6 WORLD GASTROENTEROLOGY NEWS OCTOBER 2014 Editorial | Expert Point of View | Gastro 2015: AGW/WGO | WDHD News | WGO & WGOF News | WGO Global Guidelines | Calendar of Events Mini Guts – Human Stem-Cell Derived Organoids as Tools to Study Epithelial Properties Michael Schultz, MD Department of Medicine Dunedin School of Medicine University of Otago Dunedin, New Zealand The surfaces of the body are lined by epithelia that form a barrier between the human body and the outside, the environment. This barrier is of particular importance in the gastro-intestinal tract, which is the largest barrier in the body and through sophisticated mechanisms main-tains a delicate homeostasis between absorption, secretion, tolerance and defense. This is especially true in the colon, and to a lesser extent the small intestine, both of which are adapted for colonization by bacteria. These bacteria have a number of beneficial effects on the host, but at the same time pose a serious threat of infection or inflammation if the intestinal bar-rier is compromised (1). This intestinal epithelium forms both a physical and biochemical bar-rier to commensal and pathogenic mi-croorganisms. The intestinal epithelial cells (IECs) and the dynamic network of tight junctions that connect them physically limit the entry of bacteria into the body, while the mucus and antimicrobial peptides secreted by the IECs further limit contact with the mucosal surface and translocation of bacteria by ensuring that the surface of the epithelium remains sterile. This barrier is not static and IECs respond to the luminal bacteria. This involves a range of pattern recogni-tion receptors (PRRs), such as the toll-like receptors (TLR), NOD like receptors (NLRs) and RIG like recep-tors (RLRs), which sense a variety of conserved molecular patterns (PAMP, pathogen associated molecular pat-terns) found in both commensal and pathogenic bacteria. The result can be varied with acute changes in the amount and composition of antimi-crobial peptides secreted, increased mucus secretion and modulation of the proteins in the tight junctions, all of which contribute to strengthen-ing the barrier. In addition, the IECs participate in the co-ordination of the appropriate immune responses, rang-ing from tolerance to anti pathogen immunity. In IBD, the microbiome as well as the gut-associated immune system (GALT) and the underlying genomic background has been easily assessable and therefore subject to great scientific scrutiny, leading amongst other things to the development of targeted thera-pies that have significantly increased and also refined treatment options for patients (2). In contrast our knowl-edge of the underlying pathomecha-nisms concerning the epithelial barrier that contribute to the development of IBD and other gut-related disorders is still patchy. This is due to a lack of individualized epithelial cell lines that would provide insight into the mo-lecular functions on epithelial level of the 160+ susceptibility genes for IBD. In the following, we will discuss the difficulties and recent milestones that have led to the development of a novel research tool that allows the study of epithelial barrier function in the absence of confounding variables introduced by bacteria and immune cells. The study of the human epithelium is pivotal in the understanding of processes that may lead to gut-related disorders. Recent studies indicate that dysregulation of this barrier, either through disruption of the barrier or modified host-microbial interaction, may contribute to a range of extra-intestinal autoimmune and inflam-matory conditions. However, the fundamental question regarding cause or consequence of barrier dysregula-tion in relation to the pathogenesis of these disorders remains to be an-swered. Involvement of the intestinal epithelial barrier has been shown in a variety of diseases, including type I diabetes, rheumatoid arthritis and multiple sclerosis (1). In particular, the association between increased bacterial translocation and the risk of developing inflammatory bowel disease (IBD) implicates dysregulaton A. Grant Butt, MD Department of Physiology University of Otago Dunedin, New Zealand
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