Sinapic Acid Alleviated Inflammation-Induced Intestinal Epithelial Barrier Dysfunction in Lipopolysaccharide- (LPS-) Treated Caco-2 Cells

The integrity and permeability of the intestinal epithelial barrier are important indicators of intestinal health. Impaired intestinal epithelial barrier function and increased intestinal permeability are closely linked to the onset and progression of various intestinal diseases. Sinapic acid (SA) is a phenolic acid that has anti-inflammatory, antihyperglycemic, and antioxidant activities; meanwhile, it is also effective in the protection of inflammatory bowel disease (IBD), but the specific mechanisms remain unclear. Here, we evaluated the anti-inflammatory of SA and investigated its potential therapeutic activity in LPS-induced intestinal epithelial barrier and tight junction (TJ) protein dysfunction. SA improved cell viability; attenuated epithelial permeability; restored the protein and mRNA expression of claudin-1, ZO-1, and occludin; and reversed the redistribution of the ZO-1 and claudin-1 proteins in LPS-treated Caco-2 cells. Moreover, SA reduced the inflammatory response by downregulating the activation of the TLR4/NF-κB pathway and attenuated LPS-induced intestinal barrier dysfunction by decreasing the activation of the MLCK/MLC pathway. This study demonstrated that SA has strong anti-inflammatory activity and can alleviate the occurrence of high intercellular permeability in Caco-2 cells exposed to LPS.

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Chymase-mediated intestinal epithelial permeability is regulated by a protease-activating receptor/matrix metalloproteinase-2-dependent mechanism

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00186.2012 ◽

2013 ◽

Vol 304 (5) ◽

pp. G479-G489 ◽

Cited By ~ 41

Author(s):

Katherine R. Groschwitz ◽

David Wu ◽

Heather Osterfeld ◽

Richard Ahrens ◽

Simon P. Hogan

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Barrier Function ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Barrier Dysfunction ◽

Intestinal Epithelial Barrier ◽

Epithelial Barrier Function ◽

Epithelial Barrier Dysfunction

Mast cells regulate intestinal barrier function during disease and homeostasis. Secretion of the mast cell-specific serine protease chymase regulates homeostasis. In the present study, we employ in vitro model systems to delineate the molecular pathways involved in chymase-mediated intestinal epithelial barrier dysfunction. Chymase stimulation of intestinal epithelial (Caco-2 BBe) cell monolayers induced a significant reduction in transepithelial resistance, indicating decreased intestinal epithelial barrier function. The chymase-induced intestinal epithelial barrier dysfunction was characterized by chymase-induced protease-activated receptor (PAR)-2 activation and matrix metalloproteinase (MMP)-2 expression and activation. Consistent with this observation, in vitro analysis revealed chymase-induced PAR-2 activation and increased MAPK activity and MMP-2 expression. Pharmacological and small interfering RNA-mediated antagonism of PAR-2 and MMP-2 significantly attenuated chymase-stimulated barrier dysfunction. Additionally, the chymase/MMP-2-mediated intestinal epithelial dysfunction was associated with a significant reduction in the tight junction protein claudin-5, which was partially restored by MMP-2 inhibition. Finally, incubation of Caco-2 BBe cells with chymase-sufficient, but not chymase-deficient, bone marrow-derived mast cells decreased barrier function, which was attenuated by the chymase inhibitor chymostatin. Collectively, these results suggest that mast cell/chymase-mediated intestinal epithelial barrier function is mediated by PAR-2/MMP-2-dependent pathways.

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Flaxseed oligosaccharides alleviate DSS-induced colitis through modulation of gut microbiota and repair of the intestinal barrier in mice

Food & Function ◽

10.1039/d0fo01105c ◽

2020 ◽

Vol 11 (9) ◽

pp. 8077-8088

Author(s):

Zhenxia Xu ◽

Wenchao Chen ◽

Qianchun Deng ◽

Qingde Huang ◽

Xu Wang ◽

...

Keyword(s):

Gut Microbiota ◽

Intestinal Barrier ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Barrier Dysfunction ◽

Intestinal Epithelial Barrier ◽

Epithelial Barrier Dysfunction

Intestinal epithelial barrier dysfunction with dysbiosis of gut microbiota contributes to the occurrence and acceleration of colitis.

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Polyamines are required for expression of Toll-like receptor 2 modulating intestinal epithelial barrier integrity

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00201.2007 ◽

2007 ◽

Vol 293 (3) ◽

pp. G568-G576 ◽

Cited By ~ 44

Author(s):

Jie Chen ◽

Jaladanki N. Rao ◽

Tongtong Zou ◽

Lan Liu ◽

Bernard S. Marasa ◽

...

Keyword(s):

Barrier Function ◽

Low Dose ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Barrier Dysfunction ◽

Intestinal Epithelial Barrier ◽

Tlr2 Expression ◽

Epithelial Barrier Function ◽

Cell Functions ◽

Epithelial Barrier Dysfunction

The Toll-like receptors (TLRs) allow mammalian intestinal epithelium to detect various microbes and activate innate immunity after infection. TLR2 and TLR4 have been identified in intestinal epithelial cells (IECs) as fundamental components of the innate immune response to bacterial pathogens, but the exact mechanism involved in control of TLR expression remains unclear. Polyamines are implicated in a wide variety of biological functions, and regulation of cellular polyamines is a central convergence point for the multiple signaling pathways driving different epithelial cell functions. The current study determined whether polyamines regulate TLR expression, thereby modulating intestinal epithelial barrier function. Depletion of cellular polyamines by inhibiting ornithine decarboxylase (ODC) with α-difluoromethylornithine decreased levels of TLR2 mRNA and protein, whereas increased polyamines by ectopic overexpression of the ODC gene enhanced TLR2 expression. Neither intervention changed basal levels of TLR4. Exposure of normal IECs to low-dose (5 μg/ml) LPS increased ODC enzyme activity and stimulated expression of TLR2 but not TLR4, while polyamine depletion prevented this LPS-induced TLR2 expression. Decreased TLR2 in polyamine-deficient cells was associated with epithelial barrier dysfunction. In contrast, increased TLR2 by the low dose of LPS enhanced epithelial barrier function, which was abolished by inhibition of TLR2 expression with specific, small interfering RNA. These results indicate that polyamines are necessary for TLR2 expression and that polyamine-induced TLR2 activation plays an important role in regulating epithelial barrier function.

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Rebeccamycin Attenuates TNF-α-Induced Intestinal Epithelial Barrier Dysfunction by Inhibiting Myosin Light Chain Kinase Production

Cellular Physiology and Biochemistry ◽

10.1159/000472367 ◽

2017 ◽

Vol 41 (5) ◽

pp. 1924-1934 ◽

Cited By ~ 8

Author(s):

Akihiro Watari ◽

Yuta Sakamoto ◽

Kota Hisaie ◽

Kazuki Iwamoto ◽

Miho Fueta ◽

...

Keyword(s):

Barrier Function ◽

Myosin Light Chain ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Barrier Dysfunction ◽

Intestinal Epithelial Barrier ◽

Epithelial Barrier Function ◽

Cell Monolayers ◽

Tnf Α ◽

Epithelial Barrier Dysfunction

Background/Aims: Although proinflammatory cytokine–induced disruption of intestinal epithelial barrier integrity is associated with intestinal inflammatory disease, effective treatment for barrier dysfunction is lacking. Previously, we demonstrated that rebeccamycin alleviates epithelial barrier dysfunction induced by inflammatory cytokines in Caco-2 cell monolayers; however, the underlying mechanism remained unclear. Here, we investigated the mechanism by which rebeccamycin protects the epithelial barrier function of Caco-2 cells exposed to TNF-α. Methods: To confirm the epithelial barrier function of Caco-2 cell monolayers, transepithelial electrical resistance (TER) and paracellular permeability were measured. Production levels and localization of tight junction (TJ) proteins were analyzed by immunoblot and immunofluorescence, respectively. Phosphorylated myosin light chain (pMLC) and MLC kinase (MLCK) mRNA expression levels were determined by immunoblot and quantitative RT-PCR, respectively. Results: Rebeccamycin attenuated the TNF-α-induced reduction in TER and increase in paracellular permeability. Rebeccamycin increased claudin-5 expression, but not claudin-1, -2, -4, occludin or ZO-1 expression, and prevented the TNF-α-induced changes in ZO-1 and occludin localization. Rebeccamycin suppressed the TNF-α-induced increase in MLCK mRNA expression, thus suppressing MLC phosphorylation. The rebeccamycin-mediated reduction in MLCK production and protection of epithelial barrier function were alleviated by Chk1 inhibition. Conclusion: Rebeccamycin attenuates TNF-α-induced disruption of intestinal epithelial barrier integrity by inducing claudin-5 expression and suppressing MLCK production via Chk1 activation.

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Collagen peptides ameliorate intestinal epithelial barrier dysfunction in immunostimulatory Caco-2 cell monolayers via enhancing tight junctions

Food & Function ◽

10.1039/c6fo01347c ◽

2017 ◽

Vol 8 (3) ◽

pp. 1144-1151 ◽

Cited By ~ 21

Author(s):

Qianru Chen ◽

Oliver Chen ◽

Isabela M. Martins ◽

Hu Hou ◽

Xue Zhao ◽

...

Keyword(s):

Barrier Function ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Barrier Dysfunction ◽

Intestinal Epithelial Barrier ◽

Cell Monolayers ◽

Collagen Peptides ◽

Epithelial Barrier Dysfunction

Alaska pollock skin derived collagen peptides could be considered as dietary supplements for intestinal barrier function promotion and associated diseases.

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Vitamin A inhibits the action of LPS on the intestinal epithelial barrier function and tight junction proteins

Food & Function ◽

10.1039/c8fo01123k ◽

2019 ◽

Vol 10 (2) ◽

pp. 1235-1242 ◽

Cited By ~ 22

Author(s):

Caimei He ◽

Jun Deng ◽

Xin Hu ◽

Sichun Zhou ◽

Jingtao Wu ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Intestinal Barrier ◽

Epithelial Barrier ◽

Intestinal Epithelial ◽

Tight Junction Proteins ◽

Barrier Dysfunction ◽

Intestinal Epithelial Barrier ◽

Epithelial Barrier Function ◽

Inflammatory Bowel ◽

Junction Proteins

Inflammation caused by either intrinsic or extrinsic toxins results in intestinal barrier dysfunction, contributing to inflammatory bowel disease (IBD) and other diseases.

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Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in cardiovascular disease

Clinical Science ◽

10.1042/cs20180172 ◽

2018 ◽

Vol 132 (8) ◽

pp. 901-904 ◽

Cited By ~ 13

Author(s):

Judith N. Lezutekong ◽

Anish Nikhanj ◽

Gavin Y. Oudit

Keyword(s):

Cardiovascular Disease ◽

Gut Microbiota ◽

Intestinal Barrier ◽

Epithelial Barrier ◽

Main Function ◽

Intestinal Epithelial ◽

Barrier Dysfunction ◽

Intestinal Epithelial Barrier ◽

Physiological Homeostasis ◽

Epithelial Barrier Dysfunction

The main function of the intestinal barrier is to regulate the absorption of nutrients, electrolytes, and water from the lumen into circulation and to prevent the entry of pathogenic microorganisms and toxic luminal substances. To maintain this function, an ideal microbiota balance is required and gut microbiota are critical for the intestinal epithelial barrier dysfunction and for the maintenance of physiological homeostasis. There is a demonstrable link between dysbiosis and intestinal dysfunction and diseases such as diabetes, obesity, and cardiovascular disease. However, links amongst gut pathology, microbial ecology, and blood pressure remain elusive. In a recent issue of Clinical Science (vol. 132, issue 6, 701-718), Kim et al. demonstrate a crucial link between gut microbiota and bacterial metabolites such as butyrate, gut leakiness, and hypertension.

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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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