MALAT1 maintains the intestinal mucosal homeostasis in Crohn’s disease via the miR-146b-5p-CLDN11/NUMB pathway

2021 ◽  
Author(s):  
Ying Li ◽  
Liguo Zhu ◽  
Peng Chen ◽  
Ying Wang ◽  
Guang Yang ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Knockout Mice ◽  
Experimental Colitis ◽  
Vital Role ◽  
Mucosal Barrier ◽  
Luciferase Reporter ◽  
Intestinal Homeostasis ◽  
Mucosal Homeostasis ◽  
Novel Target

Abstract Background & Aims Intestinal homeostasis disorder is critical for developing Crohn's disease (CD). Maintaining mucosal barrier integrity is essential for intestinal homeostasis, preventing intestinal injury and complications. Among the remarkably altered long non-coding RNAs (lncRNAs) in CD, we aimed to investigate whether metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) modulated CD and consequent disruption of intestinal homeostasis. Methods Microarray analyses on intestinal mucosa of CD patients and controls were performed to identify dysregulated lncRNAs. MALAT1 expression was investigated via qRT-PCR and its distribution in intestinal tissues was detected using BaseScope. Intestines from MALAT1 knockout mice with colitis were investigated using histological, molecular and biochemical approaches. Effects of intestinal epithelial cells transfected with MALAT1 lentiviruses and Smart Silencer, on monolayer permeability and apical junction complex (AJC) proteins were analysed. MiR-146b-5p were confirmed as a critical MALAT1 mediator in cells transfected with miR-146b-5p mimic/inhibitor and in colitis mice administered with agomir-146b-5p/antagomir-146b-5p. Interaction between MALAT1 and miR-146b-5p was predicted via bioinformatics and validated using Dual-luciferase reporter assay and Ago2-RIP. Results MALAT1 was aberrantly downregulated in the intestine mucosa of CD patients and mice with experimental colitis. MALAT1 knockout mice were hypersensitive to DSS-induced experimental colitis. MALAT1 regulated intestinal mucosal barrier and regained intestinal homeostasis by sequestering miR-146b-5p and maintaining the expression of the AJC proteins NUMB and CLDN11. Conclusions Downregulation of MALAT1 contributed to the pathogenesis of CD by disrupting AJC. Thus, a specific MALAT1-miR-146b-5p-NUMB/CLDN11 pathway that plays a vital role in maintaining intestinal mucosal homeostasis may serve as a novel target for CD treatment.

Environmental Microbial Factors Determine the Pattern of Inflammatory Lesions in a Murine Model of Crohn’s Disease–Like Inflammation

2019 ◽  
Vol 26 (1) ◽  
pp. 66-79 ◽  
Author(s):  
Iris Stolzer ◽  
Valentina Kaden-Volynets ◽  
Barbara Ruder ◽  
Marilena Letizia ◽  
Miriam Bittel ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Murine Model ◽  
Immune Reaction ◽  
Mucosal Barrier ◽  
Bacterial Clearance ◽  
Compelling Evidence ◽  
Susceptible Host ◽  
Inflammatory Lesions ◽  
Mucosal Barrier Function

Here we provide compelling evidence that inflammation in a murine model of Crohn’s disease–like inflammation is characterized by an immune reaction presumably directed at a disease-relevant microflora in a genetically susceptible host with impaired mucosal barrier function and bacterial clearance.

RDP 1258, a novel immunomodulatory peptide, decreases tumor necrosis factor in Crohn's disease and suppresses inflammation in experimental colitis

2001 ◽  
Vol 120 (5) ◽  
pp. A685
Author(s):  
Armaud Bourreille ◽  
Marie Doubremelle ◽  
Diane Raingeard de Le Bletiere ◽  
Claire Toquet ◽  
Roland Buelow ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Tumor Necrosis Factor ◽  
Crohn's Disease ◽  
Tumor Necrosis ◽  
Experimental Colitis ◽  
Necrosis Factor

scholarly journals Genetic and pharmacological targeting of TPL-2 kinase ameliorates experimental colitis: a potential target for the treatment of Crohn's disease?

2011 ◽  
Vol 5 (2) ◽  
pp. 129-139 ◽  
Author(s):  
M Lawrenz ◽  
A Visekruna ◽  
A Kühl ◽  
N Schmidt ◽  
S H E Kaufmann ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Experimental Colitis ◽  
Potential Target

scholarly journals DOP22 Integrative -omic analysis reveals microbiota mediated molecular mechanisms influencing host mucosal gene expression in Crohn’s Disease

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S061-S062
Author(s):  
P Sudhakar ◽  
T Andrighetti ◽  
S Verstockt ◽  
C Caenepeel ◽  
M Ferrante ◽  
...  
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Molecular Mechanisms ◽  
Bacterial Species ◽  
Differentially Expressed ◽  
Mucosal Barrier ◽  
Bacterial Proteins ◽  
The Impact ◽  
Hub Proteins

Abstract Background Mechanistic evidence linking gut microbial changes and host mucosal barrier responses in patients with Crohn’s disease (CD) is lacking. In this study, we used a computational approach to integrate gut microbial and intestinal gene expression in CD patients. Methods Bacterial species, bacterial genes/transcripts with enhanced abundances/transcriptional activity in CD (t-statistic of > 2 and Q-value < 0.05), as well as mucosal (ileum/rectum) differentially expressed genes (DEGs) between CD (n =43) and non-IBD (n=22) subjects were retrieved from the Inflammatory Bowel Disease Meta -Omics Database (IBDMDB). The impact of bacterial proteins on host gene expression was inferred using MicrobioLink, a computational tool for inferring microbe-host interactions. Drug target information was retrieved from OpenTargets. Paired 16S read-outs from stool samples and gene expression data from ileal biopsies in CD patients (n=20) and non-IBD controls (n=15), cross-sectionally collected at our IBD referral center, were used for independent validation. Results Across the 8 identified bacterial species enriched in CD, 3.7% (n= 743) of the orthologous groups were identified as being able to bind to human proteins. Network diffusion analysis uncovered bacterial proteins which could cumulatively modulate the expression of 42% of the genes differentially expressed in the ileum of CD patients. Topological and pathway analysis of the inferred signaling network modulated by the microbiota revealed several key hub proteins and immune-related pathways associated with IL-4, IL-2 and IL-13 signaling, receptor tyrosine-kinases, NFkB, and toll-like receptors including TLR4. Seventy-eight percent of the DEGs in our discovery cohort were also differentially expressed in the validation cohort (R2 = 0.907). Bacterial proteins post-translationally modifying host receptors resulted in the up-regulation of several pro-inflammatory cytokines via critical hub proteins such as NFkB (Figure 1). We observed different levels of locational specificity (from 35 to 61%) for the top regulators such as SPI1, STAT1 and NFKB1in terms of genes regulated by them in ileum and rectum. 24 proteins including ITGA4 and JAK1 from the ileal and rectal signaling networks are existing targets of CD drugs such as vedolizumab and tofacitinib, filgotinib and upadacitinib respectively. Conclusion Our findings outline the potential mechanisms of microbiome-induced host responses and provide insights into designing microbiome-mediated therapies to prevent and/or treat CD.

scholarly journals Endoplasmic Reticulum Stress in Subepithelial Myofibroblasts Increases the TGF-β1 Activity That Regulates Fibrosis in Crohn’s Disease

2020 ◽  
Vol 26 (6) ◽  
pp. 809-819 ◽  
Author(s):  
Chao Li ◽  
John R Grider ◽  
Karnam S Murthy ◽  
Jaime Bohl ◽  
Emily Rivet ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Direct Interaction ◽  
Binding Activity ◽  
Luciferase Reporter ◽  
Stress Components ◽  
Tgf Β1

Abstract Background Endoplasmic reticulum (ER) stress is an essential response of epithelial and immune cells to inflammation in Crohn’s disease. The presence and mechanisms that might regulate the ER stress response in subepithelial myofibroblasts (SEMFs) and its role in the development of fibrosis in patients with Crohn’s disease have not been examined. Methods Subepithelial myofibroblasts were isolated from the affected ileum and normal ileum of patients with each Montreal phenotype of Crohn’s disease and from normal ileum in non-Crohn’s subjects. Binding of GRP78 to latent TGF-β1 and its subcellular trafficking was examined using proximity ligation-hybridization assay (PLA). The effects of XBP1 and ATF6 on TGF-β1 expression were measured using DNA-ChIP and luciferase reporter assay. Endoplasmic reticulum stress components, TGF-β1, and collagen levels were analyzed in SEMF transfected with siRNA-mediated knockdown of DNMT1 and GRP78 or with DNMT1 inhibitor 5-Azacytidine or with overexpression of miR-199a-5p. Results In SEMF of strictured ileum from patients with B2 Crohn’s disease, expression of ER stress sensors increased significantly. Tunicamycin elicited time-dependent increase in GRP78 protein levels, direct interaction with latent TGF-β1, and activated TGF-β1 signaling. The TGFB1 DNA-binding activity of ATF-6α and XBP1 were significantly increased and elicited increased TGFB1 transcription in SEMF-isolated from affected ileum. The levels of ER stress components, TGF-β1, and collagen expression in SEMF were significantly decreased following knockdown of DNMT1 or GRP78 by 5-Azacytidine treatment or overexpression of miR-199a-5p. Conclusions Endoplasmic reticulum stress is present in SEMF of patients susceptible to fibrostenotic Crohn’s disease and can contribute to development of fibrosis. Targeting ER stress may represent a novel therapeutic target to prevent fibrosis in patients with fibrostenotic Crohn’s disease.

scholarly journals Immunotherapy of Crohn's disease

1998 ◽  
Vol 7 (3) ◽  
pp. 149-152 ◽  
Author(s):  
C. van Montfrans ◽  
L. Camoglio ◽  
S. J. H. van Deventer
Keyword(s):  
Crohn’S Disease ◽  
T Lymphocytes ◽  
Crohn's Disease ◽  
Experimental Colitis ◽  
Interleukin 10 ◽  
Term Treatment ◽  
Mucosal Inflammation ◽  
Open Label ◽  
Tnf Α ◽  
Long Term Treatment

Although the initiating events of Crohn's disease are unknown, models of experimental colitis have provided new insights in the immunologically mediated pathways of mucosal inflammation. In Crohn's disease activated mucosal T lymphocytes produce proinflammatory cytokines within the mucosal compartment. With this understanding, there has been a shift in past years from the use of unspecific anti-inflammatory agents (corticosteroids, aminosalicylates) to the use of immunomodulatory drugs (azathioprine, methotrexate). Moreover, novel strategies have been designed for specific targets in Crohn's disease, in particular T lymphocytes and cytokines. In an open label study treatment of steroid-refractory Crohn's disease with anti- CD4+ antibodies was well tolerated and showed clinical benefit. However, a sustained depletion of the CD4+ cells precluded further clinical trials. In controlled clinical studies, anti-tumour necrosis factor (TNF-α) antibodies induced com plete remissions and few side effects were observed. One study suggested efficacy in active Crohn's disease of recombinant interleukin-10. Long term treatment studies will have to answer questions about the indications for use, benefit and toxicity. Altogether, these results hold promise for future management of Crohn's disease, where disease-modifying interventions and strategies that effectively maintain disease remission will play a key role.

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