Home LiteratureArticle Details
PMID: 17332878 Published · ppublish English Journal Article Review

The fundamental basis of inflammatory bowel disease.

The Journal of clinical investigation ·Vol. 117 ·No. 3 ·2007-03-00 ·Pages 514-21

Strober W, Fuss I, Mannon P

Abstract

Two broad hypotheses have arisen regarding the fundamental nature of the pathogenesis of inflammatory bowel diseases (IBDs, which include ulcerative colitis and Crohn disease). The first contends that primary dysregulation of the mucosal immune system leads to excessive immunologic responses to normal microflora. The second suggests that changes in the composition of gut microflora and/or deranged epithelial barrier function elicits pathologic responses from the normal mucosal immune system. Here we examine these hypotheses and conclude that IBD is indeed characterized by an abnormal mucosal immune response but that microbial factors and epithelial cell abnormalities can facilitate this response.

MeSH Terms
Humans Immunity, Mucosal Inflammatory Bowel Diseases/immunology,microbiology Intestinal Mucosa/immunology,microbiology
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Strober Warren
Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. wstrober@niaid.nih.gov
Fuss Ivan
Mannon Peter
References (80)
80 references, click to expand
  1. The nature of colitis in chronic granulomatous disease.
    J Pediatr Gastroenterol Nutr. 2003 May;36(5):623-31 PMID: 12717086
  2. Toll-like receptor-dependent production of IL-12p40 causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice.
    J Clin Invest. 2003 May;111(9):1297-308 PMID: 12727921
  3. NODs: intracellular proteins involved in inflammation and apoptosis.
    Nat Rev Immunol. 2003 May;3(5):371-82 PMID: 12766759
  4. Basiliximab (anti-CD25) in combination with steroids may be an effective new treatment for steroid-resistant ulcerative colitis.
    Aliment Pharmacol Ther. 2003 Jul 1;18(1):65-75 PMID: 12848627
  5. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma.
    Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8372-7 PMID: 12826605
  6. Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis.
    N Engl J Med. 2003 Jul 24;349(4):350-7 PMID: 12878742
  7. Inducible and constitutive beta-defensins are differentially expressed in Crohn's disease and ulcerative colitis.
    Inflamm Bowel Dis. 2003 Jul;9(4):215-23 PMID: 12902844
  8. Protein microarrays guide tolerizing DNA vaccine treatment of autoimmune encephalomyelitis.
    Nat Biotechnol. 2003 Sep;21(9):1033-9 PMID: 12910246
  9. Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn's disease.
    Gastroenterology. 1998 Dec;115(6):1405-13 PMID: 9834268
  10. Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense.
    Science. 1999 Oct 1;286(5437):113-7 PMID: 10506557
  11. Anti-interleukin-12 antibody for active Crohn's disease.
    N Engl J Med. 2004 Nov 11;351(20):2069-79 PMID: 15537905
  12. Muramyldipeptide and diaminopimelic acid-containing desmuramylpeptides in combination with chemically synthesized Toll-like receptor agonists synergistically induced production of interleukin-8 in a NOD2- and NOD1-dependent manner, respectively, in human monocytic cells in culture.
    Cell Microbiol. 2005 Jan;7(1):53-61 PMID: 15617523
  13. The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO.
    Curr Biol. 2004 Dec 29;14(24):2217-27 PMID: 15620648
  14. Ribosomal DNA sequence analysis of mucosa-associated bacteria in Crohn's disease.
    Inflamm Bowel Dis. 2004 Nov;10(6):824-33 PMID: 15626901
  15. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance.
    Science. 2005 Jan 14;307(5707):254-8 PMID: 15653504
  16. A risk haplotype in the Solute Carrier Family 22A4/22A5 gene cluster influences phenotypic expression of Crohn's disease.
    Gastroenterology. 2005 Feb;128(2):260-9 PMID: 15685536
  17. Signalling pathways and molecular interactions of NOD1 and NOD2.
    Nat Rev Immunol. 2006 Jan;6(1):9-20 PMID: 16493424
  18. A phase II dose ranging, double-blind, placebo-controlled study of alicaforsen enema in subjects with acute exacerbation of mild to moderate left-sided ulcerative colitis.
    Aliment Pharmacol Ther. 2006 May 15;23(10):1415-25 PMID: 16669956
  19. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6.
    J Clin Invest. 2006 May;116(5):1310-6 PMID: 16670770
  20. Treatment of ulcerative colitis with oral mesalamine: advances in drug formulation, efficacy expectations and dose response, compliance, and chemoprevention.
    Rev Gastroenterol Disord. 2006 Spring;6(2):97-105 PMID: 16699478
  21. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease.
    Clin Gastroenterol Hepatol. 2006 Jun;4(6):754-9 PMID: 16716759
  22. Pilot feasibility studies of leukocytapheresis with the Adacolumn Apheresis System in patients with active ulcerative colitis or Crohn disease.
    J Clin Gastroenterol. 2006 Jul;40(6):482-9 PMID: 16825929
  23. Fontolizumab, a humanised anti-interferon gamma antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn's disease.
    Gut. 2006 Aug;55(8):1131-7 PMID: 16507585
  24. The bacteriology of biopsies differs between newly diagnosed, untreated, Crohn's disease and ulcerative colitis patients.
    J Med Microbiol. 2006 Aug;55(Pt 8):1141-9 PMID: 16849736
  25. A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon.
    Am J Hum Genet. 2006 Sep;79(3):439-48 PMID: 16909382
  26. Role of toll-like receptors in spontaneous commensal-dependent colitis.
    Immunity. 2006 Aug;25(2):319-29 PMID: 16879997
  27. Excess IL-12 but not IL-23 accompanies the inflammatory bowel disease associated with common variable immunodeficiency.
    Gastroenterology. 2006 Sep;131(3):748-56 PMID: 16952544
  28. Review article: the role of bacteria in onset and perpetuation of inflammatory bowel disease.
    Aliment Pharmacol Ther. 2006 Oct;24 Suppl 3:11-8 PMID: 16961738
  29. Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of antigen-specific colitis.
    Immunity. 2006 Sep;25(3):473-85 PMID: 16949315
  30. Daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), for the treatment of moderately to severely active ulcerative colitis: a randomised, double blind, placebo controlled, dose ranging trial.
    Gut. 2006 Nov;55(11):1568-74 PMID: 16603634
  31. Current limitations of IBD treatment: where do we go from here?
    Ann N Y Acad Sci. 2006 Aug;1072:1-8 PMID: 17057185
  32. Helminths and mucosal immune modulation.
    Ann N Y Acad Sci. 2006 Aug;1072:356-64 PMID: 17057216
  33. Surgery for inflammatory bowel diseases.
    Dig Dis. 2003;21(2):168-79 PMID: 14571114
  34. Maintenance therapy for inflammatory bowel disease.
    Am J Gastroenterol. 2003 Dec;98(12 Suppl):S6-S17 PMID: 14697913
  35. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria.
    Science. 2004 Mar 12;303(5664):1662-5 PMID: 15016999
  36. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease.
    Gastroenterology. 2004 Apr;126(4):989-96; discussion 947 PMID: 15057738
  37. Functional variants of OCTN cation transporter genes are associated with Crohn disease.
    Nat Genet. 2004 May;36(5):471-5 PMID: 15107849
  38. Bacterial flagellin is a dominant antigen in Crohn disease.
    J Clin Invest. 2004 May;113(9):1296-306 PMID: 15124021
  39. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis.
    J Clin Invest. 2004 May;113(10):1490-7 PMID: 15146247
  40. Enhanced Escherichia coli adherence and invasion in Crohn's disease and colon cancer.
    Gastroenterology. 2004 Jul;127(1):80-93 PMID: 15236175
  41. NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses.
    Nat Immunol. 2004 Aug;5(8):800-8 PMID: 15220916
  42. Bacterial overgrowth in the cystic fibrosis transmembrane conductance regulator null mouse small intestine.
    Infect Immun. 2004 Oct;72(10):6040-9 PMID: 15385508
  43. Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin.
    Science. 1995 Nov 17;270(5239):1203-7 PMID: 7502046
  44. Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD)
    Clin Exp Immunol. 1995 Dec;102(3):448-55 PMID: 8536356
  45. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract.
    Science. 2005 Feb 4;307(5710):731-4 PMID: 15692051
  46. Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-beta-bearing regulatory cells.
    J Immunol. 2005 Mar 15;174(6):3237-46 PMID: 15749854
  47. Autologous hematopoietic stem cell transplantation in patients with refractory Crohn's disease.
    Gastroenterology. 2005 Mar;128(3):552-63 PMID: 15765390
  48. Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial.
    Gastroenterology. 2005 Apr;128(4):825-32 PMID: 15825065
  49. Sargramostim for active Crohn's disease.
    N Engl J Med. 2005 May 26;352(21):2193-201 PMID: 15917384
  50. Antibodies to CBir1 flagellin define a unique response that is associated independently with complicated Crohn's disease.
    Gastroenterology. 2005 Jun;128(7):2020-8 PMID: 15940634
  51. Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin.
    N Engl J Med. 2005 Jun 16;352(24):2499-507 PMID: 15958805
  52. Review article: practical management of inflammatory bowel disease patients taking immunomodulators.
    Aliment Pharmacol Ther. 2005 Jul 1;22(1):1-16 PMID: 15963074
  53. A phase I clinical trial of the treatment of Crohn's fistula by adipose mesenchymal stem cell transplantation.
    Dis Colon Rectum. 2005 Jul;48(7):1416-23 PMID: 15933795
  54. Natalizumab and progressive multifocal leukoencephalopathy.
    N Engl J Med. 2005 Jul 28;353(4):432-3 PMID: 15947083
  55. Leukocytapheresis therapy for steroid-naïve patients with active ulcerative colitis: its clinical efficacy and adverse effects compared with those of conventional steroid therapy.
    J Gastroenterol Hepatol. 2005 Oct;20(10):1567-71 PMID: 16174075
  56. Natalizumab induction and maintenance therapy for Crohn's disease.
    N Engl J Med. 2005 Nov 3;353(18):1912-25 PMID: 16267322
  57. Cdcs1, a major colitogenic locus in mice, regulates innate and adaptive immune response to enteric bacterial antigens.
    Gastroenterology. 2005 Nov;129(5):1473-84 PMID: 16285949
  58. Complications of biological therapy for inflammatory bowel diseases.
    Curr Opin Gastroenterol. 2006 Jan;22(1):30-43 PMID: 16319674
  59. Infliximab for induction and maintenance therapy for ulcerative colitis.
    N Engl J Med. 2005 Dec 8;353(23):2462-76 PMID: 16339095
  60. Reduced Paneth cell alpha-defensins in ileal Crohn's disease.
    Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18129-34 PMID: 16330776
  61. Both IL-12p70 and IL-23 are synthesized during active Crohn's disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody.
    Inflamm Bowel Dis. 2006 Jan;12(1):9-15 PMID: 16374252
  62. Intestinal disease in Hermansky-Pudlak syndrome: occurrence of colitis and relation to genotype.
    Clin Gastroenterol Hepatol. 2006 Jan;4(1):73-80 PMID: 16431308
  63. ABCB1/MDR1 gene determines susceptibility and phenotype in ulcerative colitis: discrimination of critical variants using a gene-wide haplotype tagging approach.
    Hum Mol Genet. 2006 Mar 1;15(5):797-805 PMID: 16434479
  64. Spontaneously colitic C3H/HeJBir mice demonstrate selective antibody reactivity to antigens of the enteric bacterial flora.
    J Immunol. 1997 Jul 1;159(1):44-52 PMID: 9200437
  65. 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. 1998 Mar 16;187(6):855-64 PMID: 9500788
  66. A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis.
    J Immunol. 1998 Nov 15;161(10):5733-44 PMID: 9820555
  67. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria.
    Nat Immunol. 2001 Apr;2(4):361-7 PMID: 11276208
  68. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.
    Nature. 2001 May 31;411(6837):599-603 PMID: 11385576
  69. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.
    Nature. 2001 May 31;411(6837):603-6 PMID: 11385577
  70. Extracorporeal photochemotherapy in patients with steroid-dependent Crohn's disease: a prospective pilot study.
    Aliment Pharmacol Ther. 2001 Sep;15(9):1313-22 PMID: 11552901
  71. CD4 T cells monospecific to ovalbumin produced by Escherichia coli can induce colitis upon transfer to BALB/c and SCID mice.
    Int Immunol. 2001 Dec;13(12):1561-70 PMID: 11717197
  72. Mucosal flora in inflammatory bowel disease.
    Gastroenterology. 2002 Jan;122(1):44-54 PMID: 11781279
  73. T helper 1 and T helper 2 cells are pathogenic in an antigen-specific model of colitis.
    J Exp Med. 2002 Jan 7;195(1):71-84 PMID: 11781367
  74. The immunology of mucosal models of inflammation.
    Annu Rev Immunol. 2002;20:495-549 PMID: 11861611
  75. RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems.
    Nature. 2002 Mar 14;416(6877):194-9 PMID: 11894098
  76. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial.
    Lancet. 2002 May 4;359(9317):1541-9 PMID: 12047962
  77. Selective adherence of IgA to murine Peyer's patch M cells: evidence for a novel IgA receptor.
    J Immunol. 2002 Aug 15;169(4):1844-51 PMID: 12165508
  78. Inflammatory bowel disease.
    N Engl J Med. 2002 Aug 8;347(6):417-29 PMID: 12167685
  79. Understanding immune-microbial homeostasis in intestine.
    Immunol Res. 2002;26(1-3):87-94 PMID: 12403348
  80. CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells.
    Gastroenterology. 2003 Apr;124(4):993-1000 PMID: 12671896
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI30587
Email
wstrober@niaid.nih.gov
Published
2007-03-00
Pages
514-21
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1804356
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI30587 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2