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Mechanisms of Disease: pathogenesis of Crohn's disease and ulcerative colitis

Abstract

Crohn's disease and ulcerative colitis are idiopathic, chronic, relapsing, inflammatory conditions that are immunologically mediated. Although their exact etiologies remain uncertain, results from research in animal models, human genetics, basic science and clinical trials have provided important new insights into the pathogenesis of chronic, immune-mediated, intestinal inflammation. These studies indicate that Crohn's disease and ulcerative colitis are heterogeneous diseases characterized by various genetic abnormalities that lead to overly aggressive T-cell responses to a subset of commensal enteric bacteria. The onset and reactivation of disease are triggered by environmental factors that transiently break the mucosal barrier, stimulate immune responses or alter the balance between beneficial and pathogenic enteric bacteria. Different genetic abnormalities can lead to similar disease phenotypes; these genetic changes can be broadly characterized as causing defects in mucosal barrier function, immunoregulation or bacterial clearance. These new insights will help develop better diagnostic approaches that identify clinically important subsets of patients for whom the natural history of disease and response to treatment are predictable.

Key Points

  • Genes involved in Crohn's disease and experimental ileocolitis regulate innate immune responses, bacterial killing, immune responses to endrogenous microbial antigens and epithelial function

  • Chronic intestinal inflammation requires the presence of commensal enteric bacteria and activated T lymphocytes

  • Patients with inflammatory bowel diseases and rodents with chronic intestinal inflammation exhibit loss of immunologic tolerance to normal enteric bacteria

  • Some enteric bacteria are detrimental and some are protective

  • Defective innate immune responses can lead to lack of clearance of invading bacteria and to the activation of pathogenic T cells

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Figure 1: Interaction of various factors contributing to chronic intestinal inflammation in a genetically susceptible host.
Figure 2: Binding of microbial adjuvants to extracellular and intracellular pattern-recognition receptors.
Figure 3: The interaction between antigen-presenting cells and naive T cells triggers T-cell activation and differentiation.
Figure 4: Different responses to transient intestinal injury in genetically susceptible versus genetically resistant hosts.

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Acknowledgements

Original research was supported by NIH RO1 grants DK40249 and DK 53347. The author thanks S May for her expert secretarial assistance.

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Correspondence to R Balfour Sartor.

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The author has received research grant support from VSL Pharmaceuticals, Salix Pharmaceuticals, and Procter & Gamble. He is a consultant for Danone/Yakult companies and has given talks sponsored by Salix and Berlex companies.

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Sartor, R. Mechanisms of Disease: pathogenesis of Crohn's disease and ulcerative colitis. Nat Rev Gastroenterol Hepatol 3, 390–407 (2006). https://doi.org/10.1038/ncpgasthep0528

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