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Pathway-based approaches to the treatment of inflammatory bowel disease

  • Giorgos Bamias
    Affiliations
    First Department of Gastroenterology, Ethnikon and Kapodistriakon University of Athens, Laikon Hospital, Athens, Greece
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  • Theresa T. Pizarro
    Affiliations
    Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio

    Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio

    Digestive Health Research Institute, Case Western Reserve University, Cleveland, Ohio
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  • Fabio Cominelli
    Correspondence
    Reprint requests: Fabio Cominelli, Division of Gastroenterology, Case Western Reserve University School of Medicine, 11100 Euclid Avenue, Cleveland, OH 44106-5066
    Affiliations
    Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio

    Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio

    Digestive Health Research Institute, Case Western Reserve University, Cleveland, Ohio
    Search for articles by this author
Published:September 07, 2015DOI:https://doi.org/10.1016/j.trsl.2015.09.002
      Crohn's disease and ulcerative colitis, collectively termed inflammatory bowel disease (IBD), are immunologic disorders that represent the prototypes of chronic intestinal inflammation. Their pathogenesis involves the dysregulated interaction between the intestinal microbiota and the gut-associated mucosal immune system that takes place when genetically predisposed individuals are exposed to detrimental environmental triggers. In recent years, the therapeutic dogma in IBD has shifted away from the administration of nonspecific immunosuppressives toward a pathway-based approach. In this review, we present an outlook of IBD treatment based on this new conceptual approach. Firstly, we will provide an overview of the major aspects of IBD pathogenesis with emphasis on specific pathway-based defects. Secondly, we will examine in detail the development of novel therapeutic approaches that can be used to target genetics, dysbiosis, the epithelial barrier, proinflammatory cytokines, and leukocyte trafficking. Most of these strategies are still in the developmental phase, but promising approaches include fecal microbiota transplantation as a means to correct IBD-related dysbiosis; administration of modified phosphatidylcholine to enhance the function of the intestinal mucous and tighten the defective epithelial barrier; the reduction of over-reactive proinflammatory pathways through the blockade of novel, nontumor necrosis factor inflammatory mediators via monoclonal antibodies against the common p40 chain of interleukin (IL-12) and IL-23, Janus kinase inhibitors, or antisense oligonucleotides against inhibitors of the immunosuppressive cytokine transforming growth factor-β1; and finally, inhibition of leukocyte trafficking to the gut via neutralization of the gut-specific α4β7 integrin. Availability of such diverse treatment modalities with specific pathway-based targets will increase the therapeutic options for patients with IBD.

      Abbreviations:

      CAI (Colitis Activity Index), CCL25 (Chemokine C Ligand 25), CD (Crohn's Disease), FMT (Fecal Microbiota Transplantation), GI (Gastroeintestinal), HSCT (Hematopoietic Stem Cell Transplantation), IBD (Inflammatory Bowel Disease), IL (Interleukin), JAK (Janus Kinase), JK (Janus Kinase), MAdCAM-1 (Mucosal Addressin Cell Adhesion Molecule-1), PC (Phosphatidylcholine), PML (Progressive Multifocal Leukoencephalopahty), SCCAI (Simple Clinical Colitis Activity Index), SMAD (Similar to Mothers against Decapentaplegic), TECK (Thymus-Expressed Chemokine), TGF (Transforming Growth Factor), Th (T helper), TNF (Tumor Necrosis Factor), UC (Ulcerative Colitis)
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