scholarly journals The Role of Organoids as a Novel Platform for Modeling of Inflammatory Bowel Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Lauren O'Connell ◽  
Des C. Winter ◽  
Carol M. Aherne
Keyword(s):  
Inflammatory Bowel Disease ◽  
Cell Culture ◽  
Bowel Disease ◽  
Cell Types ◽  
Mucosal Barrier ◽  
Intestinal Cell ◽  
Monolayer Cell Culture ◽  
Monolayer Cell ◽  
Advantages And Disadvantages ◽  
Inflammatory Bowel

Inflammatory bowel disease (IBD) is a chronic relapsing-remitting immune-mediated disorder affecting the gut. It is common in Westernized regions and is increasing in incidence in developing countries. At a molecular level, intrinsic deficiencies in epithelial integrity, mucosal barrier function, and mechanisms of immune response and resolution contribute to the development of IBD. Traditionally two platforms have been utilized for disease modeling of IBD;in-vitromonolayer cell culture andin-vivoanimal models. Both models have limitations, including cost, lack of representative cell types, lack of complexity of cellular interactions in a living organism, and xenogeneity. Organoids, three-dimensional cellular structures which recapitulate the basic architecture and functional processes of the organ of origin, hold potential as a third platform with which to investigate the pathogenesis and molecular defects which give rise to IBD. Organoids retain the genetic and transcriptomic profile of the tissue of origin over time and unlike monolayer cell culture can be induced to differentiate into most adult intestinal cell types. They may be used to model intestinal host-microbe interactions occurring at the mucosal barrier, are amenable to genetic manipulation and can be co-cultured with other cell lines of interest. Bioengineering approaches may be applied to render a more faithful representation of the intestinal epithelial niche. In this review, we outline the concept of intestinal organoids, discuss the advantages and disadvantages of the platform comparative to alternative models, and describe the translational applications of organoids in IBD.

scholarly journals An interspecies translation model implicates integrin signaling in infliximab-resistant inflammatory bowel disease

2020 ◽  
Vol 13 (643) ◽  
pp. eaay3258
Author(s):  
Douglas K. Brubaker ◽  
Manu P. Kumar ◽  
Evan L. Chiswick ◽  
Cecil Gregg ◽  
Alina Starchenko ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Mouse Models ◽  
Bowel Disease ◽  
Cell Types ◽  
Therapy Resistance ◽  
Model Systems ◽  
Intestinal Cell ◽  
Integrin Signaling ◽  
Proteomics Data ◽  
Inflammatory Bowel

Anti–tumor necrosis factor (anti-TNF) therapy resistance is a major clinical challenge in inflammatory bowel disease (IBD), due, in part, to insufficient understanding of disease-site, protein-level mechanisms. Although proteomics data from IBD mouse models exist, data and phenotype discrepancies contribute to confounding translation from preclinical animal models of disease to clinical cohorts. We developed an approach called translatable components regression (TransComp-R) to overcome interspecies and trans-omic discrepancies between mouse models and human subjects. TransComp-R combines mouse proteomic data with patient pretreatment transcriptomic data to identify molecular features discernable in the mouse data that are predictive of patient response to therapy. Interrogating the TransComp-R models revealed activated integrin pathway signaling in patients with anti–TNF-resistant colonic Crohn’s disease (cCD) and ulcerative colitis (UC). As a step toward validation, we performed single-cell RNA sequencing (scRNA-seq) on biopsies from a patient with cCD and analyzed publicly available immune cell proteomics data to characterize the immune and intestinal cell types contributing to anti-TNF resistance. We found that ITGA1 was expressed in T cells and that interactions between these cells and intestinal cell types were associated with resistance to anti-TNF therapy. We experimentally showed that the α1 integrin subunit mediated the effectiveness of anti-TNF therapy in human immune cells. Thus, TransComp-R identified an integrin signaling mechanism with potential therapeutic implications for overcoming anti-TNF therapy resistance. We suggest that TransComp-R is a generalizable framework for addressing species, molecular, and phenotypic discrepancies between model systems and patients to translationally deliver relevant biological insights.

scholarly journals An objective in vivo diagnostic method for inflammatory bowel disease

2018 ◽  
Vol 5 (3) ◽  
pp. 180107 ◽  
Author(s):  
Sophie C. Payne ◽  
Robert K. Shepherd ◽  
Alicia Sedo ◽  
James B. Fallon ◽  
John B. Furness
Keyword(s):  
Inflammatory Bowel Disease ◽  
Real Time ◽  
Bowel Disease ◽  
Experimental Models ◽  
Mucosal Barrier ◽  
Trinitrobenzene Sulfonic Acid ◽  
Inflammatory Damage ◽  
Mucosal Barrier Function ◽  
Inflammatory Bowel

Inflammatory damage to the bowel, as occurs in inflammatory bowel disease (IBD), is debilitating to patients. In both patients and animal experimental models, histological analyses of biopsies and endoscopic examinations are used to evaluate the disease state. However, such measurements often have delays and are invasive, while endoscopy is not quantitatively objective. Therefore, a real-time quantitative method to assess compromised mucosal barrier function is advantageous. We investigated the correlation of in vivo changes in electrical transmural impedance with histological measures of inflammation. Four platinum (Pt) ball electrodes were placed in the lumen of the rat small intestine, with a return electrode under the skin. Electrodes placed within the non-inflamed intestine generated stable impedances during the 3 h testing period. Following an intraluminal injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS), an established animal model of IBD, impedances in the inflamed region significantly decreased relative to a region not exposed to TNBS ( p  < 0.05). Changes in intestinal transmural impedance were correlated ( p  < 0.05) with histologically assessed damage to the mucosa and increases in neutrophil, eosinophil and T-cell populations at 3 h compared with tissue from control regions. This quantitative, real-time assay may have application in the diagnosis and clinical management of IBD.

scholarly journals Inflammatory Bowel Disease Through the Lens of Single-cell RNA-seq Technologies

2020 ◽  
Vol 26 (11) ◽  
pp. 1658-1668 ◽  
Author(s):  
Daniele Corridoni ◽  
Thomas Chapman ◽  
Agne Antanaviciute ◽  
Jack Satsangi ◽  
Alison Simmons
Keyword(s):  
Inflammatory Bowel Disease ◽  
Single Cell ◽  
Intestinal Mucosa ◽  
Bowel Disease ◽  
Drug Targets ◽  
Complex Disease ◽  
Cell Types ◽  
Inflammatory Bowel ◽  
Mucosa Cell ◽  
Definition Of

Abstract The intestinal mucosa represents a unique environment where the coordinated function of diverse epithelial, mesenchymal, and immune cells maintains a physiologically balanced environment in the presence of gut microbiota. The intestinal mucosa plays a central role in the pathogenesis of inflammatory bowel disease (IBD), yet the molecular and cellular composition of this diverse environment is poorly understood. However, the recent advent of multimodal single-cell technologies, including single-cell RNA sequencing (scRNA-seq), now provides an opportunity to accurately map the tissue architecture, characterize rare cell types that were previously overlooked, and define function at a single-cell level. In this review, we summarize key advances in single-cell technology and provide an overview of important aspects of computational analysis. We describe emerging data in the field of IBD and discuss how the characterization of novel intestinal mucosa cell populations is reshaping our understanding of this complex disease. We conclude by considering the potential clinical applications, including the definition of novel drug targets and the opportunity for personalization of care in this exciting new era of precision medicine.

scholarly journals Extracellular Vesicles in Inflammatory Bowel Disease: Small Particles, Big Players

2020 ◽  
Author(s):  
M Valter ◽  
S Verstockt ◽  
J A Finalet Ferreiro ◽  
I Cleynen
Keyword(s):  
Inflammatory Bowel Disease ◽  
Extracellular Vesicles ◽  
Bowel Disease ◽  
Intestinal Barrier ◽  
Cell Types ◽  
Physiological Status ◽  
Intestinal Epithelial ◽  
Functional Roles ◽  
Physiological Processes ◽  
Inflammatory Bowel

Abstract Extracellular vesicles are nanovesicles released by many cell types into the extracellular space. They are important mediators of intercellular communication, enabling the functional transfer of molecules from one cell to another. Moreover, their molecular composition reflects the physiological status of the producing cell and tissue. Consequently, these vesicles have been involved in many [patho]physiological processes such as immunomodulation and intestinal epithelial repair, both key processes involved in inflammatory bowel disease. Given that these vesicles are present in many body fluids, they also provide opportunities for diagnostic, prognostic, and therapeutic applications. In this review, we summarise functional roles of extracellular vesicles in health and disease, with a focus on immune regulation and intestinal barrier integrity, and review recent studies on extracellular vesicles and inflammatory bowel disease. We also elaborate on their clinical potential in inflammatory bowel disease.

Pathogenesis of Intestinal Fibrosis in Inflammatory Bowel Disease and Perspectives for Therapeutic Implication

2017 ◽  
Vol 35 (1-2) ◽  
pp. 25-31 ◽  
Author(s):  
Dominik Bettenworth ◽  
Florian Rieder
Keyword(s):  
Inflammatory Bowel Disease ◽  
Chronic Inflammation ◽  
Bowel Disease ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Stricture Formation ◽  
Intestinal Fibrosis ◽  
Conventional View ◽  
Multiple Cell ◽  
Inflammatory Bowel

Background: Intestinal fibrosis with stricture formation is a common feature of inflammatory bowel disease (IBD) and leads to a significantly impaired quality of life in affected patients, intestinal obstruction as well as to the need for surgical intervention. This constitutes a major treatment challenge. Key Messages: Fibrosis results from the response of gut tissue to the insult inflicted by chronic inflammation. Similarly to what occurs in other organs, the underlying fibrogenic mechanisms are complex and dynamic, involving multiple cell types, interrelated cellular events, and a large number of soluble factors. Owing to a breakdown of the epithelial barrier in IBD, luminal bacterial products leak into the interstitium and induce an innate immune response mediated by the activation of both immune and non-immune cells. Other environmental factors as well as chronic inflammation will certainly impact the quality and quantity of intestinal fibrosis. Finally, the composition of the intestinal extracellular matrix is dramatically altered in chronic gut inflammation and actively promotes fibrosis through its mechanical properties. The conventional view that intestinal fibrosis is an inevitable and irreversible process is gradually changing in light of an improved understanding of the cellular and molecular mechanisms that underline its pathogenesis. In addition, clinical observations in patients who undergo strictureplasty have shown that stricture formation is reversible. Conclusions: Identification of the unique mechanisms of intestinal fibrogenesis should create a practical framework to target and block specific fibrogenic pathways, estimate the risk of fibrotic complications, permit the detection of early fibrotic changes and, eventually, allow the development of treatment methods customized to each patient's type and degree of intestinal fibrosis.

scholarly journals Intestinal Permeability in Inflammatory Bowel Disease: Pathogenesis, Clinical Evaluation, and Therapy of Leaky Gut

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Andrea Michielan ◽  
Renata D’Incà
Keyword(s):  
Inflammatory Bowel Disease ◽  
Intestinal Permeability ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Mucosal Barrier ◽  
Mucosal Inflammation ◽  
Confocal Laser Endomicroscopy ◽  
Confocal Laser ◽  
Sugar Absorption ◽  
Inflammatory Bowel

The pathogenesis of inflammatory bowel disease (IBD) is multifactorial with data suggesting the role of a disturbed interaction between the gut and the intestinal microbiota. A defective mucosal barrier may result in increased intestinal permeability which promotes the exposition to luminal content and triggers an immunological response that promotes intestinal inflammation. IBD patients display several defects in the many specialized components of mucosal barrier, from the mucus layer composition to the adhesion molecules that regulate paracellular permeability. These alterations may represent a primary dysfunction in Crohn’s disease, but they may also perpetuate chronic mucosal inflammation in ulcerative colitis. In clinical practice, several studies have documented that changes in intestinal permeability can predict IBD course. Functional tests, such as the sugar absorption tests or the novel imaging technique using confocal laser endomicroscopy, allow anin vivoassessment of gut barrier integrity. Antitumor necrosis factor-α(TNF-α) therapy reduces mucosal inflammation and restores intestinal permeability in IBD patients. Butyrate, zinc, and some probiotics also ameliorate mucosal barrier dysfunction but their use is still limited and further studies are needed before considering permeability manipulation as a therapeutic target in IBD.

scholarly journals OP13 Mucosal organoids capture Innate Lymphoid Cells (ILC) tissue-specific development and reveal that Inflammatory Bowel Disease-associated ILC modulate intestinal remodelling

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S013-S014
Author(s):  
G M Jowett ◽  
E Read ◽  
M D Norman ◽  
P A Arevalo ◽  
M Vilà González ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Tissue Specific ◽  
Final Maturation ◽  
Inflammatory Bowel ◽  
The Impact

Abstract Background Innate Lymphoid Cells (ILC) develop from Common Lymphoid Precursors in the bone marrow, and ILC precursors (ILCP) migrate to mucosa where they mature, promote homeostasis, and provide a potent, antigen-non-specific sources of cytokines. Deciphering what local stimuli drive the final stages of ILCP maturation in these tissues remains a pressing question, as ILC frequencies can become dysregulated during chronic infection and inflammatory diseases. For example, Type-1 innate lymphoid cells (ILC1) are enriched in the mucosa of patients with active inflammatory bowel disease (IBD) and the impact of this accumulation remains elusive. Methods Here, we develop and use co-cultures of both murine and human iPSC-derived gut and lung organoids with ILCP and with mature ILC isolated from IBD patients’ intestinal biopsies. Results Harnessing these versatile models, we demonstrate that epithelial cells provide a complex niche capable of supporting the final maturation of all helper-like ILC1, ILC2, and ILC3. Notably, organoid identity was sufficient to robustly recapitulate tissue-specific ILC imprints and frequencies, even in the absence of microbial stimuli, other cell types, or cytokine supplementation. In addition, we show that that ILC1 drive expansion of the epithelial stem cell crypt through p38γ phosphorylation, driving a potentially pathological proliferative feedback loop between β-catenin and Cd44v6. We harnessed this model to elucidate that this phenotype was unexpectedly regulated by ILC1-derived TGFβ1. We further show that human gut ILC1 also secrete TGFβ1, and drive CD44v6 expression in both HIO epithelium and mesenchyme. As TGFβ1 is a master regulator of fibrosis, the leading indicator for surgery in IBD, we next characterised the ability of ILC1 to regulate matrix remodelling using a functionalized, synthetic hydrogel system. We show that ILC1 drive both matrix stiffening and degradation, which we posit occurs through a balance of MMP9 degradation and TGFβ1-induced fibronectin deposition. Conclusion Taken together, our work provides unprecedented insight into in situ ILC maturation, which we show to be driven by epithelial signals, and into ILC function. We also report that intestinal ILC1 modulate epithelial and matrix remodelling, which may drive either wound healing in homeostasis, but may tip toward pathology when enriched in IBD. Moreover, our work introduces a modular organoid platform, which provides exquisite control over both environmental stimuli and host genetics, making it a powerful tool for dissecting the interactions between complex mucosal tissues and rare cell subtypes in development and disease.

scholarly journals P059 Cytokine responsive transcriptional networks in inflammatory bowel disease

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S164-S164
Author(s):  
A Treveil ◽  
P Pavlidis ◽  
A Tsakmaki ◽  
G Bewick ◽  
T Korcsmaros ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Inflammatory Diseases ◽  
Mucosal Healing ◽  
Mucosal Barrier ◽  
Transcriptional Networks ◽  
Intestinal Epithelial ◽  
Transcriptomics Data ◽  
Inflammatory Bowel ◽  
Regulatory Effects

Abstract Background Interactions between the immune system and the intestinal epithelium play an important role in the pathogenesis of chronic immune mediated inflammatory diseases, including inflammatory bowel disease (IBD). In IBD, debilitating symptoms and complications including abscesses and cancer are associated with aberrant cytokine production and resulting intestinal epithelial damage. Despite the advent of biological therapies targeting key pathogenic cytokines, like tumour necrosis α (TNF), only 18% of IBD patients will achieve complete disease control and mucosal healing. Here, we provide new insights into the epithelial response to cytokines using network analysis of transcriptomics data from colonic organoids (colonoids). Methods We generated an atlas of the transcriptomic effects of cytokines by treating human-derived colonoids with IFNg, IL13, IL9, IL17A and TNF (independently). By integrating the observed transcriptional changes with previously published signalling and regulatory interactions, we generated causal networks to elucidate the effect of cytokine cues on epithelial cells. These networks comprised experimentally verified protein–protein and transcription factor (TF)–target gene interactions, forming signalling pathways linking cytokines to TFs and from TFs to differentially expressed genes. Results With this analysis, we identified previously unrecognised levels of shared and distinct transcriptional regulation of colonic epithelial function by different cytokines. While IL9 had a negligible impact on the transcriptome, the transcripts with differential expression induced by IFNg, IL13, IL17A or TNF were consistent with their recognised function in other tissues. IFNg and TNF exhibited similar magnitude and directional effects on key immune pathways while IL13 had the opposite effect. Using a network approach, we found that regulatory effects of cytokines are primarily transduced through unique signalling routes, some of which converge on the same key transcription factors; CEBPA, E2F1, E2F2, ETS1, FOS, IRF1 and MAZ. We observed independent regulatory mechanisms of the different cytokines as well as complementarity in the epithelial responses regulated by different canonical cytokines. Conclusion The generated cytokine transcriptional atlas provides a unique insight into the immune-epithelial interactome by allowing the identification of shared and distinct transcriptional pathways across different types of immunity at the mucosal barrier. In addition, it provides the unique opportunity to study cytokine responses in the context of human disease and generate novel hypotheses.

scholarly journals Considerations for Choosing Appropriate Animal Models to Study Inflammatory Bowel Disease

2016 ◽  
Vol 8 (7) ◽  
pp. 1
Author(s):  
Richard R. E. Uwiera ◽  
Trina C. Uwiera ◽  
Janelle A. Jiminez ◽  
G. Douglas Inglis
Keyword(s):  
Inflammatory Bowel Disease ◽  
Animal Model ◽  
Animal Models ◽  
Bowel Disease ◽  
Intestinal Inflammation ◽  
Disease Process ◽  
Careful Consideration ◽  
Complete Understanding ◽  
Advantages And Disadvantages ◽  
Inflammatory Bowel

<p>This article examines several animal models used to investigate mechanisms involved in the induction and progression of inflammatory bowel disease in people. The use of appropriate animal models to study intestinal inflammation requires careful consideration as each model has strengths and limitations for investigating disease, and no single model provides a complete understanding of the disease process. In as such, it compels researchers to carefully contemplate the advantages and disadvantages of each animal model, and to consider the process of choosing the best animal model(s) as an essential component of the experimental design.</p>

Sign in / Sign up

Export Citation Format

Share Document