The tight junction and the epithelial barrier in coeliac disease

doi:10.1016/bs.ircmb.2020.09.010

International Review of Cell and Molecular Biology

Volume 358, 2021, Pages 105-132

https://doi.org/10.1016/bs.ircmb.2020.09.010 Get rights and content

Abstract

Epithelial barriers are essential to maintain multicellular organisms well compartmentalized and protected from external environment. In the intestine, the epithelial layer orchestrates a dynamic balance between nutrient absorption and prevention of microorganisms, and antigen intrusion. Intestinal barrier function has been shown to be altered in coeliac disease but whether it contributes to the pathogenesis development or if it is merely a phenomenon secondary to the aberrant immune response is still unknown. The tight junction complexes are multiprotein cell-cell adhesions that seal the epithelial intercellular space and regulate the paracellular permeability of ions and solutes. These structures have a fundamental role in epithelial barrier integrity as well as in signaling mechanisms that control epithelial-cell polarization, the formation of apical domains and cellular processes such as cell proliferation, migration, differentiation, and survival. In coeliac disease, the molecular structures and function of tight junctions appear disrupted and are not completely recovered after treatment with gluten-free diet. Moreover, zonulin, the only known physiological regulator of the tight junction permeability, appears augmented in autoimmune conditions associated with TJ dysfunction, including coeliac disease. This chapter will examine recent discoveries about the molecular architecture of tight junctions and their functions. We will discuss how different factors contribute to tight junction disruption and intestinal barrier impairment in coeliac disease. To conclude, new insights into zonulin-driven disruption of tight junction structures and barrier integrity in coeliac disease are presented together with the advancements in novel therapy to treat the barrier defect seen in pathogenesis.

Section snippets

Intestinal epithelial barrier: Definition and function

The intestinal epithelium is the single layer of cells that define the gastrointestinal wall. It is composed of several elements; (i) the luminal mucus layer with the commensal gut microbiota and immune regulators; (ii) the central epithelial monolayer with specialized intestinal epithelial cells; and (iii) the inner lamina propria which is home to both innate and adaptive immune cells, such as T cells, B cells, macrophages and dendritic cells. A fundamental function of the intestinal mucosa is

Apical junctional complex

The epithelium maintains its selective barrier function through the formation of cell-cell junctions that comprise the apical junctional complex (APC). From apical-to-basal, the intercellular junctions are the tight junction or zonula occludens (TJ), the adherens junction or zonula adherens (AJ), and the desmosome (Farquhar and Palade, 1963). These complexes consist of transmembrane proteins, also called integral proteins, that interact extracellularly with adjacent cells and intracellularly

The role of the intestinal barrier in coeliac disease

Compromised intestinal barrier integrity is observed in both intestinal and systemic diseases, including CD. In active CD, paracellular permeability is increased and TJ morphology is substantially altered. The molecular mechanisms underlying the structural and functional modifications of TJs include the reduction and internalization of the TJ proteins as well as the activation of myosin light chain kinase (MLCK) phosphorylation to promote cytoskeletal contraction (Matsuda et al., 2004; Utech et

Zonulin, a reversible regulator of the epithelial barrier in coeliac disease

The only known physiological regulators of the intestinal TJ was brought forward by Alessio Fasano's group and it has been intensely discussed mechanism (Wang et al., 2000). Fasano identified zonulin, a family of paracrine proteins that reversibly modulate the permeability of TJs upon gliadin exposure. In fact, zonulin was described as an endogenous homologue to the Vibrio cholerae derived ZO toxin (Zot), an enterotoxin that modulates the intestinal TJs leading to a “leaky gut” and the

Correlation between barrier dysfunction in coeliac disease and liver injury

CD is a chronic immune-mediated multisystem disorder and one of common extraintestinal manifestations is coeliac hepatitis. Coeliac hepatitis is defined by the presence of liver injury such as histological changes in CD patients that is reversed after GFD treatment (Bardella et al., 1995; Kaukinen et al., 2002). The mechanisms by which CD cause liver injury are unknown. However, the correlation between intestinal barrier defect and the development of a transaminitis (high levels of certain

Novel therapies targeting barrier defects in coeliac disease

The only treatment for CD established to date is lifelong adherence to a gluten-free diet as it reduces symptoms and heals the mucosal damage within weeks to months. However, evidence indicate that observed barrier disruption in disease remains affected, being only partially restored. Recent advances and insights in the pathogenesis of CD together with the challenge in establishing a lifelong adherence to gluten-free diet has opened the gates for development of newer targeted drugs. Increased

Concluding remarks

All evidences confirm the involvement of tight junction genes related to permeability, polarity, and cell proliferation in the epithelial destruction observed in CD. Barrier loss as a consequence of reduced TJ protein expression and altered distribution is a common feature in CD. However, gut permeability and its role in the pathogenesis of CD remains controversial. It is not yet clear the aberrant immune system reaction causes barrier defect or inversely. While the association between CD and

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Cited by (22)

Serum zonulin level as a novel approach in diagnosis and follow-up of patients with celiac disease. A systematic review and meta-analysis
2024, Nutrition Clinique et Metabolisme
It has been proposed that zonulin, a tight junction protein regulator, is involved in the pathogenesis of celiac disease (CD). In this regard, various studies compared the mean serum zonulin in patients with CD and healthy controls. However, this remains a subject of controversy due to contradictory results. Therefore, the goal of the present study was to summarize the findings of studies comparing CD patients’ serum zonulin levels to healthy controls.
We searched PubMed, Scopus, and ISI Web of Science databases up to May 2022. All observational studies measured serum zonulin in adult patients with CD and healthy controls were included without language or date restrictions. The standardized mean differences (SMDs) and standard deviations were pooled using a random-effects model.
Of 708 studies, six studies with 184 CD and 206 control participants were included in the systematic review and meta-analysis. According to a pooled analysis, CD patients had significantly higher zonulin levels than healthy controls (SMD = 1.08 ng/mL; 95% CI = 0.64, 1.52; P < 0.001). Subgroup analyses were performed according to adherence to a gluten-free diet (GFD), zonulin assessment method, and CD diagnosis. The significant effect was maintained in all subgroups.
CD is significantly correlated with a higher level of serum zonulin. Thus, zonulin could be a potential biomarker for the diagnosis of CD, which deserves further investigation.
WbuB, a glycosyltransferase family 4 protein, regulates the activation of NLRP3 inflammasome and contributes to the virulence of Aeromonas hydrophila CCL1
2024, Reproduction and Breeding
Aeromonas hydrophila is an opportunistic pathogen of fishes and aquatic animals. A. hydrophila has a strong ability to disrupt gut integrity and cause inflammation and septicemia in fish, however, the mechanism is not fully understood. In this study, we identified the function of a galactosaminogalactan (GAG) synthase (named WbuB) in the pathogenic A. hydrophila CCL1. WbuB belongs to the family 4 of glycosyltransferases (GT4) and is composed of 407 amino acids (aa). For virulence analysis, the mutant which has an in-frame deletion of the WbuB gene in CCL1 was created (named ΔWbuB). ΔWbuB had the decreased biofilm formation, as well as adhesion ability and cytotoxicity. Animal infection study in crucian carps showed that, compared to CCL1, ΔWbuB caused the decreased expression levels of ASC, NLRP3, caspase-1 and IL-1β in gut. Moreover, the expression levels of ZO-1 and Occludin were increased by ΔWbuB infection. In line with the results, the intestinal permeability and tissue dissemination capacity of ΔWbuB were attenuated significantly. These lost virulence capacities of ΔWbuB were restored by complementation with the WbuB gene. Taken together, these results indicate that WbuB is essential for the activation of NLRP3 inflammasome and is a novel virulent factor for tight junction barrier during A. hydrophila infection.
Rhei Radix et Rhizoma in Xuanbai-Chengqi decoction strengthens the intestinal barrier function and promotes lung barrier repair in preventing severe viral pneumonia induced by influenza A virus
2024, Journal of Ethnopharmacology
Xuanbai-Chengqi decoction (XCD) is a traditional prescription for treating multiple organ injuries, which has been used to manage pneumonia caused by various pathogens. However, the effects of XCD on repairing pulmonary/intestinal barrier damage remain unclear, and there is a need to understand the compatibility mechanism of rhubarb.
This work aims to investigate the protective effect and mechanism of XCD on the pulmonary/intestinal barrier guided by the theory of “gut-lung concurrent treatment”. Moreover, we elucidate the compatibility mechanism of rhubarb in XCD.
An H1N1 virus-infected mouse model was adopted to investigate the reparative effects of XCD on the lung-intestinal barrier by assessing lung-intestinal permeability. Additionally, the characterization of type I alveolar epithelial cells (AT1) and type II alveolar epithelial cells (AT2) was performed to evaluate the damage to the alveolar epithelial barrier. The specific barrier-protective mechanisms of XCD were elucidated by detecting tight junction proteins and the epithelial cell repair factor IL-22. The role of rhubarb in XCD to pneumonia treatment was investigated through lung tissue transcriptome sequencing and flow cytometry.
XCD significantly improved lung tissue edema, inflammation, and alveolar epithelial barrier damage by regulating IL-6, IL-10, and IL-22, which, could further improve pulmonary barrier permeability when combined with the protection of alveolar epithelial cells (AT1 and AT2) as well as inhibition of H1N1 virus replication. Simultaneously, XCD significantly reduced intestinal inflammation and barrier damage by regulating IL-6, IL-1β, and tight junction protein levels (Claudin-1 and ZO-1), improving intestinal barrier permeability. The role of rhubarb in the treatment of pneumonia is clarified for the first time. In the progression of severe pneumonia, rhubarb can significantly protect the intestinal barrier, promote the repair of AT2 cells, and inhibit the accumulation of CD11b⁺Ly6G^variable aberrant neutrophils by regulating the S100A8 protein.
In summary, our findings suggest that rhubarb in XCD plays a critical role in protecting intestinal barrier function and promoting lung barrier repair in preventing severe viral pneumonia caused by influenza A virus.
Cell-cell communication analysis for single-cell RNA sequencing and its applications in carcinogenesis and COVID-19
2022, Biosafety and Health
Citation Excerpt :
And the process of cell communication with each other is called the cell junction. There are mainly three cell junctions: gap junctions, tight junctions, and desmosomes [2,9,10,37–42]. Most cancer cells communicate with gap junctions, and the proteins types of gap junctions are known as connexins [39,40].
Cell-cell communication is the basis of physiological processes and cell signals. The disease occurs when the cells do not adequately communicate and the messages are blocked. With ligand-receptor interaction databases and single-cell RNA sequencing (scRNA-seq) databases, we can detect intercellular signaling and reconstruct the cell–cell communications among different cell types. This review summarized the computational approaches for analyzing the cell–cell communication based on scRNA-seq data and discussed its applications in carcinogenesis and COVID-19. We believe that this review will accelerate the scRNA-seq data deciphering and facilitate the cell–cell communication studies for complex physiological processes, such as carcinogenesis and SARS-CoV-2 infection.
Advanced oral vaccine delivery strategies for improving the immunity
2021, Advanced Drug Delivery Reviews
Citation Excerpt :
Paracellular transport is advantageous in mucosal vaccination because the paracellular delivery efficiency of antigen could be much more efficient than active and passive transport via transcytosis. However, paracellular spaces are sealed off by TJ complexes, which prevent even the tiniest NPs from passing through [235,222]. As a result, functionalized vehicles that can regulate TJ opening are preferred for the paracellular delivery of oral vaccines.
Infectious diseases continue to inflict a high global disease burden. The consensus is that vaccination is the most effective option against infectious diseases. Oral vaccines have unique advantages in the prevention of global pandemics due to their ease of use, high compliance, low cost, and the ability to induce both systemic and mucosal immune responses. However, challenges of adapting vaccines for oral administration remain significant. Foremost among these are enzymatic and pH-dependent degradation of antigens in the stomach and intestines, the low permeability of mucus barrier, the nonspecific uptake of antigens at the intestinal mucosal site, and the immune suppression result from the elusive immune tolerance mechanisms. Innovative delivery techniques promise great potential for improving the flexibility and efficiency of oral vaccines. A better understanding of the delivery approaches and the immunological mechanisms of oral vaccine delivery systems may provide new scientific insight and tools for developing the next-generation oral vaccine. Here, an overview of the advanced technologies in the field of oral vaccination is proposed, including mucus-penetrating nanoparticle (NP), mucoadhesive delivery vehicles, targeting antigen-presenting cell (APC) nanocarriers and enhanced paracellular delivery strategies and so on. Meanwhile, the mechanisms of delivery vectors interact with mucosal barriers are discussed.
Increased intestinal permeability with elevated peripheral blood endotoxin and inflammatory indices for e-waste lead exposure in children
2021, Chemosphere
Citation Excerpt :
The intestinal mucosal barrier consists of commensal microbiota, mucus layer, epithelial barrier, and lamina propria, and its integrity is essential for avoiding abnormal intestinal permeability (Hanning et al., 2021). Especially, the epithelial barrier is composed of a single layer of epithelial cells and intercellular tight junctions that seal the gap of epithelial cells and form a paracellular pathway of substance transport (Jauregi-Miguel, 2021). With this complex system, intestinal mucosa plays a semipermeability barrier that selectively absorbs small molecular nutrients, ions, and water, while limits the translocation of large molecular antigens, pathogens, and bacterial byproducts (Vancamelbeke and Vermeire, 2017).
Lead (Pb) entering the body through different channels can damage the function of intestinal mucosal barrier and cause the body stressful inflammatory response to enhance. This study conducted a cross-sectional study to investigate the effects of Pb exposure on intestinal permeability in children by measuring the level of bacterial endotoxin and index of inflammatory cell types in peripheral blood. From November to December 2018, we recruited 187 participants aged 3–6 years by stratified randomization, from an electronic-waste-exposed group (n = 82) and a referent group (n = 105). General demographic information, past history of the digestive system in child, and family situation were informed by children's guardians with questionnaires. Children in the exposed group showed lower weight, height, and body mass index while more diarrhea in a month. Blood Pb and plasma endotoxin were elevated in exposed children than referent children and the positive relationship between them was shown in all children [B (95% CI): 0.072 (0.008, 0.137), P = 0.033]. Peripheral monocyte counts and leukotriene B₄ (LTB₄) levels were significantly increased in the exposed group. Endotoxin levels were positively correlated with neutrophils, monocytes, and LTB₄ [B (95% CI): 0.054 (0.015, 0.093), 0.018 (0.005, 0.031), and 0.049 (0.011, 0.087), respectively, P < 0.05]. To sum up, the exposed children showed lower physical growth levels, poorer gut health, and increased intestinal permeability, which was related to high blood Pb and peripheral inflammatory indices. These results suggest the possible adverse impact of environmental Pb exposure on the intestinal health of children.

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Chapter Four - The tight junction and the epithelial barrier in coeliac disease

Abstract

Section snippets

Intestinal epithelial barrier: Definition and function

Apical junctional complex

The role of the intestinal barrier in coeliac disease

Zonulin, a reversible regulator of the epithelial barrier in coeliac disease

Correlation between barrier dysfunction in coeliac disease and liver injury

Novel therapies targeting barrier defects in coeliac disease

Concluding remarks

Hepatology

Cell

Exp. Cell Res.

Biochim. Biophys. Acta

Prog. Mol. Biol. Transl. Sci.

J. Biol. Chem.

Biochim. Biophys. Acta

Peptides

Lancet

J. Biol. Chem.

Gene Expr. Patterns

BBA-Mol. Cell. Res.

Gastroenterology

Biochim. Biophys. Acta

Gastroenterology

Gastroenterology

J. Biol. Chem.

Lancet

Lancet

Cell

Dig. Liver Dis.

Semin. Cell Dev. Biol.

Am. J. Med.

Cytokine

FEBS Lett.

Serum zonulin as a marker of intestinal mucosal barrier function: may not be what it seems

PLoS ONE

Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant

Hum. Mol. Genet.

Occludin regulates macromolecule flux across the intestinal epithelial tight junction barrier

Am. J. Physiol. Gastrointest. Liver Physiol.

miRNAs and their role in the pathogenesis of celiac disease: a review

Gliadin peptide P31-43 localises to endocytic vesicles and interferes with their maturation

PLoS One

In vitro determination of small intestinal permeability: demonstration of a persistent defect in patients with coeliac disease

Gut

The minimal cadherin-catenin complex binds to actin filaments under force

Science

Occludin OCEL-domain interactions are required for maintenance and regulation of the tight junction barrier to macromolecular flux

Mol. Biol. Cell

Depletion of E-cadherin disrupts establishment but not maintenance of cell junctions in Madin-Darby canine kidney epithelial cells

Mol. Biol. Cell

A role for myosin IXb, a motor-RhoGAP chimera, in epithelial wound healing and tight junction regulation

Mol. Biol. Cell

Altered expression, localization, and phosphorylation of epithelial junctional proteins in celiac disease

Am. J. Clin. Pathol.

The transcriptomic analysis of circulating immune cells in a celiac family unveils further insights into disease pathogenesis

Front. Med.

Intestinal permeability assessed by excretion ratios of two molecules: results in coeliac disease

Br. Med. J.

Cingulin contains globular and coiled-coil domains and interacts with ZO-1, ZO-2, ZO-3, and myosin

J. Cell Biol.

Understanding epithelial homeostasis in the intestine

Tissue Barriers

Claudin-2 expression increases tumorigenicity of colon cancer cells: role of epidermal growth factor receptor activation

Oncogene

Multiple common variants for celiac disease influencing immune gene expression

Nat. Genet.

Junctional adhesion molecules (JAMs): cell adhesion receptors with pleiotropic functions in cell physiology and development

Physiol. Rev.

Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure

Gastroenterology

Messages from the inside. The dynamic environment that favors intestinal homeostasis

Front. Immunol.

Junctional complexes in various epithelia

J. Cell Biol.

Surprise from celiac disease

Sci. Am.

Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer

Physiol. Rev.