Regulation of intestinal epithelial permeability by tight junctions
01 Feb 2013-Cellular and Molecular Life Sciences (SP Birkhäuser Verlag Basel)-Vol. 70, Iss: 4, pp 631-659
TL;DR: The regulation of the intestinal TJ barrier is discussed together with its implications for the pathogenesis of diseases.
Abstract: The gastrointestinal epithelium forms the boundary between the body and external environment. It effectively provides a selective permeable barrier that limits the permeation of luminal noxious molecules, such as pathogens, toxins, and antigens, while allowing the appropriate absorption of nutrients and water. This selective permeable barrier is achieved by intercellular tight junction (TJ) structures, which regulate paracellular permeability. Disruption of the intestinal TJ barrier, followed by permeation of luminal noxious molecules, induces a perturbation of the mucosal immune system and inflammation, and can act as a trigger for the development of intestinal and systemic diseases. In this context, much effort has been taken to understand the roles of extracellular factors, including cytokines, pathogens, and food factors, for the regulation of the intestinal TJ barrier. Here, I discuss the regulation of the intestinal TJ barrier together with its implications for the pathogenesis of diseases.
Citations
More filters
TL;DR: A team from South Korea led by Sung Ho Ryu from Pohang University of Science and Technology review the regulatory mechanisms that help maintain the intestinal epithelial barrier and discusses the role of tight junction proteins in forming a seal between adjacent cells and the various signaling pathways that loosen or tighten these junctions to enable limited transport.
Abstract: The gastrointestinal tract is a specialized organ in which dynamic interactions between host cells and the complex environment occur in addition to food digestion. Together with the chemical barrier of the mucosal layer and the cellular immune system, the epithelial cell layer performs a pivotal role as the first physical barrier against external factors and maintains a symbiotic relationship with commensal bacteria. The tight junction proteins, including occludin, claudins, and zonula occludens, are crucial for the maintenance of epithelial barrier integrity. To allow the transport of essential molecules and restrict harmful substances, the intracellular signaling transduction system and a number of extracellular stimuli such as cytokines, small GTPases, and post-translational modifications dynamically modulate the tight junction protein complexes. An imbalance in these regulations leads to compromised barrier integrity and is linked with pathological conditions. Despite the obscurity of the causal relationship, the loss of barrier integrity is considered to contribute to inflammatory bowel disease, obesity, and metabolic disorders. The elucidation of the role of diseases in barrier integrity and the underlying regulatory mechanisms have improved our understanding of the intestinal barrier to allow the development of novel and potent therapeutic approaches. A better understanding of how the cells that line the inside of the intestines allow nutrients in, while keeping harmful substances and pathogens out could lead to new therapies for inflammatory bowel disease, obesity, and other conditions. A team from South Korea led by Sung Ho Ryu from Pohang University of Science and Technology review the regulatory mechanisms that help maintain the intestinal epithelial barrier. They discuss the role of tight junction proteins in forming a seal between adjacent cells and the various signaling pathways that loosen or tighten these junctions to enable limited transport. Loss of barrier integrity because of genetics, gut microbes, auto-immunity, diet, or other factors is often implicated in disease, and restoring barrier function with drugs or probiotics could help ameliorate many health problems.
679 citations
TL;DR: It is suggested that local and specific alteration of microbial metabolites has direct salutary effects on GVHD target tissues and can mitigate disease severity.
Abstract: The effect of alterations in intestinal microbiota on microbial metabolites and on disease processes such as graft-versus-host disease (GVHD) is not known. Here we carried out an unbiased analysis to identify previously unidentified alterations in gastrointestinal microbiota-derived short-chain fatty acids (SCFAs) after allogeneic bone marrow transplant (allo-BMT). Alterations in the amount of only one SCFA, butyrate, were observed only in the intestinal tissue. The reduced butyrate in CD326(+) intestinal epithelial cells (IECs) after allo-BMT resulted in decreased histone acetylation, which was restored after local administration of exogenous butyrate. Butyrate restoration improved IEC junctional integrity, decreased apoptosis and mitigated GVHD. Furthermore, alteration of the indigenous microbiota with 17 rationally selected strains of high butyrate-producing Clostridia also decreased GVHD. These data demonstrate a heretofore unrecognized role of microbial metabolites and suggest that local and specific alteration of microbial metabolites has direct salutary effects on GVHD target tissues and can mitigate disease severity.
486 citations
TL;DR: Treatment with L.reuteri emerges as promising non-invasive microbial-based avenue to combat ASD-related social dysfunction and rescues social interaction-induced synaptic plasticity in the ventral tegmental area of ASD mice.
425 citations
Cites background from "Regulation of intestinal epithelial..."
...If the integrity of the host’s intestinal barrier is damaged and rendered more permeable (so-called ‘‘leaky gut’’), which occurs when the gut epithelium tight junctions are impaired (Suzuki, 2013), bacteria and/or metabolites produced by bacteria can enter the blood circulation....
[...]
TL;DR: It is hypothesized that commonly used industrial food additives abrogate human epithelial barrier function, thus, increasing intestinal permeability through the opened tight junction, resulting in entry of foreign immunogenic antigens and activation of the autoimmune cascade.
347 citations
Cites background from "Regulation of intestinal epithelial..."
...Evidence exists that intestinal barrier defects have a role in initiating celiac disease [72,86,87]....
[...]
...In general, fatty acids like EPA, DHA, γLA, capric and lauric acids increase TJ permeability [72]....
[...]
TL;DR: It is hypothesized that modulating the gut microbiota can serve as a potential method for regulating intestinal permeability and may help to alter the course of autoimmune diseases in susceptible individuals.
Abstract: The intestinal epithelial lining, together with factors secreted from it, forms a barrier that separates the host from the environment. In pathologic conditions, the permeability of the epithelial lining may be compromised allowing the passage of toxins, antigens, and bacteria in the lumen to enter the blood stream creating a “leaky gut.” In individuals with a genetic predisposition, a leaky gut may allow environmental factors to enter the body and trigger the initiation and development of autoimmune disease. Growing evidence shows that the gut microbiota is important in supporting the epithelial barrier and therefore plays a key role in the regulation of environmental factors that enter the body. Several recent reports have shown that probiotics can reverse the leaky gut by enhancing the production of tight junction proteins; however, additional and longer-term studies are still required. Conversely, pathogenic bacteria that can facilitate a leaky gut and induce autoimmune symptoms can be ameliorated with the use of antibiotic treatment. Therefore, it is hypothesized that modulating the gut microbiota can serve as a potential method for regulating intestinal permeability and may help to alter the course of autoimmune diseases in susceptible individuals.
345 citations
Cites background from "Regulation of intestinal epithelial..."
...Diet-induced Gut Leakiness Nutrients and food ingredients have been reported to contribute to the maintenance or alterations of gut microbiota and the intestinal barrier function (82)....
[...]
References
More filters
TL;DR: Identification of CAR as a receptor for these two unrelated and structurally distinct viral pathogens is important for understanding viral pathogenesis and has implications for therapeutic gene delivery with adenovirus vectors.
Abstract: A complementary DNA clone has been isolated that encodes a coxsackievirus and adenovirus receptor (CAR). When transfected with CAR complementary DNA, nonpermissive hamster cells became susceptible to coxsackie B virus attachment and infection. Furthermore, consistent with previous studies demonstrating that adenovirus infection depends on attachment of a viral fiber to the target cell, CAR-transfected hamster cells bound adenovirus in a fiber-dependent fashion and showed a 100-fold increase in susceptibility to virus-mediated gene transfer. Identification of CAR as a receptor for these two unrelated and structurally distinct viral pathogens is important for understanding viral pathogenesis and has implications for therapeutic gene delivery with adenovirus vectors.
3,128 citations
"Regulation of intestinal epithelial..." refers background in this paper
...CAR is concentrated at cell-cell contacts and is co-localized with ZO-1 in intestinal T84 cells [77]....
[...]
...CAR (*46 kDa) is a JAM family protein, and the heterophilic interaction of its extracellular domain with coxsackievirus and adenovirus appears to limit virus invasion [71]....
[...]
...In intestinal epithelial cells, JAM-A, JAM-4, and CAR are expressed and involved in TJ regulation....
[...]
...In contrast, JAM-4 [70], coxsackievirus and adenovirus receptor (CAR) [71], endothelial selective adhesion molecule (ESAM) [72], and the brain- and testisspecific immunoglobulin superfamily (BT-IgSF) [73] have class I PDZ-binding motifs....
[...]
...The recombinant soluble CAR protein, which encodes the extracellular domain and inhibits the intercellular interaction of CAR, delays the recovery of TER after calcium repletion [77]....
[...]
TL;DR: Recent advances have uncovered mechanisms by which the intestinal mucosal barrier is regulated in response to physiological and immunological stimuli, along with evidence that this regulation shapes mucosal immune responses in the gut and, when dysfunctional, may contribute to disease.
Abstract: Mucosal surfaces are lined by epithelial cells. These cells establish a barrier between sometimes hostile external environments and the internal milieu. However, mucosae are also responsible for nutrient absorption and waste secretion, which require a selectively permeable barrier. These functions place the mucosal epithelium at the centre of interactions between the mucosal immune system and luminal contents, including dietary antigens and microbial products. Recent advances have uncovered mechanisms by which the intestinal mucosal barrier is regulated in response to physiological and immunological stimuli. Here I discuss these discoveries along with evidence that this regulation shapes mucosal immune responses in the gut and, when dysfunctional, may contribute to disease.
2,795 citations
"Regulation of intestinal epithelial..." refers background in this paper
...studies indicate that the intestinal TJ barrier has a critical role in the pathogenesis of intestinal and systemic diseases [8, 10, 11]....
[...]
...As described above, the intestinal TJs provide a physical barrier against luminal noxious molecules such as pathogens, toxins, and allergens [8, 11]....
[...]
...The cytokinemediated dysfunction of the TJ barrier, resulting in immune activation and tissue inflammation, is thought to be important in the initiation and/or development of several intestinal and systemic diseases [8, 11]....
[...]
...They regulate the paracellular passage of ions, solutes, and water, and are also known to act as a fence to maintain cell polarity by blocking the free diffusion of proteins and lipids between the apical and basolateral domains of the plasma membrane [8, 11]....
[...]
TL;DR: Resistant starch is a prebiotic, but knowledge of its other interactions with the microflora is limited and the contribution of RS to fermentation and colonic physiology seems to be greater than that of NSP.
Abstract: Resistant starch (RS) is starch and products of its small intestinal digestion that enter the large bowel. It occurs for various reasons including chemical structure, cooking of food, chemical modification, and food mastication. Human colonic bacteria ferment RS and nonstarch polysaccharides (NSP; major components of dietary fiber) to short-chain fatty acids (SCFA), mainly acetate, propionate, and butyrate. SCFA stimulate colonic blood flow and fluid and electrolyte uptake. Butyrate is a preferred substrate for colonocytes and appears to promote a normal phenotype in these cells. Fermentation of some RS types favors butyrate production. Measurement of colonic fermentation in humans is difficult, and indirect measures (e.g., fecal samples) or animal models have been used. Of the latter, rodents appear to be of limited value, and pigs or dogs are preferable. RS is less effective than NSP in stool bulking, but epidemiological data suggest that it is more protective against colorectal cancer, possibly via butyrate. RS is a prebiotic, but knowledge of its other interactions with the microflora is limited. The contribution of RS to fermentation and colonic physiology seems to be greater than that of NSP. However, the lack of a generally accepted analytical procedure that accommodates the major influences on RS means this is yet to be established.
2,702 citations
"Regulation of intestinal epithelial..." refers background in this paper
...The production of SCFAs is important for normal intestinal biology such as energy salvage, cell proliferation, and barrier function [201, 202]....
[...]
TL;DR: Understanding the specific molecular events that regulate the production of IL-10 will help to answer the remaining questions that are important for the design of new strategies of immune intervention.
Abstract: Interleukin-10 (IL-10), a cytokine with anti-inflammatory properties, has a central role in infection by limiting the immune response to pathogens and thereby preventing damage to the host. Recently, an increasing interest in how IL10 expression is regulated in different immune cells has revealed some of the molecular mechanisms involved at the levels of signal transduction, epigenetics, transcription factor binding and gene activation. Understanding the specific molecular events that regulate the production of IL-10 will help to answer the remaining questions that are important for the design of new strategies of immune intervention.
2,491 citations
"Regulation of intestinal epithelial..." refers background in this paper
...Interleukin-10 (IL-10), a homodimeric cytokine mainly produced by Th2 cells, regulatory T cells, monocytes/ macrophages, and dendritic cells, is regarded as an antiinflammatory cytokine [130, 131]....
[...]
TL;DR: An integral membrane protein localizing at tight junctions is now identified, which is designated as "occludin," which was revealed by a hydrophilicity plot that was very similar to that of connexin, an integral membraneprotein in gap junctions.
Abstract: Recently, we found that ZO-1, a tight junction-associated protein, was concentrated in the so called isolated adherens junction fraction from the liver (Itoh, M., A. Nagafuchi, S. Yonemura, T. Kitani-Yasuda, Sa. Tsukita, and Sh. Tsukita. 1993. J. Cell Biol. 121:491-502). Using this fraction derived from chick liver as an antigen, we obtained three monoclonal antibodies specific for a approximately 65-kD protein in rats. This antigen was not extractable from plasma membranes without detergent, suggesting that it is an integral membrane protein. Immunofluorescence and immunoelectron microscopy with these mAbs showed that this approximately 65-kD membrane protein was exclusively localized at tight junctions of both epithelial and endothelial cells: at the electron microscopic level, the labels were detected directly over the points of membrane contact in tight junctions. To further clarify the nature and structure of this membrane protein, we cloned and sequenced its cDNA. We found that the cDNA encoded a 504-amino acid polypeptide with 55.9 kDa. A search of the data base identified no proteins with significant homology to this membrane protein. A most striking feature of its primary structure was revealed by a hydrophilicity plot: four putative membrane-spanning segments were included in the NH2-terminal half. This hydrophilicity plot was very similar to that of connexin, an integral membrane protein in gap junctions. These findings revealed that an integral membrane protein localizing at tight junctions is now identified, which we designated as "occludin."
2,469 citations
"Regulation of intestinal epithelial..." refers background in this paper
...Four integral transmembrane proteins, occludin [15], claudins [16], junctional adhesion molecule (JAM) [17], and tricellulin [18], have been identified, with the claudin family consisting of at least 24 members....
[...]
...Occludin (*65 kDa) was the first integral membrane TJ protein identified in 1993 [15]....
[...]