Function of the intestinal epithelium and its dysregulation in inflammatory bowel disease

2011 ◽  
Vol 17 (1) ◽  
pp. 382-395 ◽  
Author(s):  
Paul Henderson ◽  
Johan E. van Limbergen ◽  
Jürgen Schwarze ◽  
David C. Wilson
Keyword(s):  
Inflammatory Bowel Disease ◽  
Intestinal Epithelium ◽  
Bowel Disease ◽  
Inflammatory Bowel

P140 3D BIOENGINEERED TISSUE MODEL OF THE LARGE INTESTINE TO STUDY INFLAMMATORY BOWEL DISEASE

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S34-S35
Author(s):  
Terrence Roh ◽  
Ying Chen ◽  
Harry Paul ◽  
Chengchen Guo ◽  
David Kaplan
Keyword(s):  
Inflammatory Bowel Disease ◽  
Large Intestine ◽  
Intestinal Epithelium ◽  
Bowel Disease ◽  
Tissue Model ◽  
Inflammatory Bowel ◽  
Silk Scaffold ◽  
Subepithelial Layer ◽  
Migration Of Macrophages

Abstract An in vitro model of intestine epithelium with an immune compartment was bioengineered to mimic immunologic responses seen in inflammatory bowel disease [1]. While aspects of intestinal immunity can be modeled in transwells and 2D culture systems, 3D tissue models improve physiological relevance by providing a 3D substrate which enable migration of macrophages towards the epithelium. An intestinal epithelium comprised of non-transformed human colon organoid cells and a subepithelial layer laden with monocyte-derived macrophages was bioengineered to mimic native intestinal mucosa cell organization using spongy silk scaffolds. Confluent epithelial monolayers with microvilli, a mucus layer, and infiltration of macrophages to the basal side of the epithelium were observed. Inflammation, induced by E. coli O111:B4 lipopolysaccharide and interferon γ resulted in morphology changes to the epithelium, resulting in ball-like structures, decreased epithelial coverage, and migration of macrophages to the epithelium. Analysis of cytokines present in the inflamed tissue model demonstrated significantly upregulated secretion of pro-inflammatory cytokines associated with active inflammatory bowel disease, including CXCL10, IL-1β, IL-6, MCP-2, and MIP-1β. The macrophage layer enhanced epithelial and biochemical responses to inflammatory stimuli, and this new tissue system may be useful to study and develop potential therapies for inflammatory bowel disease. References: 6 Roh, T.T., et al., 3D bioengineered tissue model of the large intestine to study inflammatory bowel disease. Biomaterials, 2019: p. 119517. 7 In, J., et al., Enterohemorrhagic Escherichia coli reduce mucus and intermicrovillar bridges in human stem cell-derived colonoids. Cellular and molecular gastroenterology and hepatology, 2015. 2(1): p. 48–62.e3. 8 Chen, Y., et al., In vitro enteroid-derived three-dimensional tissue model of human small intestinal epithelium with innate immune responses. PLoS ONE, 2017. 12(11): p. e0187880. Colonoid and macrophage cultivation scheme in the 3D bilayer system. (A) Human monocytes were isolated from whole blood and human colonoids from large intestine biopsies were cultured according to established protocols [2]. (B) Cell suspensions of colonoids were seeded on the film surface on the inner silk scaffold and monocyte-derived macrophages were seeded throughout the porous outer silk scaffold using established protocols [3]. (C) The model is cultured for 3 weeks total with 2 weeks in High WNT media and 1 week in differentiation media based on established protocol. Colonoids are present in the model throughout the 3 week culture time. 2 sets of macrophages are added with the first set added after the first week of culture and the second set replacing the first set after the second week.

scholarly journals Differential Alteration in Intestinal Epithelial Cell Expression of Toll-Like Receptor 3 (TLR3) and TLR4 in Inflammatory Bowel Disease

2000 ◽  
Vol 68 (12) ◽  
pp. 7010-7017 ◽  
Author(s):  
Elke Cario ◽  
Daniel K. Podolsky
Keyword(s):  
Inflammatory Bowel Disease ◽  
Epithelial Cell ◽  
Intestinal Epithelium ◽  
Bowel Disease ◽  
Intestinal Epithelial Cell ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Innate Response ◽  
Response System ◽  
Inflammatory Bowel

ABSTRACT Initiation and perpetuation of the inflammatory intestinal responses in inflammatory bowel disease (IBD) may result from an exaggerated host defense reaction of the intestinal epithelium to endogenous lumenal bacterial flora. Intestinal epithelial cell lines constitutively express several functional Toll-like receptors (TLRs) which appear to be key regulators of the innate response system. The aim of this study was to characterize the expression pattern of TLR2, TLR3, TLR4, and TLR5 in primary intestinal epithelial cells from patients with IBD. Small intestinal and colonic biopsy specimens were collected from patients with IBD (Crohn's disease [CD], ulcerative colitis [UC]) and controls. Non-IBD specimens were assessed by immunofluorescence histochemistry using polyclonal antibodies specific for TLR2, TLR3, TLR4, and TLR5. Primary intestinal epithelial cells (IEC) of normal mucosa constitutively expressed TLR3 and TLR5, while TLR2 and TLR4 were only barely detectable. In active IBD, the expression of TLR3 and TLR4 was differentially modulated in the intestinal epithelium. TLR3 was significantly downregulated in IEC in active CD but not in UC. In contrast, TLR4 was strongly upregulated in both UC and CD. TLR2 and TLR5 expression remained unchanged in IBD. These data suggest that IBD may be associated with distinctive changes in selective TLR expression in the intestinal epithelium, implying that alterations in the innate response system may contribute to the pathogenesis of these disorders.

P148 COLONIC SPROUTY2 IS ELEVATED IN INFLAMMATORY BOWEL DISEASE PATIENTS

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S28-S29
Author(s):  
Keren Appel ◽  
Michael Schumacher ◽  
Mark Frey
Keyword(s):  
Inflammatory Bowel Disease ◽  
Surgical Resection ◽  
Intestinal Epithelium ◽  
Bowel Disease ◽  
Primary Cultures ◽  
Secretory Cells ◽  
Cell Markers ◽  
Endoscopic Biopsies ◽  
Tuft Cell ◽  
Inflammatory Bowel

Abstract Background The intestinal epithelium plays a central role in protecting against the development of colitis, and is disrupted in inflammatory bowel disease (IBD). It serves as the physical barrier that, when breached, allows luminal contents (i.e. bacteria, antigens) to stimulate inflammatory responses. Sprouty2 (SPRY2) is an intracellular regulator of growth factor receptor signaling that is downregulated in a compensatory response to inflammatory stimuli in cell lines and a mouse model of colitis. Additionally, mice with intestine-specific Spry2 deletion are protected against colitis and have elevated tuft and goblet cell numbers, cell types thought to protect the intestinal epithelium. This may represent a feedback mechanism to reinforce the intestinal epithelium during the initial stages of injury. However, the regulation of SPRY2 in IBD patients is unknown. We hypothesized that SPRY2 expression might be dysregulated in patients with IBD. Methods SPRY2 levels were measured by quantitative PCR analysis of human colonic tissue from endoscopic biopsies and surgical resection specimens from pediatric IBD and non-IBD patients. Human colonoids (primary cultures of colonic epithelium) were grown from surgical resection specimens of non-IBD control patients. SPRY2 expression was measured via qPCR in response to treatment with TNF for 24 hrs. Results SPRY2 expression decreased by an average of 24.41% (p = 0.0002, n =4) in colonoids from non-IBD patients treated with tumor necrosis factor (TNF) 10 ng/mL and 18.13% (p = 0.0016) for 100 ng/mL. However, SPRY2 expression in endoscopic biopsies from IBD patients was 2.325 ± 0.9846 fold higher in ulcerative colitis (UC) patients (p= 0.0242, n =8) and 9.825 ± 2.800 fold higher in Crohn’s disease patients (p= 0.0014, n=6) compared to non-IBD controls (n=27). In surgical specimens, SPRY2 levels were 37.10 ± 21.96 (p= 0.0459) fold higher in IBD (n=6) vs. non-IBD (n=4) patients. Furthermore, data mining of Gene Expression Omnibus dataset GDS3268 (biopsies from UC patients) revealed a significant negative correlation between SPRY2 and the protective tuft cell markers DCLK1 and TRPM5. Conclusion Acute TNF signaling repressed SPRY2 expression in a human colonoid model. In contrast, SPRY2 levels appear to be increased in human IBD and negatively correlate with tuft cell markers. Together these data suggest that, while acute inflammation can downregulate SPRY2 to drive increased numbers of protective secretory cells, in chronic disease this response either does not occur or is lost. A failure to down-regulate SPRY2 in response to early mucosal damage may be a factor in the development of IBD.

scholarly journals Telomere dysfunction instigates inflammation in inflammatory bowel disease

2021 ◽  
Vol 118 (29) ◽  
pp. e2024853118
Author(s):  
Deepavali Chakravarti ◽  
Rumi Lee ◽  
Asha S. Multani ◽  
Andrea Santoni ◽  
Zachery Keith ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Dna Damage ◽  
Intestinal Epithelium ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Telomere Maintenance ◽  
Intestinal Biopsy ◽  
Telomere Dysfunction ◽  
Chronic Inflammatory Condition ◽  
Inflammatory Bowel

Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Here, we sought to determine the relevance of the ATM/YAP1/pro-IL-18 pathway as a potential driver of IBD, particularly older-onset IBD. Analysis of intestinal biopsy specimens and organoids from older-onset IBD patients documented the presence of telomere dysfunction and activation of the ATM/YAP1/precursor of interleukin 18 (pro-IL-18) pathway in the intestinal epithelium. Employing intestinal organoids from healthy individuals, we demonstrated that experimental induction of telomere dysfunction activates this inflammatory pathway. In organoid models from ulcerative colitis and Crohn’s disease patients, pharmacological interventions of telomerase reactivation, suppression of DNA damage signaling, or YAP1 inhibition reduced pro-IL-18 production. Together, these findings support a model wherein telomere dysfunction in the intestinal epithelium can initiate the inflammatory process in IBD, pointing to therapeutic interventions for this disease.

scholarly journals HIF-Dependent NFATC1 Activation Upregulates ITGA5 and PLAUR in Intestinal Epithelium in Inflammatory Bowel Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Evgeny Knyazev ◽  
Diana Maltseva ◽  
Maria Raygorodskaya ◽  
Maxim Shkurnikov
Keyword(s):  
Inflammatory Bowel Disease ◽  
Rna Sequencing ◽  
Intestinal Epithelium ◽  
Bowel Disease ◽  
Intestinal Epithelial Cells ◽  
Core Gene ◽  
Intestinal Epithelial ◽  
Gene Set ◽  
The Core ◽  
Inflammatory Bowel

Intestinal epithelial cells exist in physiological hypoxia, leading to hypoxia-inducible factor (HIF) activation and supporting barrier function and cell metabolism of the intestinal epithelium. In contrast, pathological hypoxia is a common feature of some chronic disorders, including inflammatory bowel disease (IBD). This work was aimed at studying HIF-associated changes in the intestinal epithelium in IBD. In the first step, a list of genes responding to chemical activation of hypoxia was obtained in an in vitro intestinal cell model with RNA sequencing. Cobalt (II) chloride and oxyquinoline treatment of both undifferentiated and differentiated Caco-2 cells activate the HIF-signaling pathway according to gene set enrichment analysis. The core gene set responding to chemical hypoxia stimulation in the intestinal model included 115 upregulated and 69 downregulated genes. Of this set, protein product was detected for 32 genes, and fold changes in proteome and RNA sequencing significantly correlate. Analysis of publicly available RNA sequencing set of the intestinal epithelial cells of patients with IBD confirmed HIF-1 signaling pathway activation in sigmoid colon of patients with ulcerative colitis and terminal ileum of patients with Crohn’s disease. Of the core gene set from the gut hypoxia model, expression activation of ITGA5 and PLAUR genes encoding integrin α5 and urokinase-type plasminogen activator receptor (uPAR) was detected in IBD specimens. The interaction of these molecules can activate cell migration and regenerative processes in the epithelium. Transcription factor analysis with the previously developed miRGTF tool revealed the possible role of HIF1A and NFATC1 in the regulation of ITGA5 and PLAUR gene expression. Detected genes can serve as markers of IBD progression and intestinal hypoxia.

The C-X-C chemokine ENA-78 is preferentially expressed in intestinal epithelium in inflammatory bowel disease

1997 ◽  
Vol 113 (3) ◽  
pp. 808-816 ◽  
Author(s):  
K Z'Graggen ◽  
A Walz ◽  
L Mazzucchelli ◽  
RM Strieter ◽  
C Mueller
Keyword(s):  
Inflammatory Bowel Disease ◽  
Intestinal Epithelium ◽  
Bowel Disease ◽  
Inflammatory Bowel
Sign in / Sign up

Export Citation Format

Share Document