Intestinal enteroids/organoids: A novel platform for drug discovery in inflammatory bowel diseases

World J Gastroenterol. 2019 Aug 14;25(30):4125-4147. doi: 10.3748/wjg.v25.i30.4125.

Abstract

The introduction of biologics such as anti-tumor necrosis factor (TNF) monoclonal antibodies followed by anti-integrins has dramatically changed the therapeutic paradigm of inflammatory bowel diseases (IBD). Furthermore, a newly developed anti-p40 subunit of interleukin (IL)-12 and IL-23 (ustekinumab) has been recently approved in the United States for patients with moderate to severe Crohn's disease who have failed treatment with anti-TNFs. However, these immunosuppressive therapeutics which focus on anti-inflammatory mechanisms or immune cells still fail to achieve long-term remission in a significant percentage of patients. This strongly underlines the need to identify novel treatment targets beyond immune suppression to treat IBD. Recent studies have revealed the critical role of intestinal epithelial cells (IECs) in the pathogenesis of IBD. Physical, biochemical and immunologic driven barrier dysfunctions of epithelial cells contribute to the development of IBD. In addition, the recent establishment of adult stem cell-derived intestinal enteroid/organoid culture technology has allowed an exciting opportunity to study human IECs comprising all normal epithelial cells. This long-term epithelial culture model can be generated from endoscopic biopsies or surgical resections and recapitulates the tissue of origin, representing a promising platform for novel drug discovery in IBD. This review describes the advantages of intestinal enteroids/organoids as a research tool for intestinal diseases, introduces studies with these models in IBD, and gives a description of the current status of therapeutic approaches in IBD. Finally, we provide an overview of the current endeavors to identify a novel drug target for IBD therapy based on studies with human enteroids/organoids and describe the challenges in using enteroids/organoids as an IBD model.

Keywords: Crohn’s disease; Enteroids; Inflammatory bowel diseases; Organoids; Ulcerative colitis.

Publication types

  • Review

MeSH terms

  • Biological Products / pharmacology
  • Biological Products / therapeutic use
  • Biopsy
  • Drug Discovery / methods*
  • Drug Evaluation, Preclinical / methods
  • Epithelial Cells
  • Humans
  • Immunosuppressive Agents / pharmacology*
  • Immunosuppressive Agents / therapeutic use
  • Induced Pluripotent Stem Cells
  • Inflammatory Bowel Diseases / drug therapy*
  • Inflammatory Bowel Diseases / immunology
  • Inflammatory Bowel Diseases / pathology
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / immunology
  • Organoids / drug effects*
  • Organoids / immunology
  • Primary Cell Culture / methods

Substances

  • Biological Products
  • Immunosuppressive Agents