Human gut derived-organoids provide model to study gluten response and effects of microbiota-derived molecules in celiac disease
Open Access
- 7 May 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 9 (1), 1-15
- https://doi.org/10.1038/s41598-019-43426-w
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.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (RO1DK104344, 1U19AI082655, RO1DK104344, 1U19AI082655, RO1DK104344, 1U19AI082655, RO1DK104344, 1U19AI082655, 1U19AI082655, RO1DK104344)
- Egan Family Foundation
This publication has 86 references indexed in Scilit:
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- IL-37 is a fundamental inhibitor of innate immunityNature Immunology, 2010
- Inducible Foxp3 + regulatory T-cell development by a commensal bacterium of the intestinal microbiotaProceedings of the National Academy of Sciences of the United States of America, 2010
- edgeR: a Bioconductor package for differential expression analysis of digital gene expression dataBioinformatics, 2009
- Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2Proceedings of the National Academy of Sciences of the United States of America, 2009
- Gliadin Induces an Increase in Intestinal Permeability and Zonulin Release by Binding to the Chemokine Receptor CXCR3Gastroenterology, 2008
- Analyzing real-time PCR data by the comparative CT methodNature Protocols, 2008
- Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammationThe Journal of Experimental Medicine, 2008
- A bacterial carbohydrate links innate and adaptive responses through Toll-like receptor 2The Journal of Experimental Medicine, 2006
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005