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. 2019 Feb 27;85(1):33–56. doi: 10.3184/003685002783238861

Inflammatory Bowel Disease: Is the Intestine a Trojan Horse?

Christelle Basset 1, John Holton 2
PMCID: PMC10361205  PMID: 11969118

Abstract

Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory condition of the intestines that is clinically heterogenous. The cause(s) of IBD are currently unknown but the mechanisms of injury are immunological. Increasingly there is an emphasis on the study of the complex interactions at the interface of self and non-self- the gastrointestinal epithelial surface- in relationship to the pathogenesis of disease. There is mounting evidence that a lack of tolerance to the normal commensal flora of the intestine may underly the disease pathogenesis. Several genetic loci that are markers of disease susceptibility have been identified. These loci map to areas of the genome that are concerned with antigen presentation or cytokine secretion and suggest a genetic heterogeneity that underlies the clinical differences. Overall a picture is emerging of defects in epithelial barrier function and, or immunoregulation leading to immune responses that are triggered or exaggerated by the antigenic components of the normal flora.

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References

  • 1.Jewell J.P. Crohn's Disease; Ulcerative Colitis. (1996) In: Wetherall D.J., Ledingham J.G.G., Warrell D.A. (eds) Oxford Textbook of Medicine 3rd edn, Vol. 2. pp. 1936–1950. OUP. [Google Scholar]
  • 2.Le Roy D., Di Padova F., Adachi Y., Glauser M.P., Calandra T., & Heumann D. (2001) Critical role of lipopolysaccharide-binding protein and CD14 in immune responses against gram-negative bacteria. J. Immunol., 167, 2759–2765. [DOI] [PubMed] [Google Scholar]
  • 3.Hayashi F., Smith K.D., Ozinsky A., Hawn T.R., Yi E.C., Goodlett D.R., Eng J.K., Akira S., Underhill D.M., & Aderem A. (2001) The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature, 410, 1099–1103. [DOI] [PubMed] [Google Scholar]
  • 4.Nizet V., Ohtake T., Lauth X., Trowbridge J., Rudisill J., Dorschner R.A., Pestonjamasp V., Piraino J., Huttner K., & Gallo R.L. (2001) Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature, 414, 454–457. [DOI] [PubMed] [Google Scholar]
  • 5.Curfs J.H., Meis J.F., & Hoogkamp-Korstanje J.A. (1997) A primer on cytokines: sources, receptors, effectors and inducers. Clin. Microbiol. Rev., 10, 742–780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Delves P.J., & Roitt I.M. (2000) The Immune system. First of two parts. N. Engl. J. Med., 343, 37–49. [DOI] [PubMed] [Google Scholar]
  • 7.Delves P.J., & Roitt I.M. (2000) The Immune system. Second of two parts. N. Engl. J. Med., 343, 108–117. [DOI] [PubMed] [Google Scholar]
  • 8.Berin M.C., McKay D.M., & Perdue M.H. (1999) Immune-epithelial interactions in host defense. Am. J. Trop. Med. Hyg., 60, 16–25. [DOI] [PubMed] [Google Scholar]
  • 9.Kronenberg M., & Cheroutre H. (2000) Do mucosal T cells prevent intestinal inflammation? Gastroenterology, 118, 974–977. [DOI] [PubMed] [Google Scholar]
  • 10.Lamm M.E. (1997) Interactions of antigens and antibodies at mucosal surfaces. Ann. Rev. Microbiol., 51, 311–340. [DOI] [PubMed] [Google Scholar]
  • 11.Kagnoff M.F., & Eckmann L. (1997) Epithelial cells as sensors for microbial infection. J. Clin. Invest., 100, 6–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Barnes P.J., & Karin M. (1997) Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med., 336, 1066–1071. [DOI] [PubMed] [Google Scholar]
  • 13.French N., & Pettersson S. (2000) Microbe-host interactions in the alimentary tract: the gateway to understanding inflammatory bowel disease. Gut, 47, 162–163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Holdeman L.V., Good I.J., & Moore W.E.C. (1976) Human fecal flora: variation in bacterial composition within individuals and a possible effect of emotional stress. Appl. Environ. Microbiol., 31, 359–375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Savage D.C. (1983) Morphological diversity among members of the gastrointestinal microflora. Int. Rev. Cytol., 82, 305–334. [DOI] [PubMed] [Google Scholar]
  • 16.Steege J.C., Buurman W.A., & Forge P.P. (1997) The neonatal development of intraepithelial and lamina propria lymphocytes in the murine small intestine. Dev. Immunol., 5, 121–128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Hooper L.V., Wong M.H., Thelin A., Hansson L., Falk P.G., & Gordon J.I. (2001) Molecular analysis of commensal host-microbial relationships in the intestine. Science, 291, 881–884. [DOI] [PubMed] [Google Scholar]
  • 18.Simecka J.W. (1998) Mucosal immunity of the gastrointestinal tract and oral tolerance. Adv. Drug. Deliv. Rev., 34, 235–259. [DOI] [PubMed] [Google Scholar]
  • 19.Ernst P.B., Song F., Klimpel G.R., Haeberle H., Bamford K.B., Crowe S.E., Ye G., & Reyes V.E. (1999) Regulation of the mucosal immune response. Am. J. Trop. Med. Hyg., 60, 2–9. [DOI] [PubMed] [Google Scholar]
  • 20.Iwasaki A., & Kelsall B.L. (1999) Mucosal immunity and inflammation. I Mucosal dendritic cells: their specialized role in initiating T cell responses. Am. J. Physiol. Gastrointest. Liver Physiol., 276, G1074–G1078. [DOI] [PubMed] [Google Scholar]
  • 21.Mac Donald T.T., & Monteleone G. (2001) IL-12 and Th1 immune responses in human Peyer's patches. Trends Immunol., 22, 244–247. [DOI] [PubMed] [Google Scholar]
  • 22.van Parijs L., & Abbas A.K. (1998) Homeostasis and self-tolerance in the immune system: turning lymphocytes off. Science, 280, 243–248. [DOI] [PubMed] [Google Scholar]
  • 23.Fowler E., & Weiner H.L. (1997) Oral tolerance: Elucidation of mechanisms and application to treatment of autoimmune diseases. Biopoly, 43, 323–335. [DOI] [PubMed] [Google Scholar]
  • 24.Strober W., Kelsall B., & Marth T. (1998) Oral tolerance. J. Clin. Immunol., 18, 1–30. [DOI] [PubMed] [Google Scholar]
  • 25.Groux H., O'Garra A., Bigler M., Rouleau M., Antonenko S., de Vries J.E., & Roncarolo M.G. (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature, 389, 737–742. [DOI] [PubMed] [Google Scholar]
  • 26.Groux H., & Powrie F. (1999) Regulatory T cells and inflammatory bowel disease. Immunol. Today., 20, 442–445. [DOI] [PubMed] [Google Scholar]
  • 27.van de Merwe J.P., Schroder A.M., Wensinck F., & Hazenberg M.P. (1988) The obligate anaerobic faecal flora of patients with Crohn's disease and their first-degree relatives. Scand. J. Gastroenterol., 23, 1125–1131. [DOI] [PubMed] [Google Scholar]
  • 28.Duchmann R., Kaiser I., Hermann E., Mayet W., Ewe K., & Meyerzum Buschenfelde K.H. (1995) Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD). Clin. Exp. Immunol., 102, 448–455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Satsangi J., Parkes M., Louis E., Hashimoto L., Kato N., Welsh K., Terwilliger J.D., Lathrop G.M., Bell J.I., & Jewell D.P. (1996) Two stage genome wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nature (Genet), 14, 199–202. [DOI] [PubMed] [Google Scholar]
  • 30.Toyoda H., Wang S.J., Yang H.Y., Redford A., Magalong D., Tyan D., McElree C.K., Pressman S.R., Shanahan F., & Targan S.R. (1993) Distinct associations of HLA class II genes with inflammatory bowel disease. Gastroenterology, 104, 741–748. [DOI] [PubMed] [Google Scholar]
  • 31.Stokkers P.C., Reitsma P.H., Tytgat G.N., & van Deventer S.J. (1999) HLA-DR and DQ phenotypes in IBD- a meta analysis. Gut, 45, 395–401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.de la Concha E.G., Fernandez-Arquero M., Lopez-Nava G., Martin E., Allcock R.J., Conejero L., Paredes J.G., & Diaz-Rubio M. (2000) Susceptibility to severe ulcerative colitis is associated with polymorphism in the central MHC gene IKBL. Gastroenterology. 119, 1491–1495. [DOI] [PubMed] [Google Scholar]
  • 33.Ogura Y., Bonen D.K., Inohara N, Nicolae D.L., Chen F.F., Ramos R, Britton H, Moran T., Karaliuskas R., Duerr R.H., Achkar J.P., Brant S.R., Bayless T.M., Kirschner B.S., Hanauer S.B., Nunez G., & Cho J.H. (2001) A frameshift mutation in NOD 2 associated with susceptibility to Crohn's disease. Nature, 411, 603–606. [DOI] [PubMed] [Google Scholar]
  • 34.Elson C.O., Sartor R.B., Tennyson G.S., & Riddell R.H. (1995) Experimental models of inflammatory bowel disease. Gastroenterology, 109, 1344–1367. [DOI] [PubMed] [Google Scholar]
  • 35.Dombrowicz D., Nutten S., Desreumaux P., Neut C., Torpier G., Peeters M., Colombel J.F., & Capron M. (2001) Role of the high affinity immunoglobulin E receptor in bacterial translocation and intestinal inflammation. J. Exp. Med., 193, 25–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Rath H.C., Schultz M., Freitag R., Dieman L.A., Li F., Linde H.J., Scholmerich J., & Sartor R.B. (2001) Different subsets of enteric bacteria induce and perpetuate experimental colitis in rats and mice. Infect. Immun., 69, 2277–2285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Cahill R.J., Foltz C.J., Fox J.G., Dangler C.A., Powrie F., & Schauer D.B. (1997) Inflammatory bowel disease: an immunity-mediated condition triggered by bacterial infection with Helicobacter hepaticus. Infect. Immun., 65, 3126–3131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Shomer N.H., Dangler C.A., Schrenzel M.D., & Fox J.G. (1997) Helicobacter bilis-induced inflammatory bowel disease in scid mice with defined flora. Infect. Immun., 65, 4858–4864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Kullberg M.C., Ward J.M., Gorelick P.L., Caspar P., Hieny S., Cheever A., Jankovic D., & Sher A. (1998) Helicobacter hepaticus triggers colitis in specific-pathogen-free interleukin-10 (IL-10)-deficient mice though an IL-12-and gamma interferon-dependent mechanism. Infect. Immun., 66, 5157–5166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Martin H.M., & Rhodes M.J. (2000) Bacteria and Inflammatory Bowel Disease. Curr. Opin. Infect. Dis., 13, 503–509. [DOI] [PubMed] [Google Scholar]
  • 41.Campieri M., & Gionchetti P. (2001) Bacteria as the cause of ulcerative colitis. Gut, 48, 132–135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Caradonna L., Amati L., Magrone T., Pellegrino N.M., Jirillo E., & Caccavo D. (2000) Enteric bacteria, lipopolysaccharides and related cytokines in inflammatory bowel disease: biological and clinical significance. J. Endotoxin. Res., 6, 205–214. [PubMed] [Google Scholar]
  • 43.Blaser M.J. (1999) Hypothesis: the changing relationships of Helicobacter pylori and humans: Implications for health and disease. J. Infect. Dis., 179, 1523–1530. [DOI] [PubMed] [Google Scholar]
  • 44.Totten P.A., Fennell C.L., Tenover P.C., Wezenberg J.M., Perine P.L., Stamm W.E., & Holmes K.K. (1985) Campylobacter cinaedi and Campylobacter fennelliae two new campylobacter species associated with enteric disease in homosexual men. J. Infect. Dis., 151, 131–139. [DOI] [PubMed] [Google Scholar]
  • 45.Saunders K.E., Shen Z., Dewhirst F.E., Paster B.J., Dangler C.A., & Fox J.G.(1999) Novel intestinal Helicobacter species isolated from Cotton-Top Tamarins (Saguinus Oedipus) with Chronic Colitis. J. Clin. Microbiol., 37, 146–151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Danon S.J., Goh K.L., Parasakthi N., Neilan B.A., Grehan M.J., & Lee A. (2000) The human colon: a reservoir for Helicobacter species. Gut, 47, A2. [Google Scholar]
  • 47.Oliveira A.G., Queiroz D.M.M.M., Rocha G.A., Rocha A.M.C., Santos A., Sana M.G.P., Moura S.B., Correa P.R.V., & Camargos E.R.S. (2001) Isolation of Helicobacter strains from the colonic mucosa of inflammatory bowel disease (IBD) patients. Gut, 49, A1.11603378 [Google Scholar]
  • 48.Grehan M.J., & Danon S.J. (2001) Absence of Helicobacter species in the ileum and colon of Australians with and without inflammatory bowel disease (IBD) – Should we be looking at other mucus-associated bacteria Gastroenterology, 120 (Supp. 1), A-337. [Google Scholar]
  • 49.Masseret E., Boudeau J., Colombel J.F., Neut C., Desreumaux P., Joly B., Cortot A., & Darfeuille-Michaud A. (2001) Genetically related Escherichia. coli strains associated with Crohn's disease. Gut, 48, 320–325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Glasser A.L., Boudeau J., Barnich N., Perruchot M.H., Colombel J.F., & Darfeuille-Michaud A. (2001) Adherent invasive Escherichia coli strains from patients with Crohn's disease survive and replicate within the macrophage without inducing host cell death. Infect. Immun., 69, 5529–5537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Prindiville T.P., Sheikh R.A., Cohen S.H., Tang Y.J., Cantrell M.C., & Silva J. Jr. (2000) Bacteroides fragilis enterotoxin gene sequences in patients with inflammatory bowel disease. Emerg. Infect. Dis., 6, 171–174. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Duchmann R., May E., Heike M., Knoll C.P., Neurath K.H., & Meyer zum Buschenfelde K.H. (1999) T cell specificity and cross reactivity towards entero-bacteria, Bacteroides, Bifidobacterium and antigens from resident intestinal flora in humans. Gut, 44, 812–818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Muyzer G., & Smalla K. (1998) Application of denaturing gradient gel electrophoresis (DGGE) and temperature gradient gel electrophoresis (TGGE) in microbial ecology. Antonie van Leeuwenhoek, 73, 127–141. [DOI] [PubMed] [Google Scholar]
  • 54.Rhodes J.M. (1997) Colonic mucus and ulcerative colitis. Gut, 40, 807–808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Buisine M.P., Desreumaux P., Leteurtre E., Copin M.C., Colombel J.F., Porchet N., & Aubert J.P. (2001) Mucin gene expression in intestinal epithelial cells in Crohn's disease. Gut, 49, 544–551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Favier C., Neut C., Mizon C., Cortot A., Colombel J.F., & Mizon J. (1997) Fecal b-D-galactosidase production and Bifidobacteria are decreased in Crohn's disease. Dig. Dis. Sci., 42, 817–822. [DOI] [PubMed] [Google Scholar]
  • 57.Madsen K.L., Doyle J.S., Jewell L.D., Tavernini M.M., & Fedorak R.N. (1999) Lactobacillus species prevents colitis in interleukin 10 gene-deficient mice. Gastroenterology, 116, 1107–1114. [DOI] [PubMed] [Google Scholar]
  • 58.Gionchetti P., Rizzello F., Venturi A., & Campieri M. (2000) Probiotics in infective diarrhoea and inflammatory bowel diseases. J. Gastroenterol. Hepatol., 15, 489–493. [DOI] [PubMed] [Google Scholar]
  • 59.Alvarez-Olmos M.I., & Oberhelman R.A. (2001) Probiotic agents and infectious diseases: a modern perspective on a traditional therapy. Clin. Infect. Dis., 32, 1567–1576. [DOI] [PubMed] [Google Scholar]
  • 60.Ulisse S., Gionchetti P., D'Alo S., Russo F.P., Pesce I., Ricci G., Rizzello F., Helwig U., Cifone M.G., Campieri M., & De Simone C. (2001) Expression of cytokines, inducible nitric oxide synthase, and matrix metallo-proteinases in pouchitis: effects of probiotic treatment. Am. J. Gastroenterol., 96, 2691–2699. [DOI] [PubMed] [Google Scholar]
  • 61.Blumberg R.S., Saubermann L.J., & Strober W. (1999) Animal models of mucosal inflammation and their relation to human inflammatory bowel disease. Curr. Opin. Immunol., 11, 648–656. [DOI] [PubMed] [Google Scholar]
  • 62.Okamoto S., Watanabe M., Yamazaki M., Yajima T., Hayashi T., Ishii H., Mukai M., Yamada T., Watanabe N., Jameson BA., & Hibi T. (1999) A synthetic mimetic of CD4 is able to suppress disease in a rodent model of immune colitis. Eur. J. Immunol., 29, 355–366. [DOI] [PubMed] [Google Scholar]
  • 63.Pizarro T.T., Arseneau K.O., & Cominelli F. (2000) Lessons from genetically engineered animal models XI. Novel mouse models to study pathogenic mechanisms of Crohn's disease. Am. J. Physiol. Gastrointest. Liver Physiol., 278, G665–669. [DOI] [PubMed] [Google Scholar]
  • 64.Plevy S.E., Landers C.J., Prehn J., Carramanzana N.M., Deem R.L., Shealy D., & Targan S.R. (1997) A role for TNF alpha and mucosal Th1 cytokines in the pathogenesis of Crohn's disease. J. Immunol., 159, 6276–6282. [PubMed] [Google Scholar]
  • 65.Neurath M.F., Finotto S., Fuss I., Boirivant M., Galle P.R., & Strober W. (2001) Regulation of T cell apoptosis in IBD: to die or not to die that is the mucosal question. Trends Immunol., 22, 21–26. [DOI] [PubMed] [Google Scholar]
  • 66.Ueyama H., Kiyohara T., Sawada N., Isozaki K., Kitamura S., Kondo S., Miyagawa J., Kanayama S., Shinomura Y., Ishikawa H., Ohtani T., Nezu R., Nagata S., & Matsuzawa Y. (1998) High Fas ligand expression on lymphocytes in lesions of ulcerative colitis. Gut, 43, 48–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Kohout P., & Koref P. (2001) Intestinal permeability in relatives of patients with Crohn's disease. Vnitr. Lek., 47, 371–374. [PubMed] [Google Scholar]
  • 68.Irvine E.J., & Marshall J.K. (2000) Increased intestinal permeability precedes the onset of Crohn's disease in a subject with familial risk. Gastroenterology, 119, 1740–1744. [DOI] [PubMed] [Google Scholar]
  • 69.Zareie M., Singh P.K., Irvine E.J., Sherman P.M., McKay D.M., & Perdue M.H. (2001) Monocyte/macrophage activation by normal bacteria and bacterial products. Implications for altered epithelial function in Crohn's disease. Am. J. Pathol., 158, 1101–1109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Gassler N., Rohr C., Schneider A., Kartenbeck J., Bach A., Obermuller N., Otto H.F., & Autschbach F. (2001) Inflammatory bowel disease is associated with changes of enterocyte junctions. Am. J. Physiol. Gastrointest. Liver Physiol., 281, G216–G228. [DOI] [PubMed] [Google Scholar]
  • 71.Cario E., & Podolsky D.K. (2000) Differential alteration in intestinal epithelial cell expression of Toll-like receptor 3 (TLR 3) and TLR4 in inflammatory bowel disease. Infect. Immun., 68, 7010–7117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Abreu M.T., Vora P., Faure E., Thomas L.S., Arnold E.T., & Arditi M. (2001) Decreased expression of Toll-like receptor 4 and MD2 correlate with intestinal epithelial cell protection against dysregulated proinflammatory gene expression in response to bacterial lipopolysaccharide. J. Immunol., 167, 1609–1617. [DOI] [PubMed] [Google Scholar]

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