991 – Matrix Metalloproteinase 7 Contributes to Intestinal Barrier Dysfunction by Suppressing Tight Junction Proteins

Disruption of the intestinal barrier is a causal factor in the development of alcoholic endotoxemia and hepatitis. This study was undertaken to determine whether zinc deficiency is related to the deleterious effects of alcohol on the intestinal barrier. Mice were pair fed an alcohol or isocaloric liquid diet for 4 wk, and hepatitis was detected in association with elevated blood endotoxin level. Alcohol exposure significantly increased the permeability of the ileum but did not affect the barrier function of the duodenum or jejunum. Reduction of tight-junction proteins at the ileal epithelium was detected in alcohol-fed mice although alcohol exposure did not cause apparent histopathological changes. Alcohol exposure significantly reduced the ileal zinc concentration in association with accumulation of reactive oxygen species. Caco-2 cell culture demonstrated that alcohol exposure increases the intracellular free zinc because of oxidative stress. Zinc deprivation caused epithelial barrier disruption in association with disassembling of tight junction proteins in the Caco-2 monolayer cells. Furthermore, minor zinc deprivation exaggerated the deleterious effect of alcohol on the epithelial barrier. In conclusion, epithelial barrier dysfunction in the distal small intestine plays an important role in alcohol-induced gut leakiness, and zinc deficiency attributable to oxidative stress may interfere with the intestinal barrier function by a direct action on tight junction proteins or by sensitizing to the effects of alcohol.

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Adalimumab prevents barrier dysfunction and antagonizes distinct effects of TNF-α on tight junction proteins and signaling pathways in intestinal epithelial cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00183.2012 ◽

2013 ◽

Vol 304 (11) ◽

pp. G970-G979 ◽

Cited By ~ 60

Author(s):

Andreas Fischer ◽

Markus Gluth ◽

Ulrich-Frank Pape ◽

Bertram Wiedenmann ◽

Franz Theuring ◽

...

Keyword(s):

Tight Junction ◽

Inflammatory Bowel Diseases ◽

Intestinal Barrier ◽

Model Systems ◽

Tight Junction Proteins ◽

Barrier Dysfunction ◽

Tnf Α ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Junction Proteins

Intestinal barrier dysfunction is pivotal in the etiology of inflammatory bowel diseases. Combined clinical and endoscopic remission (“mucosal healing”) in patients who received anti-TNF-α therapies suggests restitution of the intestinal barrier, but the mechanisms involved are largely unknown. We therefore investigated the impact of the anti-TNF-α antibody adalimumab on barrier function in two in vitro models. Combined stimulation of Caco-2 and T-84 cells with interferon-γ and TNF-α resulted in a significant decrease of transepithelial electrical resistance (TEER) within 6 h that was prevented by adalimumab in concentrations down to 100 ng/ml. Adalimumab furthermore antagonized the appearance of irregular membrane undulations and prevented internalization of tight junction proteins upon cytokine exposure. In addition, TNF-α induced a downregulation of claudin-1, claudin-2, claudin-4, and occludin as well as activation of phosphatidylinositol 3-kinase signaling in T-84 but not Caco-2 cells, which was reversed by adalimumab. At the signaling level, adalimumab prevented increased phosphorylation of myosin light chain as well as activation of p38 MAPK and NF-κB accompanying the decline in TEER in both model systems. Pharmacological inhibition of NF-κB signaling partially prevented the TNF-α-induced TEER loss, whereas inhibition of p38 worsened barrier dysfunction in Caco-2 but not T-84 cells. Taken together, these data demonstrate that adalimumab prevents barrier dysfunction induced by TNF-α both functionally and structurally as well as at the level of signal transduction. Barrier protection might therefore constitute a novel mechanism how anti-TNF-α therapy contributes to epithelial restitution and tissue repair in inflammatory bowel diseases.

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Acrolein Disrupts Tight Junction Proteins and Causes Endoplasmic Reticulum Stress-Mediated Epithelial Cell Death Leading to Intestinal Barrier Dysfunction and Permeability

American Journal Of Pathology ◽

10.1016/j.ajpath.2017.08.015 ◽

2017 ◽

Vol 187 (12) ◽

pp. 2686-2697 ◽

Cited By ~ 29

Author(s):

Wei-Yang Chen ◽

Min Wang ◽

Jingwen Zhang ◽

Shirish S. Barve ◽

Craig J. McClain ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Epithelial Cell ◽

Endoplasmic Reticulum Stress ◽

Tight Junction ◽

Intestinal Barrier ◽

Tight Junction Proteins ◽

Barrier Dysfunction ◽

Epithelial Cell Death ◽

Junction Proteins

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Severe burn injury alters intestinal microbiota composition and impairs intestinal barrier in mice

Burns & Trauma ◽

10.1186/s41038-019-0156-1 ◽

2019 ◽

Vol 7 ◽

Cited By ~ 4

Author(s):

Yanhai Feng ◽

Yalan Huang ◽

Yu Wang ◽

Pei Wang ◽

Fengjun Wang

Keyword(s):

Microbial Community ◽

Tight Junction ◽

Inflammatory Cytokines ◽

Burn Injury ◽

Intestinal Barrier ◽

Tight Junction Proteins ◽

Severe Burn ◽

Barrier Dysfunction ◽

Severe Burn Injury ◽

Junction Proteins

Abstract Background The intestinal barrier integrity is crucial for maintaining intestinal homeostasis, and the mechanisms of intestinal barrier disruption induced by burn injury remain obscure. This study was aimed to investigate the changes of intestinal microbiota and barrier function in burned mice to further comprehend the mechanisms of burn-induced intestinal barrier dysfunction. Methods Samples were from mice inflicted with 30% total body surface area (TBSA) full-thickness burns. The intestinal permeability, tight junction proteins expressions, zonula occludens-1 (ZO-1) localization, inflammatory cytokines expressions, and short-chain fatty acids (SCFAs) contents were determined. The microbial community was assessed via 16S rDNA Illumina sequencing. Results The intestinal permeability was increased after severe burn injury, peaking at 6 h post-burn, with approximately 20-folds of the control (p < 0.001). The expression of tight junction proteins (ZO-1, occludin, claudin-1, and claudin-2) was significantly altered (p < 0.05). The ZO-1 morphology was dramatically changed following burn injury. The fecal SCFAs’ contents (acetate, propionate, butyrate, isobutyrate, and isovalerate) were noticeably declined after burn injury (p < 0.05). The expressions of pro-inflammatory cytokines (interleukin (IL)-1β and IL-6) in ileal mucosa were increased, whereas the expressions of anti-inflammatory cytokines (IL-4 and IL-13) were decreased following burn injury (p < 0.05). In addition, burned mice showed an alteration of intestinal microbial community, such as decreased diversity, reduced Bacteroidetes abundance, and increased Firmicutes abundance. Conclusions The severe burn-induced intestinal barrier dysfunction is along with the alterations of microbial community.

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Cystine reduces tight junction permeability and intestinal inflammation induced by oxidative stress in Caco-2 cells

Amino Acids ◽

10.1007/s00726-021-03001-y ◽

2021 ◽

Author(s):

Tatsuya Hasegawa ◽

Ami Mizugaki ◽

Yoshiko Inoue ◽

Hiroyuki Kato ◽

Hitoshi Murakami

Keyword(s):

Oxidative Stress ◽

Tight Junction ◽

Mrna Expression ◽

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Intestinal Barrier ◽

Barrier Dysfunction ◽

Whole Cells ◽

Intestinal Barrier Dysfunction ◽

Pro Inflammatory Cytokines

AbstractIntestinal oxidative stress produces pro-inflammatory cytokines, which increase tight junction (TJ) permeability, leading to intestinal and systemic inflammation. Cystine (Cys2) is a substrate of glutathione (GSH) and inhibits inflammation, however, it is unclear whether Cys2 locally improves intestinal barrier dysfunction. Thus, we investigated the local effects of Cys2 on oxidative stress-induced TJ permeability and intestinal inflammatory responses. Caco-2 cells were cultured in a Cys2-supplemented medium for 24 h and then treated with H2O2 for 2 h. We assessed TJ permeability by measuring transepithelial electrical resistance and the paracellular flux of fluorescein isothiocyanate–dextran 4 kDa. We measured the concentration of Cys2 and GSH after Cys2 pretreatment. The mRNA expression of pro-inflammatory cytokines was assessed. In addition, the levels of TJ proteins were assessed by measuring the expression of TJ proteins in the whole cells and the ratio of TJ proteins in the detergent-insoluble fractions to soluble fractions (IS/S ratio). Cys2 treatment reduced H2O2-induced TJ permeability. Cys2 did not change the expression of TJ proteins in the whole cells, however, suppressed the IS/S ratio of claudin-4. Intercellular levels of Cys2 and GSH significantly increased in cells treated with Cys2. Cys2 treatment suppressed the mRNA expression of pro-inflammatory cytokines, and the mRNA levels were significantly correlated with TJ permeability. In conclusion, Cys2 treatment locally reduced oxidative stress-induced intestinal barrier dysfunction possively due to the mitigation of claudin-4 dislocalization. Furthermore, the effect of Cys2 on the improvement of intestinal barrier function is related to the local suppression of oxidative stress-induced pro-inflammatory responses.

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