Shared Genetics in Celiac Disease and Inflammatory Bowel Disease Specify a Greater Role for Intestinal Epithelial Cells
Abstract
1. Introduction
2. Intestinal Barrier Disfunction in CeD and IBD
3. Genes in Shared CeD and IBD Loci Contribute to Intestinal Epithelial Barrier Function
3.1. IECs as Non-Conventional Antigen-Presenting Cells
3.2. Regulation of Immune Response in IECs
3.3. IECs Express T-Cell-Regulating Genes
3.4. Interferon Signaling Genes in IECs
3.5. Genetic Impact on Intestinal Epithelial Cell Differentiation
4. Conclusions and Future Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
CeD | Celiac disease |
IBD | Inflammatory bowel disease |
CD | Chron’s disease |
UC | Ulcerative colitis |
IEC | Intestinal epithelial cell |
IEL | Intraepithelial lymphocyte |
Appendix A
Glossary
- Apicobasal polarity: Cell polarity of epithelial cells in the intestine. The apical side faces the lumen. The basolateral side faces the lamina propria.
- cis-expression Quantitative Trait Locus (cis-eQTL): A genomic locus that affects the expression of a gene located nearby in the genome.
- Crypt hyperplasia: Elongation of the intestinal crypt.
- Dysbiosis: Disruption in the body’s microbiota composition and/or function.
- Enhancer: A DNA region to which transcription factors can bind to regulate the genes with which they interact.
- Epitope: Part of an antigen molecule that is recognized by the immune system.
- Genome-Wide Association Study (GWAS): Observational study that looks at the whole genome of individuals to identify genetic variation associated with a trait.
- Gliadin: Protein component of gluten and main trigger of CeD. Deaminated gliadin is recognized by HLA-QD2/8 and presented to gluten-specific CD4+ T cells.
- Gluten: A group of proteins naturally found in cereal grains such as wheat, barley, and rye
- Haploinsufficiency: When one copy of a gene is inactivated or deleted and the remaining functional copy is not enough to maintain normal function.
- HLA: The group of genes that encode cell-surface proteins of the major histocompatibility complexes (MHC) that are responsible for the presentation of antigens.
- Ileitis: Inflammation of the ileum, the last part of the small intestine.
- JAK-STAT: A highly conserved signal transduction pathway involved in cell division, cell death, inflammation response, and carcinogenesis. This pathway responds to stimuli by cytokines and growth factors.
- Locus: (Plural: Loci), A genomic locus is a specific region of the genome that is defined based on an area of interest, such as a transcribed RNA, a single exon, or a region associated with differences in expression. It is typically chosen to encompass the feature of interest while minimizing the inclusion of unrelated genomic regions.
- M-like cell: Microfold cells (M cells) are epithelial cells specialized in antigen uptake that are found in the Peyer’s patches of the small intestine and the mucosa-associated lymphoid tissue along the gastrointestinal tract.
- Monogenic: Describes a genetic trait that is influenced only by one gene.
- NETosis: A type of cell death mediated by neutrophils that release a web-like structure made of DNA and bactericidal proteins.
- NLRP3 inflammasome: Component of the innate immune system that mediates caspase activation and release of proinflammatory cytokines in response to microbial infection and cellular damage.
- Over-representation analysis: A statistical method to determine whether a predefined gene set is present more than would be expected by chance in a subset of genes.
- Polygenic: Describes a genetic trait that is influenced by two or more genes.
- Promoter: A DNA region to which regulatory proteins bind to initiate RNA transcription of a gene.
- Pyroptosis: A type of programmed cell death that leads to cell lysis and release of inflammatory signal. Pyroptosis is less controlled than apoptosis.
- Single nucleotide polymorphism (SNP): A variation in a single nucleotide at a specific position in the genome.
- Stricturing: An abnormal narrowing of a bodily passage.
Appendix B
Immunopathology of Celiac Disease and Inflammatory Bowel Disease
- Celiac Disease (CeD): An autoimmune disorder that affects the small intestine. In CeD patients, gluten-derived peptides initiate a cascade of immune reactions. HLA-DQ2 or -DQ8 encoded MHC class II receptors on the surface of antigen-presenting cells present the peptides to gluten-specific CD4+ T cells, which then produce elevated levels of proinflammatory cytokines including IFN-γ and IL-21 [102]. Subsequently, plasma cells are generated, producing anti-gliadin and anti-tissue transglutaminase antibodies (Figure A1). Gliadin may also interact directly with intestinal cells and impair tight junctions, increasing gut permeability [103]. Another hallmark of CeD is the accumulation of activated CD8+ intraepithelial lymphocytes (IELs), which kill intestinal epithelial cells [104]. All these immune activities eventually cause villus atrophy and crypt hyperplasia, leading to intestinal and extra-intestinal symptoms.
- Inflammatory Bowel Disease (IBD): A chronic inflammatory condition comprising two clinical features: Crohn’s disease (CD) and ulcerative colitis (UC). Although the exact trigger for IBD is unknown, genetics, gut microbiota, other environmental factors, and immunological abnormalities all likely contribute to the disease. IBD is marked by episodes of abdominal pain, diarrhea, bloody stools, weight loss, and the infiltration of neutrophils and macrophages. Immune cells produce cytokines, proteolytic enzymes, and free radicals, leading to inflammation and ulceration [105]. Despite common features between CD and UC, there are several distinct pathophysiological attributes. CD can occur anywhere in the intestine, in a discontinuous pattern, whereas UC is restricted to the large intestine in a continuous pattern [105]. In contrast to CD, which is primarily Th1-/Th17-driven with an elevated expression of major cytokines like IL-12, IL-23, IFN-γ, and IL-17, UC is more associated with a Th2/Th9 response and their cytokines, including IL-13, IL-5, and IL-9 [106,107] (Figure A1). However, these Th cell types are not exclusive to UC or CD and may be present in both. Another important IBD hallmark is that the composition of the gut microbiota is altered, influencing gut homeostasis [108].
Appendix C
Intestinal Epithelial Cell Barrier
Appendix D
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Gene | Function 1 | Differential Expression Status in Epithelial Cells | SNPs with cis-eQTL Effect | ||
---|---|---|---|---|---|
CeD 2 | IBD 3 | CeD | IBD | ||
TAPBPL | Links MHC I molecules to TAP transporter | ||||
HLA-DQA2 | Antigen-presentation via MHC class II | ||||
HLA-DRB5 | Antigen-presentation via MHC class II | Down [26] | Up [25,27] | rs424232 [28] | rs3135005, rs693797, rs9267911 [28] |
HLA-DRB1 | Antigen-presentation via MHC class II | Up [27] | |||
HLA-DQA1 | Antigen-presentation via MHC class II | Down [26] | Up (7) | rs3135005, rs9268403, rs693797 [28] | |
TNFRSF14 | TNF receptor superfamily | Down [27] | |||
IL10 | Immunoregulatory cytokine | Up [26] | |||
ZMIZ1 | Transcriptional coactivator | Up [27] | rs1250567 [26] | ||
ETS1 | Transcription factor | ||||
SH2B3 | Negative regulator of cytokine signaling | Down [26], Up [29] | |||
EFNB2 | Ephrin receptor | Up [27] | |||
SOCS1 | Negative regulator of interferon signaling | Up [27] | |||
PTPN2 | Protein tyrosine phosphatase (signaling) | Down [27] | |||
TYK2 | Tyrosine kinase (signaling) | ||||
IRF1 | Transcription factor of interferon genes | Up [26,30,31] | Up [27] | ||
NOTCH4 | Membrane receptor of Notch signaling | ||||
CDC37 | Molecular chaperone | Down [27,32] | |||
STAT1 | Signal transducer in response to interferon | Up [26,30,31] | Up [25,27,32] | ||
HES5 | Transcription repressor | ||||
TNFRSF1A | TNF receptor superfamily | Up [32] | rs2364484 [26] | ||
DENND1B | Regulates T-cell receptor internalization | Up [27] | |||
INAVA/C1ORF106 | Cytokine production, adherens junctions | ||||
MAPKAPK2 | Stress-activated serine/threonine-protein kinase | ||||
SPHK2 | Catalyzes the phosphorylation of sphingosine | ||||
AGPAT1 | Converts lysophosphatidic acid into phosphatidic acid | Up [27] | |||
GPSM3 | Regulator of GTPase activity | Up [32] | |||
REL | Proto-oncogene involved in lymphopoiesis | Down [27] | |||
GSDMB | Pore-forming protein | Up [27] | rs2305480, rs2872507, rs10852936, rs2305479, rs11557467, rs12950743, rs8067378 [28] | rs8069176, rs2305480, rs2872507, rs10852936, rs2305479, rs10445308, rs11557467, rs12950743, rs8067378, rs4795405, rs3902025, rs11078927 [28,33,34] | |
SEH1L | Component of nuclear pore complex | ||||
CCR5 | Beta chemokine receptor family | ||||
SLC22A5 | Cation transporter | Down [26] | Down [27] | ||
RNF5 | Membrane-bound ubiquitin ligase | Down [27] | |||
KEAP1 | Sensor of oxidative stress | ||||
SULT2B1 | Sulfation of cholesterol | Down [26] | Up (colon), Down (ileum) [27] | ||
LTBR | TNF receptor superfamily | Down [27] | rs10849448 [35], rs2364480, rs9669611, rs12354 [28], rs2364484 [26,28] | ||
LURAP1L | Regulation of NFkB signaling | ||||
GPR35 | G-protein coupled receptor | Down [26] | Down [27] | ||
CCRL2 | Chemokine receptor |
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Ribeiro, N.V.; Anwar, S.; Withoff, S.; Jonkers, I.H. Shared Genetics in Celiac Disease and Inflammatory Bowel Disease Specify a Greater Role for Intestinal Epithelial Cells. Int. J. Mol. Sci. 2025, 26, 2982. https://doi.org/10.3390/ijms26072982
Ribeiro NV, Anwar S, Withoff S, Jonkers IH. Shared Genetics in Celiac Disease and Inflammatory Bowel Disease Specify a Greater Role for Intestinal Epithelial Cells. International Journal of Molecular Sciences. 2025; 26(7):2982. https://doi.org/10.3390/ijms26072982
Chicago/Turabian StyleRibeiro, Nathan Vinícius, Sajid Anwar, Sebo Withoff, and Iris H. Jonkers. 2025. "Shared Genetics in Celiac Disease and Inflammatory Bowel Disease Specify a Greater Role for Intestinal Epithelial Cells" International Journal of Molecular Sciences 26, no. 7: 2982. https://doi.org/10.3390/ijms26072982
APA StyleRibeiro, N. V., Anwar, S., Withoff, S., & Jonkers, I. H. (2025). Shared Genetics in Celiac Disease and Inflammatory Bowel Disease Specify a Greater Role for Intestinal Epithelial Cells. International Journal of Molecular Sciences, 26(7), 2982. https://doi.org/10.3390/ijms26072982