Clostridium butyricum Ameliorates Salmonella Enteritis Induced Inflammation by Enhancing and Improving Immunity of the Intestinal Epithelial Barrier at the Intestinal Mucosal Level

Abstract Background Disruption of the gut barrier is an essential mechanism of inflammatory bowel diseases (IBDs) contributing to the development of mucosal inflammation. A hallmark of barrier disruption is the disassembly of epithelial adherens junctions (AJs) driven by decreased expression of a major AJ protein, E-cadherin. A group of isoxazole compounds, such as E-cadherin-upregulator (ECU) and ML327, were previously shown to stimulate E-cadherin expression in poorly differentiated human cancer cells. This study was designed to examine whether these isoxazole compounds can enhance and protect model intestinal epithelial barriers in vitro. Methods The study was conducted using T84, SK-CO15, and HT-29 human colonic epithelial cell monolayers. Disruption of the epithelial barrier was induced by pro-inflammatory cytokines, tumor necrosis factor-α, and interferon-γ. Barrier integrity and epithelial junction assembly was examined using different permeability assays, immunofluorescence labeling, and confocal microscopy. Epithelial restitution was analyzed using a scratch wound healing assay. Results E-cadherin-upregulator and ML327 treatment of intestinal epithelial cell monolayers resulted in several barrier-protective effects, including reduced steady-state epithelial permeability, inhibition of cytokine-induced barrier disruption and junction disassembly, and acceleration of epithelial wound healing. Surprisingly, these effects were not due to upregulation of E-cadherin expression but were mediated by multiple mechanisms including inhibition of junction protein endocytosis, attenuation of cytokine-induced apoptosis, and activation of promigratory Src and AKT signaling. Conclusions Our data highlight ECU and ML327 as promising compounds for developing new therapeutic strategies to protect the integrity and accelerate the restitution of the intestinal epithelial barrier in IBD and other inflammatory disorders.

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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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Butyrate-producing bacteria supplemented in vitro to Crohn’s disease patient microbiota increased butyrate production and enhanced intestinal epithelial barrier integrity

Scientific Reports ◽

10.1038/s41598-017-11734-8 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 102

Author(s):

Annelies Geirnaert ◽

Marta Calatayud ◽

Charlotte Grootaert ◽

Debby Laukens ◽

Sarah Devriese ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Disease Patient ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Intestinal Epithelial Barrier ◽

Barrier Integrity ◽

Butyrate Production

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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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Intestinal Epithelial Barrier Dysfunction in Food Hypersensitivity

Journal of Allergy ◽

10.1155/2012/596081 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 11

Author(s):

Linda Chia-Hui Yu

Keyword(s):

Mast Cell ◽

Cell Surface ◽

Critical Role ◽

Mast Cell Activation ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Barrier Dysfunction ◽

Intestinal Epithelial Barrier ◽

Food Antigens ◽

Epithelial Barrier Dysfunction

Intestinal epithelial barrier plays a critical role in the maintenance of gut homeostasis by limiting the penetration of luminal bacteria and dietary allergens, yet allowing antigen sampling for the generation of tolerance. Undigested proteins normally do not gain access to the lamina propria due to physical exclusion by tight junctions at the cell-cell contact sites and intracellular degradation by lysosomal enzymes in enterocytes. An intriguing question then arises: how do macromolecular food antigens cross the epithelial barrier? This review discusses the epithelial barrier dysfunction in sensitized intestine with special emphasis on the molecular mechanism of the enhanced transcytotic rates of allergens. The sensitization phase of allergy is characterized by antigen-induced cross-linking of IgE bound to high affinity FcεRI on mast cell surface, leading to anaphylactic responses. Recent studies have demonstrated that prior to mast cell activation, food allergens are transported in large quantity across the epithelium and are protected from lysosomal degradation by binding to cell surface IgE and low-affinity receptor CD23/FcεRII. Improved immunotherapies are currently under study including anti-IgE and anti-CD23 antibodies for the management of atopic disorders.

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Intestinal epithelial barrier function in liver cirrhosis: an extensive review of the literature

Liver International ◽

10.1111/liv.12271 ◽

2013 ◽

Vol 33 (10) ◽

pp. 1457-1469 ◽

Cited By ~ 27

Author(s):

Kirsten E. Pijls ◽

Daisy M. A. E. Jonkers ◽

Elhaseen E. Elamin ◽

Ad A. M. Masclee ◽

Ger H. Koek

Keyword(s):

Liver Cirrhosis ◽

Barrier Function ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Extensive Review ◽

Review Of The Literature ◽

Intestinal Epithelial Barrier ◽

Epithelial Barrier Function

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Lactobacillus fermentum L930BB and Bifidobacterium animalis subsp. animalis IM386 initiate signalling pathways involved in intestinal epithelial barrier protection

Beneficial Microbes ◽

10.3920/bm2017.0107 ◽

2018 ◽

Vol 9 (3) ◽

pp. 515-525 ◽

Cited By ~ 11

Author(s):

D. Paveljšek ◽

P. Juvan ◽

R. Košir ◽

D. Rozman ◽

B. Hacin ◽

...

Keyword(s):

Growth Factor ◽

Actin Cytoskeleton ◽

Lactobacillus Fermentum ◽

Signalling Pathways ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Intestinal Epithelial Barrier ◽

Apoptotic Pathway ◽

Promising Alternative ◽

Bifidobacterium Animalis

The manipulation of intestinal microbiota with beneficial microbes represents a promising alternative or adjunct therapy in gastrointestinal disorders and inflammation. The current study aims to clarify the signalling pathways and evaluate the possible beneficial effects of the combination of two strains. We used a dextran sulphate sodium (DSS)-induced mouse model of colitis. RNA extracted from the middle part of the colon tissue was used for examination of the global gene expression with Affymetrix microarrays. An enrichment analysis of the KEGG pathways was performed, and a subset of genes associated with intestinal epithelial barrier function was verified with qPCR. A clinical condition assessment of the differently treated mice revealed that the combination of these two bacterial strains was safe for use as a dietary supplement. All animals treated with DSS had affected colons and suffered weight loss. There were very small differences between the diseased groups, although the depth of inflammation was lower when cyclosporine A or the strain mixture was used. We discovered that the prophylactic administration of the Lactobacillus fermentum L930BB (L930BB) and Bifidobacterium animalis subsp. animalis IM386 (IM386) strains led to an anti-apoptotic pathway through phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt and to the activation of pathways involved in the regulation of actin cytoskeleton via protein kinase C and GTPases. Reorganisation of actin cytoskeleton and decreased apoptosis are both helpful in intestinal epithelial cell reconstitution. We confirm important previous observations, showing that these pathways are downstream targets of Toll-like receptor 2 and fibroblast growth factor initiated signalling. Taken together, these results suggest that the combination of L930BB and IM386 could aid in the regeneration of the intestinal epithelium during pathogenesis via pattern recognition receptors and the stimulation of growth factor synthesis.

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Plumericin Protects against Experimental Inflammatory Bowel Disease by Restoring Intestinal Barrier Function and Reducing Apoptosis

Biomedicines ◽

10.3390/biomedicines9010067 ◽

2021 ◽

Vol 9 (1) ◽

pp. 67 ◽

Cited By ~ 1

Author(s):

Shara Francesca Rapa ◽

Rosanna Di Paola ◽

Marika Cordaro ◽

Rosalba Siracusa ◽

Ramona D’Amico ◽

...

Keyword(s):

Barrier Function ◽

Structural Integrity ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Intestinal Epithelial Barrier ◽

Bowel Diseases ◽

Inflammatory Bowel

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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Neonatal intestinal injury induced by maternal separation: pathogenesis and pharmacological targets

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2018-0370 ◽

2019 ◽

Vol 97 (3) ◽

pp. 193-196 ◽

Cited By ~ 1

Author(s):

Bo Li ◽

Fang Zhou Yu ◽

Adam Minich ◽

Alison Hock ◽

Carol Lee ◽

...

Keyword(s):

Oxidative Stress ◽

Maternal Separation ◽

Intestinal Injury ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Intestinal Epithelial Barrier ◽

Epithelial Barrier Function ◽

Axis Ii ◽

Physiological Processes ◽

Pharmacological Targets

Maternal separation (MS) is a well-studied phenomenon thought to play a role in the pathogenesis of many diseases ranging from neuropsychiatric to early intestinal disorders such as necrotizing enterocolitis. The existing evidence suggests that MS initiates a variety of processes that in turn lead to early intestinal injury. Although there are many theories as to how MS alters normal physiological processes, the exact mechanism of action remains to be elucidated. This review aims to describe some of the pathological processes affecting the intestine that are caused by MS, including (i) brain–gut axis, (ii) intestinal epithelial barrier function, (iii) microbiome, (iv) oxidative stress and endoplasmic reticulum stress, and (v) gut inflammation.

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