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

Amino Acids ◽  
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.

scholarly journals The role of zinc deficiency in alcohol-induced intestinal barrier dysfunction

2010 ◽  
Vol 298 (5) ◽  
pp. G625-G633 ◽  
Author(s):  
Wei Zhong ◽  
Craig J. McClain ◽  
Matthew Cave ◽  
Y. James Kang ◽  
Zhanxiang Zhou
Keyword(s):  
Oxidative Stress ◽  
Tight Junction ◽  
Zinc Deficiency ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Alcohol Exposure ◽  
Epithelial Barrier ◽  
Tight Junction Proteins ◽  
Barrier Dysfunction ◽  
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.

scholarly journals Translational Approaches with Antioxidant Phytochemicals against Alcohol-Mediated Oxidative Stress, Gut Dysbiosis, Intestinal Barrier Dysfunction and Fatty Liver Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 384
Author(s):  
Jacob W. Ballway ◽  
Byoung-Joon Song
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Intestinal Barrier ◽  
Leaky Gut ◽  
Barrier Dysfunction ◽  
Intestinal Barrier Dysfunction ◽  
Gut Dysbiosis ◽  
Disease States

Emerging data demonstrate the important roles of altered gut microbiomes (dysbiosis) in many disease states in the peripheral tissues and the central nervous system. Gut dysbiosis with decreased ratios of Bacteroidetes/Firmicutes and other changes are reported to be caused by many disease states and various environmental factors, such as ethanol (e.g., alcohol drinking), Western-style high-fat diets, high fructose, etc. It is also caused by genetic factors, including genetic polymorphisms and epigenetic changes in different individuals. Gut dysbiosis, impaired intestinal barrier function, and elevated serum endotoxin levels can be observed in human patients and/or experimental rodent models exposed to these factors or with certain disease states. However, gut dysbiosis and leaky gut can be normalized through lifestyle alterations such as increased consumption of healthy diets with various fruits and vegetables containing many different kinds of antioxidant phytochemicals. In this review, we describe the mechanisms of gut dysbiosis, leaky gut, endotoxemia, and fatty liver disease with a specific focus on the alcohol-associated pathways. We also mention translational approaches by discussing the benefits of many antioxidant phytochemicals and/or their metabolites against alcohol-mediated oxidative stress, gut dysbiosis, intestinal barrier dysfunction, and fatty liver disease.

scholarly journals OP0245 MICROBIOTA-INDUCED INTESTINAL BARRIER DYSFUNCTION PRECEDES THE ONSET OF ARTHRITIS AND ALLOWS THE SHUTTLING OF IMMUNE CELLS FROM THE GUT THE JOINTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 154.2-154
Author(s):  
M. Zaiss ◽  
N. Taijc ◽  
K. Sarter ◽  
V. Azizov ◽  
L. Bucci ◽  
...  
Keyword(s):  
Tight Junction ◽  
Tight Junctions ◽  
Immune Cells ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Barrier Dysfunction ◽  
Intestinal Barrier Dysfunction ◽  
Microbial Dysbiosis ◽  
Intestinal Dysbiosis

Background:While it is known that microbial dysbiosis is associated with the onset of rheumatoid arthritis, mechanistic insights how it facilitates the development of arthritis remained largely elusive to date. It is especially interesting how microbial dysbiosis affects the transition from asymptomatic autoimmunity to arthritis. We speculated that a breakdown of intestinal barrier function caused by microbial dysbiosis allows immune cells to shuttle from the gut to the joints.Objectives:To test whether intestinal barrier function is impaired before the onset of human RA and experimental arthritis and to seek for evidence that immune cells from the gut migrate to the joints.Methods:In a longitudinal cohort of RA-at risk individuals markers of disturbed intestinal barrier function, such as zonulin, were analysed and linked to RA onset. Furthermore, new-onset RA patients were assessed for gut leakiness and their intestinal biopsies for the expression of tight junction proteins and immune cell infiltration. In the murine model of collagen-induced arthritis, sequential analysis of intestinal dysbiosis, intestinal barrier function and arthritis onset was carried out. Additionally, barrier function was assessed on intestinal organoids exposed to faecal supernatants from eu- and dysbiotic mice with and without inhibition of zonulin. Furthermore, three types of interventions restoring intestinal barrier function were carried out for testing their effects on the inhibition of arthritis onset. Finally, photo- converted cells from the gut were traced in the joints to test for cellular trafficking from one to the other compartment.Results:Zonulin, a potent regulator for intestinal tight junctions, was elevated in autoimmune mice and men before the onset of arthritis and predicted the onset of human RA. Intestinal barrier functions as well as epithelial tight junctions were decreased before the onset of experimental arthritis and at onset of human RA. In mice, induction of autoimmunity was followed by rapid intestinal dysbiosis followed by gut leakiness before arthritis started. Faecal supernatants of arthritic mice induce epithelial barrier dysfunction in intestinal organoids in zonulin dependent manner. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate, CB1R agonist or zonulin antagonist larazotide inhibited the development of arthritis. Finally, using photoconvertible mice, gut-borne immune cells were identified that homed to the joints when barrier function was impaired.Conclusion:In summary, these data show the intestinal barrier dysfunction precedes the onset of RA and allows the trafficking of immune cells from the gut to the joints. Targeting of intestinal tight junction function may therefore allow preventing the onset of RA.Acknowledgments:Funded by the DFG-FOR2886 PANDORA, DFG–CRC118, Staedtler foundation, Johannes und Frieda Marohn-Stiftung, Else Kröner-Fresenius foundation, Interdisciplinary Centre for Clinical Research, Erlangen (IZKF), BMBF-MASCARA and the IMI funded projectRTCure.Disclosure of Interests:Mario Zaiss: None declared, Narges Taijc: None declared, Kerstin Sarter: None declared, Vugar Azizov: None declared, laura Bucci: None declared, Yubin Luo: None declared, Juan de Dios Cañete: None declared, francesco ciccia Grant/research support from: pfizer, novartis, roche, Consultant of: pfizer, novartis, lilly, abbvie, Speakers bureau: pfizer, novartis, lilly, abbvie, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB

Distribution of tight junction proteins occludin and claudin-1 in cytokine-induced intestinal barrier dysfunction

2000 ◽  
Vol 118 (4) ◽  
pp. A600
Author(s):  
Heinz Schmitz ◽  
Joachim Mankertz ◽  
Natalie Buergel ◽  
Michael Fromm ◽  
Ernst O. Riecken ◽  
...  
Keyword(s):  
Tight Junction ◽  
Intestinal Barrier ◽  
Tight Junction Proteins ◽  
Barrier Dysfunction ◽  
Intestinal Barrier Dysfunction ◽  
Junction Proteins

scholarly journals Inflammatory Bowel Disease Therapies and Gut Function in a Colitis Mouse Model

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Lily Nahidi ◽  
Steven T. Leach ◽  
Hazel M. Mitchell ◽  
Nadeem O. Kaakoush ◽  
Daniel A. Lemberg ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tight Junction ◽  
Barrier Function ◽  
Short Circuit ◽  
Intestinal Barrier ◽  
Barrier Dysfunction ◽  
Gut Barrier ◽  
Intestinal Barrier Dysfunction ◽  
Gut Barrier Function ◽  
Inflammatory Changes

Background. Exclusive enteral nutrition (EEN) is a well-established approach to the management of Crohn’s disease.Aim. To determine effects of EEN upon inflammation and gut barrier function in a colitis mouse model.Methods. Interleukin-10-deficient mice (IL-10−/−) were inoculated withHelicobacter trogontumand then treated with EEN, metronidazole, hydrocortisone, or EEN and metronidazole combination. Blood and tissue were collected at 2 and 4 weeks with histology, mucosal integrity, tight junction integrity, inflammation, andH. trogontumload evaluated.Results.H. trogontuminduced colitis in IL-10−/−mice with histological changes in the cecum and colon. Elevated mucosal IL-8 mRNA in infected mice was associated with intestinal barrier dysfunction indicated by decreased transepithelial electrical resistance and mRNA of tight junction proteins and increased short-circuit current, myosin light chain kinase mRNA, paracellular permeability, and tumor necrosis factor-αand myeloperoxidase plasma levels (P<0.01for all comparisons). EEN and metronidazole, but not hydrocortisone, treatments restored barrier function, maintained gut barrier integrity, and reversed inflammatory changes along with reduction ofH. trogontumload (versus infected controlsP<0.05).Conclusion.H. trogontuminfection in IL-10−/−mice induced typhlocolitis with intestinal barrier dysfunction. EEN and metronidazole, but not hydrocortisone, modulate barrier dysfunction and reversal of inflammatory changes.

Tight junction protein ZO-1 in Kawasaki disease

2020 ◽  
Author(s):  
Wan-Tz Lai ◽  
Ying-Hsien Huang ◽  
Mao-Hung Lo ◽  
Ho-Chang Kuo
Keyword(s):  
Coronary Artery ◽  
Kawasaki Disease ◽  
Tight Junction ◽  
Statistical Significance ◽  
Intestinal Barrier ◽  
Ivig Treatment ◽  
P Value ◽  
Coronary Artery Lesions ◽  
Barrier Dysfunction ◽  
Intestinal Barrier Dysfunction

Abstract BackgroundKawasaki disease (KD) is a form of systemic febrile vasculitis that can be complicated by coronary artery lesions (CAL). A murine model of KD vasculitis showed that the vasculitis depended on intestinal barrier dysfunction, as well as that the tight junctions maintain the intestinal barrier. In this study, we aimed to investigate the role of tight junction Zonula occludens-1 (Zo-1) in intravenous immunoglobulin (IVIG) treatment response and the occurrence of CAL formation in KD patients.MethodsForty KD patients, 12 healthy controls, and 12 febrile controls were enrolled in this study. Tight junction ZO-1 levels were measured in sera by enzyme-linked immunosorbent assay.ResultsThe serum Zo-1 level was higher in the fever control group but did not achieve statistical significance. Patients who received a second dose of IVIG due to a failure to respond to the initial IVIG treatment had a higher serum tight junction Zo-1 level, but also without statistical significance (p value =0.0582). Patients who developed a coronary artery lesion had a lower serum tight junction Zo-1 level with statistical significance (p value =0.0275).ConclusionsTight junction ZO-1 levels decrease in KD patients with coronary artery lesions and are associated with the intestinal barrier dysfunction of Kawasaki disease and the occurrence of CAL in KD patients.

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