scholarly journals Leptin Downregulates Angulin-1 in Active Crohn’s Disease via STAT3

2020 ◽  
Vol 21 (21) ◽  
pp. 7824
Author(s):  
Jia-Chen Hu ◽  
Christian Bojarski ◽  
Federica Branchi ◽  
Michael Fromm ◽  
Susanne Krug
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Tight Junction ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Fat Tissue ◽  
Jak2 Inhibitor ◽  
Junction Protein ◽  
Underlying Mechanisms

Crohn’s disease (CD) has an altered intestinal barrier function, yet the underlying mechanisms remain to be disclosed. The tricellular tight junction protein tricellulin is involved in the maintenance of the paracellular macromolecule barrier and features an unchanged expression level in CD but a shifted localization. As angulins are known to regulate the localization of tricellulin, we hypothesized the involvement of angulins in CD. Using human biopsies, we found angulin-1 was downregulated in active CD compared with both controls and CD in remission. In T84 and Caco-2 monolayers, leptin, a cytokine secreted by fat tissue and affected in CD, decreased angulin-1 expression. This effect was completely blocked by STAT3 inhibitors, Stattic and WP1066, but only partially by JAK2 inhibitor AG490. The effect of leptin was also seen at a functional level as we observed in Caco-2 cells an increased permeability for FITC-dextran 4 kDa indicating an impaired barrier against macromolecule uptake. In conclusion, we were able to show that in active CD angulin-1 expression is downregulated, which leads to increased macromolecule permeability and is inducible by leptin via STAT3. This suggests that angulin-1 and leptin secretion are potential targets for intervention in CD to restore the impaired intestinal barrier.

scholarly journals Expression of tricellular tight junction proteins and the paracellular macromolecule barrier are recovered in remission of ulcerative colitis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jia-Chen E. Hu ◽  
Franziska Weiß ◽  
Christian Bojarski ◽  
Federica Branchi ◽  
Jörg-Dieter Schulzke ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Tight Junction ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Benjamin Franklin ◽  
Clinical Appearance ◽  
Ussing Chambers ◽  
Junction Protein ◽  
Underlying Mechanisms

Abstract Background Ulcerative colitis (UC) has a relapsing and remitting pattern, wherein the underlying mechanisms of the relapse might involve an enhanced uptake of luminal antigens which stimulate the immune response. The tricellular tight junction protein, tricellulin, takes charge of preventing paracellular passage of macromolecules. It is characterized by downregulated expression in active UC and its correct localization is regulated by angulins. We thus analyzed the tricellulin and angulin expression as well as intestinal barrier function and aimed to determine the role of tricellulin in the mechanisms of relapse. Methods Colon biopsies were collected from controls and UC patients who underwent colonoscopy at the central endoscopy department of Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin. Remission of UC was defined basing on the clinical appearance and a normal Mayo endoscopic subscore. Intestinal barrier function was evaluated by electrophysiological and paracellular flux measurements on biopsies mounted in Ussing chambers. Results The downregulated tricellulin expression in active UC was recovered in remission UC to control values. Likewise, angulins were in remission UC at the same levels as in controls. Also, the epithelial resistance which was decreased in active UC was restored in remission to the same range as in controls, along with the unaltered paracellular permeabilities for fluorescein and FITC-dextran 4 kDa. Conclusions In remission of UC, tricellulin expression level as well as intestinal barrier functions were restored to normal, after they were impaired in active UC. This points toward a re-sealing of the impaired tricellular paracellular pathway and abated uptake of antigens to normal rates in remission of UC.

scholarly journals Anti-TNF-α antibodies improve intestinal barrier function in Crohn's disease

2012 ◽  
Vol 6 (4) ◽  
pp. 464-469 ◽  
Author(s):  
Rainer Noth ◽  
Eckhard Stüber ◽  
Robert Häsler ◽  
Susanna Nikolaus ◽  
Tanja Kühbacher ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Tnf Α

scholarly journals Glutamine supplementation improves intestinal barrier function in a weaned piglet model of Escherichia coli infection

2011 ◽  
Vol 106 (6) ◽  
pp. 870-877 ◽  
Author(s):  
Julia B. Ewaschuk ◽  
Gordon K. Murdoch ◽  
Ian R. Johnson ◽  
Karen L. Madsen ◽  
Catherine J. Field
Keyword(s):  
Escherichia Coli ◽  
Protein Expression ◽  
Tight Junction ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Intestinal Tissue ◽  
E Coli ◽  
Tight Junction Protein Expression ◽  
Junction Protein

The weaning period is associated with an increased prevalence of gastrointestinal infection in many species. Glutamine (Gln) has been shown to improve intestinal barrier function and immune function in both in vivo and in vitro models. The objective of the present study was to determine the effect of dietary Gln supplementation on intestinal barrier function and intestinal cytokines in a model of Escherichia coli infection. We randomised 21-d-old piglets (n 20) to nutritionally complete isonitrogenous diets with or without Gln (4·4 %, w/w) for 2 weeks. Intestinal loops were isolated from anaesthetised pigs and inoculated with either saline or one of the two E. coli (K88AC or K88 wild-type)-containing solutions. Intestinal tissue was studied for permeability, cytokine expression, fluid secretion and tight-junction protein expression. Animals receiving Gln supplementation had decreased potential difference (PD) and short-circuit current (Isc) in E. coli-inoculated intestinal loops (PD 0·628 (sem 0·151) mV; Isc 13·0 (sem 3·07) μA/cm2) compared with control-fed animals (PD 1·36 (sem 0·227) mV; Isc 22·4 (sem 2·24) μA/cm2). Intestinal tissue from control, but not from Gln-supplemented, animals responded to E. coli with a significant increase in mucosal cytokine mRNA (IL-1β, IL-6, transforming growth factor-β and IL-10). Tight-junction protein expression (claudin-1 and occludin) was reduced with exposure to E. coli in control-fed animals and was not influenced in Gln-supplemented piglets. Gln supplementation may be useful in reducing the severity of weaning-related gastrointestinal infections, by reducing the mucosal cytokine response and altering intestinal barrier function.

scholarly journals PSVIII-1 Nutrient starvation induces autophagy and alters intestinal barrier function in IPEC-J2 cells

2019 ◽  
Vol 97 (Supplement_3) ◽  
pp. 284-284
Author(s):  
Enkai Li ◽  
Hang Lu ◽  
Kolapo Ajuwon
Keyword(s):  
Tight Junction ◽  
Mrna Expression ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Nutrient Starvation ◽  
Intestinal Barrier Function ◽  
Control Group ◽  
Protein Abundance ◽  
Junction Protein ◽  
Food Antigens

Abstract Autophagy is a cellular process of controlled degradation of damaged organelles and cytoplasmic macromolecules during stress for maintaining homeostasis. Intestinal epithelial cells are barriers against microorganisms, toxins and food antigens. Whether autophagy plays a role in regulating intestinal barrier function is unclear. The objective of this study was to characterize the role of autophagy in starvation-induced alteration of tight junction protein abundance and function in IPEC-J2 cells. Cells were nutrient starved in Krebs-Ringer bicarbonate (KRB) buffer for 0, 0.5, 1, 2, 3, 6, 9 and 12 h. Expression of genes implicated in autophagy regulation (AMPK, MDM2, p53 and DRAM) was determined by RT-PCR. The ratio of protein abundance of microtubule-associated protein light chain 3 (LC3-II/LC3-I) and p62, positive and negative markers of autophagy induction, respectively, was determined by western blotting. Compared with control group (0 h), the relative mRNA expression level of AMPK, MDM2, p53 and DRAM significantly decreased by an average of 52.5% (P < 0.01). Relative to 0 h, the mRNA expression of claudin 1 and claudin 4 significantly increased (108.0%) up to 6 h of starvation and then decreased (31.4%) thereafter (P < 0.01). On the contrary, abundance of claudin 1 and claudin 4 protein was downregulated (49.5%) up to 3 h of starvation and then increased (82.6%) thereafter (P < 0.01). Protein expression of claudin 3 was reduced (P < 0.01) with duration of starvation. There was no change in the protein level of occludin and ZO-1. The ratio of LC3-II/LC3-I significantly increased with duration starvation (P < 0.01), whereas p62 and phospho-AMPK levels decreased up to 6 h of starvation and then increased thereafter (P < 0.01). In summary, autophagy may be implicated in the regulation of tight junction integrity during nutrient starvation in IPEC-J2 cells.

scholarly journals Higher prevalence of Bacteroides fragilis in Crohn’s disease exacerbations and strain-dependent increase of epithelial resistance

2020 ◽  
Author(s):  
Heike E. F. Becker ◽  
Casper Jamin ◽  
Liene Bervoets ◽  
Pan Xu ◽  
Marie J. Pierik ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intestinal Barrier ◽  
Bacteroides Fragilis ◽  
Intestinal Barrier Function ◽  
Metagenome Sequencing ◽  
Underlying Mechanisms ◽  
The Impact ◽  
Epithelial Resistance

AbstractBacteroides fragilis has previously been linked to Crohn’s disease (CD) exacerbations, but results are inconsistent and underlying mechanisms unknown. This study investigates the epidemiology of B. fragilis and its virulence factors bft (enterotoxin) and ubiquitin among 181 CD patients and the impact on the intestinal epithelial barrier in vitro.The prevalence of B. fragilis was significantly higher in active (n=69/88, 78.4%) as compared to remissive (n=58/93, 62.4%, p=0.018) CD patients. Moreover, B. fragilis was associated with intestinal strictures. Interestingly, the intestinal barrier function, as examined by transepithelial electrical resistance (TEER) measurements of Caco-2 monolayers, improved when exposed to secretomes of bft-positive (increased TEER ∼160%, p<0.001) but not when exposed to bft- negative strains. Whole metagenome sequencing and metabolomics, respectively, identified 19 coding sequences and two metabolites that discriminated TEER-increasing from non-TEER-increasing strains.This study revealed a higher B. fragilis prevalence during exacerbation. Surprisingly, bft-positive secretomes improved epithelial resistance.

scholarly journals Betaine attenuates LPS-induced downregulation of Occludin and Claudin-1 and restores intestinal barrier function

2019 ◽  
Author(s):  
Jingtao Wu ◽  
Caimei He ◽  
Jie Bu ◽  
Yue Luo ◽  
Shuyuan Yang ◽  
...  
Keyword(s):  
Tight Junction ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Inflammatory Factors ◽  
Intestinal Barrier Function ◽  
Epithelial Barrier ◽  
Tight Junction Proteins ◽  
Junction Protein ◽  
Epithelial Barriers ◽  
Junction Proteins

Abstract Background: The intestinal epithelial barrier, which works as the first line of defense between the intestinal environment and the parasitifer, once destroyed, it will cause serious inflammation or other intestinal diseases. Tight junctions (TJs) play a vital role to maintain the integrity of the epithelial barrier. Lipopolysaccharide (LPS), one of the most important inflammatory factors will downregulate specific TJ proteins including Occludin and Claudin-1 and impair integrity of the epithelial barrier. Betaine (Bet) has excellent anti-inflammatory activity but whether Bet has any effect on tight junction proteins, particularly on LPS-induced dysfunction of epithelial barriers remains unknown. Intestinal porcine epithelial cells (IPEC-J2) were used as an in vitro model, the purpose of this study is to explore the pharmacological effect of Bet on improving intestinal barrier function represented by TJ proteins.Results: The results demonstrated that Bet enhanced the expression of tight junction proteins while LPS（ 1μg /m L）downregulates the expression of these proteins. Furthermore, Bet attenuates LPS-induced decreases of tight junction proteins both shown by WB and RT-PCR. The immunofluorescent images consistently revealed that LPS induced the disruption of tight junction protein Claudin-1 and reduced its expression while Bet could reverse these alterations. Similar protective role of Bet on intestinal barrier function was observed by transepithelial electrical resistance (TEER) approach. Conclusion: In conclusion, our research demonstrated that Bet attenuated LPS-induced downregulation of Occludin and Claudin-1 and restored the intestinal barrier function.

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