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      Organoid-based Models to Study the Role of Host-microbiota Interactions in IBD

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          Abstract

          The gut microbiota appears to play a central role in health, and alterations in the gut microbiota are observed in both forms of inflammatory bowel disease [IBD], namely Crohn’s disease and ulcerative colitis. Yet, the mechanisms behind host-microbiota interactions in IBD, especially at the intestinal epithelial cell level, are not yet fully understood. Dissecting the role of host-microbiota interactions in disease onset and progression is pivotal, and requires representative models mimicking the gastrointestinal ecosystem, including the intestinal epithelium, the gut microbiota, and immune cells. New advancements in organoid microfluidics technology are facilitating the study of IBD-related microbial-epithelial cross-talk, and the discovery of novel microbial therapies. Here, we review different organoid-based ex vivo models that are currently available, and benchmark their suitability and limitations for specific research questions. Organoid applications, such as patient-derived organoid biobanks for microbial screening and ’omics technologies, are discussed, highlighting their potential to gain better mechanistic insights into disease mechanisms and eventually allow personalised medicine.

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          Most cited references180

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          Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche.

          The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We have recently demonstrated the presence of about six cycling Lgr5(+) stem cells at the bottoms of small-intestinal crypts. Here we describe the establishment of long-term culture conditions under which single crypts undergo multiple crypt fission events, while simultanously generating villus-like epithelial domains in which all differentiated cell types are present. Single sorted Lgr5(+) stem cells can also initiate these cryptvillus organoids. Tracing experiments indicate that the Lgr5(+) stem-cell hierarchy is maintained in organoids. We conclude that intestinal cryptvillus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.
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            Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium.

            We previously established long-term culture conditions under which single crypts or stem cells derived from mouse small intestine expand over long periods. The expanding crypts undergo multiple crypt fission events, simultaneously generating villus-like epithelial domains that contain all differentiated types of cells. We have adapted the culture conditions to grow similar epithelial organoids from mouse colon and human small intestine and colon. Based on the mouse small intestinal culture system, we optimized the mouse and human colon culture systems. Addition of Wnt3A to the combination of growth factors applied to mouse colon crypts allowed them to expand indefinitely. Addition of nicotinamide, along with a small molecule inhibitor of Alk and an inhibitor of p38, were required for long-term culture of human small intestine and colon tissues. The culture system also allowed growth of mouse Apc-deficient adenomas, human colorectal cancer cells, and human metaplastic epithelia from regions of Barrett's esophagus. We developed a technology that can be used to study infected, inflammatory, or neoplastic tissues from the human gastrointestinal tract. These tools might have applications in regenerative biology through ex vivo expansion of the intestinal epithelia. Studies of these cultures indicate that there is no inherent restriction in the replicative potential of adult stem cells (or a Hayflick limit) ex vivo. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
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              Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

              Crohn’s disease (CD) and ulcerative colitis (UC), the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry with rising prevalence in other populations 1 . Genome-wide association studies (GWAS) and subsequent meta-analyses of CD and UC 2,3 as separate phenotypes implicated previously unsuspected mechanisms, such as autophagy 4 , in pathogenesis and showed that some IBD loci are shared with other inflammatory diseases 5 . Here we expand knowledge of relevant pathways by undertaking a meta-analysis of CD and UC genome-wide association scans, with validation of significant findings in more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional and balancing selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe striking overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
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                Author and article information

                Journal
                J Crohns Colitis
                J Crohns Colitis
                eccojc
                Journal of Crohn's & Colitis
                Oxford University Press (UK )
                1873-9946
                1876-4479
                July 2021
                20 December 2020
                20 December 2020
                : 15
                : 7
                : 1222-1235
                Affiliations
                [1 ] Earlham Institute, Norwich Research Park , Norwich, UK
                [2 ] Quadram Institute, Norwich Research Park , Norwich, UK
                [3 ] Department of Chronic Diseases, Metabolism and Ageing [CHROMETA], Translational Research Center for Gastrointestinal Disorders [TARGID], KU Leuven , Leuven, Belgium
                [4 ] Department of Development and Regeneration, Stem Cell Institute Leuven [SCIL], KU Leuven , Leuven, Belgium
                [5 ] Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven , Leuven, Belgium
                Author notes
                Corresponding author: Marc Ferrante, MD, PhD, Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. Tel.: +32 16 344225; email: marc.ferrante@ 123456uzleuven.be

                These authors contributed equally.

                Article
                jjaa257
                10.1093/ecco-jcc/jjaa257
                8256633
                33341879
                45c49444-2041-4379-be86-381e619d627c
                © The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 04 February 2021
                Page count
                Pages: 14
                Funding
                Funded by: Research Foundation Flanders, DOI 10.13039/501100003130;
                Award ID: 1S49419N
                Funded by: CREA, DOI 10.13039/100015761;
                Award ID: CREA/12/031
                Funded by: European Crohn's and Colitis Organisation;
                Award ID: ZKC4621/10143459
                Funded by: Belgian IBD Research and Development [BIRD];
                Funded by: Earlham Institute;
                Funded by: Quadram Institute;
                Funded by: BBSRC, DOI 10.13039/501100000268;
                Award ID: BB/J004529/1
                Award ID: BB/P016774/1
                Award ID: BB/CSP17270/1
                Funded by: Gut Microbes and Health;
                Award ID: BB/R012490/1
                Award ID: BBS/E/F/000PR10353,
                Award ID: BBS/E/F/000PR10355
                Funded by: BBSRC Norwich Research Park Biosciences;
                Award ID: BB/M011216/1
                Categories
                Review Articles
                AcademicSubjects/MED00260

                inflammatory bowel disease,microbiota,organoids, in vitro models

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