Sartor. 1992. Degradation of endogenous bacterial cell wall polymers by the muralytic enzyme mutanolys in prevents hepatobiliary injury in genetically susceptible rats with experimental intestinal bacteria lover growth. J. Clin. Invest. 90: 1313 1322.
60. Lichtman, S. N.,, R. B. Sartor,, J. Keku,, and J. H. Schwab. 1990. Hepatic inflammation in rats with experimental small intestinal bacterial over growth. Gastroenterology 98: 414 423.
61. Lichtman, S. N.,, J. Wang,, B. Hummel,, S. Lacey,, and R. B. Sartor. 1998. A rat model of ileal pouch-rectal anastomosis. Inflam. Bowel Dis. 4: 187 195.
62. Lichtman, S. N.,, J. Wang,, R. B. Sartor,, C. Zhang,, D. Bender,, F. G. Dalldorf,, and J. H. Schwab. 1995. Reactivation of arthritis induced by small bowel bacterial overgrowth in rats: role of cytokines, bacteria, and bacterial polymers. Infect. Immun. 63: 2295 2301.
63. Ma, A.,, M. Datta,, E. Margosian,, J. Chen,,and I. Horak. 1995. T cells, but not B cells, are required for bowel inflammation in interleukin 2-deficient mice. J. Exp. Med. 182: 1567 1572.
64. MacDonald, T. T.,, and P. B. Carter. 1979. Requirement for a bacterial flora before mice generate cells capable of mediating the delayed hypersensitivity reaction to sheep red blood cells. J. Immunol. 122: 2624 2629.
65. Macpherson, A.,, U. Y. Khoo,, I. Forgacs,, J. Philpott-Howard,, and I. Bjarnason. 1996. Mucosal antibodies in inflammatory bowel disease are directed against intestinal bacteria. Gut 38: 365 375.
66. Madsen, K. L.,, J. S. Doyle,, L. D. Jewell,, M. M. Tavernini,, and R. N. Fedorak. 1999. Lactobacillus species prevents colitis in interleukin10 gene-deficient mice. Gastroenterology 116: 1107 1114.
67. Madsen, K. L.,, S. A. Lewis,, M. M. Tavernini,, J. Hibbard,, and R. N. Fedorak. 1997. Interleukin 10 prevents cytokine-induced disruption of T84 monolayer barrier integrity and limitschloride secretion. Gastroenterology 113: 151 159.
68. Makkink, M. K.,, N. J. Schwerbrock,, M. vander Sluis,, H. A. Buller,, R. B. Sartor,, A. W. Einerhand,, and J. Dekker. 2002. Interleukin10 deficient mice are defective in colonic MUC2 synthesis both before and after induction of colitis by commensal bacteria. Gastroenterology 122: A30.
69. Mashimo, H.,, D. C. Wu,, D. K. Podolsky,, and M. C. Fishman. 1996. Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor. Science 274: 262 265.
70. Matsuda, H.,, Y. Fujiyama,, A. Andoh,, T. Ushijima,, T. Kajinami,, and T. Bamba. 2000. Characterization of antibody responses against rectal mucosa-associated bacterial flora in patients with ulcerative colitis. J. Gastroenterol. Hepatol. 15: 61 68.
71. Matsumoto, S.,, Y. Okabe,, H. Setoyama,, K. Takayama,, J. Ohtsuka,, H. Funahashi,, A. Imaoka,, Y. Okada,, and Y. Umesaki. 1998. Inflammatory bowel disease-like enteritis and caecitis in a senescence accelerated mouse P1/Yitstrain. Gut 43: 71 78.
72. McCall, R. D.,, S. Haskill,, E. M. Zimmermann,, P. K. Lund,, R. C. Thompson,, and R. B. Sartor. 1994. Tissue interleukin 1 and interleukin-1 receptor antagonist expression in enterocolitisin resistant and susceptible rats. Gastroenterology 106: 960 972.
73. Michalek, S. M.,, H. Kiyono,, M. J. Wannemuehler,, L. M. Mosteller,, and J. R. Mc-Ghee. 1982. Lipopolysaccharide (LPS) regulation of the immune response: LPS influence on oral tolerance induction. J. Immunol. 128: 1992 1998.
74. Mizoguchi, A.,, E. Mizoguchi,, R. N. Smith,, F. I. Preffer,, and A. K. Bhan. 1997. Suppressive role of B cells in chronic colitis of T cell receptor alpha mutant mice. J. Exp. Med. 186: 1749 1756.
75. Moreau, M. C.,, and V. Gaboriau-Routhiau. 1996. The absence of gut flora, the doses of antigeningested and aging affect the long-term peripheral tolerance induced by ovalbumin feeding in mice. Res. Immunol. 147: 49 59.
76. Morteau, O.,, S. G. Morham,, R. Sellon,, L. A. Dieleman,, R. Langenbach,, O. Smithies,, and R. B. Sartor. 2000. Impaired mucosal defense to acute colonic injury in mice lackingcyclooxygenase-1 or cyclooxygenase-2. J. Clin. Invest. 105: 469 478.
77. Neurath, M. F.,, I. Fuss,, B. L. Kelsall,, E. Stuber,, and W. Strober. 1995. Antibodies to interleukin12 abrogate established experimental colitis in mice. J. Exp. Med. 182: 1281 1290.
78. Ogura, Y.,, D. K. Bonen,, N. Inohara,, D. L. Nicolae,, F. Chen,, R. Ramos,, H. Britton, Tomogram, R. Karaliuskas, R. H. Duerr, J. P. Achkar, S. R. Brant, T. M. Bayless, B. S. Kirschner, S. B. Hanauer, G. Nunez, and J. H. Cho. 2001. A frame shift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411: 603 606.
79. Ogura, Y.,, N. Inohara,, A. Benito,, F. F. Chen,, S. Yamaoka,, and G. Nunez. 2001. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J. Biol. Chem. 276: 4812 4818.
80. Onderdonk, A. B.,, M. L. Franklin,, and R. L. Cisneros. 1981. Production of experimental ulcerative colitis in gnotobiotic guinea pigs with simplified microflora. Infect. Immun. 32: 225 231.
81. Onderdonk, A. B.,, J. A. Richardson,, R. E. Hammer,, and J. D. Taurog. 1998. Correlation of cecal microflora of HLA-B27 transgenicrats with inflammatory bowel disease. Infect. Immun. 66: 6022 6023.
82. Oyama, N.,, N. Sudo,, H. Sogawa,, and C. Kubo. 2001. Antibiotic use during infancy promotesa shift in the T(H)1/T(H)2 balance toward T(H)2-dominant immunity in mice. J. Allergy Clin. Immunol. 107: 153 159.
83. Podolsky, D. K. 1999. Mucosal immunity and inflammation. V. Innate mechanisms of mucosal defense and repair: the best offense is a good defense. Am. J. Physiol. 277: G495 G499.
84. Powrie, F. 1995. T cells in inflammatory bowel disease: protective and pathogenic roles. Immunity 3: 171 174.
85. Powrie, F.,, J. Carlino,, M. W. Leach,, S. Mauze,, and R. L. Coffman. 1996. A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type1-mediated colitis by CD45RB(low) CD4 + T cells. J. Exp. Med. 183: 2669 2674.
86. Powrie, F.,, M. W. Leach,, S. Mauze,, L. B. Caddle,, and R. L. Coffman. 1993. Phenotypically distinct subsets of CD 4 + T cells induce or protect from chronic intestinal inflammation inc. B-17 SCID mice. Int. Immunol. 5: 1461 1471.
87. Rachmilewitz, D.,, F. Karmeli,, J. Lee,, and E. Raz. 2002. Immunostimulatory DNA sequences decrease the enhanced colonic TNFα and IL-1β generation in IBD. Gastroenterology 122: A148.
88. Rachmilewitz, D.,, F. Karmeli,, K. Takabayashi,, T. Hayashi,, L. Leider-Trejo,, J. Lee,, L. M. Leoni,, and E. Raz. 2002. Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis. Gastroenterology 122: 1428 1441.
89. Rath, H. C.,, H. H. Herfarth,, J. S. Ikeda,, W. B. Grenther,, T. E. J. Hamm,, E. Balish,, J. D. Taurog,, R. E. Hammer,, K. H. Wilson,, and R. B. Sartor. 1996. Normal luminal bacteria, especially Bacteroides species, mediatechronic colitis, gastritis, and arthritis in HLAB27/human beta2 microglobulin transgenic rats. J. Clin. Invest. 98: 945 953.
90. Rath, H. C.,, J. S. Ikeda,, H. J. Linde,, J. Scholmerich,, K. H. Wilson,, and R. B. Sartor. 1999. Varying cecal bacterial loads influencescolitis and gastritis in HLA-B27 transgenicrats. Gastroenterology 116: 310 319.
91. Rath, H. C.,, M. Schultz,, R. Freitag,, L. A. Dieleman,, F. Li,, H. J. Linde,, J. Scholmerich,, and R. B. Sartor. 2001. Different subsets of enteric bacteria induce and perpetuate experimental colitis in rats and mice. Infect. Immun. 69: 2277 2285.
92. Rath, H. C.,, K. H. Wilson,, and R. B. Sartor. 1999. Differential induction of colitis and gastritis in HLA-B27 transgenic rats selectively colonized with Bacteroides vulgatus and Escherichiacoli. Infect. Immun. 67: 2969 2974.
93. Read, S.,, V. Malmstrom,, and F. Powrie. 2000. Cytotoxic T lymphocyte-associated antigen4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that controlintestinal inflammation. J. Exp. Med. 192: 295 302.
94. Riehl, T.,, S. Cohn,, T. Tessner,, S. Schloemann,,and W. F. Stenson. 2000. Lipopolysaccharideis radio protective in the mouse intestine through a prostaglandin-mediated mechanism. Gastroenterology 118: 1106 1166.
95. Rietdijk, S. T.,, W. Faubion,, C. Albright,, Y. P. de Jong,, A. Abadia,, K. Clarke,, R. B. Sartor,, and C. Terhorst. 2002. CD4 + CD25 + regulatory T cells originating from germfree mice have impaired suppressive abilities. Gastroenterology 122: A387.
96. Roediger, W. E. 1980. The colonic epitheliumin ulcerative colitis: an energy-deficiency disease? Lancet ii: 712 715.
97. Roediger, W. E.,, A. Duncan,, O. Kapaniris,,and S. Millard. 1993. Reducing sulfur compounds of the colon impair colonocyte nutrition: implications for ulcerative colitis. Gastroenterology 104: 802 809.
98. Rutgeerts, P.,, K. Goboes,, M. Peeters,, M. Hiele,, F. Penninckx,, R. Aerts,, R. Kerremans,, and G. Vantrappen. 1991. Effect of faecal stream diversion on recurrence of Crohn’s disease in the neoterminal ileum. Lancet 338: 771 774.
99. Sadlack, B.,, H. Merz,, H. Schorle,, A. Schimpl,, A. C. Feller,, and I. Horak. 1993. Ulcerative colitis-like disease in mice with a disruptedinterleukin-2 gene. Cell 75: 253 261.
100. Sartor, R. B. 1997. Pathogenesis and immune mechanisms of chronic inflammatory bowel diseases. Am. J. Gastroenterol. 92: 5S 11S.
101. Sartor, R. B., 1999. Microbial factors in the pathogenesis of Crohn’s disease, ulcerative colitis and experimental intestinal inflammation, p. 153 178. In J. B. Kirsner (ed.), Inflammatory Bowel Diseases, 5th ed. The W. B. Saunders Co., Philadelphia, Pa.
102. Sartor, R. B., 2000. Antibiotics as therapeutic agents in Crohn’s disease, p. 359 362. In T. M. Bayless, and S. Hanauer (ed.), Current Advanced Therapy of Inflammatory Bowel Disease. BC Decker, Inc., Hamilton, Ontario, Canada.
103. Sartor, R. B. 2000. Colitis in HLA-B27/beta2 macroglobulin transgenic rats. Int. Rev. Immunol. 19: 39 50.
104. Sartor, R. B.,, D. E. Bender,, W. B. Grenther,, and L. C. Holt. 1994. Absolute requirement for ubiquitous luminal bacteria in the pathogenesis of chronic intestinal inflammation. Gastroenterology 106: A767.
105. Sartor, R. B.,, D. E. Bender,, and L. C. Holt. 1992. Susceptibility of inbred rat strains to intestinal and extraintestinal inflammation induced by indomethacin. Gastroenterology 102: A690.
106. Sartor, R. B.,, T. M. Bond,, and J. H. Schwab. 1988. Systemic uptake and intestinal inflammatory effects of luminal bacterial cell wall polymers in rats with acute colonic injury. Infect. Immun. 56: 2101 2108.
107. Sartor, R. B.,, R. A. De La Cadena,, K. D. Green,, S. W. Davis,, A. A. Adam,, B. Raymond,, F. Legris,, and R. W. Colman. 1996. Selective kallikrein-kinin system activation in inbred rats differentially susceptible to granulomatous enterocolitis. Gastroenterology 110: 1467 1481.
108. Schultz, M.,, S. L. Tonkonogy,, R. K. Sellon,, C. Veltkamp,, V. L. Godfrey,, J. Kwon,, W. B. Grenther,, E. Balish,, I. Horak,, and R. B. Sartor. 1999. IL-2-deficient mice raised under germfree conditions develop delayed mild focal intestinal inflammation. Am. J. Physiol. 276: G1461 G1472.
109. Schultz, M.,, C. Veltkamp,, L. A. Dieleman,, W. B. Grenther,, P. B. Wyrick,, S. L. Tonkonogy,, and R. B. Sartor. 2002. Lactobacillus plantarum 299V in the treatment and prevention of spontaneous colitis in interleukin-10 deficientmice. Inflame. Bowel Dis. 8: 71 80.
110. Schwab, J. H. 1993. Phlogiston properties of peptidoglycan-polysaccharide polymers from cell walls of pathogenic and normal-flora bacteria which colonize humans. Infect. Immun. 61: 4535 4539.
111. Sellon, R. K.,, S. Tonkonogy,, M. Schultz,, L. A. Dieleman,, W. Grenther,, E. Balish,, D. M. Rennick,, and R. B. Sartor. 1998. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficientmice. Infect. Immun. 66: 5224 5231.
112. Steinhart, A. H.,, B. G. Feagan,, C. J. Wong,, M. Vandervoort,, S. Mikolainis,, K. Croitoru,, E. Seidman,, D. J. Leddin,, A. Bitton,, E. Drouin,, A. Cohen,, and G. R. Greenberg. 2002. Combined budesonide and antibiotic therapy for active Crohn’s disease: a randomized controlled trial. Gastroenterology 123: 33 40.
113. Strober, W.,, B. Kelsall,, I. Fuss,, T. Marth,, B. Ludviksson,, R. Ehrhardt,, and M. Neurath. 1997. Reciprocal IFN-gamma and TGF beta responses regulate the occurrence of mucosal inflammation. Immunol. Today 18: 61 64.
114. Strober, W.,, B. R. Ludviksson,, and I. J. Fuss. 1998. The pathogenesis of mucosal inflammationin murine models of inflammatory bowel disease and Cohn's disease. Ann. Intern. Med. 128: 848 856.
115. Sutherland, L.,, J. Singleton,, J. Sessions,, S. Hanauer,, E. Krawitt,, G. Rankin,, R. Summers,, H. Mekhjian,, N. Greenberger,, and M. Kelly. 1991. Double blind, placebo controlled trial of metronidazole in Crohn’s disease. Gut 32: 1071 1075.
116. Sutton, C. L.,, J. Kim,, A. Yamane,, H. Dalwadi,, B. Wei,, C. Landers,, S. R. Targan,, and J. Braun. 2000. Identification of a novel bacterial sequence associated with Crohn’s disease. Gastroenterology 119: 23 31.
117. Swidsinski, A.,, A. Ladhoff,, A. Pernthaler,, S. Swidsinski,, V. Loening-Baucke,, M. Ortner,, J. Weber,, U. Hoffmann,, S. Schreiber,, M. Dietel,, and H. Lochs. 2002. Mucosal flora in inflammatory bowel disease. Gastroenterology 122: 44 54.
118. Sydora, B. C.,, M. M. Tavernini,, L. D. Jewell,, A. Wessler,, R. P. Rennie,, and R. N. Fedorak. 2001. Effect of bacterial monoassociation on tolerance and intestinal inflammation in IL-10 gene-deficient mice. Gastroenterology 120: A517.
119. Tabaqchali, S.,, D. P. O’Donoghue,, and K. A. Bettelheim. 1978. Escherichia coli anti bodiesin patients with inflammatory bowel disease. Gut 19: 108 113.
120. Taurog, J. D.,, J. A. Richardson,, J. T. Croft,, W. A. Simmons,, M. Zhou,, J. L. Fernandez-Sueiro,, E. Balish,, and R. E. Hammer. 1994. The germfree state prevents development of gut and joint inflammatory diseasein HLA-B27 transgenic rats. J. Exp. Med. 180: 2359 2364.
121. Tessner, T. G.,, S. M. Cohn,, S. Schloemann,, and W. F. Stenson. 1998. Prostaglandins prevent decreased epithelial cell proliferation associated with dextrin sodium sulfate injury in mice. Gastroenterology 115: 874 882.
122. Tlaskalova, H.,, R. Stepankova,, T. Hudcovic,, B. Cukrowska,, E. Verdu,, L. Tuckova,, L. Jelinkova,, F. Bend-Jelloul,, Z. Rehakova,, J. Sinkora,, D. Sokol,, P. Bercik,, D. Funda,, P. Michetti,, and J. Cebra. 1999. The role of bacterial microflora in development of dextran sodium sulphate (DSS) induced colitisin immuno competent and immuno deficient mice. Microbial. Ecol. Health Dis. 11: 115 116.
123. Turunen, U.,, M. A. Farkkila,, and V. Valtonen. 1999. Long-term treatment of ulcerative colitis with ciprofloxacin. Gastroenterology 117: 282 283.
124. Ulisse, S.,, P. Gionchetti,, S. D’Alo,, F. P. Russo,, I. Pesce,, G. Ricci,, F. Rizzello,, U. Helwig,, M. G. Cifone,, M. Campieri,, and C. De Simone. 2001. Expression of cytokines, inducible nitric oxide synthase, and matrix metalloproteinasesin pouchitis: effects of probiotic treatment. Am. J. Gastroenterol. 96: 2691 2699.
125. Veltkamp, C.,, S. L. Tonkonogy,, Y. P. deJong,, C. Albright,, W. B. Grenther,, E. Balish,, C. Terrorist,, and R. B. Sartor. 2001. Continuous stimulation by normal luminal bacteriais essential for the development and perpetuation of colitis in Tg(epsilon26) mice. Gastroenterology 120: 900 913.
126. Veltkamp, C.,, S. L. Tonkonogy,, M. Schultz,, and R. B. Sartor. 1999. Lactobacillus plantarum is superior to Lactobacillus GG in preventing colitis in IL-10 deficient mice. Gastroenterology 116: A838.
127. Wannemuehler, M. J.,, H. Kiyono,, J. L. Babb,, S. M. Michalek,, and J. R. McGhee. 1982. Lipopolysaccharide (LPS) regulation of the immune response: LPS converts germ free mice to sensitivity to oral tolerance induction. J. Immunol. 129: 959 965.
128. Yamada, T.,, E. Deitch,, R. D. Specian,, M. A. Perry,, R. B. Sartor,, and M. B. Grisham. 1993. Mechanisms of acute and chronic intestinal inflammation induced by indomethacin. Inflammation 17: 641 662.


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Animal models that do not develop intestinal inflammation in a germfree (sterile) environment

Citation: Sartor R. 2003. Role of Commensal Enteric Bacteria in Intestinal Inflammation: Lessons from Animal Models, p 223-240. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch13
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Specificity of induction of colitis in gnotobiotic rodent models by defined bacterial species

Citation: Sartor R. 2003. Role of Commensal Enteric Bacteria in Intestinal Inflammation: Lessons from Animal Models, p 223-240. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch13
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Relative balance of protective versus detrimental commensal enteric bacterial species determines intestinal inflammation versus mucosal homeostasis

Citation: Sartor R. 2003. Role of Commensal Enteric Bacteria in Intestinal Inflammation: Lessons from Animal Models, p 223-240. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch13

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