11
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Human gut derived-organoids provide model to study gluten response and effects of microbiota-derived molecules in celiac disease

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Celiac disease (CD) is an immune-mediated disorder triggered by gluten exposure. The contribution of the adaptive immune response to CD pathogenesis has been extensively studied, but the absence of valid experimental models has hampered our understanding of the early steps leading to loss of gluten tolerance. Using intestinal organoids developed from duodenal biopsies from both non-celiac (NC) and celiac (CD) patients, we explored the contribution of gut epithelium to CD pathogenesis and the role of microbiota-derived molecules in modulating the epithelium’s response to gluten. When compared to NC, RNA sequencing of CD organoids revealed significantly altered expression of genes associated with gut barrier, innate immune response, and stem cell functions. Monolayers derived from CD organoids exposed to gliadin showed increased intestinal permeability and enhanced secretion of pro-inflammatory cytokines compared to NC controls. Microbiota-derived bioproducts butyrate, lactate, and polysaccharide A improved barrier function and reduced gliadin-induced cytokine secretion. We concluded that: (1) patient-derived organoids faithfully express established and newly identified molecular signatures characteristic of CD. (2) microbiota-derived bioproducts can be used to modulate the epithelial response to gluten. Finally, we validated the use of patient-derived organoids monolayers as a novel tool for the study of CD.

          Related collections

          Most cited references51

          • Record: found
          • Abstract: found
          • Article: not found

          Isolation and in vitro expansion of human colonic stem cells.

          Here we describe the isolation of stem cells of the human colonic epithelium. Differential cell surface abundance of ephrin type-B receptor 2 (EPHB2) allows the purification of different cell types from human colon mucosa biopsies. The highest EPHB2 surface levels correspond to epithelial colonic cells with the longest telomeres and elevated expression of intestinal stem cell (ISC) marker genes. Moreover, using culturing conditions that recreate the ISC niche, a substantial proportion of EPHB2-high cells can be expanded in vitro as an undifferentiated and multipotent population.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient-based assays.

            The technology for the growth of human intestinal epithelial cells is rapidly progressing. An exciting possibility is that this system could serve as a platform for individualised medicine and research. However, to achieve this goal, human epithelial culture must be enhanced so that biopsies from individuals can be used to reproducibly generate cell lines in a short time frame so that multiple, functional assays can be performed (ie, barrier function and host-microbial interactions).
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Cell Biology of Tight Junction Barrier Regulation and Mucosal Disease.

              Mucosal surfaces are lined by epithelial cells. In the intestine, the epithelium establishes a selectively permeable barrier that supports nutrient absorption and waste secretion while preventing intrusion by luminal materials. Intestinal epithelia therefore play a central role in regulating interactions between the mucosal immune system and luminal contents, which include dietary antigens, a diverse intestinal microbiome, and pathogens. The paracellular space is sealed by the tight junction, which is maintained by a complex network of protein interactions. Tight junction dysfunction has been linked to a variety of local and systemic diseases. Two molecularly and biophysically distinct pathways across the intestinal tight junction are selectively and differentially regulated by inflammatory stimuli. This review discusses the mechanisms underlying these events, their impact on disease, and the potential of using these as paradigms for development of tight junction-targeted therapeutic interventions.
                Bookmark

                Author and article information

                Contributors
                ssenger@mgh.harvard.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                7 May 2019
                7 May 2019
                2019
                : 9
                : 7029
                Affiliations
                [1 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Mucosal Immunology and Biology Research Center and Center for Celiac Research and Treatment, Department of Pediatrics, , Massachusetts General Hospital, ; Boston, MA USA
                [2 ]ISNI 000000041936754X, GRID grid.38142.3c, Harvard Medical School, ; Boston, MA USA
                [3 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Department of Molecular Biology, , Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, ; Boston, MA USA
                [4 ]GRID grid.430126.2, Present Address: PatientsLikeMe, Inc., ; Cambridge, MA USA
                [5 ]ISNI 0000 0004 0447 7762, GRID grid.419849.9, Present Address: Translational Research and Early Clinical (TREC), , GI, Takeda Pharmaceuticals International Co., ; Boston, MA USA
                [6 ]European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy
                Article
                43426
                10.1038/s41598-019-43426-w
                6505524
                31065051
                92983210-a8fc-4b4a-b3cf-850e3b5cfe75
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 4 November 2018
                : 24 April 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000062, U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases);
                Award ID: RO1DK104344
                Award ID: 1U19AI082655
                Award ID: RO1DK104344
                Award ID: 1U19AI082655
                Award ID: RO1DK104344
                Award ID: 1U19AI082655
                Award ID: RO1DK104344
                Award ID: 1U19AI082655
                Award ID: 1U19AI082655
                Award ID: RO1DK104344
                Award Recipient :
                Funded by: Egan Family Foundation
                Categories
                Article
                Custom metadata
                © The Author(s) 2019

                Uncategorized
                intestinal stem cells,coeliac disease
                Uncategorized
                intestinal stem cells, coeliac disease

                Comments

                Comment on this article