scholarly journals Leaky Gut and Autoimmunity: An Intricate Balance in Individuals Health and the Diseased State

2020 ◽  
Vol 21 (24) ◽  
pp. 9770
Author(s):  
Bilal Ahmad Paray ◽  
Mohammed Fahad Albeshr ◽  
Arif Tasleem Jan ◽  
Irfan A. Rather
Keyword(s):  
Tight Junctions ◽  
Intestinal Barrier ◽  
Intestinal Wall ◽  
Vital Role ◽  
Intestinal Epithelial ◽  
Leaky Gut ◽  
New Paradigm ◽  
Environmental Causes ◽  
Diseased State ◽  
Autoimmune Pathogenesis

Damage to the tissue and the ruining of functions characterize autoimmune syndromes. This review centers around leaky gut syndromes and how they stimulate autoimmune pathogenesis. Lymphoid tissue commonly associated with the gut, together with the neuroendocrine network, collaborates with the intestinal epithelial wall, with its paracellular tight junctions, to maintain the balance, tolerance, and resistance to foreign/neo-antigens. The physiological regulator of paracellular tight junctions plays a vital role in transferring macromolecules across the intestinal barrier and thereby maintains immune response equilibrium. A new paradigm has explained the intricacies of disease development and proposed that the processes can be prevented if the interaction between the genetic factor and environmental causes is barred by re-instituting the intestinal wall function. The latest clinical evidence and animal models reinforce this current thought and offer the basis for innovative methodologies to thwart and treat autoimmune syndromes.

Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer

2011 ◽  
Vol 91 (1) ◽  
pp. 151-175 ◽  
Author(s):  
Alessio Fasano
Keyword(s):  
Gastrointestinal Tract ◽  
Tight Junctions ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Intestinal Epithelial ◽  
New Paradigm ◽  
Intestinal Epithelial Barrier ◽  
Neoplastic Disorders

The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and to electrolytes and water homeostasis. A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiological modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the finely tuned zonulin pathway is deregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune, inflammatory, and neoplastic disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing the zonulin-dependent intestinal barrier function. This review is timely given the increased interest in the role of a “leaky gut” in the pathogenesis of several pathological conditions targeting both the intestine and extraintestinal organs.

MicroRNA Determines the Fate of Intestinal Epithelial Cell Differentiation and Regulates Intestinal Diseases

2019 ◽  
Vol 20 (7) ◽  
pp. 666-673 ◽  
Author(s):  
Sujuan Ding ◽  
Gang Liu ◽  
Hongmei Jiang ◽  
Jun Fang
Keyword(s):  
Target Genes ◽  
Gastrointestinal Disease ◽  
Intestinal Barrier ◽  
Vital Role ◽  
Intestinal Barrier Function ◽  
Intestinal Epithelial ◽  
Intestinal Function ◽  
Cell Fates ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation

The rapid self-renewal of intestinal epithelial cells enhances intestinal function, promotes the nutritional needs of animals and strengthens intestinal barrier function to resist the invasion of foreign pathogens. MicroRNAs (miRNAs) are a class of short-chain, non-coding RNAs that regulate stem cell proliferation and differentiation by down-regulating hundreds of conserved target genes after transcription via seed pairing to the 3' untranslated regions. Numerous studies have shown that miRNAs can improve intestinal function by participating in the proliferation and differentiation of different cell populations in the intestine. In addition, miRNAs also contribute to disease regulation and therefore not only play a vital role in the gastrointestinal disease management but also act as blood or tissue biomarkers of disease. As changes to the levels of miRNAs can change cell fates, miRNA-mediated gene regulation can be used to update therapeutic strategies and approaches to disease treatment.

New ways of thinking about (and teaching about) intestinal epithelial function

2008 ◽  
Vol 32 (1) ◽  
pp. 25-34 ◽  
Author(s):  
Kim E. Barrett
Keyword(s):  
Ion Transport ◽  
Tight Junctions ◽  
Hydrogen Exchange ◽  
De Novo ◽  
Intestinal Barrier ◽  
Barrier Properties ◽  
Chloride Secretion ◽  
Sodium Absorption ◽  
Intestinal Epithelial ◽  
The Impact

This article summarizes a presentation made at the Teaching Refresher Course of the American Physiological Society, which was held at the Experimental Biology meeting in 2007. The intestinal epithelium has important ion transport and barrier functions that contribute pivotally to normal physiological functioning of the intestine and other body systems. These functions are also frequently the target of dysfunction that, in turn, results in specific digestive disease states, such as diarrheal illnesses. Three emerging concepts are discussed with respect to ion transport: the complex interplay of intracellular signals that both activate and inhibit chloride secretion; the role of multiprotein complexes in the regulation of ion transport, taking sodium/hydrogen exchange as an example; and acute and chronic regulation of colonic sodium absorption, involving both sodium channel internalization and de novo synthesis of new channels. Similarly, recently obtained information about the molecular components of epithelial tight junctions and the ways in which tight junctions are regulated both in health and disease are discussed to exemplify ways to teach about intestinal barrier properties. Finally, both genetically determined intestinal diseases and those arising as a result of infections and/or inflammation are described, and these can be used as the means to enhance the basic and clinical relevance of teaching about intestinal epithelial physiology as well as the impact that the understanding of such physiology has had on associated therapeutics. The article also indicates, where relevant, how different approaches may be used effectively to teach related concepts to graduate versus medical/professional student audiences.

scholarly journals Dual Action of the PN159/KLAL/MAP Peptide: Increase of Drug Penetration across Caco-2 Intestinal Barrier Model by Modulation of Tight Junctions and Plasma Membrane Permeability

Pharmaceutics ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 73 ◽  
Author(s):  
Alexandra Bocsik ◽  
Ilona Gróf ◽  
Lóránd Kiss ◽  
Ferenc Ötvös ◽  
Ottó Zsíros ◽  
...  
Keyword(s):  
Tight Junction ◽  
Tight Junctions ◽  
Efflux Pump ◽  
Intestinal Barrier ◽  
Cell Penetrating Peptides ◽  
Intestinal Epithelial ◽  
Plasma Membrane Permeability ◽  
Cell Penetrating ◽  
Dual Action ◽  
Epithelial Barriers

The absorption of drugs is limited by the epithelial barriers of the gastrointestinal tract. One of the strategies to improve drug delivery is the modulation of barrier function by the targeted opening of epithelial tight junctions. In our previous study the 18-mer amphiphilic PN159 peptide was found to be an effective tight junction modulator on intestinal epithelial and blood–brain barrier models. PN159, also known as KLAL or MAP, was described to interact with biological membranes as a cell-penetrating peptide. In the present work we demonstrated that the PN159 peptide as a penetration enhancer has a dual action on intestinal epithelial cells. The peptide safely and reversibly enhanced the permeability of Caco-2 monolayers by opening the intercellular junctions. The penetration of dextran molecules with different size and four efflux pump substrate drugs was increased several folds. We identified claudin-4 and -7 junctional proteins by docking studies as potential binding partners and targets of PN159 in the opening of the paracellular pathway. In addition to the tight junction modulator action, the peptide showed cell membrane permeabilizing and antimicrobial effects. This dual action is not general for cell-penetrating peptides (CPPs), since the other three CPPs tested did not show barrier opening effects.

Dietary l-tryptophan alleviated LPS-induced intestinal barrier injury by regulating tight junctions in a Caco-2 cell monolayer model

2019 ◽  
Vol 10 (5) ◽  
pp. 2390-2398 ◽  
Author(s):  
Mengdie Chen ◽  
Yuyu Liu ◽  
Shanbai Xiong ◽  
Moucheng Wu ◽  
Bin Li ◽  
...  
Keyword(s):  
Tight Junctions ◽  
Cell Monolayer ◽  
Intestinal Barrier ◽  
Intestinal Epithelial ◽  
Epithelial Layer ◽  
Infection And Inflammation ◽  
Monolayer Model ◽  
Cell Cell

The intestinal epithelial layer forms a barrier through cell–cell tight junctions and breaking or even slightly disrupting this barrier can lead to serious pathological consequences, including infection and inflammation.

scholarly journals Probiotics, Prebiotics and Epithelial Tight Junctions: A Promising Approach to Modulate Intestinal Barrier Function

2021 ◽  
Vol 22 (13) ◽  
pp. 6729
Author(s):  
Elizabeth C. Rose ◽  
Jack Odle ◽  
Anthony T. Blikslager ◽  
Amanda L. Ziegler
Keyword(s):  
Tight Junctions ◽  
Barrier Function ◽  
Intestinal Barrier ◽  
In Vivo Studies ◽  
Intestinal Barrier Function ◽  
Preterm Neonates ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Intestinal Epithelial Barrier ◽  
Stimulation Of

Disruptions in the intestinal epithelial barrier can result in devastating consequences and a multitude of disease syndromes, particularly among preterm neonates. The association between barrier dysfunction and intestinal dysbiosis suggests that the intestinal barrier function is interactive with specific gut commensals and pathogenic microbes. In vitro and in vivo studies demonstrate that probiotic supplementation promotes significant upregulation and relocalization of interepithelial tight junction proteins, which form the microscopic scaffolds of the intestinal barrier. Probiotics facilitate some of these effects through the ligand-mediated stimulation of several toll-like receptors that are expressed by the intestinal epithelium. In particular, bacterial-mediated stimulation of toll-like receptor-2 modulates the expression and localization of specific protein constituents of intestinal tight junctions. Given that ingested prebiotics are robust modulators of the intestinal microbiota, prebiotic supplementation has been similarly investigated as a potential, indirect mechanism of barrier preservation. Emerging evidence suggests that prebiotics may additionally exert a direct effect on intestinal barrier function through mechanisms independent of the gut microbiota. In this review, we summarize current views on the effects of pro- and prebiotics on the intestinal epithelial barrier as well as on non-epithelial cell barrier constituents, such as the enteric glial cell network. Through continued investigation of these bioactive compounds, we can maximize their therapeutic potential for preventing and treating gastrointestinal diseases associated with impaired intestinal barrier function and dysbiosis.

scholarly journals Tight Junctions as a Key for Pathogens Invasion in Intestinal Epithelial Cells

2021 ◽  
Vol 22 (5) ◽  
pp. 2506
Author(s):  
Tracy Paradis ◽  
Hervé Bègue ◽  
Louise Basmaciyan ◽  
Frédéric Dalle ◽  
Fabienne Bon
Keyword(s):  
Epithelial Cells ◽  
Signaling Pathways ◽  
Tight Junctions ◽  
Intestinal Mucosa ◽  
Molecular Mechanisms ◽  
State Of The Art ◽  
Intestinal Epithelial Cells ◽  
Intestinal Barrier ◽  
Intestinal Epithelial ◽  
Gut Barrier

Tight junctions play a major role in maintaining the integrity and impermeability of the intestinal barrier. As such, they act as an ideal target for pathogens to promote their translocation through the intestinal mucosa and invade their host. Different strategies are used by pathogens, aimed at directly destabilizing the junctional network or modulating the different signaling pathways involved in the modulation of these junctions. After a brief presentation of the organization and modulation of tight junctions, we provide the state of the art of the molecular mechanisms leading to permeability breakdown of the gut barrier as a consequence of tight junctions’ attack by pathogens, including bacteria, viruses, fungi, and parasites.

scholarly journals Leaky Gut: Effect of Dietary Fiber and Fats on Microbiome and Intestinal Barrier

2021 ◽  
Vol 22 (14) ◽  
pp. 7613
Author(s):  
Haruki Usuda ◽  
Takayuki Okamoto ◽  
Koichiro Wada
Keyword(s):  
Intestinal Permeability ◽  
Intestinal Tract ◽  
Inflammatory Diseases ◽  
Intestinal Barrier ◽  
Short Chain Fatty Acids ◽  
Systemic Circulation ◽  
Mucosal Tissue ◽  
Leaky Gut ◽  
Exogenous Factors ◽  
Intestinal Barrier Integrity

Intestinal tract is the boundary that prevents harmful molecules from invading into the mucosal tissue, followed by systemic circulation. Intestinal permeability is an index for intestinal barrier integrity. Intestinal permeability has been shown to increase in various diseases—not only intestinal inflammatory diseases, but also systemic diseases, including diabetes, chronic kidney dysfunction, cancer, and cardiovascular diseases. Chronic increase of intestinal permeability is termed ‘leaky gut’ which is observed in the patients and animal models of these diseases. This state often correlates with the disease state. In addition, recent studies have revealed that gut microbiota affects intestinal and systemic heath conditions via their metabolite, especially short-chain fatty acids and lipopolysaccharides, which can trigger leaky gut. The etiology of leaky gut is still unknown; however, recent studies have uncovered exogenous factors that can modulate intestinal permeability. Nutrients are closely related to intestinal health and permeability that are actively investigated as a hot topic of scientific research. Here, we will review the effect of nutrients on intestinal permeability and microbiome for a better understanding of leaky gut and a possible mechanism of increase in intestinal permeability.

scholarly journals Plectin ensures intestinal epithelial integrity and protects colon against colitis

2021 ◽  
Vol 14 (3) ◽  
pp. 691-702
Author(s):  
Alzbeta Krausova ◽  
Petra Buresova ◽  
Lenka Sarnova ◽  
Gizem Oyman-Eyrilmez ◽  
Jozef Skarda ◽  
...  
Keyword(s):  
Mechanical Stability ◽  
Intestinal Barrier ◽  
Intercellular Junctions ◽  
Protein Profiling ◽  
Cell Junctions ◽  
Intestinal Barrier Function ◽  
Intestinal Epithelial ◽  
Critical Determinant ◽  
In Vitro Feeding

AbstractPlectin, a highly versatile cytolinker protein, provides tissues with mechanical stability through the integration of intermediate filaments (IFs) with cell junctions. Here, we hypothesize that plectin-controlled cytoarchitecture is a critical determinant of the intestinal barrier function and homeostasis. Mice lacking plectin in an intestinal epithelial cell (IEC; PleΔIEC) spontaneously developed colitis characterized by extensive detachment of IECs from the basement membrane (BM), increased intestinal permeability, and inflammatory lesions. Moreover, plectin expression was reduced in the colons of ulcerative colitis (UC) patients and negatively correlated with the severity of colitis. Mechanistically, plectin deficiency in IECs led to aberrant keratin filament (KF) network organization and the formation of dysfunctional hemidesmosomes (HDs) and intercellular junctions. In addition, the hemidesmosomal α6β4 integrin (Itg) receptor showed attenuated association with KFs, and protein profiling revealed prominent downregulation of junctional constituents. Consistent with the effects of plectin loss in the intestinal epithelium, plectin-deficient IECs exhibited remarkably reduced mechanical stability and limited adhesion capacity in vitro. Feeding mice with a low-residue liquid diet that reduced mechanical stress and antibiotic treatment successfully mitigated epithelial damage in the PleΔIEC colon.

scholarly journals Protective Role of Natural and Semi-Synthetic Tocopherols on TNFα-Induced ROS Production and ICAM-1 and Cl-2 Expression in HT29 Intestinal Epithelial Cells

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 160
Author(s):  
Vladana Domazetovic ◽  
Irene Falsetti ◽  
Caterina Viglianisi ◽  
Kristian Vasa ◽  
Cinzia Aurilia ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Properties ◽  
Intestinal Barrier ◽  
Protective Role ◽  
Intercellular Adhesion Molecule ◽  
Intestinal Epithelial ◽  
Intercellular Adhesion Molecule 1 ◽  
Beneficial Effects ◽  
Bowel Diseases

Vitamin E, a fat-soluble compound, possesses both antioxidant and non-antioxidant properties. In this study we evaluated, in intestinal HT29 cells, the role of natural tocopherols, α-Toc and δ-Toc, and two semi-synthetic derivatives, namely bis-δ-Toc sulfide (δ-Toc)2S and bis-δ-Toc disulfide (δ-Toc)2S2, on TNFα-induced oxidative stress, and intercellular adhesion molecule-1 (ICAM-1) and claudin-2 (Cl-2) expression. The role of tocopherols was compared to that of N-acetylcysteine (NAC), an antioxidant precursor of glutathione synthesis. The results show that all tocopherol containing derivatives used, prevented TNFα-induced oxidative stress and the increase of ICAM-1 and Cl-2 expression, and that (δ-Toc)2S and (δ-Toc)2S2 are more effective than δ-Toc and α-Toc. The beneficial effects demonstrated were due to tocopherol antioxidant properties, but suppression of TNFα-induced Cl-2 expression seems not only to be related with antioxidant ability. Indeed, while ICAM-1 expression is strongly related to the intracellular redox state, Cl-2 expression is TNFα-up-regulated by both redox and non-redox dependent mechanisms. Since ICAM-1 and Cl-2 increase intestinal bowel diseases, and cause excessive recruitment of immune cells and alteration of the intestinal barrier, natural and, above all, semi-synthetic tocopherols may have a potential role as a therapeutic support against intestinal chronic inflammation, in which TNFα represents an important proinflammatory mediator.

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