Analysis of Genetic Association of Intestinal Permeability in Healthy First-degree Relatives of Patients with Crohn’s Disease

2019 ◽  
Vol 25 (11) ◽  
pp. 1796-1804 ◽  
Author(s):  
Williams Turpin ◽  
Osvaldo Espin-Garcia ◽  
Larbi Bedrani ◽  
Karen Madsen ◽  
Jonathan B Meddings ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intestinal Permeability ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
P Value ◽  
Gut Permeability ◽  
Barrier Dysfunction ◽  
First Degree Relatives

Abstract Excessive intestinal permeability or intestinal barrier dysfunction as measured by various assays has been observed in various diseases. However, little is known about the factors contributing to altered gut permeability in these diseases. Our objective was to determine the genetic determinants of altered gut permeability as measured by the lactulose mannitol fractional excretion ratio (LacMan ratio) in 1075 healthy first-degree relatives of patients with Crohn’s disease (CD). In a targeted analysis of single nucleotide polymorphisms (SNPs) located in genes associated with intestinal barrier function related or not to inflammatory bowel disease, we did not find a significant association with intestinal permeability. In an untargeted genome-wide association analysis, the top 100 associations were located in 22 genomic loci, although they were not statistically significant after correction for multiple testing (raw P values [1.8 × 10–7 - 1.4 × 10–5]. The lowest P value was obtained for rs9616637 (22q13.33, C22orf34), for which the minor allele A was associated with a decreased LacMan ratio. These results suggest that host genetic background has limited contribution toward intestinal permeability. Despite this, our study is currently the largest of its kind assessing gut permeability in vivo. It remains possible that smaller genetic effect sizes on LacMan ratio are not detectable in this sized cohort. Larger studies are warranted to identify the potential genetic contribution to intestinal permeability.

scholarly journals Serum Zonulin Measured by Commercial Kit Fails to Correlate With Physiologic Measures of Altered Gut Permeability in First Degree Relatives of Crohn's Disease Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Namita Power ◽  
Williams Turpin ◽  
Osvaldo Espin-Garcia ◽  
Michelle I. Smith ◽  
Kenneth Croitoru ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intestinal Permeability ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Fractional Excretion ◽  
Fatty Acid Binding Proteins ◽  
Limited Information ◽  
Gut Permeability ◽  
Fatty Acid Binding

Intestinal epithelial cell tight junctions (TJs) contribute to the integrity of the intestinal barrier allowing for control of the physical barrier between external antigens or bacterial products and the internal environment. Zonula occludens-1 (ZO-1) is a protein that modulates intestinal TJs, and serum levels of ZO-1 has been suggested as a biomarker of disrupted barrier function in humans. Previous studies suggested that increased intestinal permeability was associated with evidence of TJ abnormalities. However, there is limited information on the serological measurement of ZO-1 and its relation to other tests of barrier function in healthy subjects. We investigated the correlation of serum ZO-1, with physiologic measures of intestinal permeability (as the ratio of the fractional excretion of lactulose-mannitol or LMR) in a cohort of 39 healthy FDRs of Crohn's disease (CD) patients. No significant correlation was found between LMR and ZO-1 levels (r2 = 0.004, P < 0.71), or intestinal fatty acid binding proteins (I-FABP) (r2 = 0.004, P < 0.71). In conclusion, our data show that ZO-1 and I-FABP are not a marker of gut permeability as defined by LMR.

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.

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.

scholarly journals Sauna dehydration as a new physiological challenge model for intestinal barrier function

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria Fernanda Roca Rubio ◽  
Ulrika Eriksson ◽  
Robert J. Brummer ◽  
Julia König
Keyword(s):  
Fatty Acid ◽  
Intestinal Permeability ◽  
Barrier Function ◽  
Fatty Acid Binding Protein ◽  
Binding Protein ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Fatty Acid Binding ◽  
Acid Binding Protein

AbstractThe intestinal barrier plays a crucial role in maintaining gut health, and an increased permeability has been linked to several intestinal and extra-intestinal disorders. There is an increasing demand for interventions aimed at strengthening this barrier and for in vivo challenge models to assess their efficiency. This study investigated the effect of sauna-induced dehydration on intestinal barrier function (clinicaltrials.gov: NCT03620825). Twenty healthy subjects underwent three conditions in random order: (1) Sauna dehydration (loss of 3% body weight), (2) non-steroidal anti-inflammatory drug (NSAID) intake, (3) negative control. Intestinal permeability was assessed by a multi-sugar urinary recovery test, while intestinal damage, bacterial translocation and cytokines were assessed by plasma markers. The sauna dehydration protocol resulted in an increase in gastroduodenal and small intestinal permeability. Presumably, this increase occurred without substantial damage to the enterocytes as plasma intestinal fatty acid-binding protein (I-FABP) and liver fatty acid-binding protein (L-FABP) were not affected. In addition, we observed significant increases in levels of lipopolysaccharide-binding protein (LBP), IL-6 and IL-8, while sCD14, IL-10, IFN-ɣ and TNF-α were not affected. These results suggest that sauna dehydration increased intestinal permeability and could be applied as a new physiological in vivo challenge model for intestinal barrier function.

Intestinal permeability in Crohn's disease patients and their first degree relatives

2001 ◽  
Vol 33 (8) ◽  
pp. 680-685 ◽  
Author(s):  
M. Secondulfo ◽  
L. de Magistris ◽  
R. Fiandra ◽  
L. Caserta ◽  
M. Belletta ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Intestinal Permeability ◽  
First Degree Relatives

scholarly journals Chromogranin A regulates gut permeability via the antagonistic actions of its proteolytic peptides

2020 ◽  
Author(s):  
Elke M. Muntjewerff ◽  
Kechun Tang ◽  
Lisanne Lutter ◽  
Gustaf Christoffersson ◽  
Mara J.T. Nicolasen ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Chromogranin A ◽  
Intestinal Barrier ◽  
Enteroendocrine Cells ◽  
Leaky Gut ◽  
Gut Permeability ◽  
Gut Barrier ◽  
Ultrastructural Studies ◽  
New Findings

AbstractBackground and AimsA ‘leaky’ gut barrier has been implicated in the initiation and progression of a multitude of diseases, e.g., inflammatory bowel disease, irritable bowel syndrome, celiac disease, and colorectal cancers. Here we asked how Chromogranin A (CgA), a major hormone produced by the enteroendocrine cells, and Catestatin (CST), the most abundant CgA-derived proteolytic peptide, affect the gut barrier.Methods and ResultsUltrastructural studies on the colons from Catestatin (CST: hCgA352-372) knockout (CST-KO) mice revealed (i) altered morphology of tight (TJ) and adherens (AJ) junctions and desmosomes, indicative of junctional stress and (ii) an increased infiltration of immune cells compared to controls. Flow cytometry studies confirmed these cells to be macrophages and CD4+ T cells. Gene expression studies confirmed that multiple TJ-markers were reduced, with concomitant compensatory elevation of AJ and desmosome markers. Consistently, the levels of plasma FITC-dextran were elevated in the CST-KO mice, confirming leakiness’ of the gut. Leaky gut in CST-KO mice correlated with inflammation and a higher ratio of Firmicutes to Bacteroidetes, a dysbiotic pattern commonly encountered in a multitude of diseases. Supplementation of CST-KO mice with recombinant CST reversed this leakiness and key phenotypes. Supplementation of CgA-KO mice with either CST alone, or with the pro-inflammatory proteolytic CgA fragment pancreastatin (PST: CgA250-301) showed that gut permeability is regulated by the antagonistic roles of these two peptide hormones: CST reduces and PST increases leakiness.ConclusionWe conclude that the enteroendocrine cell-derived hormone, CgA regulates gut permeability. CST is both necessary and sufficient to reduce the leakiness. CST acts primarily via antagonizing the effects of PST.What you need to knowBackground and ContextThe intestinal barrier is disrupted in many intestinal diseases such as Crohn’s disease. Chromogranin A (CgA) is produced by enteroendocrine cells in the gut. CgA is proteolytically cleaved into bioactive peptides including catestatin (CST) and pancreastatin (PST). The role of CgA in the gut is unknown.New findingsCgA is efficiently processed to CST in the gut and this processing might be decreased during active Crohn’s disease. CST promotes epithelial barrier function and reduces inflammation by counteracting PST.LimitationsThe complete mechanism of intestinal barrier regulation by CST likely involves a complex interplay between the enteroendocrine system, metabolism, the epithelium, the immune system and the gut microbiota.ImpactOur findings indicate that CST is a key modulator of the intestinal barrier and immune functions that correlates with disease severity of Crohn’s disease. CST could be a target for therapeutic interventions in Crohn’s disease.

scholarly journals Intestinal Permeability before and after Ibuprofen in Families of Children with Crohn’s Disease

1999 ◽  
Vol 13 (1) ◽  
pp. 31-37 ◽  
Author(s):  
Samuel A Zamora ◽  
Robert J Hilsden ◽  
Jon B Meddings ◽  
J Decker Butzner ◽  
R Brent Scott ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Acetylsalicylic Acid ◽  
Intestinal Permeability ◽  
Control Group ◽  
Reference Limit ◽  
First Degree Relatives ◽  
Before And After ◽  
Healthy Control ◽  
Upper Reference Limit

BACKGROUND: Members of a subset of first-degree relatives of adults with Crohn’s disease have been shown to have an increased baseline intestinal permeability and/or an exaggerated increase in intestinal permeability after the administration of acetylsalicylic acid.PURPOSE: To determine intestinal permeability in unaffected first-degree relatives of children with Crohn’s disease before and after the administration of an ibuprofen challenge.METHODS: Lactulose-mannitol ratios, a measure of intestinal permeability, were determined in 14 healthy control families (41 subjects) and 14 families with a child with Crohn’s disease (36 relatives, 14 probands) before and after ingestion of ibuprofen. An upper reference limit was defined using the control group as mean ± 2 SD.RESULTS: The proportion of healthy, first-degree relatives with an exaggerated response to ibuprofen (20%, 95% CI 7% to 33%) was significantly higher than controls (P=0.003). The exaggerated response was more common among siblings than among parents of pediatric probands.CONCLUSIONS: Members of a subset of first-degree relatives of children with Crohn’s disease have an exaggerated increase in intestinal permeability after ibuprofen ingestion. These findings are compatible with there being a genetic link between abnormalities of intestinal permeability and Crohn’s disease.

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.

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