scholarly journals A missense variant inSLC39A8confers risk for Crohn’s disease by disrupting manganese homeostasis and intestinal barrier integrity

2020 ◽  
Vol 117 (46) ◽  
pp. 28930-28938
Author(s):  
Toru Nakata ◽  
Elizabeth A. Creasey ◽  
Motohiko Kadoki ◽  
Helen Lin ◽  
Martin K. Selig ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Metabolic Diseases ◽  
Disease Risk ◽  
Intestinal Barrier ◽  
Missense Variant ◽  
Intestinal Barrier Function ◽  
Barrier Integrity ◽  
Common Genetic Variants ◽  
Intestinal Barrier Integrity

Common genetic variants interact with environmental factors to impact risk of heritable diseases. A notable example of this is a single-nucleotide variant in the Solute Carrier Family 39 Member 8 (SLC39A8)geneencoding the missense variant A391T, which is associated with a variety of traits ranging from Parkinson’s disease and neuropsychiatric disease to cardiovascular and metabolic diseases and Crohn’s disease. The remarkable extent of pleiotropy exhibited bySLC39A8A391T raises key questions regarding how a single coding variant can contribute to this diversity of clinical outcomes and what is the mechanistic basis for this pleiotropy. Here, we generate a murine model for theSlc39a8A391T allele and demonstrate that these mice exhibit Mn deficiency in the colon associated with impaired intestinal barrier function and epithelial glycocalyx disruption. Consequently,Slc39a8A391T mice exhibit increased sensitivity to epithelial injury and pathological inflammation in the colon. Taken together, our results link a genetic variant with a dietary trace element to shed light on a tissue-specific mechanism of disease risk based on impaired intestinal barrier integrity.

scholarly journals Higher Prevalence of Bacteroides fragilis in Crohn’s Disease Exacerbations and Strain-Dependent Increase of Epithelial Resistance

2021 ◽  
Vol 12 ◽  
Author(s):  
Heike E. F. Becker ◽  
Casper Jamin ◽  
Liene Bervoets ◽  
Annemarie Boleij ◽  
Pan Xu ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intestinal Barrier ◽  
Bacteroides Fragilis ◽  
Causative Factor ◽  
Intestinal Barrier Function ◽  
Metagenome Sequencing ◽  
The Impact ◽  
Epithelial Resistance

Bacteroides 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, increased when exposed to secretomes of bft-positive (bft-1 and bft-2 isotype; increased TEER ∼160%, p < 0.001) but not when exposed to bft-negative strains. Whole metagenome sequencing and metabolomics, respectively, identified nine 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 increased epithelial resistance, but we excluded Bft as the likely causative factor.

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

PKC-ζ is required in EGF protection of microtubules and intestinal barrier integrity against oxidant injury

2002 ◽  
Vol 282 (5) ◽  
pp. G794-G808 ◽  
Author(s):  
A. Banan ◽  
J. Z. Fields ◽  
D. A. Talmage ◽  
L. Zhang ◽  
A. Keshavarzian
Keyword(s):  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Oxidant Injury ◽  
Microtubule Cytoskeleton ◽  
Barrier Integrity ◽  
Kinase C ◽  
Epidermal Growth ◽  
Intestinal Barrier Integrity ◽  
High Doses ◽  
Pkc Ζ

Using monolayers of human intestinal (Caco-2) cells, we showed that epidermal growth factor (EGF) protects intestinal barrier integrity against oxidant injury by protecting the microtubules and that protein kinase C (PKC) is required. Because atypical PKC-ζ isoform is abundant in wild-type (WT) Caco-2 cells, we hypothesized that PKC-ζ mediates, at least in part, EGF protection. Intestinal cells (Caco-2 or HT-29) were transfected to stably over- or underexpress PKC-ζ. These clones were preincubated with low or high doses of EGF or a PKC activator [1-oleoyl-2-acetyl- sn-glycerol (OAG)] before oxidant (0.5 mM H2O2). Relative to WT cells exposed to oxidant, only monolayers of transfected cells overexpressing PKC-ζ (2.9-fold) were protected against oxidant injury as indicated by increases in polymerized tubulin and decreases in monomeric tubulin, enhancement of architectural stability of the microtubule cytoskeleton, and increases in monolayer barrier integrity toward control levels (62% less leakiness). Overexpression-induced protection was OAG independent and even EGF independent, but EGF significantly potentiated PKC-ζ protection. Most overexpressed PKC-ζ (92%) resided in membrane and cytoskeletal fractions, indicating constitutive activation of PKC-ζ. Stably inhibiting PKC-ζ expression (95%) with antisense transfection substantially attenuated EGF protection as demonstrated by reduced tubulin assembly and increased microtubule disassembly, disruption of the microtubule cytoskeleton, and loss of monolayer barrier integrity. We conclude that 1) activation of PKC-ζ is necessary for EGF-induced protection, 2) PKC-ζ appears to be an endogenous stabilizer of the microtubule cytoskeleton and of intestinal barrier function against oxidative injury, and 3) we have identified a novel biological function (protection) among the atypical isoforms of PKC.

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 A β-Glucan-Based Dietary Fiber Reduces Mast Cell-Induced Hyperpermeability in Ileum From Patients With Crohn’s Disease and Control Subjects

2017 ◽  
Vol 24 (1) ◽  
pp. 166-178 ◽  
Author(s):  
John-Peter Ganda Mall ◽  
Maite Casado-Bedmar ◽  
Martin E Winberg ◽  
Robert J Brummer ◽  
Ida Schoultz ◽  
...  
Keyword(s):  
Mast Cell ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Barrier Dysfunction ◽  
Ussing Chambers ◽  
Beneficial Effects ◽  
And Control

Abstract Background Administration of β-glucan has shown immune-enhancing effects. Our aim was to investigate whether β-glucan could attenuate mast cell (MC)-induced hyperpermeability in follicle-associated epithelium (FAE) and villus epithelium (VE) of patients with Crohn’s disease (CD) and in noninflammatory bowel disease (IBD)-controls. Further, we studied mechanisms of β-glucan uptake and effects on MCs in vitro. Methods Segments of FAE and VE from 8 CD patients and 9 controls were mounted in Ussing chambers. Effects of the MC-degranulator compound 48/80 (C48/80) and yeast-derived β-1,3/1,6 glucan on hyperpermeability were investigated. Translocation of β-glucan and colocalization with immune cells were studied by immunofluorescence. Caco-2-cl1- and FAE-cultures were used to investigate β-glucan-uptake using endocytosis inhibitors and HMC-1.1 to study effects on MCs. Results β-glucan significantly attenuated MC-induced paracellular hyperpermeability in CD and controls. Transcellular hyperpermeability was only significantly attenuated in VE. Baseline paracellular permeability was higher in FAE than VE in both groups, P<0.05, and exhibited a more pronounced effect by C48/80 and β-glucan P<0.05. No difference was observed between CD and controls. In vitro studies showed increased passage, P<0.05, of β-glucan through FAE-culture compared to Caco-2-cl1. Passage was mildly attenuated by the inhibitor methyl-β-cyclodextrin. HMC-1.1 experiments showed a trend to decreasing MC-degranulation and levels of TNF-α but not IL-6 by β-glucan. Immunofluorescence revealed more β-glucan-uptake and higher percentage of macrophages and dendritic cells close to β-glucan in VE of CD compared to controls. Conclusions We demonstrated beneficial effects of β-glucan on intestinal barrier function and increased β-glucan-passage through FAE model. Our results provide important and novel knowledge on possible applications of β-glucan in health disorders and diseases characterized by intestinal barrier dysfunction.

A polysaccharide from Fagopyrum esculentum Moench bee pollen alleviates microbiota dysbiosis to improve intestinal barrier function in antibiotic-treated mice

2020 ◽  
Vol 11 (12) ◽  
pp. 10519-10533
Author(s):  
Liuying Zhu ◽  
Juan Li ◽  
Changhao Wei ◽  
Ting Luo ◽  
Zeyuan Deng ◽  
...  
Keyword(s):  
Immune Function ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Fagopyrum Esculentum ◽  
Intestinal Barrier Function ◽  
Barrier Integrity ◽  
Bee Pollen ◽  
Intestinal Barrier Integrity ◽  
Fagopyrum Esculentum Moench

A polysaccharide from Fagopyrum esculentum Moench bee pollen relieves antibiotic-induced microbiota dysbiosis to improve immune function and intestinal barrier integrity by increasing intestinal sIgA secretion and inhibiting inflammation.

scholarly journals Exploring the genetic architecture of inflammatory bowel disease by whole genome sequencing identifies association at ADCY7

2016 ◽  
Author(s):  
Yang Luo ◽  
Katrina M. de Lange ◽  
Luke Jostins ◽  
Loukas Moutsianas ◽  
Joshua Randall ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Statistical Power ◽  
Genetic Architecture ◽  
Disease Risk ◽  
Low Frequency ◽  
Missense Variant ◽  
Sequencing Studies ◽  
Inflammatory Bowel

AbstractIn order to further resolve the genetic architecture of the inflammatory bowel diseases, ulcerative colitis and Crohn’s disease, we sequenced the whole genomes of 4,280 patients at low coverage, and compared them to 3,652 previously sequenced population controls across 73.5 million variants. To increase power we imputed from these sequences into new and existing GWAS cohorts, and tested for association at ~12 million variants in a total of 16,432 cases and 18,843 controls. We discovered a 0.6% frequency missense variant in ADCY7 that doubles risk of ulcerative colitis, and offers insight into a new aspect of disease biology. Despite good statistical power, we did not identify any other new low-frequency risk variants, and found that such variants as a class explained little heritability. We did detect a burden of very rare, damaging missense variants in known Crohn’s disease risk genes, suggesting that more comprehensive sequencing studies will continue to improve our understanding of the biology of complex diseases.

scholarly journals Different intestinal permeability patterns in relatives and spouses of patients with Crohn’s disease: an inherited defect in mucosal defence?

Gut ◽  
1999 ◽  
Vol 44 (1) ◽  
pp. 96-100 ◽  
Author(s):  
J D Söderholm ◽  
G Olaison ◽  
E Lindberg ◽  
U Hannestad ◽  
A Vindels ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Acetylsalicylic Acid ◽  
Intestinal Permeability ◽  
Intestinal Barrier ◽  
Mucosal Barrier ◽  
Intestinal Barrier Function ◽  
Barrier Defect ◽  
Hereditary Factors ◽  
The Difference

BackgroundA familial defect in intestinal barrier function has been found in Crohn’s disease.AimTo investigate possible genetic and environmental influences on this barrier defect by studying intestinal permeability in both relatives and spouses of patients with Crohn’s disease.SubjectsThe study included 39 patients with Crohn’s disease, 34 healthy first degree relatives, and 22 spouses. Twenty nine healthy volunteers served as controls.MethodsIntestinal permeability was assessed as the lactulose:mannitol ratio in five hour urinary excretion after oral load, both before (baseline) and after ingestion of acetylsalicylic acid. The permeability response represents the difference between the two tests. A ratio above the 95th percentile for controls was classified as abnormal.ResultsBaseline permeability was higher in patients and spouses than in controls. An abnormal baseline permeability was seen in 36% of the patients, 23% of the spouses, 18% of the relatives, and 3% of the controls. After ingestion of acetylsalicylic acid, permeability increased significantly in all groups. Relatives were similar to patients with regard to permeability after exposure to acetylsalicylic acid, whereas spouses were similar to controls. The proportions with an abnormal permeability response to acetylsalicylic acid were 32% in patients, 14% in spouses, 41% in relatives, and 3% in controls.ConclusionThe findings suggest that baseline permeability is determined by environmental factors, whereas permeability provoked by acetylsalicylic acid is a function of the genetically determined state of the mucosal barrier, and support the notion that environmental and hereditary factors interact in the pathogenesis of Crohn’s disease.

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