DOP006. Gut-homing adipose tissue T-cells might influence intestinal barrier function in Crohn’s disease and obesity

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.

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LACTOBACILLUS GG (L-GG) IMPROVES INTESTINAL BARRIER FUNCTION IN CHILDREN WITH CROHN'S DISEASE

Journal of Pediatric Gastroenterology and Nutrition ◽

10.1097/00005176-199905000-00069 ◽

1999 ◽

Vol 28 (5) ◽

pp. 556

Author(s):

S. Guandalini ◽

P. Gupta ◽

H. Andrews ◽

B. Kirschner

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Barrier Function ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Lactobacillus Gg

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598 PROTOCADHERIN 20 DEFICIENCY IMPAIRS INTESTINAL BARRIER FUNCTION BY TARGETING ATF6 RELATED PATHWAY IN CROHN'S DISEASE

Gastroenterology ◽

10.1016/s0016-5085(21)01030-1 ◽

2021 ◽

Vol 160 (6) ◽

pp. S-116-S-117

Author(s):

Shanshan Huang ◽

Sheng-Hong Zhang ◽

Minhu Chen

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Barrier Function ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Related Pathway

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The way to infected necrosis during severe acute pancreatitis: How regulatory T-cells impact on the intestinal barrier function

Pancreatology ◽

10.1016/j.pan.2021.05.047 ◽

2021 ◽

Vol 21 ◽

pp. S19

Author(s):

J. Glaubitz ◽

A. Wilden ◽

F.U. Weiss ◽

F. Frost ◽

A.A. Aghdassi ◽

...

Keyword(s):

T Cells ◽

Acute Pancreatitis ◽

Regulatory T Cells ◽

Severe Acute Pancreatitis ◽

Barrier Function ◽

Intestinal Barrier ◽

Intestinal Barrier Function ◽

Infected Necrosis ◽

The Way

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Microbial Signature in Adipose Tissue of Crohn’s Disease Patients

Journal of Clinical Medicine ◽

10.3390/jcm9082448 ◽

2020 ◽

Vol 9 (8) ◽

pp. 2448

Author(s):

Carolina Serena ◽

Maribel Queipo-Ortuño ◽

Monica Millan ◽

Lidia Sanchez-Alcoholado ◽

Aleidis Caro ◽

...

Keyword(s):

Adipose Tissue ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Pathogenic Bacteria ◽

Sulfur Metabolism ◽

Clinical Status ◽

Subcutaneous Fat ◽

Intestinal Barrier ◽

Fecal Calprotectin ◽

Inactive Disease

Crohn’s disease (CD) is characterized by compromised immune tolerance to the intestinal commensal microbiota, intestinal barrier inflammation, and hyperplasia of creeping fat (CF) and mesenteric adipose tissue (AT), which seems to be directly related to disease activity. Gut microbiota dysbiosis might be a determining factor in CD etiology, manifesting as a low microbial diversity and a high abundance of potentially pathogenic bacteria. We tested the hypothesis that CF is a reservoir of bacteria through 16S-rRNA sequencing of several AT depots of patients with active and inactive disease and controls. We found a microbiome signature within CF and mesenteric AT from patients, but not in subcutaneous fat. We failed to detect bacterial DNA in any fat depot of controls. Proteobacteria was the most abundant phylum in both CF and mesenteric AT, and positively correlated with fecal calprotectin/C-reactive protein. Notably, the clinical status of patients seemed to be related to the microbiome signature, as those with the inactive disease showed a reduction in the abundance of pathogenic bacteria. Predictive functional profiling revealed many metabolic pathways including lipopolysaccharide biosynthesis and sulfur metabolism overrepresented in active CD relative to that in inactive CD. Our findings demonstrate that microbiota dysbiosis associated with CD pathophysiology is reflected in AT and might contribute to disease severity.

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Macrophage Deficiency Makes Intestinal Epithelial Cells Susceptible to NSAID-Induced Damage

BioMed Research International ◽

10.1155/2020/6757495 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Xinxin Wang ◽

Jiayang Wang ◽

Tianyu Xie ◽

Shuo Li ◽

Di Wu ◽

...

Keyword(s):

T Cells ◽

Barrier Function ◽

Molecular Mechanisms ◽

Intestinal Barrier ◽

Mucosal Barrier ◽

Intestinal Barrier Function ◽

Intestinal Epithelial ◽

Epithelial Proliferation ◽

Gm Csf ◽

Mucosal Barrier Function

Objectives. In Crohn’s disease (CD), the mechanisms underlying the regulation by granulocyte-macrophage colony-stimulating factor (GM-CSF) of mucosal barrier function in the ileum are unclear. We analyzed the molecular mechanisms underlying the regulation by GM-CSF of the mucosal barrier function. Methods. We examined the role of GM-CSF in the intestinal barrier function in CD at the molecular-, cellular-, and animal-model levels. Results. Macrophages directly secreted GM-CSF, promoting intestinal epithelial proliferation and inhibiting apoptosis, which maintained intestinal barrier function. Macrophages were absent in NSAID-induced ileitis, causing GM-CSF deficiency, increasing the apoptosis rate, decreasing the proliferation rate, increasing inter- and paracellular permeabilities, decreasing the TJP levels, and reducing the numbers of mesenteric lymph nodes, memory T cells, and regulatory T cells in Csf1op/op transgenic mice. Conclusions. GM-CSF is required for the maintenance of intestinal barrier function. Macrophages directly secrete GM-CSF, promoting intestinal epithelial proliferation and inhibiting apoptosis.

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

Frontiers in Microbiology ◽

10.3389/fmicb.2021.598232 ◽

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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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

Frontiers in Physiology ◽

10.3389/fphys.2021.645303 ◽

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.

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