Evaluation of Intestinal Epithelial Barrier Function in Inflammatory Bowel Diseases Using Murine Intestinal Organoids

Intestinal epithelial barrier impairment plays a key pathogenic role in inflammatory bowel diseases (IBDs). In particular, together with oxidative stress, intestinal epithelial barrier alteration is considered as upstream event in ulcerative colitis (UC). In order to identify new products of natural origin with a potential activity for UC treatment, this study evaluated the effects of plumericin, a spirolactone iridoid, present as one of the main bioactive components in the bark of Himatanthus sucuuba (Woodson). Plumericin was evaluated for its ability to improve barrier function and to reduce apoptotic parameters during inflammation, both in intestinal epithelial cells (IEC-6), and in an animal experimental model of 2, 4, 6-dinitrobenzene sulfonic acid (DNBS)-induced colitis. Our results indicated that plumericin increased the expression of adhesion molecules, enhanced IEC-6 cells actin cytoskeleton rearrangement, and promoted their motility. Moreover, plumericin reduced apoptotic parameters in IEC-6. These results were confirmed in vivo. Plumericin reduced the activity of myeloperoxidase, inhibited the expression of ICAM-1, P-selectin, and the formation of PAR, and reduced apoptosis parameters in mice colitis induced by DNBS. These results support a pharmacological potential of plumericin in the treatment of UC, due to its ability to improve the structural integrity of the intestinal epithelium and its barrier function.

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Dietary fibre-based SCFA mixtures promote both protection and repair of intestinal epithelial barrier function in a Caco-2 cell model

Food & Function ◽

10.1039/c6fo01532h ◽

2017 ◽

Vol 8 (3) ◽

pp. 1166-1173 ◽

Cited By ~ 48

Author(s):

Tingting Chen ◽

Choon Young Kim ◽

Amandeep Kaur ◽

Lisa Lamothe ◽

Maliha Shaikh ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Barrier Function ◽

Cell Model ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Intestinal Epithelial Barrier ◽

Epithelial Barrier Function ◽

Gut Barrier Function ◽

Inflammatory Bowel

Impaired gut barrier function plays an important role in the development of many diseases such as obesity, inflammatory bowel disease, and in HIV infection.

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Eosinophils alter colonic epithelial barrier function: role for major basic protein

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00015.2005 ◽

2005 ◽

Vol 289 (5) ◽

pp. G890-G897 ◽

Cited By ~ 90

Author(s):

Glenn T. Furuta ◽

Edward E. S. Nieuwenhuis ◽

Jorn Karhausen ◽

Gerald Gleich ◽

Richard S. Blumberg ◽

...

Keyword(s):

Inflammatory Bowel Diseases ◽

Barrier Function ◽

Basic Protein ◽

Gastrointestinal Diseases ◽

Epithelial Barrier ◽

Major Basic Protein ◽

Epithelial Barrier Function ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Granule Proteins

Mucosal eosinophils increase in a number of gastrointestinal diseases that are often associated with altered epithelial barrier function, including food allergic enteropathies and inflammatory bowel diseases. Although eosinophils are known to secrete biologically active mediators including granule proteins, their role in gastrointestinal diseases is uncertain. The aim of this study was to determine the impact of eosinophils on intestinal barrier function. Epithelial barrier function was determined in a coculture of eosinophils and T84 epithelial cells and in a murine model of T helper (Th) type 2-mediated colitis. Coculture conditions resulted in decreased transepithelial resistance (TER) and increased transepithelial flux. Cell-free coculture supernatants contained a ≥5-kDa soluble factor that also diminished TER; these supernatants contained the eosinophil-granule proteins major basic protein (MBP) and eosinophil-derived neurotoxin (EDN). T84 barrier function decreased significantly when basolateral surfaces were exposed to native human MBP but not EDN. Additional studies identified downregulation of the tight junctional molecule occludin as at least one mechanism for MBP action. MBP-null mice were protected from inflammation associated with oxazolone colitis compared with wild-type mice. In conclusion, MBP decreases epithelial barrier function and in this manner contributes to the pathogenesis of inflammatory bowel diseases.

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Pharmacological activation of ERβ by arctigenin maintains the integrity of intestinal epithelial barrier in inflammatory bowel diseases

The FASEB Journal ◽

10.1096/fj.201901638rr ◽

2019 ◽

Vol 34 (2) ◽

pp. 3069-3090 ◽

Cited By ~ 1

Author(s):

Yu Tao ◽

Mengfan Yue ◽

Changjun Lv ◽

Xinming Yun ◽

Simiao Qiao ◽

...

Keyword(s):

Inflammatory Bowel Diseases ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Intestinal Epithelial Barrier ◽

Bowel Diseases ◽

Inflammatory Bowel

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A new role for reticulon-4B/NOGO-B in the intestinal epithelial barrier function and inflammatory bowel disease

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00309.2014 ◽

2015 ◽

Vol 308 (12) ◽

pp. G981-G993 ◽

Cited By ~ 8

Author(s):

Juan Antonio Rodríguez-Feo ◽

Marta Puerto ◽

Carolina Fernández-Mena ◽

Cristina Verdejo ◽

José Manuel Lara ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Barrier Function ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Intestinal Epithelial Barrier ◽

Epithelial Barrier Function ◽

Inflammatory Bowel ◽

E Cadherin

Inflammatory bowel disease (IBD) is characterized by an impaired intestinal barrier function. We aimed to investigate the role of reticulon-4B (RTN-4B/NOGO-B), a structural protein of the endoplasmic reticulum, in intestinal barrier function and IBD. We used immunohistochemistry, confocal microscopy, real-time PCR, and Western blotting to study tissue distribution and expression levels of RTN-4B/NOGO-B in control and IBD samples from mouse and humans. We also targeted RTN-4B/NOGO-B using siRNAs in cultured human intestinal epithelial cell (IECs). Epithelial barrier permeability was assessed by transepithelial electrical resistance (TEER) measurement. RTN-4B/NOGO-B is expressed in the intestine mainly by IECs. Confocal microscopy revealed a colocalization of RTN-4B, E-cadherin, and polymerized actin fibers in tissue and cultured IECs. RTN-4B mRNA and protein expression were lower in the colon of IL-10−/− compared with wild-type mice. Colocalization of RTN-4B/E-cadherin/actin was reduced in the colon of IL-10−/− mice. Analysis of endoscopic biopsies from IBD patients showed a significant reduction of RTN-4B/NOGO-B expression in inflamed mucosa compared with control. Treatment of IECs with H2O2 reduced TEER values and triggered phosphorylation of RTN-4B in serine 107 residues as well as downregulation of RTN-4B expression. Acute RTN-4B/NOGO-B knockdown by siRNAs resulted in a decreased TEER values and reduction of E-cadherin and α-catenin expression and in the amount of F-actin-rich filaments in IECs. Epithelial RTN-4B/NOGO-B was downregulated in human and experimental IBD. RTN-4B participates in the intestinal epithelial barrier function, most likely via its involvement in E-cadherin, α-catenin expression, and actin cytoskeleton organization at sites of cell-to-cell contacts.

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The enteric nervous system as a regulator of intestinal epithelial barrier function in health and disease

Expert Review of Gastroenterology & Hepatology ◽

10.1586/egh.10.51 ◽

2010 ◽

Vol 4 (5) ◽

pp. 637-651 ◽

Cited By ~ 34

Author(s):

Susanne A Snoek ◽

Marleen I Verstege ◽

Guy E Boeckxstaens ◽

René M van den Wijngaard ◽

Wouter J de Jonge

Keyword(s):

Nervous System ◽

Enteric Nervous System ◽

Barrier Function ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Intestinal Epithelial Barrier ◽

Epithelial Barrier Function ◽

Health And Disease

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JunD Represses Transcription and Translation of the Tight Junction Protein Zona Occludens-1 Modulating Intestinal Epithelial Barrier Function

Molecular Biology of the Cell ◽

10.1091/mbc.e08-02-0175 ◽

2008 ◽

Vol 19 (9) ◽

pp. 3701-3712 ◽

Cited By ~ 45

Author(s):

Jie Chen ◽

Lan Xiao ◽

Jaladanki N. Rao ◽

Tongtong Zou ◽

Lan Liu ◽

...

Keyword(s):

Epithelial Cells ◽

Tight Junction ◽

Barrier Function ◽

Intestinal Epithelial Cells ◽

Binding Protein ◽

Mrna Translation ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Intestinal Epithelial Barrier ◽

Epithelial Barrier Function

The AP-1 transcription factor JunD is highly expressed in intestinal epithelial cells, but its exact role in maintaining the integrity of intestinal epithelial barrier remains unknown. The tight junction (TJ) protein zonula occludens (ZO)-1 links the intracellular domain of TJ-transmembrane proteins occludin, claudins, and junctional adhesion molecules to many cytoplasmic proteins and the actin cytoskeleton and is crucial for assembly of the TJ complex. Here, we show that JunD negatively regulates expression of ZO-1 and is implicated in the regulation of intestinal epithelial barrier function. Increased JunD levels by ectopic overexpression of the junD gene or by depleting cellular polyamines repressed ZO-1 expression and increased epithelial paracellular permeability. JunD regulated ZO-1 expression at the levels of transcription and translation. Transcriptional repression of ZO-1 by JunD was mediated through cAMP response element-binding protein-binding site within its proximal region of the ZO-1-promoter, whereas induced JunD inhibited ZO-1 mRNA translation by enhancing the interaction of the ZO-1 3′-untranslated region with RNA-binding protein T cell-restricted intracellular antigen 1-related protein. These results indicate that JunD is a biological suppressor of ZO-1 expression in intestinal epithelial cells and plays a critical role in maintaining epithelial barrier function.

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