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Logo of jcinvestThe Journal of Clinical Investigation
J Clin Invest. 1996 August 15; 98(4): 945–953.
PMCID: PMC507509

Normal luminal bacteria, especially Bacteroides species, mediate chronic colitis, gastritis, and arthritis in HLA-B27/human beta2 microglobulin transgenic rats.


Genetic and environmental factors are important in the pathogenesis of clinical and experimental chronic intestinal inflammation. We investigated the influence of normal luminal bacteria and several groups of selected bacterial strains on spontaneous gastrointestinal and systemic inflammation in HLA-B27 transgenic rats. Rats maintained germfree for 3-9 mo were compared with littermates conventionalized with specific pathogen-free bacteria. Subsequently, germfree transgenic rats were colonized with groups of five to eight bacteria that were either facultative or strictly anaerobic. Transgenic germfree rats had no gastroduodenitis, colitis, or arthritis, but developed epididymitis and dermatitis to the same degree as conventionalized rats. Colonic proinflammatory cytokine expression was increased in transgenic conventionalized rats but was undetectable in germfree and nontransgenic rats. Colitis progressively increased over the first 4 wk of bacterial exposure, then plateaued. Only transgenic rats colonized with defined bacterial cocktails which contained Bacteroides spp. had colitis and gastritis. Normal luminal bacteria predictably and uniformly induce chronic colonic, gastric and systemic inflammation in B27 transgenic F344 rats, but all bacterial species do not have equal activities.

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Selected References

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  • Sartor RB. Current concepts of the etiology and pathogenesis of ulcerative colitis and Crohn's disease. Gastroenterol Clin North Am. 1995 Sep;24(3):475–507. [PubMed]
  • Sutherland L, Singleton J, Sessions J, Hanauer S, Krawitt E, Rankin G, Summers R, Mekhjian H, Greenberger N, Kelly M, et al. Double blind, placebo controlled trial of metronidazole in Crohn's disease. Gut. 1991 Sep;32(9):1071–1075. [PMC free article] [PubMed]
  • Peppercorn MA. Is there a role for antibiotics as primary therapy in Crohn's ileitis? J Clin Gastroenterol. 1993 Oct;17(3):235–237. [PubMed]
  • McCall RD, Haskill S, Zimmermann EM, Lund PK, Thompson RC, Sartor RB. Tissue interleukin 1 and interleukin-1 receptor antagonist expression in enterocolitis in resistant and susceptible rats. Gastroenterology. 1994 Apr;106(4):960–972. [PubMed]
  • Sartor RB, Cromartie WJ, Powell DW, Schwab JH. Granulomatous enterocolitis induced in rats by purified bacterial cell wall fragments. Gastroenterology. 1985 Sep;89(3):587–595. [PubMed]
  • Lichtman SN, Keku J, Schwab JH, Sartor RB. Hepatic injury associated with small bowel bacterial overgrowth in rats is prevented by metronidazole and tetracycline. Gastroenterology. 1991 Feb;100(2):513–519. [PubMed]
  • Lichtman SN, Wang J, Sartor RB, Zhang C, Bender D, Dalldorf FG, Schwab JH. Reactivation of arthritis induced by small bowel bacterial overgrowth in rats: role of cytokines, bacteria, and bacterial polymers. Infect Immun. 1995 Jun;63(6):2295–2301. [PMC free article] [PubMed]
  • Yamada T, Deitch E, Specian RD, Perry MA, Sartor RB, Grisham MB. Mechanisms of acute and chronic intestinal inflammation induced by indomethacin. Inflammation. 1993 Dec;17(6):641–662. [PubMed]
  • Krook A, Lindström B, Kjellander J, Järnerot G, Bodin L. Relation between concentrations of metronidazole and Bacteroides spp in faeces of patients with Crohn's disease and healthy individuals. J Clin Pathol. 1981 Jun;34(6):645–650. [PMC free article] [PubMed]
  • Van de Merwe JP, Schröder AM, Wensinck F, Hazenberg MP. The obligate anaerobic faecal flora of patients with Crohn's disease and their first-degree relatives. Scand J Gastroenterol. 1988 Nov;23(9):1125–1131. [PubMed]
  • Auer IO, Röder A, Wensinck F, van de Merwe JP, Schmidt H. Selected bacterial antibodies in Crohn's disease and ulcerative colitis. Scand J Gastroenterol. 1983 Mar;18(2):217–223. [PubMed]
  • Onderdonk AB, Franklin ML, Cisneros RL. Production of experimental ulcerative colitis in gnotobiotic guinea pigs with simplified microflora. Infect Immun. 1981 Apr;32(1):225–231. [PMC free article] [PubMed]
  • Severijnen AJ, van Kleef R, Hazenberg MP, van de Merwe JP. Cell wall fragments from major residents of the human intestinal flora induce chronic arthritis in rats. J Rheumatol. 1989 Aug;16(8):1061–1068. [PubMed]
  • Stimpson SA, Brown RR, Anderle SK, Klapper DG, Clark RL, Cromartie WJ, Schwab JH. Arthropathic properties of cell wall polymers from normal flora bacteria. Infect Immun. 1986 Jan;51(1):240–249. [PMC free article] [PubMed]
  • Inman RD, Scofield RH. Etiopathogenesis of ankylosing spondylitis and reactive arthritis. Curr Opin Rheumatol. 1994 Jul;6(4):360–370. [PubMed]
  • Hammer RE, Maika SD, Richardson JA, Tang JP, Taurog JD. Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m: an animal model of HLA-B27-associated human disorders. Cell. 1990 Nov 30;63(5):1099–1112. [PubMed]
  • Taurog JD, Maika SD, Simmons WA, Breban M, Hammer RE. Susceptibility to inflammatory disease in HLA-B27 transgenic rat lines correlates with the level of B27 expression. J Immunol. 1993 May 1;150(9):4168–4178. [PubMed]
  • Taurog JD, Richardson JA, Croft JT, Simmons WA, Zhou M, Fernández-Sueiro JL, Balish E, Hammer RE. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med. 1994 Dec 1;180(6):2359–2364. [PMC free article] [PubMed]
  • Brinster RL, Chen HY, Trumbauer ME, Yagle MK, Palmiter RD. Factors affecting the efficiency of introducing foreign DNA into mice by microinjecting eggs. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4438–4442. [PubMed]
  • MacDonald TT, Carter PB. Contact sensitivity in the germ-free mouse. J Reticuloendothel Soc. 1978 Sep;24(3):287–293. [PubMed]
  • Grisham MB, Benoit JN, Granger DN. Assessment of leukocyte involvement during ischemia and reperfusion of intestine. Methods Enzymol. 1990;186:729–742. [PubMed]
  • Siegling A, Lehmann M, Platzer C, Emmrich F, Volk HD. A novel multispecific competitor fragment for quantitative PCR analysis of cytokine gene expression in rats. J Immunol Methods. 1994 Dec 28;177(1-2):23–28. [PubMed]
  • Crofford LJ, Sano H, Karalis K, Webster EL, Goldmuntz EA, Chrousos GP, Wilder RL. Local secretion of corticotropin-releasing hormone in the joints of Lewis rats with inflammatory arthritis. J Clin Invest. 1992 Dec;90(6):2555–2564. [PMC free article] [PubMed]
  • Dijkema R, van der Meide PH, Dubbeld M, Caspers M, Wubben J, Schellekens H. Cloning, expression, and purification of rat IFN-gamma. Methods Enzymol. 1986;119:453–464. [PubMed]
  • Eisenberg SP, Brewer MT, Verderber E, Heimdal P, Brandhuber BJ, Thompson RC. Interleukin 1 receptor antagonist is a member of the interleukin 1 gene family: evolution of a cytokine control mechanism. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5232–5236. [PubMed]
  • Kwon J, Chung IY, Benveniste EN. Cloning and sequence analysis of the rat tumor necrosis factor-encoding genes. Gene. 1993 Oct 15;132(2):227–236. [PubMed]
  • Nishida T, Nishino N, Takano M, Sekiguchi Y, Kawai K, Mizuno K, Nakai S, Masui Y, Hirai Y. Molecular cloning and expression of rat interleukin-1 alpha cDNA. J Biochem. 1989 Mar;105(3):351–357. [PubMed]
  • Nudel U, Zakut R, Shani M, Neuman S, Levy Z, Yaffe D. The nucleotide sequence of the rat cytoplasmic beta-actin gene. Nucleic Acids Res. 1983 Mar 25;11(6):1759–1771. [PMC free article] [PubMed]
  • Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC, Horak I. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell. 1993 Oct 22;75(2):253–261. [PubMed]
  • Kühn R, Löhler J, Rennick D, Rajewsky K, Müller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993 Oct 22;75(2):263–274. [PubMed]
  • Bjarnason I, Hayllar J, Smethurst P, Price A, Gumpel MJ. Metronidazole reduces intestinal inflammation and blood loss in non-steroidal anti-inflammatory drug induced enteropathy. Gut. 1992 Sep;33(9):1204–1208. [PMC free article] [PubMed]
  • Videla S, Vilaseca J, Guarner F, Salas A, Treserra F, Crespo E, Antolín M, Malagelada JR. Role of intestinal microflora in chronic inflammation and ulceration of the rat colon. Gut. 1994 Aug;35(8):1090–1097. [PMC free article] [PubMed]
  • Wells CL, van de Westerlo EM, Jechorek RP, Feltis BA, Wilkins TD, Erlandsen SL. Bacteroides fragilis enterotoxin modulates epithelial permeability and bacterial internalization by HT-29 enterocytes. Gastroenterology. 1996 May;110(5):1429–1437. [PubMed]
  • Lichtman SN, Okoruwa EE, Keku J, Schwab JH, Sartor RB. Degradation of endogenous bacterial cell wall polymers by the muralytic enzyme mutanolysin prevents hepatobiliary injury in genetically susceptible rats with experimental intestinal bacterial overgrowth. J Clin Invest. 1992 Oct;90(4):1313–1322. [PMC free article] [PubMed]
  • Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992 Oct 22;359(6397):693–699. [PubMed]
  • Aiko S, Grisham MB. Spontaneous intestinal inflammation and nitric oxide metabolism in HLA-B27 transgenic rats. Gastroenterology. 1995 Jul;109(1):142–150. [PubMed]
  • Sartor RB. Cytokines in intestinal inflammation: pathophysiological and clinical considerations. Gastroenterology. 1994 Feb;106(2):533–539. [PubMed]
  • Esser RE, Stimpson SA, Cromartie WJ, Schwab JH. Reactivation of streptococcal cell wall-induced arthritis by homologous and heterologous cell wall polymers. Arthritis Rheum. 1985 Dec;28(12):1402–1411. [PubMed]
  • Stimpson SA, Esser RE, Carter PB, Sartor RB, Cromartie WJ, Schwab JH. Lipopolysaccharide induces recurrence of arthritis in rat joints previously injured by peptidoglycan-polysaccharide. J Exp Med. 1987 Jun 1;165(6):1688–1702. [PMC free article] [PubMed]
  • Sartor RB, Rath HC, Lichtman SN, van Tol EA. Animal models of intestinal and joint inflammation. Baillieres Clin Rheumatol. 1996 Feb;10(1):55–76. [PubMed]
  • Sartor RB, Bond TM, Schwab JH. Systemic uptake and intestinal inflammatory effects of luminal bacterial cell wall polymers in rats with acute colonic injury. Infect Immun. 1988 Aug;56(8):2101–2108. [PMC free article] [PubMed]
  • Lichtman SN, Keku J, Schwab JH, Sartor RB. Evidence for peptidoglycan absorption in rats with experimental small bowel bacterial overgrowth. Infect Immun. 1991 Feb;59(2):555–562. [PMC free article] [PubMed]
  • Granfors K, Jalkanen S, von Essen R, Lahesmaa-Rantala R, Isomäki O, Pekkola-Heino K, Merilahti-Palo R, Saario R, Isomäki H, Toivanen A. Yersinia antigens in synovial-fluid cells from patients with reactive arthritis. N Engl J Med. 1989 Jan 26;320(4):216–221. [PubMed]
  • Granfors K, Jalkanen S, Lindberg AA, Mäki-Ikola O, von Essen R, Lahesmaa-Rantala R, Isomäki H, Saario R, Arnold WJ, Toivanen A. Salmonella lipopolysaccharide in synovial cells from patients with reactive arthritis. Lancet. 1990 Mar 24;335(8691):685–688. [PubMed]

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