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Sample records for intestinal barrier permeability

  1. The food contaminant deoxynivalenol, decreases intestinal barrier permeability and reduces claudin expression

    SciTech Connect

    Pinton, Philippe; Nougayrede, Jean-Philippe; Del Rio, Juan-Carlos; Moreno, Carolina; Marin, Daniela E.; Ferrier, Laurent; Bracarense, Ana-Paula; Kolf-Clauw, Martine; Oswald, Isabelle P.

    2009-05-15

    'The gastrointestinal tract represents the first barrier against food contaminants as well as the first target for these toxicants. Deoxynivalenol (DON) is a mycotoxin that commonly contaminates cereals and causes various toxicological effects. Through consumption of contaminated cereals and cereal products, human and pigs are exposed to this mycotoxin. Using in vitro, ex vivo and in vivo approaches, we investigated the effects of DON on the intestinal epithelium. We demonstrated that, in intestinal epithelial cell lines from porcine (IPEC-1) or human (Caco-2) origin, DON decreases trans-epithelial electrical resistance (TEER) and increases in a time and dose-dependent manner the paracellular permeability to 4 kDa dextran and to pathogenic Escherichia coli across intestinal cell monolayers. In pig explants treated with DON, we also observed an increased permeability of intestinal tissue. These alterations of barrier function were associated with a specific reduction in the expression of claudins, which was also seen in vivo in the jejunum of piglets exposed to DON-contaminated feed. In conclusion, DON alters claudin expression and decreases the barrier function of the intestinal epithelium. Considering that high levels of DON may be present in food or feed, consumption of DON-contaminated food/feed may induce intestinal damage and has consequences for human and animal health.

  2. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders.

    PubMed

    Kelly, John R; Kennedy, Paul J; Cryan, John F; Dinan, Timothy G; Clarke, Gerard; Hyland, Niall P

    2015-01-01

    The emerging links between our gut microbiome and the central nervous system (CNS) are regarded as a paradigm shift in neuroscience with possible implications for not only understanding the pathophysiology of stress-related psychiatric disorders, but also their treatment. Thus the gut microbiome and its influence on host barrier function is positioned to be a critical node within the brain-gut axis. Mounting preclinical evidence broadly suggests that the gut microbiota can modulate brain development, function and behavior by immune, endocrine and neural pathways of the brain-gut-microbiota axis. Detailed mechanistic insights explaining these specific interactions are currently underdeveloped. However, the concept that a "leaky gut" may facilitate communication between the microbiota and these key signaling pathways has gained traction. Deficits in intestinal permeability may underpin the chronic low-grade inflammation observed in disorders such as depression and the gut microbiome plays a critical role in regulating intestinal permeability. In this review we will discuss the possible role played by the gut microbiota in maintaining intestinal barrier function and the CNS consequences when it becomes disrupted. We will draw on both clinical and preclinical evidence to support this concept as well as the key features of the gut microbiota which are necessary for normal intestinal barrier function.

  3. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders

    PubMed Central

    Kelly, John R.; Kennedy, Paul J.; Cryan, John F.; Dinan, Timothy G.; Clarke, Gerard; Hyland, Niall P.

    2015-01-01

    The emerging links between our gut microbiome and the central nervous system (CNS) are regarded as a paradigm shift in neuroscience with possible implications for not only understanding the pathophysiology of stress-related psychiatric disorders, but also their treatment. Thus the gut microbiome and its influence on host barrier function is positioned to be a critical node within the brain-gut axis. Mounting preclinical evidence broadly suggests that the gut microbiota can modulate brain development, function and behavior by immune, endocrine and neural pathways of the brain-gut-microbiota axis. Detailed mechanistic insights explaining these specific interactions are currently underdeveloped. However, the concept that a “leaky gut” may facilitate communication between the microbiota and these key signaling pathways has gained traction. Deficits in intestinal permeability may underpin the chronic low-grade inflammation observed in disorders such as depression and the gut microbiome plays a critical role in regulating intestinal permeability. In this review we will discuss the possible role played by the gut microbiota in maintaining intestinal barrier function and the CNS consequences when it becomes disrupted. We will draw on both clinical and preclinical evidence to support this concept as well as the key features of the gut microbiota which are necessary for normal intestinal barrier function. PMID:26528128

  4. Effects of soybean agglutinin on intestinal barrier permeability and tight junction protein expression in weaned piglets.

    PubMed

    Zhao, Yuan; Qin, Guixin; Sun, Zewei; Che, Dongsheng; Bao, Nan; Zhang, Xiaodong

    2011-01-01

    This study was developed to provide further information on the intestinal barrier permeability and the tight junction protein expression in weaned piglets fed with different levels of soybean agglutinin (SBA). Twenty-five weaned crossbred barrows (Duroc × Landrace × Yorkshire) were selected and randomly allotted to five groups, each group with five replicates. The piglets in the control group were not fed with leguminous products. 0.05, 0.1, 0.15 and 0.2% SBA was added to the control diet to form four experimental diets, respectively. After the experimental period of 7 days (for each group), all the piglets were anesthetized with excess procaine and slaughtered. The d-lactic acid in plasma and the Ileal mucosa diamine oxidase (DAO) was analyzed to observe the change in the intestinal permeability. The tight junction proteins occludin and ZO-1 in the jejunum tissue distribution and relative expression were detected by immunohistochemistry and Western Blot. The results illustrated that a high dose of SBA (0.1-0.2%) could increase the intestinal permeability and reduce piglet intestinal epithelial tight junction protein occludin or ZO-1 expression, while low dose of SBA (0.05% of total diet) had no significant affects. The contents of DAO, d-lactic acid, occludin or ZO-1, had a linear relationship with the SBA levels (0-0.2%) in diets. The high dose SBA (0.1-0.2%) could increase the intestinal permeability and reduce piglet intestinal epithelial tight junction protein occludin or ZO-1 expression, while low dose of SBA (0.05% of total diet) had no affects.

  5. Low Dosage of Chitosan Supplementation Improves Intestinal Permeability and Impairs Barrier Function in Mice

    PubMed Central

    Peng, Hanhui; Li, Guanya

    2016-01-01

    The purpose of this study was to explore relationships between low dose dietary supplementation with chitosan (COS) and body weight, feed intake, intestinal barrier function, and permeability in mice. Twenty mice were randomly assigned to receive an unadulterated control diet (control group) or a dietary supplementation with 30 mg/kg dose of chitosan (COS group) for two weeks. Whilst no significant differences were found between the conditions for body weight or food and water intake, mice in the COS group had an increased serum D-lactate content (P < 0.05) and a decreased jejunal diamine oxidase (DAO) activity (P < 0.05). Furthermore, mice in COS group displayed a reduced expression of occludin and ZO-1 (P < 0.05) and a reduced expression of occludin in the ileum (P < 0.05). The conclusion drawn from these findings showed that although 30 mg/kg COS-supplemented diet had no effect on body weight or feed intake in mice, this dosage may compromise intestinal barrier function and permeability. This research will contribute to the guidance on COS supplements. PMID:27610376

  6. Contributions of altered permeability of intestinal barrier and defecation behavior to toxicity formation from graphene oxide in nematode Caenorhabditis elegans.

    PubMed

    Wu, Qiuli; Yin, Li; Li, Xing; Tang, Meng; Zhang, Tao; Wang, Dayong

    2013-10-21

    Graphene oxide (GO) has been extensively studied for potential biomedical applications. Meanwhile, potential GO toxicity arises in both biomedical applications and non-biomedical products where environmental exposures may occur. In the present study, we examined the potential adverse effects of GO and the underlying mechanism using nematode Caenorhabditis elegans as the assay system. We compared the in vivo effects of GO between acute exposure and prolonged exposure, and found that prolonged exposure to 0.5-100 mg L(-1) of GO caused damage on functions of both primary (intestine) and secondary (neuron and reproductive organ) targeted organs. In the intestine, ROS production was significantly correlated with the formation of adverse effects on functions of both primary and secondary targeted organs. GO could be translocated into intestinal cells with loss of microvilli, and distributed to be adjacent to or surrounding mitochondria. Prolonged exposure to GO resulted in a hyper-permeable state of the intestinal barrier, an increase in mean defecation cycle length, and alteration of genes required for intestinal development and defecation behavior. Thus, our data suggest that prolonged exposure to GO may cause potential risk to environmental organisms after release into the environment. GO toxicity may be due to the combinational effects of oxidative stress in the intestinal barrier, enhanced permeability of the biological barrier, and suppressed defecation behavior in C. elegans.

  7. Intestinal permeability, leaky gut, and intestinal disorders.

    PubMed

    Hollander, D

    1999-10-01

    A major task of the intestine is to form a defensive barrier to prevent absorption of damaging substances from the external environment. This protective function of the intestinal mucosa is called permeability. Clinicians can use inert, nonmetabolized sugars such as mannitol, rhamnose, or lactulose to measure the permeability barrier or the degree of leakiness of the intestinal mucosa. Ample evidence indicates that permeability is increased in most patients with Crohn's disease and in 10% to 20% of their clinically healthy relatives. The abnormal leakiness of the mucosa in Crohn's patients and their relatives can be greatly amplified by aspirin preadministration. Permeability measurements in Crohn's patients reflect the activity, extent, and distribution of the disease and may allow us to predict the likelihood of recurrence after surgery or medically induced remission. Permeability is also increased in celiac disease and by trauma, burns, and nonsteroidal anti-inflammatory drugs. The major determinant of the rate of intestinal permeability is the opening or closure of the tight junctions between enterocytes in the paracellular space. As we broaden our understanding of the mechanisms and agents that control the degree of leakiness of the tight junctions, we will be increasingly able to use permeability measurements to study the etiology and pathogenesis of various disorders and to design or monitor therapies for their management.

  8. Intestinal Barrier and Behavior.

    PubMed

    Julio-Pieper, M; Bravo, J A

    2016-01-01

    The intestinal barrier function contributes to gut homeostasis by modulating absorption of water, electrolytes, and nutrients from the lumen into the circulation while restricting the passage of noxious luminal substances and microorganisms. Chronic conditions such as rheumatoid arthritis, inflammatory bowel disease, and celiac disease are associated to intestinal barrier dysfunction. Here, the hypothesis is that a leaky intestinal wall allowing for indiscriminate passage of intraluminal compounds to the vascular compartment could in turn lead to systemic inflammation. An increasing number of studies are now investigating the association between gut permeability and CNS disorders, under the premise that translocation of intestinal luminal contents could affect CNS function, either directly or indirectly. Still, it is unknown whether disruption of intestinal barrier is a causative agent or a consequence in these situations. Here, we discuss the latest evidence pointing to an association between increased gut permeability and disrupted behavioral responses.

  9. Intestinal and Blood-Brain Barrier Permeability of Ginkgolides and Bilobalide: In Vitro and In Vivo Approaches

    USDA-ARS?s Scientific Manuscript database

    In this study intestinal and blood brain barrier (BBB) transport of ginkgolides A, B, C, J and bilobalide, isolated from Ginkgo biloba (Family-Ginkgoaceae), was evaluated in Caco-2 and MDR1-MDCK cell monolayer models. Transepithelial transport was examined for 2 hours in both absorptive and secretor...

  10. Exercise, intestinal barrier dysfunction and probiotic supplementation.

    PubMed

    Lamprecht, Manfred; Frauwallner, Anita

    2012-01-01

    Athletes exposed to high-intensity exercise show an increased occurrence of gastrointestinal (GI) symptoms like cramps, diarrhea, bloating, nausea, and bleeding. These problems have been associated with alterations in intestinal permeability and decreased gut barrier function. The increased GI permeability, a so-called 'leaky gut', also leads to endotoxemia, and results in increased susceptibility to infectious and autoimmune diseases, due to absorption of pathogens/toxins into tissue and the bloodstream. Key components that determine intestinal barrier function and GI permeability are tight junctions, protein structures located in the paracellular channels between epithelial cells of the intestinal wall. The integrity of tight junctions depends on sophisticated interactions between the gut residents and their expressed substances, the intestinal epithelial cell metabolism and the activities of the gut-associated lymphoid tissue. Probiotic supplements are an upcoming group of nutraceuticals that could offer positive effects on athlete's gut and entire health. Some results demonstrate promising benefits for probiotic use on the athlete's immune system. There is also evidence that probiotic supplementation can beneficially influence intestinal barrier integrity in acute diseases. With regard to exercise-induced GI permeability problems, there is still a lack of studies with appropriate data and a gap to understand the underlying mechanisms to support such health beneficial statements implicitly. This article refers (i) to exercise-induced intestinal barrier dysfunction, (ii) provides suggestions to estimate increased gut barrier permeability in athletes, and (iii) discusses the potential of probiotic supplementation to counteract an exercise-induced leaky gut.

  11. Glutamine and intestinal barrier function.

    PubMed

    Wang, Bin; Wu, Guoyao; Zhou, Zhigang; Dai, Zhaolai; Sun, Yuli; Ji, Yun; Li, Wei; Wang, Weiwei; Liu, Chuang; Han, Feng; Wu, Zhenlong

    2015-10-01

    The intestinal barrier integrity is essential for the absorption of nutrients and health in humans and animals. Dysfunction of the mucosal barrier is associated with increased gut permeability and development of multiple gastrointestinal diseases. Recent studies highlighted a critical role for glutamine, which had been traditionally considered as a nutritionally non-essential amino acid, in activating the mammalian target of rapamycin cell signaling in enterocytes. In addition, glutamine has been reported to enhance intestinal and whole-body growth, to promote enterocyte proliferation and survival, and to regulate intestinal barrier function in injury, infection, weaning stress, and other catabolic conditions. Mechanistically, these effects were mediated by maintaining the intracellular redox status and regulating expression of genes associated with various signaling pathways. Furthermore, glutamine stimulates growth of the small intestinal mucosa in young animals and also enhances ion transport by the gut in neonates and adults. Growing evidence supports the notion that glutamine is a nutritionally essential amino acid for neonates and a conditionally essential amino acid for adults. Thus, as a functional amino acid with multiple key physiological roles, glutamine holds great promise in protecting the gut from atrophy and injury under various stress conditions in mammals and other animals.

  12. Intestinal permeability defects: is it time to treat?

    PubMed

    Odenwald, Matthew A; Turner, Jerrold R

    2013-09-01

    An essential role of the intestinal epithelium is to separate luminal contents from the interstitium, a function primarily determined by the integrity of the epithelium and the tight junction that seals the paracellular space. Intestinal tight junctions are selectively permeable, and intestinal permeability can be increased physiologically in response to luminal nutrients or pathologically by mucosal immune cells and cytokines, the enteric nervous system, and pathogens. Compromised intestinal barrier function is associated with an array of clinical conditions, both intestinal and systemic. Although most available data are correlative, some studies support a model where cycles of increased intestinal permeability, intestinal immune activation, and subsequent immune-mediated barrier loss contribute to disease progression. This model is applicable to intestinal and systemic diseases. However, it has not been proven, and both mechanistic and therapeutic studies are ongoing. Nevertheless, the correlation between increased intestinal permeability and disease has caught the attention of the public, leading to a rise in popularity of the diagnosis of "leaky gut syndrome," which encompasses a range of systemic disorders. Proponents claim that barrier restoration will cure underlying disease, but this has not been demonstrated in clinical trials. Moreover, human and mouse studies show that intestinal barrier loss alone is insufficient to initiate disease. It is therefore uncertain whether increased permeability in these patients is a cause or effect of the underlying disorder. Although drug targets that may mediate barrier restoration have been proposed, none have been proven effective. As such, current treatments for barrier dysfunction should target the underlying disease. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

  13. Intestinal permeability defects: Is it time to treat?

    PubMed Central

    Odenwald, Matthew A.; Turner, Jerrold R.

    2013-01-01

    An essential role of the intestinal epithelium is to separate luminal contents from the interstitium, a function primarily determined by the integrity of the epithelium and the tight junction that seals the paracellular space. Intestinal tight junctions are selectively-permeable, and intestinal permeability can be increased physiologically in response to luminal nutrients or pathologically by mucosal immune cells and cytokines, the enteric nervous system, and pathogens. Compromised intestinal barrier function is associated with an array of clinical conditions, both intestinal and systemic. While most available data are correlative, some studies support a model where cycles of increased intestinal permeability, intestinal immune activation, and subsequent immune-mediated barrier loss contribute to disease progression. This model is applicable to intestinal and systemic diseases. However, it has not been proven and both mechanistic and therapeutic studies are ongoing. Nevertheless, the correlation between increased intestinal permeability and disease has caught the attention of the public, leading to a rise in popularity of the diagnosis of “leaky gut syndrome,” which encompasses a range of systemic disorders. Proponents claim that barrier restoration will cure underlying disease, but this has not been demonstrated in clinical trials. Moreover, human and mouse studies show that intestinal barrier loss alone is insufficient to initiate disease. It is therefore uncertain if increased permeability in these patients is a cause or effect of the underlying disorder. Although drug targets that may mediate barrier restoration have been proposed, none have been proven effective. As such, current treatments for barrier dysfunction should target the underlying disease. PMID:23851019

  14. Helminths and intestinal barrier function.

    PubMed

    McKay, Derek M; Shute, Adam; Lopes, Fernando

    2017-01-02

    Approximately one-sixth of the worlds' population is infected with helminths and this class of parasite takes a major toll on domestic livestock. The majority of species of parasitic helminth that infect mammals live in the gut (the only niche for tapeworms) where they contact the hosts' epithelial cells. Here, the helminth-intestinal epithelial interface is reviewed in terms of the impact on, and regulation of epithelial barrier function, both intrinsic (epithelial permeability) and extrinsic (mucin, bacterial peptides, commensal bacteria) elements of the barrier. The data available on direct effects of helminths on epithelial permeability are scant, fragmentary and pales in comparison with knowledge of mobilization of immune reactions and effector cells in response to helminth parasites and how these impact intestinal barrier function. The interaction of helminth-host and helminth-host-bacteria is an important determinant of gut form and function and precisely defining these interactions will radically alter our understanding of normal gut physiology and pathophysiological reactions, revealing new approaches to infection with parasitic helminths, bacterial pathogens and idiopathic auto-inflammatory disease.

  15. Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical consequences: summary of a symposium.

    PubMed

    Purohit, Vishnudutt; Bode, J Christian; Bode, Christiane; Brenner, David A; Choudhry, Mashkoor A; Hamilton, Frank; Kang, Y James; Keshavarzian, Ali; Rao, Radhakrishna; Sartor, R Balfour; Swanson, Christine; Turner, Jerrold R

    2008-08-01

    This report is a summary of the symposium on Alcohol, Intestinal Bacterial Growth, Intestinal Permeability to Endotoxin, and Medical Consequences, organized by National Institute on Alcohol Abuse and Alcoholism, Office of Dietary Supplements, and National Institute of Diabetes and Digestive and Kidney Diseases of National Institutes of Health in Rockville, Maryland, October 11, 2006. Alcohol exposure can promote the growth of Gram-negative bacteria in the intestine, which may result in accumulation of endotoxin. In addition, alcohol metabolism by Gram-negative bacteria and intestinal epithelial cells can result in accumulation of acetaldehyde, which in turn can increase intestinal permeability to endotoxin by increasing tyrosine phosphorylation of tight junction and adherens junction proteins. Alcohol-induced generation of nitric oxide may also contribute to increased permeability to endotoxin by reacting with tubulin, which may cause damage to microtubule cytoskeleton and subsequent disruption of intestinal barrier function. Increased intestinal permeability can lead to increased transfer of endotoxin from the intestine to the liver and general circulation where endotoxin may trigger inflammatory changes in the liver and other organs. Alcohol may also increase intestinal permeability to peptidoglycan, which can initiate inflammatory response in liver and other organs. In addition, acute alcohol exposure may potentiate the effect of burn injury on intestinal bacterial growth and permeability. Decreasing the number of Gram-negative bacteria in the intestine can result in decreased production of endotoxin as well as acetaldehyde which is expected to decrease intestinal permeability to endotoxin. In addition, intestinal permeability may be preserved by administering epidermal growth factor, l-glutamine, oats supplementation, or zinc, thereby preventing the transfer of endotoxin to the general circulation. Thus reducing the number of intestinal Gram-negative bacteria

  16. Protozoon infections and intestinal permeability.

    PubMed

    Dagci, Hande; Ustun, Sebnem; Taner, Memduh S; Ersoz, Galip; Karacasu, Ferit; Budak, Seza

    2002-01-01

    Intestinal permeability (IP) studies using some macromolecules have been assumed to demonstrate the intactness of intestinal mucosa. The aim of the present study is to determine the changes in IP among patients with protozoan infections. Thirty nine patients with protozoan infections and ten healthy controls were enrolled in the study. Protozoa were diagnosed by Native-lugol, Richie and Trichrome staining of faeces. IP was evaluated by diethyl triamine penta acetic acid labeled with 99m Technetium (99mTc labeled DTPA) assay. The IP was found to have increased in patients with protozoan infections compared with control patients (7.20+/-5.52 vs. 4.47+/-0.65%, P=0.0017). The IP values were 9.91+/-10.05% in Giardia intestinalis group, 6.81+/-2.25% in Blastocystis hominis group, 5.78+/-2.84% in Entamoeba coli group. In comparison with the control group, the IP was significantly higher in G. intestinalis and B. hominis patients (P=0.0025, P=0.00037, respectively), but not in E. coli patients. In conclusion, the IP increases in patients with G. intestinalis and B. hominis but not with E. coli infection. This finding supports the view that IP increases during the course of protozoan infections which cause damage to the intestinal wall while non-pathogenic protozoan infections have no effect on IP. The increase in IP in patients with B. hominis brings forth the idea that B. hominis can be a pathogenic protozoan.

  17. Transport of decursin and decursinol angelate across Caco-2 and MDR-MDCK cell monolayers: in vitro models for intestinal and blood-brain barrier permeability.

    PubMed

    Madgula, Vamsi L; Avula, Bharathi; Reddy V L, Niranjan; Khan, Ikhlas A; Khan, Shabana I

    2007-04-01

    Decursin (DE) and decursinol angelate (DA) were isolated from the roots of Angelica gigas (Apiaceae) and purified by HPLC. DE and DA have been reported to exhibit significant neuropharmacological activities, but their intestinal transport and permeability in terms of CNS penetration across the blood-brain barrier (BBB) are unknown. This study was undertaken to evaluate the IN VITRO intestinal and BBB transport of DE and DA using Caco-2 and MDR-MDCK cell monolayer models, respectively. The bidirectional transport of DE and DA across Caco-2 and MDR-MDCK monolayers was examined for 2 hours. Integrity of the monolayer was determined by TEER value and by monitoring the transport of Lucifer yellow (Ly) across the monolayers. Quantitation of DE and DA was performed by HPLC. DE and DA exhibited bidirectional transport with a Papp value in the range of 9.0-12.0x10(-6) cm/sec and 7.2-11.7x10(-6) cm/sec in Caco-2 and MDR-MDCK monolayers, respectively. The TEER values were in the range of 410-440 and 1170-1230 ohm cm2 for Caco-2 and MDR-MDCK monolayers, respectively. Ly measurement, the fluorescent marker of passive paracellular diffusion, resulted in Papp values of 2.5-5.0x10(-6) in Caco-2 and 6.0-8.0x10(-6) cm/sec in MDR-MDCK monolayers, confirming that the monolayer integrity was intact at the end of the experiment. Caco-2:human colonic adenocarcinoma DA:decursinol angelate DE:decursin Ly:Lucifer yellow MDCK:Madin-Darby canine kidney MDR:multidrug resistant Papp:apparent permeability TEER:transepithelial electrical resistance.

  18. Nutritional Keys for Intestinal Barrier Modulation

    PubMed Central

    De Santis, Stefania; Cavalcanti, Elisabetta; Mastronardi, Mauro; Jirillo, Emilio; Chieppa, Marcello

    2015-01-01

    The intestinal tract represents the largest interface between the external environment and the human body. Nutrient uptake mostly happens in the intestinal tract, where the epithelial surface is constantly exposed to dietary antigens. Since inflammatory response toward these antigens may be deleterious for the host, a plethora of protective mechanisms take place to avoid or attenuate local damage. For instance, the intestinal barrier is able to elicit a dynamic response that either promotes or impairs luminal antigens adhesion and crossing. Regulation of intestinal barrier is crucial to control intestinal permeability whose increase is associated with chronic inflammatory conditions. The cross talk among bacteria, immune, and dietary factors is able to modulate the mucosal barrier function, as well as the intestinal permeability. Several nutritional products have recently been proposed as regulators of the epithelial barrier, even if their effects are in part contradictory. At the same time, the metabolic function of the microbiota generates new products with different effects based on the dietary content. Besides conventional treatments, novel therapies based on complementary nutrients are now growing. Fecal therapy has been recently used for the clinical treatment of refractory Clostridium difficile infection instead of the classical antibiotic therapy. In the present review, we will outline the epithelial response to nutritional components derived from dietary intake and microbial fermentation focusing on the consequent effects on the integrity of the epithelial barrier. PMID:26697008

  19. Regulation of intestinal permeability: The role of proteases

    PubMed Central

    Van Spaendonk, Hanne; Ceuleers, Hannah; Witters, Leonie; Patteet, Eveline; Joossens, Jurgen; Augustyns, Koen; Lambeir, Anne-Marie; De Meester, Ingrid; De Man, Joris G; De Winter, Benedicte Y

    2017-01-01

    The gastrointestinal barrier is - with approximately 400 m2 - the human body’s largest surface separating the external environment from the internal milieu. This barrier serves a dual function: permitting the absorption of nutrients, water and electrolytes on the one hand, while limiting host contact with noxious luminal antigens on the other hand. To maintain this selective barrier, junction protein complexes seal the intercellular space between adjacent epithelial cells and regulate the paracellular transport. Increased intestinal permeability is associated with and suggested as a player in the pathophysiology of various gastrointestinal and extra-intestinal diseases such as inflammatory bowel disease, celiac disease and type 1 diabetes. The gastrointestinal tract is exposed to high levels of endogenous and exogenous proteases, both in the lumen and in the mucosa. There is increasing evidence to suggest that a dysregulation of the protease/antiprotease balance in the gut contributes to epithelial damage and increased permeability. Excessive proteolysis leads to direct cleavage of intercellular junction proteins, or to opening of the junction proteins via activation of protease activated receptors. In addition, proteases regulate the activity and availability of cytokines and growth factors, which are also known modulators of intestinal permeability. This review aims at outlining the mechanisms by which proteases alter the intestinal permeability. More knowledge on the role of proteases in mucosal homeostasis and gastrointestinal barrier function will definitely contribute to the identification of new therapeutic targets for permeability-related diseases. PMID:28405139

  20. Intestinal permeability in a patient with liver cirrhosis

    PubMed Central

    Aguirre Valadez, Jonathan Manuel; Rivera-Espinosa, Liliana; Méndez-Guerrero, Osvely; Chávez-Pacheco, Juan Luis; García Juárez, Ignacio; Torre, Aldo

    2016-01-01

    Liver cirrhosis is a worldwide public health problem, and patients with this disease are at high risk of developing complications, bacterial translocation from the intestinal lumen to the mesenteric nodes, and systemic circulation, resulting in the development of severe complications related to high mortality rate. The intestinal barrier is a structure with a physical and biochemical activity to maintain balance between the external environment, including bacteria and their products, and the internal environment. Patients with liver cirrhosis develop a series of alterations in different components of the intestinal barrier directly associated with the severity of liver disease that finally increased intestinal permeability. A “leaky gut” is an effect produced by damaged intestinal barrier; alterations in the function of tight junction proteins are related to bacterial translocation and their products. Instead, increasing serum proinflammatory cytokines and hemodynamics modification, which results in the appearance of complications of liver cirrhosis such as hepatic encephalopathy, variceal hemorrhage, bacterial spontaneous peritonitis, and hepatorenal syndrome. The intestinal microbiota plays a fundamental role in maintaining the proper function of the intestinal barrier; bacterial overgrowth and dysbiosis are two phenomena often present in people with liver cirrhosis favoring bacterial translocation. Increased intestinal permeability has an important role in the genesis of these complications, and treating it could be the base for prevention and partial treatment of these complications. PMID:27920543

  1. Genetic aspects of intestinal permeability in inflammatory bowel disease.

    PubMed

    Takeuchi, Ken; Maiden, Laurence; Bjarnason, Ingvar

    2004-01-01

    There is a long-standing belief that disruption of the intestinal barrier function may lead to systemic and local intestinal disease. The role of increased intestinal permeability in Crohn's disease is reviewed here. What is not in doubt is that intestinal permeability in patients with Crohn's disease is increased proportional to disease activity; it can be used to predict clinical relapse of disease and prognosis; and a small proportion of first-degree relatives have increased intestinal permeability. This last finding has been subject to much speculation. In particular it has been suggested that it represents a genetically determined abnormality. If so it might play an important pathogenic process in the disease. However this permeability change in relatives does not conform to a classical inheritance pattern and in some studies it is found in the patients' spouses. This suggests an environmental cause for the changes. However proponents of an environmental factor have been singularly inactive in attempting to identify this agent(s). In view of recent research it seems likely that the increased intestinal permeability in relatives of Crohn's patients may be secondary to sub-clinical intestinal inflammation. This inflammation conforms to an inherited additive trait. The genetic basis for this inflammation is being studied.

  2. Validation of UHPLC-MS/MS methods for the determination of kaempferol and its metabolite 4-hydroxyphenyl acetic acid, and application to in vitro blood-brain barrier and intestinal drug permeability studies.

    PubMed

    Moradi-Afrapoli, Fahimeh; Oufir, Mouhssin; Walter, Fruzsina R; Deli, Maria A; Smiesko, Martin; Zabela, Volha; Butterweck, Veronika; Hamburger, Matthias

    2016-09-05

    Sedative and anxiolytic-like properties of flavonoids such as kaempferol and quercetin, and of some of their intestinal metabolites, have been demonstrated in pharmacological studies. However, routes of administration were shown to be critical for observing in vivo activity. Therefore, the ability to cross intestinal and blood-brain barriers was assessed in cell-based models for kaempferol (KMF), and for the major intestinal metabolite of KMF, 4-hydroxyphenylacetic acid (4-HPAA). Intestinal transport studies were performed with Caco-2 cells, and blood-brain barrier transport studies with an immortalized monoculture human model and a primary triple-co-culture rat model. UHPLC-MS/MS methods for KMF and 4-HPAA in Ringer-HEPES buffer and in Hank's balanced salt solution were validated according to industry guidelines. For all methods, calibration curves were fitted by least-squares quadratic regression with 1/X(2) as weighing factor, and mean coefficients of determination (R(2)) were >0.99. Data obtained with all barrier models showed high intestinal and blood-brain barrier permeation of KMF, and no permeability of 4-HPAA, when compared to barrier integrity markers. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Permeability Barrier Generation in the Martian Lithosphere

    NASA Astrophysics Data System (ADS)

    Schools, Joe; Montési, Laurent

    2015-11-01

    Permeability barriers develop when a magma produced in the interior of a planet rises into the cooler lithosphere and crystallizes more rapidly than the lithosphere can deform (Sparks and Parmentier, 1991). Crystallization products may then clog the porous network in which melt is propagating, reducing the permeability to almost zero, i.e., forming a permeability barrier. Subsequent melts cannot cross the barrier. Permeability barriers have been useful to explain variations in crustal thickness at mid-ocean ridges on Earth (Magde et al., 1997; Hebert and Montési, 2011; Montési et al., 2011). We explore here under what conditions permeability barriers may form on Mars.We use the MELTS thermodynamic calculator (Ghiorso and Sack, 1995; Ghiorso et al., 2002; Asimow et al., 2004) in conjunction with estimated Martian mantle compositions (Morgan and Anders, 1979; Wänke and Dreibus, 1994; Lodders and Fegley, 1997; Sanloup et al., 1999; Taylor 2013) to model the formation of permeability barriers in the lithosphere of Mars. In order to represent potential past and present conditions of Mars, we vary the lithospheric thickness, mantle potential temperature (heat flux), oxygen fugacity, and water content.Our results show that permeability layers can develop in the thermal boundary layer of the simulated Martian lithosphere if the mantle potential temperature is higher than ~1500°C. The various Martian mantle compositions yield barriers in the same locations, under matching variable conditions. There is no significant difference in barrier location over the range of accepted Martian oxygen fugacity values. Water content is the most significant influence on barrier development as it reduces the temperature of crystallization, allowing melt to rise further into the lithosphere. Our lower temperature and thicker lithosphere model runs, which are likely the most similar to modern Mars, show no permeability barrier generation. Losing the possibility of having a permeability

  4. Alterations in Intestinal Permeability After Thermal Injury,

    DTIC Science & Technology

    1992-01-01

    disaccharide with a The cause of the altered intestinal permeability in our molecular weight of 342, and mannitol, a monosaccharide patients who...and linear regression analyses were used as indicated. Differences •P<.01 vs controls and uninfected patients by analysis of were considered

  5. Berberine Reduces Uremia-Associated Intestinal Mucosal Barrier Damage.

    PubMed

    Yu, Chao; Tan, Shanjun; Zhou, Chunyu; Zhu, Cuilin; Kang, Xin; Liu, Shuai; Zhao, Shuang; Fan, Shulin; Yu, Zhen; Peng, Ai; Wang, Zhen

    2016-11-01

    Berberine is one of the main active constituents of Rhizoma coptidis, a traditional Chinese medicine, and has long been used for the treatment of gastrointestinal disorders. The present study was designed to investigate the effects of berberine on the intestinal mucosal barrier damage in a rat uremia model induced by the 5/6 kidney resection. Beginning at postoperative week 4, the uremia rats were treated with daily 150 mg/kg berberine by oral gavage for 6 weeks. To assess the intestinal mucosal barrier changes, blood samples were collected for measuring the serum D-lactate level, and terminal ileum tissue samples were used for analyses of intestinal permeability, myeloperoxidase activity, histopathology, malondialdehyde (MDA) level, and superoxide dismutase (SOD) activity. Berberine treatment resulted in significant decreases in the serum D-lactate level, intestinal permeability, intestinal myeloperoxidase activity, and intestinal mucosal and submucosal edema and inflammation, and the Chiu's scores assessed for intestinal mucosal injury. The intestinal MDA level was reduced and the intestinal SOD activity was increased following berberine treatment. In conclusion, berberine reduces intestinal mucosal barrier damage induced by uremia, which is most likely due to its anti-oxidative activity. It may be developed as a potential treatment for preserving intestinal mucosal barrier function in patients with uremia.

  6. Pathophysiology of increased intestinal permeability in obstructive jaundice

    PubMed Central

    Assimakopoulos, Stelios F; Scopa, Chrisoula D; Vagianos, Constantine E

    2007-01-01

    Despite advances in preoperative evaluation and postoperative care, intervention, especially surgery, for relief of obstructive jaundice still carries high morbidity and mortality rates, mainly due to sepsis and renal dysfunction. The key event in the pathophysiology of obstructive jaundice-associated complications is endotoxemia of gut origin because of intestinal barrier failure. This breakage of the gut barrier in obstructive jaundice is multi-factorial, involving disruption of the immunologic, biological and mechanical barrier. Experimental and clinical studies have shown that obstructive jaundice results in increased intestinal permeability. The mechanisms implicated in this phenomenon remain unresolved, but growing research interest during the last decade has shed light in our knowledge in the field. This review summarizes the current concepts in the pathophysiology of obstructive jaundice-induced gut barrier dysfunction, analyzing pivotal factors, such as altered intestinal tight junctions expression, oxidative stress and imbalance of enterocyte proliferation and apoptosis. Clinicians handling patients with obstructive jaundice should not neglect protecting the intestinal barrier function before, during and after intervention for the relief of this condition, which may improve their patients’ outcome. PMID:18161914

  7. PERMEABLE REACTIVE BARRIERS FOR GROUNDWATER REMEDIATION

    EPA Science Inventory

    Permeable reactive barriers (PRB's) are an emerging, alternative in-situ approach for remediating groundwater contamination that combine subsurface fluid flow management with a passive chemical treatment zone. Removal of contaminants from the groundwater plume is achieved by alt...

  8. PERMEABLE REACTIVE BARRIERS FOR GROUND WATER REMEDIATION

    EPA Science Inventory

    Permeable reactive barriers (PRB's) are an emerging, alternative in-situ approach for remediating groundwater contamination that combine subsurface fluid flow management with a passive chemical treatment zone. Removal of contaminants from the groundwater plume is achieved by alt...

  9. Intestinal permeability in patients with yersinia triggered reactive arthritis.

    PubMed Central

    Lahesmaa-Rantala, R; Magnusson, K E; Granfors, K; Leino, R; Sundqvist, T; Toivanen, A

    1991-01-01

    The passive intestinal permeability of patients with yersinia triggered reactive arthritis was studied using different sized polyethylene glycols (PEGs) contained in a mixture of PEG 400 and PEG 1000. The investigation was carried out at least one year after the onset of yersinia infection, and patients had neither acute gastrointestinal nor joint symptoms. The control groups included patients with uncomplicated yersiniosis as well as healthy subjects who were either HLA-B27 positive or negative. An altered intestinal barrier function to PEG molecules was detected in patients with a history of yersinia infection compared with healthy controls. No significant differences in the permeability were found between patients with or without reactive arthritis, nor was there any association of increased permeability with HLA-B27. The passive permeability of the intestinal mucosa to the larger molecules was increased for an unexpectedly long time after the acute yersinia infection, probably contributing to the perpetuation of joint symptoms in subjects susceptible to a chronic joint disease. PMID:1998397

  10. Evaluation of Barley's Beta-glucan Food Fortification through Investigation of Intestinal Permeability in Healthy Adults.

    PubMed

    Skouroliakou, Maria; Ntountaniotis, Dimitrios; Kastanidou, Olympia; Massara, Paraskevi

    2016-01-01

    Intestinal permeability is an index of the adequate function of the intestinal barrier and its modification is associated with intestinal diseases. The aim of the study is to investigate the hypothesis that barley's beta-glucan can inhibit the alteration of intestinal permeability and maintain intestinal integrity after a period of consumption of a carbohydrate snack (cake) rich in sugars. Volunteers participated in a placebo-controlled intervention study for 1 month. In this double-blind methodology, they were randomly assigned to (1) the intervention group (daily consumption of one portion of cake fortified with barley's beta-glucan) or (2) the placebo group (daily consumption of the same cake without the enrichment). Intestinal permeability was assessed using the lactulose/mannitol test. Athens, Greece. Twenty-three healthy volunteers (age > 40 years). Intestinal permeability did not differ between the 2 groups, both at the beginning and at the end of the intervention. In addition, the intestinal permeability was not significantly modified at the end of the intervention in each group. The results of the lactulose/mannitol test for the intervention and placebo groups were comparable. For healthy adults, the daily consumption of a simple cake (placebo) and the consumption of the cake fortified with barley's beta-glucan resulted in similar impact for intestinal permeability; thus, beta-glucans did not exert a protective role in intestinal permeability of healthy adults.

  11. Human Intestinal Barrier Function in Health and Disease

    PubMed Central

    König, Julia; Wells, Jerry; Cani, Patrice D; García-Ródenas, Clara L; MacDonald, Tom; Mercenier, Annick; Whyte, Jacqueline; Troost, Freddy; Brummer, Robert-Jan

    2016-01-01

    The gastrointestinal tract consists of an enormous surface area that is optimized to efficiently absorb nutrients, water, and electrolytes from food. At the same time, it needs to provide a tight barrier against the ingress of harmful substances, and protect against a reaction to omnipresent harmless compounds. A dysfunctional intestinal barrier is associated with various diseases and disorders. In this review, the role of intestinal permeability in common disorders such as infections with intestinal pathogens, inflammatory bowel disease, irritable bowel syndrome, obesity, celiac disease, non-celiac gluten sensitivity, and food allergies will be discussed. In addition, the effect of the frequently prescribed drugs proton pump inhibitors and non-steroidal anti-inflammatory drugs on intestinal permeability, as well as commonly used methods to assess barrier function will be reviewed. PMID:27763627

  12. Abnormal intestinal permeability and microbiota in patients with autoimmune hepatitis

    PubMed Central

    Lin, Rui; Zhou, Lu; Zhang, Jie; Wang, Bangmao

    2015-01-01

    Background: Autoimmune hepatitis (AIH) is a chronic, progressive, and immunologically mediated inflammatory liver disorder. The etiology of AIH still remains unknown. The aim of this study was to investigate the changes in intestinal permeability, bacterial translocation, and intestinal microbiome in patients with AIH and to evaluate the correlations of those changes with the stages of the disease. Methods: 24 patients with autoimmune hepatitis and 8 healthy volunteers were recruited for this study. We assessed (1) the integrity of tight junctions within the gut by immunohistochemical analysis of zona occludens-1 and occludin expression in duodenal biopsy specimens; (2) changes in the enteric microbiome by 16S rDNA quantitative PCR; and (3) the presence of bacterial translocation by the level of lipopolysaccharide (LPS) using ELISA. Results: Increased intestinal permeability, derangement of the microbiome and bacterial translocation occurred in AIH, which correlated with the severity of the disease. Conclusions: Autoimmune hepatitis is associated with leaky gut and intestinal microbiome dysbiosis. The impaired intestinal barrier may play an important role in the pathogenesis of AIH. PMID:26191211

  13. Ghrelin Attenuates Intestinal Barrier Dysfunction Following Intracerebral Hemorrhage in Mice

    PubMed Central

    Cheng, Yijun; Wei, Yongxu; Yang, Wenlei; Cai, Yu; Chen, Bin; Yang, Guoyuan; Shang, Hanbing; Zhao, Weiguo

    2016-01-01

    Intestinal barrier dysfunction remains a critical problem in patients with intracerebral hemorrhage (ICH) and is associated with poor prognosis. Ghrelin, a brain-gut peptide, has been shown to exert protection in animal models of gastrointestinal injury. However, the effect of ghrelin on intestinal barrier dysfunction post-ICH and its possible underlying mechanisms are still unknown. This study was designed to investigate whether ghrelin administration attenuates intestinal barrier dysfunction in experimental ICH using an intrastriatal autologous blood infusion mouse model. Our data showed that treatment with ghrelin markedly attenuated intestinal mucosal injury at both histomorphometric and ultrastructural levels post-ICH. Ghrelin reduced ICH-induced intestinal permeability according to fluorescein isothiocyanate conjugated-dextran (FITC-D) and Evans blue extravasation assays. Concomitantly, the intestinal tight junction-related protein markers, Zonula occludens-1 (ZO-1) and claudin-5 were upregulated by ghrelin post-ICH. Additionally, ghrelin reduced intestinal intercellular adhesion molecule-1 (ICAM-1) expression at the mRNA and protein levels following ICH. Furthermore, ghrelin suppressed the translocation of intestinal endotoxin post-ICH. These changes were accompanied by improved survival rates and an attenuation of body weight loss post-ICH. In conclusion, our results suggest that ghrelin reduced intestinal barrier dysfunction, thereby reducing mortality and weight loss, indicating that ghrelin is a potential therapeutic agent in ICH-induced intestinal barrier dysfunction therapy. PMID:27929421

  14. Testosterone perturbs epidermal permeability barrier homeostasis.

    PubMed

    Kao, J S; Garg, A; Mao-Qiang, M; Crumrine, D; Ghadially, R; Feingold, K R; Elias, P M

    2001-03-01

    Although there are no known gender-related differences in permeability barrier function in adults, estrogens accelerate whereas testosterone retards barrier development in fetal skin, and male fetuses demonstrate slower barrier development than female littermates. Moreover, prenatal administration of the androgen receptor antagonist, flutamide, equalizes developmental rates in male and female fetuses. Therefore, we evaluated the effects of changes in testosterone on barrier homeostasis in adult murine and human skin. Hypogonadal mice (whether by castration or by treatment with systemic flutamide) displayed significantly faster barrier recovery at 3, 6, and 12 h than did controls, and testosterone replacement slowed barrier recovery in castrated mice. Moreover, testosterone directly effects the skin, as topical flutamide also accelerated barrier recovery in normal male mice. These findings appear to be of physiologic significance, since prepubertal male mice (age 5 wk) displayed accelerated barrier recovery in comparison with adult postpubertal (11 wk) males. These studies also appear to be relevant for humans, as a hypopituitary human subject demonstrated repeated changes in barrier recovery in parallel with peaks and nadirs in serum testosterone levels during intermittent testosterone replacement. Mechanistic studies showed that differences in epidermal lipid synthesis do not account for the testosterone-induced functional alterations. Instead, epidermal lamellar body (LB) formation and secretion both decrease, resulting in decreased extracellular lamellar bilayers in testosterone-replete animals. These studies demonstrate that fluctuations in testosterone modulate barrier function, and that testosterone repletion can have negative consequences for permeability barrier homeostasis.

  15. Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability.

    PubMed

    Alhamoruni, A; Wright, K L; Larvin, M; O'Sullivan, S E

    2012-04-01

    Activation of cannabinoid receptors decreases emesis, inflammation, gastric acid secretion and intestinal motility. The ability to modulate intestinal permeability in inflammation may be important in therapy aimed at maintaining epithelial barrier integrity. The aim of the present study was to determine whether cannabinoids modulate the increased permeability associated with inflammation in vitro. Confluent Caco-2 cell monolayers were treated for 24 h with IFNγ and TNFα (10 ng·mL(-1) ). Monolayer permeability was measured using transepithelial electrical resistance and flux measurements. Cannabinoids were applied either apically or basolaterally after inflammation was established. Potential mechanisms of action were investigated using antagonists for CB(1) , CB(2) , TRPV1, PPARγ and PPARα. A role for the endocannabinoid system was established using inhibitors of the synthesis and degradation of endocannabinoids. Δ(9) -Tetrahydrocannabinol (THC) and cannabidiol accelerated the recovery from cytokine-induced increased permeability; an effect sensitive to CB(1) receptor antagonism. Anandamide and 2-arachidonylglycerol further increased permeability in the presence of cytokines; this effect was also sensitive to CB(1) antagonism. No role for the CB(2) receptor was identified in these studies. Co-application of THC, cannabidiol or a CB(1) antagonist with the cytokines ameliorated their effect on permeability. Inhibiting the breakdown of endocannabinoids worsened, whereas inhibiting the synthesis of endocannabinoids attenuated, the increased permeability associated with inflammation. These findings suggest that locally produced endocannabinoids, acting via CB(1) receptors play a role in mediating changes in permeability with inflammation, and that phytocannabinoids have therapeutic potential for reversing the disordered intestinal permeability associated with inflammation. This article is part of a themed section on Cannabinoids in Biology and Medicine. To view

  16. Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability

    PubMed Central

    Alhamoruni, A; Wright, KL; Larvin, M; O'Sullivan, SE

    2012-01-01

    BACKGROUND AND PURPOSE Activation of cannabinoid receptors decreases emesis, inflammation, gastric acid secretion and intestinal motility. The ability to modulate intestinal permeability in inflammation may be important in therapy aimed at maintaining epithelial barrier integrity. The aim of the present study was to determine whether cannabinoids modulate the increased permeability associated with inflammation in vitro. EXPERIMENTAL APPROACH Confluent Caco-2 cell monolayers were treated for 24 h with IFNγ and TNFα (10 ng·mL−1). Monolayer permeability was measured using transepithelial electrical resistance and flux measurements. Cannabinoids were applied either apically or basolaterally after inflammation was established. Potential mechanisms of action were investigated using antagonists for CB1, CB2, TRPV1, PPARγ and PPARα. A role for the endocannabinoid system was established using inhibitors of the synthesis and degradation of endocannabinoids. KEY RESULTS Δ9-Tetrahydrocannabinol (THC) and cannabidiol accelerated the recovery from cytokine-induced increased permeability; an effect sensitive to CB1 receptor antagonism. Anandamide and 2-arachidonylglycerol further increased permeability in the presence of cytokines; this effect was also sensitive to CB1 antagonism. No role for the CB2 receptor was identified in these studies. Co-application of THC, cannabidiol or a CB1 antagonist with the cytokines ameliorated their effect on permeability. Inhibiting the breakdown of endocannabinoids worsened, whereas inhibiting the synthesis of endocannabinoids attenuated, the increased permeability associated with inflammation. CONCLUSIONS AND IMPLICATIONS These findings suggest that locally produced endocannabinoids, acting via CB1 receptors play a role in mediating changes in permeability with inflammation, and that phytocannabinoids have therapeutic potential for reversing the disordered intestinal permeability associated with inflammation. LINKED ARTICLES This

  17. Borosilicate films as permeability barriers

    NASA Astrophysics Data System (ADS)

    Applegate, J. R.; Steinmetz, C. E.; Hettinger, J. D.; Carroll, J. F.; Krchnavek, R.

    2009-03-01

    Borosilicate films have been deposited using rf-sputtering techniques from a composite target at room temperature onto polypropylene (PP), high density polyethylene(HDPE), low density polyethylene(LDPE), and polyethylene terephthalate (PETG) substrates. Films were found to be smooth, flexible, with excellent adhesion to the substrates. Repeated rolling the coated substrates on a radius of 0.5mm resulted in no discernable damage for films less than 200nm in thickness. Creasing the substrates did result in local damage. However excellent adhesion did not allow the fractured glass to come off the substrate. Heat generated during deposition only influenced the films grown on LDPE where the thermal expansion mismatch between the film and substrate induced strains caused fractures in thick films. Modifications to processing parameters allowed thick films to be grown without fractures. Permeability measurements of nitrogen resulted in significant improvements in comparison to uncoated substrates.

  18. Intestinal permeability and bacterial translocation following small bowel transplantation in the rat

    SciTech Connect

    Grant, D.; Hurlbut, D.; Zhong, R.; Wang, P.Z.; Chen, H.F.; Garcia, B.; Behme, R.; Stiller, C.; Duff, J. )

    1991-08-01

    In addition to its role in absorbing nutrients, the intestinal mucosa provides an important barrier against toxins and bacteria in the bowel lumen. The present study evaluated gut barrier function following orthotopic (in continuity) intestinal grafting in rats. Graft histology, intestinal permeability, and bacterial translocation to the grafted mesenteric lymph nodes, the host's liver, and the host's spleen were assessed on the 3rd, 5th, and 7th postoperative days. The study group received no immunosuppression after allotransplantation. The two control groups included rats with isografts and rats with cyclosporine-treated allografts. On the 7th POD, the study animals had moderate transmural inflammation due to rejection, with normal histology in the isografts and CsA-treated allografts; increased intestinal permeability, measured by urinary excretion of oral 51Cr-EDTA (P less than 0.01); and increased number of bacteria in the MLN and spleen (P less than 0.05). The number of bacteria in the MLN and spleen of the study group positively correlated with the changes in intestinal permeability (P less than 0.05). Rejection of the orthotopic intestinal graft leads to increased intestinal permeability and bacterial translocation from the lumen of the graft to the host's reticuloendothelial system. Measures to improve gut barrier function and antibiotic therapy during rejection episodes may help reduce the incidence of septic complications after intestinal grafting.

  19. EVALUATION OF PERMEABLE REACTIVE BARRIER PERFORMANCE

    EPA Science Inventory

    The permeable reactive barrier (PRB) technology represents a passive option for long-term treatment of ground-water contamination. PRBs are a potentially more cost-effective treatment option for a variety of dissolved contaminants, such as certain types of chlorinated solvents, ...

  20. EVALUATION OF PERMEABLE REACTIVE BARRIER PERFORMANCE

    EPA Science Inventory

    The permeable reactive barrier (PRB) technology represents a passive option for long-term treatment of ground-water contamination. PRBs are a potentially more cost-effective treatment option for a variety of dissolved contaminants, such as certain types of chlorinated solvents, ...

  1. Hepatic Injury in Nonalcoholic Steatohepatitis Contributes to Altered Intestinal Permeability.

    PubMed

    Luther, Jay; Garber, John J; Khalili, Hamed; Dave, Maneesh; Bale, Shyam Sundhar; Jindal, Rohit; Motola, Daniel L; Luther, Sanjana; Bohr, Stefan; Jeoung, Soung Won; Deshpande, Vikram; Singh, Gurminder; Turner, Jerrold R; Yarmush, Martin L; Chung, Raymond T; Patel, Suraj J

    2015-03-01

    Emerging data suggest that changes in intestinal permeability and increased gut microbial translocation contribute to the inflammatory pathway involved in nonalcoholic steatohepatitis (NASH) development. Numerous studies have investigated the association between increased intestinal permeability and NASH. Our meta-analysis of this association investigates the underlying mechanism. A meta-analysis was performed to compare the rates of increased intestinal permeability in patients with NASH and healthy controls. To further address the underlying mechanism of action, we studied changes in intestinal permeability in a diet-induced (methionine-and-choline-deficient; MCD) murine model of NASH. In vitro studies were also performed to investigate the effect of MCD culture medium at the cellular level on hepatocytes, Kupffer cells, and intestinal epithelial cells. Nonalcoholic fatty liver disease (NAFLD) patients, and in particular those with NASH, are more likely to have increased intestinal permeability compared with healthy controls. We correlate this clinical observation with in vivo data showing mice fed an MCD diet develop intestinal permeability changes after an initial phase of liver injury and tumor necrosis factor-α (TNFα) induction. In vitro studies reveal that MCD medium induces hepatic injury and TNFα production yet has no direct effect on intestinal epithelial cells. Although these data suggest a role for hepatic TNFα in altering intestinal permeability, we found that mice genetically resistant to TNFα-myosin light chain kinase (MLCK)-induced intestinal permeability changes fed an MCD diet still develop increased permeability and liver injury. Our clinical and experimental results strengthen the association between intestinal permeability increases and NASH and also suggest that an early phase of hepatic injury and inflammation contributes to altered intestinal permeability in a fashion independent of TNFα and MLCK.

  2. Biomimetic PVPA in vitro model for estimation of the intestinal drug permeability using fasted and fed state simulated intestinal fluids.

    PubMed

    Naderkhani, Elenaz; Vasskog, Terje; Flaten, Gøril Eide

    2015-06-20

    A prerequisite for successful oral drug therapy is the drug's ability to cross the gastrointestinal barrier. Considering the increasing number of new chemical entities in modern drug discovery, reliable and fast in vitro models are required for early and efficient prediction of intestinal permeability. To mimic the intestinal environment, use of biorelevant media may provide valuable information on in vivo drug permeation. The present study aims at improving the novel biomimetic phospholipid vesicle-based permeation assay's (PVPAbiomimetic) biorelevance by investigating the applicability of the biorelevant media; fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF). The FaSSIF and FeSSIF's influence on the permeability of the model drugs acyclovir, indomethacin, griseofulvin and nadolol was then assessed. The barriers' robustness in terms of storage stability was also evaluated. The barriers were found to maintain their integrity in presence of FaSSIF and FeSSIF. The model drugs showed changes in permeability in presence of the different simulated intestinal fluids that were in agreement with previous reports. Moreover, the barrier showed improved storage stability by maintaining its integrity for 6months. Altogether, this study moves the PVPAbiomimetic an important step towards a better in vitro permeability model for use in drug development.

  3. Intestinal Permeability in Inflammatory Bowel Disease: Pathogenesis, Clinical Evaluation, and Therapy of Leaky Gut.

    PubMed

    Michielan, Andrea; D'Incà, Renata

    2015-01-01

    The pathogenesis of inflammatory bowel disease (IBD) is multifactorial with data suggesting the role of a disturbed interaction between the gut and the intestinal microbiota. A defective mucosal barrier may result in increased intestinal permeability which promotes the exposition to luminal content and triggers an immunological response that promotes intestinal inflammation. IBD patients display several defects in the many specialized components of mucosal barrier, from the mucus layer composition to the adhesion molecules that regulate paracellular permeability. These alterations may represent a primary dysfunction in Crohn's disease, but they may also perpetuate chronic mucosal inflammation in ulcerative colitis. In clinical practice, several studies have documented that changes in intestinal permeability can predict IBD course. Functional tests, such as the sugar absorption tests or the novel imaging technique using confocal laser endomicroscopy, allow an in vivo assessment of gut barrier integrity. Antitumor necrosis factor-α (TNF-α) therapy reduces mucosal inflammation and restores intestinal permeability in IBD patients. Butyrate, zinc, and some probiotics also ameliorate mucosal barrier dysfunction but their use is still limited and further studies are needed before considering permeability manipulation as a therapeutic target in IBD.

  4. Claudins, dietary milk proteins, and intestinal barrier regulation.

    PubMed

    Kotler, Belinda M; Kerstetter, Jane E; Insogna, Karl L

    2013-01-01

    The family of claudin proteins plays an important role in regulating the intestinal barrier by modulating the permeability of tight junctions. The impact of dietary protein on claudin biology has not been studied extensively. Whey proteins have been reported to improve intestinal barrier function, but their mechanism of action is not clear. Recent studies, however, have demonstrated increased intestinal claudin expression in response to milk protein components. Reviewed here are new findings suggesting that whey-protein-derived transforming growth factor β transcriptionally upregulates claudin-4 expression via a Smad-4-dependent pathway. These and other data, including limited clinical studies, are summarized below and, in the aggregate, suggest a therapeutic role for whey protein in diseases of intestinal barrier dysfunction, perhaps, in part, by regulating claudin expression. © 2013 International Life Sciences Institute.

  5. Bacterial chemotactic oligopeptides and the intestinal mucosal barrier

    SciTech Connect

    Ferry, D.M.; Butt, T.J.; Broom, M.F.; Hunter, J.; Chadwick, V.S.

    1989-07-01

    Intestinal absorption and enterohepatic circulation of N-formyl-methionyl-leucyl-/sup 125/I-tyrosine, a bioactive synthetic analog of the bacterial chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine has been investigated in the rat. In ileum and proximal and distal colon, dithiothreitol, which increases mucosal permeability, increased peptide absorption and biliary recovery fourfold, 70-fold, and 20-fold over control values, respectively. When dithiothreitol was combined with d-l-benzyl succinate, a potent inhibitor of intestinal carboxypeptidase, absorption and biliary recovery from ileal loops increased markedly to 40-fold over control, whereas there was no further increase in absorption from colon loops. There was a strong correlation between biliary N-formyl-methionyl-leucyl-/sup 125/I-tyrosine recovery and intestinal absorption of /sup 51/Cr-ethylenediaminetetraacetate, a marker of passive mucosal permeability (r = 0.97). We conclude that in the ileum both enzymic degradation and restricted mucosal permeability contribute to the intestinal barrier to luminal bacterial formyl oligopeptides. In the colon, however, enzymic mechanisms are less active and restricted mucosal permeability is the major factor. Abnormalities of the intestinal mucosal barrier to proinflammatory bacterial peptides could play a role in inflammatory disorders of the gut.

  6. Clamshell excavation of a permeable reactive barrier

    NASA Astrophysics Data System (ADS)

    Molfetta, Antonio Di; Sethi, Rajandrea

    2006-06-01

    Nowadays, permeable reactive barriers (PRB) are one of the most widespread techniques for the remediation of contaminated aquifers. Over the past 10 years, the use of iron-based PRBs has evolved from innovative to accepted standard practice for the treatment of a variety of groundwater contaminants (ITRC in: Permeable reactive barriers: lessons learned/new directions. The Interstate Technology and Regulatory Council, Permeable Reactive Barriers Team 2005). Although, a variety of excavation methods have been developed, backhoe excavators are often used for the construction of PRBs. The aim of this study is to describe the emplacement of a full-scale PRB and the benefits deriving from the use of a crawler crane equipped with a hydraulic grab (also known as clamshell excavator) in the excavation phases. The studied PRB was designed to remediate a chlorinated hydrocarbons plume at an old industrial landfill site, in Avigliana, near the city of Torino, in Italy. The continuous reactive barrier was designed to be 120 m long, 13 m deep, and 0.6 m thick. The installation of the barrier was accomplished using a clamshell for the excavation of the trench and a guar-gum slurry to support the walls. The performance of this technique was outstanding and allowed the installation of the PRB in 7 days. The degree of precision of the excavation was very high because of the intrinsic characteristics of this excavation tool and of the use of a concrete curb to guide the hydraulic grab. Moreover, the adopted technique permitted a saving of bioslurry thus minimizing the amount of biocide required.

  7. Mechanism of Interleukin-1β Induced-Increase in Mouse Intestinal Permeability In Vivo

    PubMed Central

    Al-Sadi, Rana; Guo, Shuhong; Dokladny, Karol; Smith, Matthew A.; Ye, Dongmei; Kaza, Archana; Watterson, D. Martin

    2012-01-01

    Interleukin-1β (IL-1β) has been shown to play an essential role in mediating intestinal inflammation of Crohn's disease and other inflammatory conditions of the gut. Previous studies from our laboratory have shown that IL-1β causes an increase in intestinal tight-junction permeability in Caco-2 monolayers in vitro. However, the IL-1β effect on the intestinal epithelial barrier in vivo remains unclear. Aims: the major aims of this study were to examine the effect of IL-1β on mouse intestinal epithelial barrier in vivo and to delineate the mechanisms involved using an in vivo model system consisting of a recycling perfusion of mouse small intestine. Intraperitonial injection of IL-1β at varying doses (0–10 μg) caused a concentration-dependent increase in mouse intestinal permeability to the paracellular marker dextran (10 KD), and the maximal increase in dextran flux occurred at IL-1β dose of 5 μg. IL-1β treatment caused an increase in myosin light-chain kinase (MLCK) mRNA and protein expression in the small intestinal tissue starting at 24 h, which continued up to 72 h. Additionally, IL-1β did not cause an increase in intestinal permeability in MLCK-deficient mice (C57BL/6 MLCK−/−). MLCK inhibitor ML-7 (2 mg/kg body weight) also inhibited the IL-1β-induced increase in small intestinal permeability. The IL-1β-induced increase in mouse intestinal permeability was associated with an increase in NF-κB activation. The intestinal tissue-specific silencing of NF-κB p65 inhibited the IL-1β-induced increase in intestinal permeability and increase in MLCK expression. These data show for the first time that IL-1β causes an increase in mouse intestinal permeability in vivo. These data suggested that the mechanism of IL-1β-induced increase in mouse intestinal permeability in vivo involved NF-κB p65-induced activation of the mouse enterocyte MLCK gene. PMID:22817402

  8. "Green" synthesized and coated nanaosilver alters the membrance permeability of barrier (intestinal, brain, endothelial) cells and stimulates oxidative stress pathways in neurons.

    EPA Science Inventory

    Nanosilver's (nanoAg) use in medical applications and consumer products is increasing. Because of this, its "green" synthesis and surface modification with beneficial coatings are desirable. Given nanoAg's potential exposure routes (e.g., dermal, intestin...

  9. "Green" synthesized and coated nanaosilver alters the membrance permeability of barrier (intestinal, brain, endothelial) cells and stimulates oxidative stress pathways in neurons.

    EPA Science Inventory

    Nanosilver's (nanoAg) use in medical applications and consumer products is increasing. Because of this, its "green" synthesis and surface modification with beneficial coatings are desirable. Given nanoAg's potential exposure routes (e.g., dermal, intestin...

  10. Rebamipide suppresses diclofenac-induced intestinal permeability via mitochondrial protection in mice.

    PubMed

    Diao, Lei; Mei, Qiao; Xu, Jian-Ming; Liu, Xiao-Chang; Hu, Jing; Jin, Juan; Yao, Qiang; Chen, Mo-Li

    2012-03-14

    To investigate the protective effect and mechanism of rebamipide on small intestinal permeability induced by diclofenac in mice. Diclofenac (2.5 mg/kg) was administered once daily for 3 d orally. A control group received the vehicle by gavage. Rebamipide (100 mg/kg, 200 mg/kg, 400 mg/kg) was administered intragastrically once a day for 3 d 4 h after diclofenac administration. Intestinal permeability was evaluated by Evans blue and the FITC-dextran method. The ultrastructure of the mucosal barrier was evaluated by transmission electron microscopy (TEM). Mitochondrial function including mitochondrial swelling, mitochondrial membrane potential, mitochondrial nicotinamide adenine dinucleotide-reduced (NADH) levels, succinate dehydrogenase (SDH) and ATPase activities were measured. Small intestinal mucosa was collected for assessment of malondialdehyde (MDA) content and myeloperoxidase (MPO) activity. Compared with the control group, intestinal permeability was significantly increased in the diclofenac group, which was accompanied by broken tight junctions, and significant increases in MDA content and MPO activity. Rebamipide significantly reduced intestinal permeability, improved inter-cellular tight junctions, and was associated with decreases in intestinal MDA content and MPO activity. At the mitochondrial level, rebamipide increased SDH and ATPase activities, NADH level and decreased mitochondrial swelling. Increased intestinal permeability induced by diclofenac can be attenuated by rebamipide, which partially contributed to the protection of mitochondrial function.

  11. Rebamipide suppresses diclofenac-induced intestinal permeability via mitochondrial protection in mice

    PubMed Central

    Diao, Lei; Mei, Qiao; Xu, Jian-Ming; Liu, Xiao-Chang; Hu, Jing; Jin, Juan; Yao, Qiang; Chen, Mo-Li

    2012-01-01

    AIM: To investigate the protective effect and mechanism of rebamipide on small intestinal permeability induced by diclofenac in mice. METHODS: Diclofenac (2.5 mg/kg) was administered once daily for 3 d orally. A control group received the vehicle by gavage. Rebamipide (100 mg/kg, 200 mg/kg, 400 mg/kg) was administered intragastrically once a day for 3 d 4 h after diclofenac administration. Intestinal permeability was evaluated by Evans blue and the FITC-dextran method. The ultrastructure of the mucosal barrier was evaluated by transmission electron microscopy (TEM). Mitochondrial function including mitochondrial swelling, mitochondrial membrane potential, mitochondrial nicotinamide adenine dinucleotide-reduced (NADH) levels, succinate dehydrogenase (SDH) and ATPase activities were measured. Small intestinal mucosa was collected for assessment of malondialdehyde (MDA) content and myeloperoxidase (MPO) activity. RESULTS: Compared with the control group, intestinal permeability was significantly increased in the diclofenac group, which was accompanied by broken tight junctions, and significant increases in MDA content and MPO activity. Rebamipide significantly reduced intestinal permeability, improved inter-cellular tight junctions, and was associated with decreases in intestinal MDA content and MPO activity. At the mitochondrial level, rebamipide increased SDH and ATPase activities, NADH level and decreased mitochondrial swelling. CONCLUSION: Increased intestinal permeability induced by diclofenac can be attenuated by rebamipide, which partially contributed to the protection of mitochondrial function. PMID:22416180

  12. Intestinal barriers to bacteria and their toxins

    SciTech Connect

    Walker, R.I.; Owen, R.L. )

    1990-01-01

    Immunologic and nonimmunologic processes work together to protect the host from the multitude of microorganisms residing within the intestinal lumen. Mechanical integrity of the intestinal epithelium, mucus in combination with secretory antibody, antimicrobial metabolites of indigenous microorganisms, and peristalsis each limit proliferation and systemic dissemination of enteric pathogens. Uptake of microorganisms by Peyer's patches and other intestinal lymphoid structures and translocation circumvent the mucosal barrier, especially in immunosuppressed individuals. Improved understanding of the composition and limitation of the intestinal barrier, coupled with advances in genetic engineering of immunogenic bacteria, development of oral delivery systems, and immunomodulators, now make enhancement of mucosal barriers feasible. 32 references.

  13. Prolactin and blood-brain barrier permeability.

    PubMed

    Rosas-Hernandez, Hector; Cuevas, Elvis; Lantz, Susan M; Hamilton, W Ryan; Ramirez-Lee, Manuel A; Ali, Syed F; Gonzalez, Carmen

    2013-11-01

    The blood-brain barrier (BBB) consists in part of a highly specialized set of cells which separates the brain from the vascular system. The BBB controls the entry and exit of substances from the brain tissue through tight junctions (TJs) between endothelial cells. It is known that the hormone prolactin (PRL) is able to regulate endothelial-dependent processes, like the balance between proliferation and apoptosis and the mammary epithelial permeability. However, the effects of PRL and the role it plays in the BBB permeability are still not well understood. A primary culture of bovine brain microvessel endothelial cells was used as in vitro model of BBB. Cells were treated with PRL (0.1, 1, 10 and 100 nM) for 24 hours. PRL significantly increased cellular proliferation at 10 and 100 nM, but did not modify basal apoptosis. These effects were dependent on the production of the mitogenic factor nitric oxide (NO). PRL significantly decreased the permeability and promoted an increase in trans-endothelial electrical resistance in a NO-independent way. PRL also increased the expression of the TJs proteins claudin-5 and occludin. The short form of the PRL receptor was detected in these cells but its expression was not modified by PRL. Together, these results suggest that PRL has the ability to increase cellular proliferation associated with a decrease on BBB permeability by increasing the expression of TJs proteins.

  14. Intestinal permeability and nutritional status in developmental disorders.

    PubMed

    Souza, Nilian Carla Silva; Mendonca, Jacqueline Nakau; Portari, Guilherme Vannucchi; Jordao Junior, Alceu Afonso; Marchini, Julio Sergio; Chiarello, Paula Garcia

    2012-01-01

    Autism is a developmental disorder with a possible connection between dietary components and triggering or worsening of symptoms. An altered intestinal permeability might allow absorption of incompletely digested peptides (gluten and casein) that could produce opioid-like activity on the brain, causing significant changes in behavior. To assess the intestinal permeability and nutritional status of participants with developmental disorders to determine if changes in the intestinal mucosal barrier and/or injury to the intercellular junctions have occurred that might justify application of further dietary modifications. To assess intestinal permeability, the research team analyzed participants urine under fasting conditions, using gas chromatography to determine chromatographic peaks. To assess nutritional status, the team determined participants heights and weights and performed a bioelectric bioimpedance examination at least 4 hours after their most recent meal. In addition, the team determined food intake using three diet diaries. They asked participants and caregivers to register each food consumed during 2 nonconsecutive weekdays and 1 weekend day. The study occurred at the Ribeirao Preto School of Medicine, Sao Paulo University. Seven participants aged 9 to 23 years with developmental disorders (the developmental group, DG) completed the study. The research team recruited them through the Association of Friends of the Autistic Persons of Ribeirao Preto in Ribeirao Preto, Brazil. The control group (CG) consisted of nonsmoking healthy volunteers in the general population who were similar in age to the experimental group and did not suffer from diseases that potentially could influence nutritional status and intestinal function. To assess intestinal permeability, participants ingested 150 mL of an isosmolar solution of the sugars mannitol (2 g) and lactulose (7.5 g) under fasting conditions and the researchers collected all voided urine over a period of 5 hours

  15. EPA/ITRC-RTDF permeable reactive barrier short course. Permeable reactive barriers: Application and deployment

    SciTech Connect

    1999-11-01

    This report focuses on the following: Permeable Reactive Barriers: Application and Deployment; Introduction to Permeable Reactive Barriers (PRBs) for Remediating and Managing Contaminated Groundwater in Situ; Collection and Interpretation of Design Data 1: Site Characterization for PRBs; Reactive Materials: Zero-Valent Iron; Collection and Interpretation of Design Data 2: Laboratory and Pilot Scale Tests; Design Calculations; Compliance Monitoring, Performance Monitoring and Long-Term Maintenance for PRBs; PRB Emplacement Techniques; PRB Permitting and Implementation; Treatment of Metals; Non-Metallic Reactive Materials; Economic Considerations for PRB Deployment; and Bibliography.

  16. EPA/ITRC-RTDF permeable reactive barrier short course. Permeable reactive barriers: Application and deployment

    SciTech Connect

    Not Available

    1999-01-01

    This report focuses on the following: Permeable Reactive Barriers: Application and Deployment; Introduction to Permeable Reactive Barriers (PRBs) for Remediating and Managing Contaminated Groundwater in Situ; Collection and Interpretation of Design Data 1: Site Characterization for PRBs; Reactive Materials: Zero-Valent Iron; Collection and Interpretation of Design Data 2: Laboratory and Pilot Scale Tests; Design Calculations; Compliance Monitoring, Performance Monitoring and Long-Term Maintenance for PRBs; PRB Emplacement Techniques; PRB Permitting and Implementation; Treatment of Metals; Non-Metallic Reactive Materials; Economic Considerations for PRB Deployment; and Bibliography.

  17. Intestinal Membrane Permeability and Hypersensitivity In the Irritable Bowel Syndrome

    PubMed Central

    Zhou, QiQi; Zhang, Buyi; Verne, G. Nicholas

    2009-01-01

    Irritable bowel syndrome (IBS) is a common gastrointestinal disorder in which the underlying pathophysiology is poorly understood; however, increased intestinal permeability in diarrhea-predominant IBS patients has been reported. Here we demonstrate diarrhea-predominant IBS patients (D-IBS) that display increased intestinal permeability. We have also found that increased intestinal membrane permeability is associated with visceral and thermal hypersensitivity in this subset of D-IBS patients. We evaluated 54 D-IBS patients and 22 controls for intestinal membrane permeability using the lactulose / mannitol method. All subjects ingested 5 g laclulose and 2 g mannitol in 100 ml of water after which their urine was collected. We also evaluated the mean mechanical visual analogue (MVAS) pain rating to nociceptive thermal and visceral stimulation in all subjects. All study participants also completed the FBDSI scale. Approximately 39% of diarrhea-predominant IBS patients have increased intestinal membrane permeability as measured by the lactulose / mannitol ratio. These IBS patients also demonstrated higher M-VAS pain intensity reading scale. Interestingly, the IBS patients with hypersensitivity and increased intestinal permeability had a higher FBDSI score (100.8±5.4) compared to IBS patients with normal membrane permeability and sensitivity (51.6±12.7) and controls (6.1 ± 5.6) (p<0.001). A subset of D-IBS patients have increased intestinal membrane permeability that is associated with an increased FBDSI score and increased hypersensitivity to visceral and thermal nociceptive pain stimuli. Thus, increased intestinal membrane permeability in D-IBS patients may lead to more severe IBS symptoms and hypersensitivity to somatic and visceral stimuli. PMID:19595511

  18. Intestinal membrane permeability and hypersensitivity in the irritable bowel syndrome.

    PubMed

    Zhou, QiQi; Zhang, Buyi; Verne, G Nicholas

    2009-11-01

    Irritable bowel syndrome (IBS) is a common gastrointestinal disorder in which the underlying pathophysiology is poorly understood; however, increased intestinal permeability in diarrhea-predominant IBS patients has been reported. Here we demonstrate that diarrhea-predominant IBS (D-IBS) patients display increased intestinal permeability. We have also found that increased intestinal membrane permeability is associated with visceral and thermal hypersensitivity in this subset of D-IBS patients. We evaluated 54 D-IBS patients and 22 controls for intestinal membrane permeability using the lactulose/mannitol method. All subjects ingested 5g of lactulose and 2g of mannitol in 100ml of water after which their urine was collected. We also evaluated the mean mechanical visual analogue scale (M-VAS) pain rating to nociceptive thermal and visceral stimulation in all subjects. All study participants also completed the FBDSI scale. Approximately 39% of diarrhea-predominant IBS patients had increased intestinal membrane permeability as measured by the lactulose/mannitol ratio. These IBS patients also demonstrated higher M-VAS pain intensity reading scale. Interestingly, the IBS patients with hypersensitivity and increased intestinal permeability had a higher FBDSI score (100.8 + or - 5.4) than IBS patients with normal membrane permeability and sensitivity (51.6 + or - 12.7) and controls (6.1 + or - 5.6) (p<0.001). A subset of D-IBS patients had increased intestinal membrane permeability that was associated with an increased FBDSI score and increased hypersensitivity to visceral and thermal nociceptive pain stimuli. Thus, increased intestinal membrane permeability in D-IBS patients may lead to more severe IBS symptoms and hypersensitivity to somatic and visceral stimuli.

  19. Measurement of the intestinal permeability in chronic kidney disease

    PubMed Central

    Terpstra, Matty L; Singh, Ramandeep; Geerlings, Suzanne E; Bemelman, Frederike J

    2016-01-01

    AIM: To evaluate methods measuring the intestinal per-meability in chronic kidney disease (CKD) and clarify whether there is an increased intestinal permeability in CKD. METHODS: We reviewed the literature in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol and performed a systematic literature search through MEDline and EMBASE. All controlled trials and cohort studies using non-invasive methods to assess intestinal permeability in CKD patients were included. Excluded were: Conference abstracts and studies including patients younger than 18 years or animals. From the included studies we summarized the used methods and their advantages and disadvantages. For the comparison of their results we divided the included studies in two categories based on their included patient population, either assessing the intestinal permeability in mild to moderate CKD patients or in end stage renal disease (ESRD) patients. Results were graphically displayed in two plots, one comparing the intestinal permeability in mild to moderate CKD patients to healthy controls and one comparing the intestinal permeability in ESRD patients to healthy controls. RESULTS: From the 480 identified reports, 15 met our inclusion criteria. Methods that were used to assess the intestinal permeability varied from markers measured in plasma to methods based on calculating the urinary excretion of an orally administered test substance. None of the applied methods has been validated in CKD patients and the influence of decreased renal function on the different methods remains unclear to a certain extent. Methods that seem the least likely to be influenced by decreased renal function are the quantitative PCR (qPCR) for bacterial DNA in blood and D-lactate. Considering the results published by the included studies; the studies including patients with mild to moderate CKD conducted conflicting results. Some studies did report an increase in intestinal

  20. Epidermal Growth Factor and Intestinal Barrier Function

    PubMed Central

    Liu, Hu; Yang, Shufen; Li, Zuohua; Zhong, Jinfeng

    2016-01-01

    Epidermal growth factor (EGF) is a 53-amino acid peptide that plays an important role in regulating cell growth, survival, migration, apoptosis, proliferation, and differentiation. In addition, EGF has been established to be an effective intestinal regulator helping to protect intestinal barrier integrity, which was essential for the absorption of nutrients and health in humans and animals. Several researches have demonstrated that EGF via binding to the EGF receptor and subsequent activation of Ras/MAPK, PI3K/AKT, PLC-γ/PKC, and STATS signal pathways regulates intestinal barrier function. In this review, the relationship between epidermal growth factor and intestinal development and intestinal barrier is described, to provide a better understanding of the effects of EGF on intestine development and health. PMID:27524860

  1. Possible Links between Intestinal Permeablity and Food Processing: A Potential Therapeutic Niche for Glutamine

    PubMed Central

    Rapin, Jean Robert; Wiernsperger, Nicolas

    2010-01-01

    Increased intestinal permeability is a likely cause of various pathologies, such as allergies and metabolic or even cardiovascular disturbances. Intestinal permeability is found in many severe clinical situations and in common disorders such as irritable bowel syndrome. In these conditions, substances that are normally unable to cross the epithelial barrier gain access to the systemic circulation. To illustrate the potential harmfulness of leaky gut, we present an argument based on examples linked to protein or lipid glycation induced by modern food processing. Increased intestinal permeability should be largely improved by dietary addition of compounds, such as glutamine or curcumin, which both have the mechanistic potential to inhibit the inflammation and oxidative stress linked to tight junction opening. This brief review aims to increase physician awareness of this common, albeit largely unrecognized, pathology, which may be easily prevented or improved by means of simple nutritional changes. PMID:20613941

  2. JAM-A regulates permeability and inflammation in the intestine in vivo.

    PubMed

    Laukoetter, Mike G; Nava, Porfirio; Lee, Winston Y; Severson, Eric A; Capaldo, Christopher T; Babbin, Brian A; Williams, Ifor R; Koval, Michael; Peatman, Eric; Campbell, Jacquelyn A; Dermody, Terence S; Nusrat, Asma; Parkos, Charles A

    2007-12-24

    Recent evidence has linked intestinal permeability to mucosal inflammation, but molecular studies are lacking. Candidate regulatory molecules localized within the tight junction (TJ) include Junctional Adhesion Molecule (JAM-A), which has been implicated in the regulation of barrier function and leukocyte migration. Thus, we analyzed the intestinal mucosa of JAM-A-deficient (JAM-A(-/-)) mice for evidence of enhanced permeability and inflammation. Colonic mucosa from JAM-A(-/-) mice had normal epithelial architecture but increased polymorphonuclear leukocyte infiltration and large lymphoid aggregates not seen in wild-type controls. Barrier function experiments revealed increased mucosal permeability, as indicated by enhanced dextran flux, and decreased transepithelial electrical resistance in JAM-A(-/-) mice. The in vivo observations were epithelial specific, because monolayers of JAM-A(-/-) epithelial cells also demonstrated increased permeability. Analyses of other TJ components revealed increased expression of claudin-10 and -15 in the colonic mucosa of JAM-A(-/-) mice and in JAM-A small interfering RNA-treated epithelial cells. Given the observed increase in colonic inflammation and permeability, we assessed the susceptibility of JAM-A(-/-) mice to the induction of colitis with dextran sulfate sodium (DSS). Although DSS-treated JAM-A(-/-) animals had increased clinical disease compared with controls, colonic mucosa showed less injury and increased epithelial proliferation. These findings demonstrate a complex role of JAM-A in intestinal homeostasis by regulating epithelial permeability, inflammation, and proliferation.

  3. From Intestinal Permeability to Dysmotility: The Biobreeding Rat as a Model for Functional Gastrointestinal Disorders

    PubMed Central

    Vanheel, Hanne; Masaoka, Tatsuhiro; Salim Rasoel, Shadea; Tóth, Joran; Houben, Els; Verbeke, Kristin; De Hertogh, Gert; Berghe, Pieter Vanden; Tack, Jan; Farré, Ricard

    2014-01-01

    Background Impaired intestinal barrier function, low-grade inflammation and altered neuronal control are reported in functional gastrointestinal disorders. However, the sequence of and causal relation between these events is unclear, necessitating a spontaneous animal model. The aim of this study was to describe the natural history of intestinal permeability, mucosal and neuromuscular inflammation and nitrergic motor neuron function during the lifetime of the BioBreeding (BB) rat. Methods Normoglycemic BB-diabetes prone (DP) and control rats were sacrificed at different ages and jejunum was harvested to characterize intestinal permeability, inflammation and neuromuscular function. Results Both structural and functional evidence of increased intestinal permeability was found in young BB-DP rats from the age of 50 days. In older animals, starting in the mucosa from 70 days and in half of the animals also in the muscularis propria from 110 days, an inflammatory reaction, characterized by an influx of polymorphonuclear cells and higher myeloperoxidase activity, was observed. Finally, in animals older than 110 days, coinciding with a myenteric ganglionitis, a loss of nitrergic neurons and motor function was demonstrated. Conclusion In the BB-rat, mucosal inflammatory cell infiltration is preceded by intestinal barrier dysfunction and followed by myenteric ganglionitis and loss of nitrergic function. This sequence supports a primary role for impaired barrier function and provides an insightful model for the pathogenesis of functional gastrointestinal disorders. PMID:25354336

  4. [THE INTESTINAL BARRIER, THE MICROBIOTA, MICROBIOME].

    PubMed

    Mar'yanovich, A T

    2016-01-01

    The review examined modern condition of development directions physiology of digestion, like structure and function of the intestinal barrier, the microbiota of the digestive tract in its relations with the microorganism.

  5. Commensal microbiota-induced microRNA modulates intestinal epithelial permeability through the small GTPase ARF4.

    PubMed

    Nakata, Kazuaki; Sugi, Yutaka; Narabayashi, Hikari; Kobayakawa, Tetsuro; Nakanishi, Yusuke; Tsuda, Masato; Hosono, Akira; Kaminogawa, Shuichi; Hanazawa, Shigemasa; Takahashi, Kyoko

    2017-09-15

    The intestinal tract contains many commensal bacteria that modulate various physiological host functions. Dysbiosis of commensal bacteria triggers dysfunction of the intestinal epithelial barrier, leading to the induction or aggravation of intestinal inflammation. To elucidate whether microRNA plays a role in commensal microbiome-dependent intestinal epithelial barrier regulation, we compared transcripts in intestinal epithelial cells (IECs) from conventional and germ-free mice and found that commensal bacteria induced the expression of miR-21-5p in IECs. miR-21-5p increased intestinal epithelial permeability and up-regulated ADP ribosylation factor 4 (ARF4), a small GTPase, in the IEC line Caco-2. We also found that ARF4 expression was up-regulated upon suppression of phosphatase and tensin homolog (PTEN) and programmed cell death 4 (PDCD4), which are known miR-21-5p targets, by RNAi. Furthermore, ARF4 expression in epithelial cells of the large intestine was higher in conventional mice than in germ-free mice. ARF4 suppression in the IEC line increased the expression of tight junction proteins and decreased intestinal epithelial permeability. These results indicate that commensal microbiome-dependent miR-21-5p expression in IECs regulates intestinal epithelial permeability via ARF4, which may therefore represent a target for preventing or managing dysfunction of the intestinal epithelial barrier. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Toll-Like Receptor Signalling and the Control of Intestinal Barrier Function.

    PubMed

    Johnston, Daniel G W; Corr, Sinéad C

    2016-01-01

    Epithelial barrier function and innate immunity are fundamental to the pathogenesis of inflammatory and infectious disease. Along with plasma membranes, epithelial cells are the primary cellular determinant of epithelial barrier function. The mechanism by which polarized epithelia form a permeability barrier is of fundamental importance to the prevention of many infectious and inflammatory diseases. Moreover, epithelial cells express Toll-like receptors (TLRs) which upon recognition of conserved microbial factors such as lipopolysaccharide (LPS) induce epithelial responses including epithelial cell proliferation, secretion of secretory IgA into the lumen and production mucins and antimicrobial peptides, thereby promoting intestinal barrier function. Understanding gut barrier integrity and regulation of permeability is crucial to increase our understanding of the pathogenesis of intestinal disease. A variety of tests have been developed to assess this barrier, including assessing intestinal epithelial cell proliferation or death, intestinal tight junction status and the consequence of intestinal barrier integrity loss such as increased intestinal permeability and susceptibility to bacterial infection. Using a mouse model, this chapter describes some of the methods to assess the functional integrity of this epithelial barrier and the part played by a TLR signalling pathway.

  7. Quantitation of small intestinal permeability during normal human drug absorption

    PubMed Central

    2013-01-01

    Background Understanding the quantitative relationship between a drug’s physical chemical properties and its rate of intestinal absorption (QSAR) is critical for selecting candidate drugs. Because of limited experimental human small intestinal permeability data, approximate surrogates such as the fraction absorbed or Caco-2 permeability are used, both of which have limitations. Methods Given the blood concentration following an oral and intravenous dose, the time course of intestinal absorption in humans was determined by deconvolution and related to the intestinal permeability by the use of a new 3 parameter model function (“Averaged Model” (AM)). The theoretical validity of this AM model was evaluated by comparing it to the standard diffusion-convection model (DC). This analysis was applied to 90 drugs using previously published data. Only drugs that were administered in oral solution form to fasting subjects were considered so that the rate of gastric emptying was approximately known. All the calculations are carried out using the freely available routine PKQuest Java (http://www.pkquest.com) which has an easy to use, simple interface. Results Theoretically, the AM permeability provides an accurate estimate of the intestinal DC permeability for solutes whose absorption ranges from 1% to 99%. The experimental human AM permeabilities determined by deconvolution are similar to those determined by direct human jejunal perfusion. The small intestinal pH varies with position and the results are interpreted in terms of the pH dependent octanol partition. The permeability versus partition relations are presented separately for the uncharged, basic, acidic and charged solutes. The small uncharged solutes caffeine, acetaminophen and antipyrine have very high permeabilities (about 20 x 10-4 cm/sec) corresponding to an unstirred layer of only 45 μm. The weak acid aspirin also has a large AM permeability despite its low octanol partition at pH 7.4, suggesting

  8. Synthetic surfactant food additives can cause intestinal barrier dysfunction.

    PubMed

    Csáki, Katalin F

    2011-05-01

    In addition to genetic factors and antigen exposure, intestinal barrier dysfunction plays a key role in the pathogenesis of numerous allergic and autoimmune diseases. The hypothesis of this article is that synthetic surfactant food additives (also called emulsifiers) - which are applied in relatively high concentrations in even the most frequently consumed foods -cause increased intestinal permeability, hence they can play a significant role in the increasing incidence of numerous allergic and autoimmune diseases. In many cases the surfactants added to foods are exactly the same as the ones used in pharmaceutics as absorption enhancers. Numerous synthetic surfactant food additives have been shown to increase the intestinal permeability through paracellular and/or transcellular mechanisms and some of them were also shown to inhibit P-glycoprotein. Additionally, based on the general characteristics of surfactants it can be predicted that they decrease the hydrophobicity of the mucus layer, which has also been shown to associate with increased intestinal permeability. Copyright © 2011 Elsevier Ltd. All rights reserved.

  9. Intestinal barrier integrity and function in infants with cholestasis

    PubMed Central

    Sherif, Tahra M. K.; Mohammed, Omnia A.; Nasif, Khalid A.; El Gezawy, Ebtesam M.

    2017-01-01

    Background/Aims The safety of the human body is maintained by effective monitoring of the mucosal surface integrity and protection against potentially harmful compounds. This function of the gut called intestinal barrier function can be affected by cholestasis and the absence of bile in the intestinal lumen. We aimed to determine whether the gut barrier integrity is impaired in infants with cholestasis by evaluation of the intestinal fatty acid binding proteins (I-FABP) and ileal bile acid binding protein (I-BABP) as markers of intestinal epithelial cell damage and plasma D-lactate level as a marker of gut wall permeability. Methods This case-control study included 53 infants with cholestasis and 29 controls. Serum levels of I-FABP, I-BABP, and D-lactate were measured in all subjects. Results Both groups of patients with neonatal hepatitis and biliary atresia showed significantly higher levels of I-FABP and I-BABP than the controls. There were no differences in the serum D-lactate level between the cases and controls. There was no difference between the two groups of patients (I and II) regarding any of the parameters studied. No significant correlations between serum levels of I-FABP, I-BABP, or D-lactate and total or direct bilirubin levels were found in the cholestatic infants. Conclusions The intestinal epithelial barrier integrity is breached nearly in all parts of the intestine in infants with cholestasis. Further research is recommended to determine the impact of this finding on the management of these infants. The relationship between physical intestinal barrier damage and its functional failure remains subject for further research. PMID:28239322

  10. Increased Intestinal Permeability Correlates with Sigmoid Mucosa alpha-Synuclein Staining and Endotoxin Exposure Markers in Early Parkinson's Disease

    PubMed Central

    Forsyth, Christopher B.; Shannon, Kathleen M.; Kordower, Jeffrey H.; Voigt, Robin M.; Shaikh, Maliha; Jaglin, Jean A.; Estes, Jacob D.; Dodiya, Hemraj B.; Keshavarzian, Ali

    2011-01-01

    Parkinson's disease (PD) is the second most common neurodegenerative disorder of aging. The pathological hallmark of PD is neuronal inclusions termed Lewy bodies whose main component is alpha-synuclein protein. The finding of these Lewy bodies in the intestinal enteric nerves led to the hypothesis that the intestine might be an early site of PD disease in response to an environmental toxin or pathogen. One potential mechanism for environmental toxin(s) and proinflammatory luminal products to gain access to mucosal neuronal tissue and promote oxidative stress is compromised intestinal barrier integrity. However, the role of intestinal permeability in PD has never been tested. We hypothesized that PD subjects might exhibit increased intestinal permeability to proinflammatory bacterial products in the intestine. To test our hypothesis we evaluated intestinal permeability in subjects newly diagnosed with PD and compared their values to healthy subjects. In addition, we obtained intestinal biopsies from both groups and used immunohistochemistry to assess bacterial translocation, nitrotyrosine (oxidative stress), and alpha-synuclein. We also evaluated serum markers of endotoxin exposure including LPS binding protein (LBP). Our data show that our PD subjects exhibit significantly greater intestinal permeability (gut leakiness) than controls. In addition, this intestinal hyperpermeability significantly correlated with increased intestinal mucosa staining for E. coli bacteria, nitrotyrosine, and alpha-synuclein as well as serum LBP levels in PD subjects. These data represent not only the first demonstration of abnormal intestinal permeability in PD subjects but also the first correlation of increased intestinal permeability in PD with intestinal alpha–synuclein (the hallmark of PD), as well as staining for gram negative bacteria and tissue oxidative stress. Our study may thus shed new light on PD pathogenesis as well as provide a new method for earlier diagnosis of PD and

  11. Methods to determine intestinal permeability and bacterial translocation during liver disease

    PubMed Central

    Wang, Lirui; Llorente, Cristina; Hartmann, Phillipp; Yang, An-Ming; Chen, Peng; Schnabl, Bernd

    2015-01-01

    Liver disease is often times associated with increased intestinal permeability. A disruption of the gut barrier allows microbial products and viable bacteria to translocate from the intestinal lumen to extraintestinal organs. The majority of the venous blood from the intestinal tract is drained into the portal circulation, which is part of the dual hepatic blood supply. The liver is therefore the first organ in the body to encounter not only absorbed nutrients, but also gut-derived bacteria and pathogen associated molecular patterns (PAMPs). Chronic exposure to increased levels of PAMPs has been linked to disease progression during early stages and to infectious complications during late stages of liver disease (cirrhosis). It is therefore important to assess and monitor gut barrier dysfunction during hepatic disease. We review methods to assess intestinal barrier disruption and discuss advantages and disadvantages. We will in particular focus on methods that we have used to measure increased intestinal permeability and bacterial translocation during experimental liver disease models. PMID:25595554

  12. Development of an advanced intestinal in vitro triple culture permeability model to study transport of nanoparticles.

    PubMed

    Schimpel, Christa; Teubl, Birgit; Absenger, Markus; Meindl, Claudia; Fröhlich, Eleonore; Leitinger, Gerd; Zimmer, Andreas; Roblegg, Eva

    2014-03-03

    Intestinal epithelial cell culture models, such as Caco-2 cells, are commonly used to assess absorption of drug molecules and transcytosis of nanoparticles across the intestinal mucosa. However, it is known that mucus strongly impacts nanoparticle mobility and that specialized M cells are involved in particulate uptake. Thus, to get a clear understanding of how nanoparticles interact with the intestinal mucosa, in vitro models are necessary that integrate the main cell types. This work aimed at developing an alternative in vitro permeability model based on a triple culture: Caco-2 cells, mucus-secreting goblet cells and M cells. Therefore, Caco-2 cells and mucus-secreting goblet cells were cocultured on Transwells and Raji B cells were added to stimulate differentiation of M cells. The in vitro triple culture model was characterized regarding confluence, integrity, differentiation/expression of M cells and cell surface architecture. Permeability of model drugs and of 50 and 200 nm polystyrene nanoparticles was studied. Data from the in vitro model were compared with ex vivo permeability results (Ussing chambers and porcine intestine) and correlated well. Nanoparticle uptake was size-dependent and strongly impacted by the mucus layer. Moreover, nanoparticle permeability studies clearly demonstrated that particles were capable of penetrating the intestinal barrier mainly via specialized M cells. It can be concluded that goblet cells and M cells strongly impact nanoparticle uptake in the intestine and should thus be integrated in an in vitro permeability model. The presented model will be an efficient tool to study intestinal transcellular uptake of particulate systems.

  13. Increased pulmonary and intestinal permeability in Crohn's disease.

    PubMed Central

    Adenis, A; Colombel, J F; Lecouffe, P; Wallaert, B; Hecquet, B; Marchandise, X; Cortot, A

    1992-01-01

    We tested the hypothesis that an increased epithelial permeability may affect sites other than the intestine in patients with Crohn's disease by simultaneously evaluating their pulmonary and intestinal permeability. Pulmonary and intestinal permeability were measured by clearance of inhaled technetium-99m diethylene triamine pentacetate (99mTc-DTPA) and by urinary recovery of chromium-51 ethylene diamine tetracetate respectively in 22 patients with Crohn's disease. The half time clearance of 99mTc-DTPA from lung to blood (t1/2LB) was decreased--that is pulmonary permeability increased--in the whole group of patients with Crohn's disease as compared with 13 controls (median 45.5 minutes (8-160) v 85 minutes (34-130) (p less than 0.003)). When analysed separately only patients with active Crohn's disease (n = 15) had a decreased t1/2 lung to blood v controls (42 minutes (8-160) v 85 minutes (34-130) (p less than 0.0025)). Among patients with active Crohn's disease, six were studied again when their disease was quiescent and their t1/2 lung to blood did not differ significantly. The intestinal permeability was increased in the whole group of Crohn's disease patients as compared with 15 controls (5.25% (1.2-24) v 1.7% (0.65-5.75) (p less than 0.0002)). When analysed separately both patients with active and inactive Crohn's disease had increased intestinal permeability v controls (8.1% (1.6-24) and 3.5% (1.2.9.2) v 1.7% (0.65-5.75)) (p less than 0.0001, p = 0.05 respectively). Six patients with active Crohn's disease were studied again when their disease was quiescent and their intestinal permeability decreased significantly p less than 0.04). Pulmonary permeability was increased in patients with Crohn's disease but was not greatly influenced by Crohn's disease activity as opposed to intestinal permeability. The mechanism of this increase is unknown, but may be related in some patients to the presence of an alveolitis. PMID:1612487

  14. Postinjury Vagal Nerve Stimulation Protects Against Intestinal Epithelial Barrier Breakdown

    PubMed Central

    Krzyzaniak, Michael; Peterson, Carrie; Loomis, William; Hageny, Ann-Marie; Wolf, Paul; Reys, Luiz; Putnam, James; Eliceiri, Brian; Baird, Andrew; Bansal, Vishal; Coimbra, Raul

    2014-01-01

    Background Vagal nerve stimulation (VNS) can have a marked anti-inflammatory effect. We have previously shown that preinjury VNS prevented intestinal barrier breakdown and preserved epithelial tight junction protein expression. However, a pretreatment model has little clinical relevance for the care of the trauma patient. Therefore, we postulated that VNS conducted postinjury would also have a similar protective effect on maintaining gut epithelial barrier integrity. Methods Male balb/c mice were subjected to a 30% total body surface area, full-thickness steam burn followed by right cervical VNS at 15, 30, 60, 90, 120, and 150 minutes postinjury. Intestinal barrier dysfunction was quantified by permeability to 4 kDa fluorescein isothiocyanate-Dextran, histologic evaluation, gut tumor necrosis factor-alpha (TNF-α) enzyme-linked immunosorbent assay, and expression of tight junction proteins (myosin light chain kinase, occludin, and ZO-1) using immunoblot and immunoflourescence. Results Histologic examination documented intestinal villi appearance similar to sham if cervical VNS was performed within 90 minutes of burn insult. VNS done after injury decreased intestinal permeability to fluorescein isothiocyanate-Dextran when VNS was ≤90 minutes after injury. Burn injury caused a marked increase in intestinal TNF-α levels. VNS-treated animals had TNF-α levels similar to sham when VNS was performed within 90 minutes of injury. Tight junction protein expression was maintained at near sham values if VNS was performed within 90 minutes of burn, whereas expression was significantly altered in burn. Conclusion Postinjury VNS prevents gut epithelial breakdown when performed within 90 minutes of thermal injury. This could represent a therapeutic window and clinically relevant strategy to prevent systemic inflammatory response distant organ injury after trauma. PMID:21610431

  15. Intestinal barrier function in response to abundant or depleted mucosal glutathione in Salmonella-infected rats

    PubMed Central

    van Ampting, Marleen TJ; Schonewille, Arjan J; Vink, Carolien; Brummer, Robert Jan M; Meer, Roelof van der; Bovee-Oudenhoven, Ingeborg MJ

    2009-01-01

    Background Glutathione, the main antioxidant of intestinal epithelial cells, is suggested to play an important role in gut barrier function and prevention of inflammation-related oxidative damage as induced by acute bacterial infection. Most studies on intestinal glutathione focus on oxidative stress reduction without considering functional disease outcome. Our aim was to determine whether depletion or maintenance of intestinal glutathione changes susceptibility of rats to Salmonella infection and associated inflammation. Rats were fed a control diet or the same diet supplemented with buthionine sulfoximine (BSO; glutathione depletion) or cystine (glutathione maintenance). Inert chromium ethylenediamine-tetraacetic acid (CrEDTA) was added to the diets to quantify intestinal permeability. At day 4 after oral gavage with Salmonella enteritidis (or saline for non-infected controls), Salmonella translocation was determined by culturing extra-intestinal organs. Liver and ileal mucosa were collected for analyses of glutathione, inflammation markers and oxidative damage. Faeces was collected to quantify diarrhoea. Results Glutathione depletion aggravated ileal inflammation after infection as indicated by increased levels of mucosal myeloperoxidase and interleukin-1β. Remarkably, intestinal permeability and Salmonella translocation were not increased. Cystine supplementation maintained glutathione in the intestinal mucosa but inflammation and oxidative damage were not diminished. Nevertheless, cystine reduced intestinal permeability and Salmonella translocation. Conclusion Despite increased infection-induced mucosal inflammation upon glutathione depletion, this tripeptide does not play a role in intestinal permeability, bacterial translocation and diarrhoea. On the other hand, cystine enhances gut barrier function by a mechanism unlikely to be related to glutathione. PMID:19374741

  16. Intestinal paracellular permeability during malnutrition in guinea pigs: effect of high dietary zinc.

    PubMed Central

    Rodriguez, P; Darmon, N; Chappuis, P; Candalh, C; Blaton, M A; Bouchaud, C; Heyman, M

    1996-01-01

    BACKGROUND: Zinc has been shown to have beneficial effects in vitro on epithelial barrier function, and in vivo to reduce intestinal permeability in malnourished children with diarrhoea. AIMS: To determine whether malnutrition alters intestinal paracellular permeability, and whether zinc prevents such alterations. METHODS: Guinea pigs were fed a normal protein diet (NP group), a low protein diet (LP group), or a low protein diet enriched with 1800 ppm zinc (LPZn group) for three weeks. Intestinal permeability was measured on jejunal segments mounted in Ussing chambers by measuring ionic conductance and mucosal to serosal fluxes of 14C-mannitol, 22Na, and horseradish peroxidase. Tight junction morphology was assessed on cryofracture replicas. RESULTS: Mannitol and Na fluxes and ionic conductance increased in the LP group compared with the NP group but remained normal in the LPZn group. Accordingly, jejunal epithelia from the LP group, but not from the LPZn group, showed a small decrease in number of tight junctional strands compared with epithelia from the NP group. Neither malnutrition nor zinc treatment modified horseradish peroxidase fluxes. CONCLUSIONS: Malnutrition is associated with increased intestinal paracellular permeability to small molecules, and pharmacological doses of zinc prevent such functional abnormality. Images Figure 3 PMID:8949647

  17. Effect of anionic macromolecules on intestinal permeability of furosemide.

    PubMed

    Valizadeh, Hadi; Fahimfar, Hadi; Ghanbarzadeh, Saeed; Islambulchilar, Ziba; Zakeri-Milani, Parvin

    2015-02-01

    Furosemide is an anionic molecule and has very low absorption in gastro intestinal tract. The aim of this study was to investigate the effect of anionic macromolecules on the intestinal permeability of Furosemide. The intestinal permeability of Furosemide was determined using single-pass intestinal perfusion technique in rats. Briefly a jejunal segment of ∼10 cm was isolated and cannulated in both ends for inlet and outlet solution. The perfusate was collected every 10 min and samples were analyzed using the RP-HPLC method. Test samples containing furosemide and two anionic macromolecules, sodium carboxy methyl cellulose and sodium alginate, at different concentrations were used. The obtained data showed that existence of Sodium carboxy methyl cellulose significantly increased the Peff values in all three investigated concentrations (p < 0.05) but sodium alginate only in concentrations <0.1% increased drug permeability. It is concluded that the anionic macromolecules at specific concentrations could alter the permeability of anionic drugs across the biological membranes. Donnan phenomenon and chelating property of macromolecules could be attributed to the observed effect.

  18. Interleukin-6 Modulation of Intestinal Epithelial Tight Junction Permeability Is Mediated by JNK Pathway Activation of Claudin-2 Gene

    PubMed Central

    Boivin, Michel; Guo, Shuhong; Hashimi, Mariam; Ereifej, Lisa; Ma, Thomas Y.

    2014-01-01

    Defective intestinal epithelial tight junction (TJ) barrier has been shown to be a pathogenic factor in the development of intestinal inflammation. Interleukin-6 (IL-6) is a pleiotropic, pro-inflammatory cytokine which plays an important role in promoting inflammatory response in the gut and in the systemic circulation. Despite its key role in mediating variety inflammatory response, the effect of IL-6 on intestinal epithelial barrier remains unclear. The purpose of this study was to investigate the effect of IL-6 on intestinal epithelial TJ barrier and to delineate the intracellular mechanisms involved using in-vitro (filter-grown Caco-2 monolayers) and in-vivo model (mouse intestinal perfusion) systems. Our results indicated that IL-6 causes a site-selective increase in Caco-2 intestinal epithelia TJ permeability, causing an increase in flux of small-sized molecules having molecular radius <4 Å. The size-selective increase in Caco-2 TJ permeability was regulated by protein-specific increase in claudin-2 expression. The IL-6 increase in TJ permeability required activation of JNK signaling cascade. The JNK pathway activation of AP-1 resulted in AP-1 binding to its binding sequence on the claudin-2 promoter region, leading to promoter activation and subsequent increase in claudin-2 gene transcription and protein synthesis and TJ permeability. Our in-vivo mouse perfusion showed that IL-6 modulation of mouse intestinal permeability was also mediated by AP-1 dependent increase in claudin-2 expression. In conclusion, our studies show for the first time that the IL-6 modulation of intestinal TJ permeability was regulated by JNK activation of AP-1 and AP-1 activation of claudin-2 gene. PMID:24662742

  19. Permeability of Luminal Surface of Intestinal Mucosal Cells

    PubMed Central

    Lindemann, B.; Solomon, A. K.

    1962-01-01

    A method has been devised to measure the permeability characteristics of the intestinal mucosal cells in the rat. The method makes use of an electrical recording balance to register changes in weight when the mucosal face of a small strip of intestine is exposed to anisotonic solutions. The permeability coefficient of the luminal surface of intestinal mucosal cells to water is measured as 0.15 cm4/OSM, sec. and reasons are adduced to suggest that the true value might be higher than this. The equivalent pore radius of the luminal face of the tissue, measured in experiments in which lipid-insoluble non-electrolytes have been used according to the method of Goldstein and Solomon, appears to be 4.0 Å. PMID:14465429

  20. Berberine Attenuates Intestinal Mucosal Barrier Dysfunction in Type 2 Diabetic Rats.

    PubMed

    Gong, Jing; Hu, Meilin; Huang, Zhaoyi; Fang, Ke; Wang, Dingkun; Chen, Qingjie; Li, Jingbin; Yang, Desen; Zou, Xin; Xu, Lijun; Wang, Kaifu; Dong, Hui; Lu, Fuer

    2017-01-01

    Background: Intestinal mucosal barrier dysfunction plays an important role in the development of diabetes mellitus (DM). Berberine (BBR), a kind of isoquinoline alkaloid, is widely known to be effective for both DM and diarrhea. Here, we explored whether the anti-diabetic effect of BBR was related to the intestine mucosal barrier. Methods and Results: The rat model of T2DM was established by high glucose and fat diet feeding and intravenous injection of streptozocin. Then, those diabetic rats were treated with BBR at different concentrations for 9 weeks. The results showed, in addition to hyperglycemia and hyperlipidemia, diabetic rats were also characterized by proinflammatory intestinal changes, altered gut-derived hormones, and 2.77-fold increase in intestinal permeability. However, the treatment with BBR significantly reversed the above changes in diabetic rats, presenting as the improvement of the high glucose and triglyceride levels, the relief of the inflammatory changes of intestinal immune system, and the attenuation of the intestinal barrier damage. BBR treatment at a high concentration also decreased the intestinal permeability by 27.5% in diabetic rats. Furthermore, BBR regulated the expressions of the molecules involved in TLR4/MyD88/NF-κB signaling pathways in intestinal tissue of diabetic rats. Conclusion: The hypoglycemic effects of BBR might be related to the improvement in gut-derived hormones and the attenuation of intestinal mucosal mechanic and immune barrier damages.

  1. Berberine Attenuates Intestinal Mucosal Barrier Dysfunction in Type 2 Diabetic Rats

    PubMed Central

    Gong, Jing; Hu, Meilin; Huang, Zhaoyi; Fang, Ke; Wang, Dingkun; Chen, Qingjie; Li, Jingbin; Yang, Desen; Zou, Xin; Xu, Lijun; Wang, Kaifu; Dong, Hui; Lu, Fuer

    2017-01-01

    Background: Intestinal mucosal barrier dysfunction plays an important role in the development of diabetes mellitus (DM). Berberine (BBR), a kind of isoquinoline alkaloid, is widely known to be effective for both DM and diarrhea. Here, we explored whether the anti-diabetic effect of BBR was related to the intestine mucosal barrier. Methods and Results: The rat model of T2DM was established by high glucose and fat diet feeding and intravenous injection of streptozocin. Then, those diabetic rats were treated with BBR at different concentrations for 9 weeks. The results showed, in addition to hyperglycemia and hyperlipidemia, diabetic rats were also characterized by proinflammatory intestinal changes, altered gut-derived hormones, and 2.77-fold increase in intestinal permeability. However, the treatment with BBR significantly reversed the above changes in diabetic rats, presenting as the improvement of the high glucose and triglyceride levels, the relief of the inflammatory changes of intestinal immune system, and the attenuation of the intestinal barrier damage. BBR treatment at a high concentration also decreased the intestinal permeability by 27.5% in diabetic rats. Furthermore, BBR regulated the expressions of the molecules involved in TLR4/MyD88/NF-κB signaling pathways in intestinal tissue of diabetic rats. Conclusion: The hypoglycemic effects of BBR might be related to the improvement in gut-derived hormones and the attenuation of intestinal mucosal mechanic and immune barrier damages. PMID:28217099

  2. Mechanisms of Intestinal Epithelial Barrier Dysfunction by Adherent-Invasive Escherichia coli.

    PubMed

    Shawki, Ali; McCole, Declan F

    2017-01-01

    Pathobiont expansion, such as that of adherent-invasive Escherichia coli (AIEC), is an emerging factor associated with inflammatory bowel disease. The intestinal epithelial barrier is the first line of defense against these pathogens. Inflammation plays a critical role in altering the epithelial barrier and is a major factor involved in promoting the expansion and pathogenesis of AIEC. AIEC in turn can exacerbate intestinal epithelial barrier dysfunction by targeting multiple elements of the barrier. One critical element of the epithelial barrier is the tight junction. Increasing evidence suggests that AIEC may selectively target protein components of tight junctions, leading to increased barrier permeability. This may represent one mechanism by which AIEC could contribute to the development of inflammatory bowel disease. This review article discusses potential mechanisms by which AIEC can disrupt epithelial tight junction function and intestinal barrier function.

  3. Yoghurts containing probiotics reduce disruption of the small intestinal barrier in methotrexate-treated rats.

    PubMed

    Southcott, E; Tooley, K L; Howarth, G S; Davidson, G P; Butler, R N

    2008-07-01

    Small intestinal permeability was employed to assess the efficacy of commercially available yoghurts containing probiotics in a rat model of methotrexate (MTX)-induced mucositis. Male Sprague-Dawley rats were allocated to four groups (n = 8): MTX + water, MTX + cow's milk yoghurt (CY; fermented with Lactobacillus johnsonii), MTX + sheep's milk yoghurt (SY; containing Lactobacillus bulgaricus and Streptococcus thermophilus), and saline. Treatment gavage occurred twice daily for 7 days pre-MTX and 5 days post-MTX. Intestinal permeability was assessed on days -7, -1, 2, and 5 of the trial. Intestinal sections were collected at sacrifice for histological and biochemical analyses. Histology revealed that rats receiving CY and SY did not have a significantly damaged duodenum compared to controls. However, an improved small intestinal barrier function was evident, determined by a decreased lactulose/mannitol ratio. Probiotics containing SY and CY may be useful in preventing disruption to intestinal barrier function in MTX-induced mucositis.

  4. REGULATORY ASPECTS AND IMPLEMENTATION FOR PERMEABLE REACTIVE BARRIERS

    EPA Science Inventory

    Permeable reactive barriers (PRB's) are an emerging, alternative in-situ approach for remediating groundwater contamination that combine subsurface fluid flow management with a passive chemical treatment zone. Removal of contaminants from the groundwater plume is achieved by alt...

  5. INTRODUCTION TO PERMEABLE REACTIVE BARRIERS FOR GROUND WATER REMEDIATION

    EPA Science Inventory

    Permeable reactive barriers (PRB's) are an emerging, alternative in-situ approach for remediating groundwater contamination that combine subsurface fluid flow management with a passive chemical treatment zone. Removal of contaminants from the groundwater plume is achieved by alt...

  6. PERMEABLE REACTIVE BARRIERS FOR REMEDIATION OF CONTAMINATED GROUND WATER

    EPA Science Inventory

    Permeable reactive barriers (PRB's) are an emerging, alternative in-situ approach for remediating groundwater contamination that combine subsurface fluid flow management with a passive chemical treatment zone. Removal of contaminants from the groundwater plume is achieved by alt...

  7. TREATMENT OF INORGANIC CONTAMINANTS USING PERMEABLE REACTIVE BARRIERS

    EPA Science Inventory

    Permeable reactive barriers are an emerging alternative to traditional pump and treat systems for groundwater remediation. This technique has progressed rapidly over the past decade from laboratory bench-scale studies to full-scale implementation. Laboratory studies indicate the ...

  8. TREATMENT OF INORGANIC CONTAMINANTS USING PERMEABLE REACTIVE BARRIERS

    EPA Science Inventory

    Permeable reactive barriers are an emerging alternative to traditional pump and treat systems for groundwater remediation. This technique has progressed rapidly over the past decade from laboratory bench-scale studies to full-scale implementation. Laboratory studies indicate the ...

  9. Myosin Light Chain Kinase Mediates Intestinal Barrier Disruption following Burn Injury

    PubMed Central

    Chen, Chuanli; Wang, Pei; Su, Qin; Wang, Shiliang; Wang, Fengjun

    2012-01-01

    Background Severe burn injury results in the loss of intestinal barrier function, however, the underlying mechanism remains unclear. Myosin light chain (MLC) phosphorylation mediated by MLC kinase (MLCK) is critical to the pathophysiological regulation of intestinal barrier function. We hypothesized that the MLCK-dependent MLC phosphorylation mediates the regulation of intestinal barrier function following burn injury, and that MLCK inhibition attenuates the burn-induced intestinal barrier disfunction. Methodology/Principal Findings Male balb/c mice were assigned randomly to either sham burn (control) or 30% total body surface area (TBSA) full thickness burn without or with intraperitoneal injection of ML-9 (2 mg/kg), an MLCK inhibitor. In vivo intestinal permeability to fluorescein isothiocyanate (FITC)-dextran was measured. Intestinal mucosa injury was assessed histologically. Tight junction proteins ZO-1, occludin and claudin-1 was analyzed by immunofluorescent assay. Expression of MLCK and phosphorylated MLC in ileal mucosa was assessed by Western blot. Intestinal permeability was increased significantly after burn injury, which was accompanied by mucosa injury, tight junction protein alterations, and increase of both MLCK and MLC phosphorylation. Treatment with ML-9 attenuated the burn-caused increase of intestinal permeability, mucosa injury, tight junction protein alterations, and decreased MLC phosphorylation, but not MLCK expression. Conclusions/Significance The MLCK-dependent MLC phosphorylation mediates intestinal epithelial barrier dysfunction after severe burn injury. It is suggested that MLCK-dependent MLC phosphorylation may be a critical target for the therapeutic treatment of intestinal epithelial barrier disruption after severe burn injury. PMID:22529961

  10. Field Applications of In Situ Remediation Technologies: Permeable Reactive Barriers

    DTIC Science & Technology

    2002-01-01

    Field Applications of In Situ Remediation Technologies: Permeable Reactive Barriers United States Environmental Protection Agency PRB Remediated... Applications of In Situ Remediation Technologies: Permeable Reactive Barriers 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6...unclassified c. THIS PAGE unclassified Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std Z39-18 Field Applications of In Situ Remediation Technologies

  11. Review article: intestinal barrier dysfunction and central nervous system disorders--a controversial association.

    PubMed

    Julio-Pieper, M; Bravo, J A; Aliaga, E; Gotteland, M

    2014-11-01

    Central nervous system (CNS) development and physiopathology are greatly affected by environmental stimuli. The intestinal barrier restricts the entrance of toxins, pathogens, and antigens while modulating the expression of various neuroactive compounds. The existence of a rich gut-to-brain communication raises the possibility that intestinal barrier alterations may take part in the pathophysiology of CNS disorders. To review evidence associating intestinal barrier dysfunction with the development of CNS disorders. Literature search was conducted on PubMed using the following terms: intestinal barrier, intestinal permeability, central nervous system, mental disorders, schizophrenia, autism, stress, anxiety, depression, and neurodegeneration. Clinical and animal model studies of the association between intestinal barrier and schizophrenia, autism spectrum disorders, neurodegenerative diseases or depression were reviewed. The majority of reports concentrated on schizophrenia and autism spectrum disorders. About half of these described increased intestinal permeability/mucosal damage in patients compared with healthy controls, with up to 43% of children with autism spectrum disorders and up to 35% of schizophrenia patients displaying abnormally high urinary excretion of the sugars used as permeability markers. However, another substantial group of studies did not find such differences. In autism spectrum disorders, some reports show that the use of diets such as the gluten-free casein-free diet may contribute to the normalisation of lactulose/mannitol ratio, but to date there is no adequately controlled study showing improvement in behavioural symptoms following these dietary interventions. Evidence of altered intestinal permeability in individuals suffering from CNS disorders is limited and cannot be regarded as proven. Moreover the efficacy of targeting gut barrier in the management of neurological and behavioural aspects of CNS disorders has not yet been

  12. PERMEABLE REACTIVE BARRIER TECHNOLOGIES FOR CONTAMINANT REMEDIATION

    EPA Science Inventory

    Environmental scientists are generally familiar with the concept of barriers for restricting the movement of contaminant plumes in ground water. Such barriers are typically constructed of highly impermeable emplacements of materials such as grouts, slurries, or sheet pilings to ...

  13. PERMEABLE REACTIVE BARRIER TECHNOLOGIES FOR CONTAMINANT REMEDIATION

    EPA Science Inventory

    Environmental scientists are generally familiar with the concept of barriers for restricting the movement of contaminant plumes in ground water. Such barriers are typically constructed of highly impermeable emplacements of materials such as grouts, slurries, or sheet pilings to ...

  14. Review of potential subsurface permeable barrier emplacement and monitoring technologies

    SciTech Connect

    Riggsbee, W.H.; Treat, R.L.; Stansfield, H.J.; Schwarz, R.M.; Cantrell, K.J.; Phillips, S.J.

    1994-02-01

    This report focuses on subsurface permeable barrier technologies potentially applicable to existing waste disposal sites. This report describes candidate subsurface permeable barriers, methods for emplacing these barriers, and methods used to monitor the barrier performance. Two types of subsurface barrier systems are described: those that apply to contamination.in the unsaturated zone, and those that apply to groundwater and to mobile contamination near the groundwater table. These barriers may be emplaced either horizontally or vertically depending on waste and site characteristics. Materials for creating permeable subsurface barriers are emplaced using one of three basic methods: injection, in situ mechanical mixing, or excavation-insertion. Injection is the emplacement of dissolved reagents or colloidal suspensions into the soil at elevated pressures. In situ mechanical mixing is the physical blending of the soil and the barrier material underground. Excavation-insertion is the removal of a soil volume and adding barrier materials to the space created. Major vertical barrier emplacement technologies include trenching-backfilling; slurry trenching; and vertical drilling and injection, including boring (earth augering), cable tool drilling, rotary drilling, sonic drilling, jetting methods, injection-mixing in drilled holes, and deep soil mixing. Major horizontal barrier emplacement technologies include horizontal drilling, microtunneling, compaction boring, horizontal emplacement, longwall mining, hydraulic fracturing, and jetting methods.

  15. Stress Induces Endotoxemia and Low-Grade Inflammation by Increasing Barrier Permeability

    PubMed Central

    de Punder, Karin; Pruimboom, Leo

    2015-01-01

    Chronic non-communicable diseases (NCDs) are the leading causes of work absence, disability, and mortality worldwide. Most of these diseases are associated with low-grade inflammation. Here, we hypothesize that stresses (defined as homeostatic disturbances) can induce low-grade inflammation by increasing the availability of water, sodium, and energy-rich substances to meet the increased metabolic demand induced by the stressor. One way of triggering low-grade inflammation is by increasing intestinal barrier permeability through activation of various components of the stress system. Although beneficial to meet the demands necessary during stress, increased intestinal barrier permeability also raises the possibility of the translocation of bacteria and their toxins across the intestinal lumen into the blood circulation. In combination with modern life-style factors, the increase in bacteria/bacterial toxin translocation arising from a more permeable intestinal wall causes a low-grade inflammatory state. We support this hypothesis with numerous studies finding associations with NCDs and markers of endotoxemia, suggesting that this process plays a pivotal and perhaps even a causal role in the development of low-grade inflammation and its related diseases. PMID:26029209

  16. Controlling ferrofluid permeability across the blood-brain barrier model

    NASA Astrophysics Data System (ADS)

    Shi, Di; Sun, Linlin; Mi, Gujie; Sheikh, Lubna; Bhattacharya, Soumya; Nayar, Suprabha; Webster, Thomas J.

    2014-02-01

    In the present study, an in vitro blood-brain barrier model was developed using murine brain endothelioma cells (b.End3 cells). Confirmation of the blood-brain barrier model was completed by examining the permeability of FITC-Dextran at increasing exposure times up to 96 h in serum-free medium and comparing such values with values from the literature. After such confirmation, the permeability of five novel ferrofluid (FF) nanoparticle samples, GGB (ferrofluids synthesized using glycine, glutamic acid and BSA), GGC (glycine, glutamic acid and collagen), GGP (glycine, glutamic acid and PVA), BPC (BSA, PEG and collagen) and CPB (collagen, PVA and BSA), was determined using this blood-brain barrier model. All of the five FF samples were characterized by zeta potential to determine their charge as well as TEM and dynamic light scattering for determining their hydrodynamic diameter. Results showed that FF coated with collagen passed more easily through the blood-brain barrier than FF coated with glycine and glutamic acid based on an increase of 4.5% in permeability. Through such experiments, diverse magnetic nanomaterials (such as FF) were identified for: (1) MRI use since they were less permeable to penetrate the blood-brain barrier to avoid neural tissue toxicity (e.g. GGB) or (2) brain drug delivery since they were more permeable to the blood-brain barrier (e.g. CPB).

  17. Controlling ferrofluid permeability across the blood–brain barrier model.

    PubMed

    Shi, Di; Sun, Linlin; Mi, Gujie; Sheikh, Lubna; Bhattacharya, Soumya; Nayar, Suprabha; Webster, Thomas J

    2014-02-21

    In the present study, an in vitro blood–brain barrier model was developed using murine brain endothelioma cells (b.End3 cells). Confirmation of the blood–brain barrier model was completed by examining the permeability of FITCDextran at increasing exposure times up to 96 h in serum-free medium and comparing such values with values from the literature. After such confirmation, the permeability of five novel ferrofluid (FF) nanoparticle samples, GGB (ferrofluids synthesized using glycine, glutamic acid and BSA), GGC (glycine, glutamic acid and collagen), GGP (glycine, glutamic acid and PVA), BPC (BSA, PEG and collagen) and CPB (collagen, PVA and BSA), was determined using this blood–brain barrier model. All of the five FF samples were characterized by zeta potential to determine their charge as well as TEM and dynamic light scattering for determining their hydrodynamic diameter. Results showed that FF coated with collagen passed more easily through the blood–brain barrier than FF coated with glycine and glutamic acid based on an increase of 4.5% in permeability. Through such experiments, diverse magnetic nanomaterials (such as FF) were identified for: (1) MRI use since they were less permeable to penetrate the blood–brain barrier to avoid neural tissue toxicity (e.g. GGB) or (2) brain drug delivery since they were more permeable to the blood–brain barrier (e.g. CPB).

  18. Test device for measuring permeability of a barrier material

    DOEpatents

    Reese, Matthew; Dameron, Arrelaine; Kempe, Michael

    2014-03-04

    A test device for measuring permeability of a barrier material. An exemplary device comprises a test card having a thin-film conductor-pattern formed thereon and an edge seal which seals the test card to the barrier material. Another exemplary embodiment is an electrical calcium test device comprising: a test card an impermeable spacer, an edge seal which seals the test card to the spacer and an edge seal which seals the spacer to the barrier material.

  19. Is intestinal inflammation linking dysbiosis to gut barrier dysfunction during liver disease?

    PubMed Central

    Brandl, Katharina

    2016-01-01

    Changes in the intestinal microbiota composition contribute to the pathogenesis of many disorders including gastrointestinal and liver diseases. Recent studies have broadened our understanding of the “gut-liver” axis. Dietary changes, other environmental and genetic factors can lead to alterations in the microbiota. Dysbiosis can further disrupt the integrity of the intestinal barrier leading to pathological bacterial translocation and the initiation of an inflammatory response in the liver. In this article, the authors dissect the different steps involved in disease pathogenesis to further refine approaches for the medical management of liver diseases. The authors will specifically discuss the role of dysbiosis in inducing intestinal inflammation and increasing intestinal permeability. PMID:26088524

  20. Developmental changes in distribution of the mucous gel layer and intestinal permeability in rat small intestine.

    PubMed

    Iiboshi, Y; Nezu, R; Khan, J; Chen, K; Cui, L; Yoshida, H; Wasa, M; Fukuzawa, M; Kamata, S; Takagi, Y; Okada, A

    1996-01-01

    From the developmental aspects, the distribution of fluorescein isothiocyanate dextran 70,000 (FTTC-dextran) and mucous gel across the lumen of small intestine was observed as an investigation into the role of mucous gel on intestinal permeability. Furthermore, the effect of N-acetyl cysteine (NAC), a mucolytic agent, on intestinal permeability was examined. In suckling and weaned rats, FTTC-dextran (750 mg/kg body wt) was gavage-fed. After 3 hours, blood samples were taken by cardiac puncture to analyze plasma FTTC-dextran by fluorescence spectrometry. Samples of small intestine with luminal contents were frozen and sectioned in a cryostat for fluorescence microscopy; the same sections were placed in a 0.2% celloidin solution to preserve mucous gel and were stained by periodic acid-Schiff reaction for light microscopy. In weaned rats, intestinal permeability was examined with different concentrations of intraluminally instilled NAC. The plasma level of FTTC-dextran showed a significant increase (p < .01) in suckling rats compared with the weaned rats. Morphologic findings were similar in both the jejunum and ileum: The spaces between villi were not entirely filled with mucus but filled with FTTC-dextran in suckling rats, whereas the spaces were filled with mucus and not filled with FTTC-dextran in weaned rats. Intestinal permeability in groups with NAC were significantly higher (p < .01) than that in group without NAC. These results suggest that an increase in the mucous gel layer that coats the epithelial lining according to the maturation of the gastrointestinal tract is one of the most important factors for a restriction in intestinal permeability.

  1. Permeability of microcracked fiber-reinforced containment barriers

    SciTech Connect

    Allan, M.L.; Kukacka, L.E.

    1995-11-01

    Cement-based containment barriers for waste landfills are at risk of cracking, thereby reducing effectiveness. Improved resistance to formation of permeable cracks will enhance the performance of cementitous hydraulic barriers exposed to excessive drying or to wet-dry cycles. Addition of fiber reinforcement was investigated as a potential means of improving crack resistance. Grout and soil cements with and without polypropylene fibers were subjected to different curing and exposure conditions and tested for initial and final permeability. Permeabilities under saturated flow conditions were compared to determine whether fibers could control permeable microcracking of subsurface containment barriers. Fibrillated polypropylene fibers reduced the relative change in permeability for grout and soil cement cured in water and subjected to wet-dry cycles, but did not show significant benefit for materials cured in soil and allowed to dry. Addition of monofilament fibers to barrier materials caused an increase in post-cracking permeability compared with unreinforced materials. This was attributed to increased flow paths created at failed fiber/matrix interfaces.

  2. Influence of surface-active food additives on the integrity and permeability of rat intestinal mucosa.

    PubMed

    Tagesson, C; Edling, C

    1984-11-01

    The influence of two surface-active food additives on the integrity and permeability of rat ileal mucosa has been studied. We determined the activity of N-acetyl-beta-glucosaminidase, a lysosomal enzyme, in the rat intestinal lumen after deposition of polyoxyethylene (20) sorbitan monostearate (polysorbate 60; Tween 60) or polyoxyethylene (20) sorbitan monooleate (polysorbate 80; Tween 80) in a section of ligated, cannulated gut. We also determined the activities of N-acetyl-beta-glucosaminidase, alkaline phosphatase, 5'-nucleotidase and phospholipase A2 in mixtures of isolated mucosal cells and polysorbate 60 or polysorbate 80. The activity of N-acetyl-beta-glucosaminidase was increased in the luminal contents of the cannulated gut 15 min after deposition of either polysorbate 60 or polysorbate 80 (10 mg/ml fluid instilled into gut). It was also increased in mixtures of mucosal cells and polysorbate 60 or polysorbate 80 (0.1-10 mg/ml). In contrast, the activities of alkaline phosphatase and 5'-nucleotidase were unaffected and that of phospholipase A2 was decreased by the presence of either polysorbate. These findings indicated that polysorbate 60 and polysorbate 80 released lysosomal enzymes from the intestinal mucosal cells and that these agents might damage the intestinal mucosa and increase its permeability. We therefore determined the intestinal permeability to sodium fluorescein in the absence and presence of polysorbate 60 or 80 and found that the permeability was slightly increased in the presence of either of the compounds at concentrations of 10 mg/ml fluid instilled into gut. It is possible therefore that surface-active food additives might impair the function of the mucosal barrier and increase the permeability of the gut to potentially toxic and pathogenic molecules.

  3. Amorphous azithromycin with improved aqueous solubility and intestinal membrane permeability.

    PubMed

    Aucamp, Marique; Odendaal, Roelf; Liebenberg, Wilna; Hamman, Josias

    2015-01-01

    Azithromycin (AZM) is a poorly soluble macrolide antibacterial agent. Its low solubility is considered as the major contributing factor to its relatively low oral bioavailability. The aim of this study was to improve the solubility of this active pharmaceutical ingredient (API) by preparing an amorphous form by quench cooling of the melt and to study the influence of the improved solubility on membrane permeability. The amorphous azithromycin (AZM-A) exhibited a significant increase in water solubility when compared to the crystalline azithromycin dihydrate (AZM-DH). The influence that the improved solubility could have on membrane permeability was also studied. The apparent permeability coefficient (Papp) values of AZM-A were statistically significantly higher (p < 0.05) than crystalline AZM-DH at pH values of 6.8 and 7.2. The results therefore indicated that the improved solubility of AZM in the amorphous form also produced improved permeability across excised intestinal tissue at physiological pH values found in the small intestine.

  4. Intestinal absorptive capacity, intestinal permeability and jejunal histology in HIV and their relation to diarrhoea.

    PubMed Central

    Keating, J; Bjarnason, I; Somasundaram, S; Macpherson, A; Francis, N; Price, A B; Sharpstone, D; Smithson, J; Menzies, I S; Gazzard, B G

    1995-01-01

    Intestinal function is poorly defined in patients with HIV infection. Absorptive capacity and intestinal permeability were assessed using 3-O-methyl-D-glucose, D-xylose, L-rhamnose, and lactulose in 88 HIV infected patients and the findings were correlated with the degree of immunosuppression (CD4 counts), diarrhoea, wasting, intestinal pathogen status, and histomorphometric analysis of jejunal biopsy samples. Malabsorption of 3-O-methyl-D-glucose and D-xylose was prevalent in all groups of patients with AIDS but not in asymptomatic, well patients with HIV. Malabsorption correlated significantly (r = 0.34-0.56, p < 0.005) with the degree of immune suppression and with body mass index. Increased intestinal permeability was found in all subgroups of patients. The changes in absorption-permeability were of comparable severity to those found in patients with untreated coeliac disease. Jejunal histology, however, showed only mild changes in the villus height/crypt depth ratio as compared with subtotal villus atrophy in coeliac disease. Malabsorption and increased intestinal permeability are common in AIDS patients. Malabsorption, which has nutritional implications, relates more to immune suppression than jejunal morphological changes. PMID:8549936

  5. Limited Nesting Stress Alters Maternal Behavior and In Vivo Intestinal Permeability in Male Wistar Pup Rats

    PubMed Central

    Moussaoui, Nabila; Larauche, Muriel; Biraud, Mandy; Molet, Jenny; Million, Mulugeta; Mayer, Emeran; Taché, Yvette

    2016-01-01

    A few studies indicate that limited nesting stress (LNS) alters maternal behavior and the hypothalamic pituitary adrenal (HPA) axis of dams and offspring in male Sprague Dawley rats. In the present study, we evaluated the impact of LNS on maternal behavior in Wistar rats, and on the HPA axis, glycemia and in vivo intestinal permeability of male and female offspring. Intestinal permeability is known to be elevated during the first week postnatally and influenced by glucocorticoids. Dams and neonatal litters were subjected to LNS or normal nesting conditions (control) from days 2 to 10 postnatally. At day 10, blood was collected from pups for determination of glucose and plasma corticosterone by enzyme immunoassay and in vivo intestinal permeability by oral gavage of fluorescein isothiocyanate–dextran 4kDa. Dams exposed to LNS compared to control showed an increase in the percentage of time spent building a nest (118%), self-grooming (69%), and putting the pups back to the nest (167%). LNS male and female pups exhibited a reduction of body weight by 5% and 4%, adrenal weights/100g body weight by 17% and 18%, corticosterone plasma levels by 64% and 62% and blood glucose by 11% and 12% respectively compared to same sex control pups. In male LNS pups, intestinal permeability was increased by 2.7-fold while no change was observed in females compared to same sex control. There was no sex difference in any of the parameters in control pups except the body weight. These data indicate that Wistar dams subjected to LNS during the first postnatal week have an altered repertoire of maternal behaviors which affects the development of the HPA axis in both sexes and intestinal barrier function in male offspring. PMID:27149676

  6. Yogurt inhibits intestinal barrier dysfunction in Caco-2 cells by increasing tight junctions.

    PubMed

    Putt, Kelley K; Pei, Ruisong; White, Heather M; Bolling, Bradley W

    2017-01-25

    Chronic inflammation disrupts intestinal barrier function and may contribute to the pathology of obesity and other diseases. The goal of this study was to determine the mechanism by which yogurt improves intestinal barrier function. Caco-2 cells were differentiated on Transwell inserts and used as a model of intestinal barrier permeability. Transepithelial electrical resistance (TEER) and flux of 4 kDa fluorescein isothiocyanate-dextran (FD) and lucifer yellow (LY) were used as indicators of monolayer integrity and paracellular permeability. Immunofluorescence microscopy and real time quantitative polymerase chain were used to assess the localization and expression of tight junction proteins known to regulate intestinal permeability. Differentiated cells were treated with a vehicle control (C), inflammatory stimulus (I) (interleukin-1β, tumor necrosis factor-α, interferon-γ, and lipopolysaccharide), or I and 0.03 g mL(-1) yogurt (IY). After 48 h, I reduced Caco-2 TEER by 46%, while IY reduced TEER by only 27% (P < 0.0001). FD and LY flux reflected TEER measurements, with IY having significantly lower permeability than I (P < 0.05). Yogurt also improved localization of occludin and zona occludens protein 1 (ZO-1) at tight junctions of differentiated Caco-2 cells. IY increased Caco-2 claudin-1, ZO-1, and occludin mRNA relative to I (P < 0.05). In a simulated digestion, the barrier-improving bioactivity of yogurt was maintained through the gastric phase, but was reduced to the level of I after intestinal digestion (P < 0.05). Therefore, yogurt improved inflammation-disrupted intestinal barrier function in a Caco-2 model by increasing tight junctions, but the beneficial effect on barrier function was reduced at latter stages of digestion.

  7. Clostridium difficile toxin A perturbs cytoskeletal structure and tight junction permeability of cultured human intestinal epithelial monolayers.

    PubMed Central

    Hecht, G; Pothoulakis, C; LaMont, J T; Madara, J L

    1988-01-01

    Toxin A of Clostridium difficile causes severe inflammatory enterocolitis in man and animals that appears to be mediated in part by acute inflammatory cells that migrate into the toxin A-exposed mucosa. To determine the direct effects of toxin A on intestinal epithelial permeability and structure in the absence of other modulating factors, we used cultured monolayers of a human intestinal epithelial cell line (T84). A toxin A concentration of 7 x 10(-1) micrograms/ml (3 x 10(-9) M) nearly abolished monolayer transepithelial resistance within 6-8 h. This marked permeability defect occurred while the monolayers were still confluent. Dual sodium-mannitol flux studies localized the permeability defect to the intercellular tight junction. Cytotoxicity assays and morphological evaluation using Nomarski optics and electron microscopy failed to demonstrate any evidence of cell damage at the time the maximum resistance response was observed. Fluorescent staining for F actin, however, revealed a marked decrease in fluorescent intensity in toxin-treated monolayers versus controls. These data show that toxin A can directly affect the barrier function of this model intestinal epithelium and initially does so by selectively enhancing tight junction permeability. Furthermore, cytoskeletal structure is markedly altered over the same time course, although the integrity of individual cells is maintained. Because the cytoskeleton of intestinal epithelial cells is known to be capable of regulating tight junction permeability, we speculate that the above effects of toxin A on epithelial barrier function result from alterations of the cytoskeleton. Images PMID:3141478

  8. Clostridium difficile toxin A perturbs cytoskeletal structure and tight junction permeability of cultured human intestinal epithelial monolayers.

    PubMed

    Hecht, G; Pothoulakis, C; LaMont, J T; Madara, J L

    1988-11-01

    Toxin A of Clostridium difficile causes severe inflammatory enterocolitis in man and animals that appears to be mediated in part by acute inflammatory cells that migrate into the toxin A-exposed mucosa. To determine the direct effects of toxin A on intestinal epithelial permeability and structure in the absence of other modulating factors, we used cultured monolayers of a human intestinal epithelial cell line (T84). A toxin A concentration of 7 x 10(-1) micrograms/ml (3 x 10(-9) M) nearly abolished monolayer transepithelial resistance within 6-8 h. This marked permeability defect occurred while the monolayers were still confluent. Dual sodium-mannitol flux studies localized the permeability defect to the intercellular tight junction. Cytotoxicity assays and morphological evaluation using Nomarski optics and electron microscopy failed to demonstrate any evidence of cell damage at the time the maximum resistance response was observed. Fluorescent staining for F actin, however, revealed a marked decrease in fluorescent intensity in toxin-treated monolayers versus controls. These data show that toxin A can directly affect the barrier function of this model intestinal epithelium and initially does so by selectively enhancing tight junction permeability. Furthermore, cytoskeletal structure is markedly altered over the same time course, although the integrity of individual cells is maintained. Because the cytoskeleton of intestinal epithelial cells is known to be capable of regulating tight junction permeability, we speculate that the above effects of toxin A on epithelial barrier function result from alterations of the cytoskeleton.

  9. Groundwater protection from cadmium contamination by permeable reactive barriers.

    PubMed

    Di Natale, F; Di Natale, M; Greco, R; Lancia, A; Laudante, C; Musmarra, D

    2008-12-30

    This work studies the reliability of an activated carbon permeable reactive barrier in removing cadmium from a contaminated shallow aquifer. Laboratory tests have been performed to characterize the equilibrium and kinetic adsorption properties of the activated carbon in cadmium-containing aqueous solutions. A 2D numerical model has been used to describe pollutant transport within a groundwater and the pollutant adsorption on the permeable adsorbing barrier (PRB). In particular, it has been considered the case of a permeable adsorbing barrier (PAB) used to protect a river from a Cd(II) contaminated groundwater. Numerical results show that the PAB can achieve a long-term efficiency by preventing river pollution for several months.

  10. Effect of alemtuzumab on intestinal intraepithelial lymphocytes and intestinal barrier function in cynomolgus model.

    PubMed

    Qu, Lin-Lin; Lyu, Ya-Qing; Jiang, Hai-Tao; Shan, Ting; Zhang, Jing-Bin; Li, Qiu-Rong; Li, Jie-Shou

    2015-03-05

    Alemtuzumab has been used in organ transplantation and a variety of hematologic malignancies (especially for the treatment of B-cell chronic lymphocytic leukemia). However, serious infectious complications frequently occur after treatment. The reason for increased infections postalemtuzumab treatment is unknown at this stage. We explore the effect of alemtuzumab on intestinal intraepithelial lymphocytes (IELs) and intestinal barrier function in cynomolgus model to explain the reason of infection following alemtuzumab treatment. Twelve male cynomolguses were randomly assigned to either a treatment or control group. The treatment group received alemtuzumab (3 mg/kg, intravenous injection) while the control group received the same volume of physiological saline. Intestinal IELs were isolated from the control group and the treatment group (on day 9, 35, and 70 after treatment) for counting and flow cytometric analysis. Moreover, intestinal permeability was monitored by enzymatic spectrophotometric technique and enzyme-linked immunosorbent assay. The numbers of IELs were decreased significantly on day 9 after treatment compared with the control group (0.35 ± 0.07 × 10 8 and 1.35 ± 0.09 × 10 8 , respectively; P < 0.05) and were not fully restored until day 70 after treatment. There were significant differences among four groups considering IELs subtypes. In addition, the proportion of apoptotic IELs after alemtuzumab treatment was significantly higher than in the control group (22.01 ± 3.67 and 6.01 ± 1.42, respectively; P < 0.05). Moreover, the concentration of D-lactate and endotoxin was also increased significantly on day 9 after treatment. Alemtuzumab treatment depletes lymphocytes in the peripheral blood and intestine of cynomolgus model. The induction of apoptosis is an important mechanism of lymphocyte depletion after alemtuzumab treatment. Notably, intestinal barrier function may be disrupted after alemtuzumab treatment.

  11. Effect of Alemtuzumab on Intestinal Intraepithelial Lymphocytes and Intestinal Barrier Function in Cynomolgus Model

    PubMed Central

    Qu, Lin-Lin; Lyu, Ya-Qing; Jiang, Hai-Tao; Shan, Ting; Zhang, Jing-Bin; Li, Qiu-Rong; Li, Jie-Shou

    2015-01-01

    Background: Alemtuzumab has been used in organ transplantation and a variety of hematologic malignancies (especially for the treatment of B-cell chronic lymphocytic leukemia). However, serious infectious complications frequently occur after treatment. The reason for increased infections postalemtuzumab treatment is unknown at this stage. We explore the effect of alemtuzumab on intestinal intraepithelial lymphocytes (IELs) and intestinal barrier function in cynomolgus model to explain the reason of infection following alemtuzumab treatment. Methods: Twelve male cynomolguses were randomly assigned to either a treatment or control group. The treatment group received alemtuzumab (3 mg/kg, intravenous injection) while the control group received the same volume of physiological saline. Intestinal IELs were isolated from the control group and the treatment group (on day 9, 35, and 70 after treatment) for counting and flow cytometric analysis. Moreover, intestinal permeability was monitored by enzymatic spectrophotometric technique and enzyme-linked immunosorbent assay. Results: The numbers of IELs were decreased significantly on day 9 after treatment compared with the control group (0.35 ± 0.07 × 108 and 1.35 ± 0.09 × 108, respectively; P < 0.05) and were not fully restored until day 70 after treatment. There were significant differences among four groups considering IELs subtypes. In addition, the proportion of apoptotic IELs after alemtuzumab treatment was significantly higher than in the control group (22.01 ± 3.67 and 6.01 ± 1.42, respectively; P < 0.05). Moreover, the concentration of D-lactate and endotoxin was also increased significantly on day 9 after treatment. Conclusions: Alemtuzumab treatment depletes lymphocytes in the peripheral blood and intestine of cynomolgus model. The induction of apoptosis is an important mechanism of lymphocyte depletion after alemtuzumab treatment. Notably, intestinal barrier function may be disrupted after alemtuzumab

  12. Intestinal permeability study of minoxidil: assessment of minoxidil as a high permeability reference drug for biopharmaceutics classification.

    PubMed

    Ozawa, Makoto; Tsume, Yasuhiro; Zur, Moran; Dahan, Arik; Amidon, Gordon L

    2015-01-05

    The purpose of this study was to evaluate minoxidil as a high permeability reference drug for Biopharmaceutics Classification System (BCS). The permeability of minoxidil was determined in in situ intestinal perfusion studies in rodents and permeability studies across Caco-2 cell monolayers. The permeability of minoxidil was compared with that of metoprolol, an FDA reference drug for BCS classification. In rat perfusion studies, the permeability of minoxidil was somewhat higher than that of metoprolol in the jejunum, while minoxidil showed lower permeability than metoprolol in the ileum. The permeability of minoxidil was independent of intestinal segment, while the permeability of metoprolol was region-dependent. Similarly, in mouse perfusion study, the jejunal permeability of minoxidil was 2.5-fold higher than that of metoprolol. Minoxidil and metoprolol showed similar permeability in Caco-2 study at apical pH of 6.5 and basolateral pH of 7.4. The permeability of minoxidil was independent of pH, while metoprolol showed pH-dependent transport in Caco-2 study. Minoxidil exhibited similar permeability in the absorptive direction (AP-BL) in comparison with secretory direction (BL-AP), while metoprolol had higher efflux ratio (ER > 2) at apical pH of 6.5 and basolateral pH of 7.4. No concentration-dependent transport was observed for either minoxidil or metoprolol transport in Caco-2 study. Verapamil did not alter the transport of either compounds across Caco-2 cell monolayers. The permeability of minoxidil was independent of both pH and intestinal segment in intestinal perfusion studies and Caco-2 studies. Caco-2 studies also showed no involvement of carrier mediated transport in the absorption process of minoxidil. These results suggest that minoxidil may be an acceptable reference drug for BCS high permeability classification. However, minoxidil exhibited higher jejunal permeability than metoprolol and thus to use minoxidil as a reference drug would raise the

  13. Matrix metalloproteinase 9-induced increase in intestinal epithelial tight junction permeability contributes to the severity of experimental DSS colitis

    PubMed Central

    Nighot, Prashant; Al-Sadi, Rana; Guo, Shuhong; Watterson, D. Martin; Ma, Thomas

    2015-01-01

    Recent studies have implicated a pathogenic role for matrix metalloproteinases 9 (MMP-9) in inflammatory bowel disease. Although loss of epithelial barrier function has been shown to be a key pathogenic factor for the development of intestinal inflammation, the role of MMP-9 in intestinal barrier function remains unclear. The aim of this study was to investigate the role of MMP-9 in intestinal barrier function and intestinal inflammation. Wild-type (WT) and MMP-9−/− mice were subjected to experimental dextran sodium sulfate (DSS) colitis by administration of 3% DSS in drinking water for 7 days. The mouse colonic permeability was measured in vivo by recycling perfusion of the entire colon using fluorescently labeled dextran. The DSS-induced increase in the colonic permeability was accompanied by an increase in intestinal epithelial cell MMP-9 expression in WT mice. The DSS-induced increase in intestinal permeability and the severity of DSS colitis was found to be attenuated in MMP-9−/− mice. The colonic protein expression of myosin light chain kinase (MLCK) and phospho-MLC was found to be significantly increased after DSS administration in WT mice but not in MMP-9−/− mice. The DSS-induced increase in colonic permeability and colonic inflammation was attenuated in MLCK−/− mice and MLCK inhibitor ML-7-treated WT mice. The DSS-induced increase in colonic surface epithelial cell MLCK mRNA was abolished in MMP-9−/− mice. Lastly, increased MMP-9 protein expression was detected within the colonic surface epithelial cells in ulcerative colitis cases. These data suggest a role of MMP-9 in modulation of colonic epithelial permeability and inflammation via MLCK. PMID:26514773

  14. Advances in Permeable Reactive Barrier Technologies

    DTIC Science & Technology

    2002-08-01

    technical methods, such as jetting and hydraulic fracturing , has improved the ability to access deeper aquifers. Table 1 describes the established and...34, Cape Canaveral Air Station, FL. Hydraulic Fracturing 120 A series of wells are installed along the length of the PRB. A vertical fracture is...especially helpful with deep instal- lation methods, such as hydraulic fracturing , where the barrier installed is just a few inches thick. A second, new type

  15. Assessment of Passive Intestinal Permeability Using an Artificial Membrane Insert System.

    PubMed

    Berben, Philippe; Brouwers, Joachim; Augustijns, Patrick

    2017-08-19

    Despite reasonable predictive power of current cell-based and cell-free absorption models for the assessment of intestinal drug permeability, high costs and lengthy preparation steps hamper their use. The use of a simple artificial membrane (without any lipids present) as intestinal barrier substitute would overcome these hurdles. In the present study, a set of 14 poorly water-soluble drugs, dissolved in 2 different media (fasted state simulated/human intestinal fluids [FaSSIF/FaHIF]), were applied to the donor compartment of an artificial membrane insert system (AMI-system) containing a regenerated cellulose membrane. Furthermore, to investigate the predictive capacity of the AMI-system as substitute for the well-established Caco-2 system to assess intestinal permeability, the same set of 14 drugs dissolved in FaHIF were applied to the donor compartment of a Caco-2 system. For 14 drugs, covering a broad range of physicochemical parameters, a reasonable correlation between both absorption systems was observed, characterized by a Pearson correlation coefficient r of 0.95 (FaHIF). Using the AMI-system, an excellent predictive capacity of FaSSIF as surrogate medium for FaHIF was demonstrated (r = 0.96). Based on the acquired data, the AMI-system appears to be a time- and cost-effective tool for the early-stage estimation of passive intestinal permeability for poorly water-soluble drugs. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  16. Arctigenin from Fructus Arctii (Seed of Burdock) Reinforces Intestinal Barrier Function in Caco-2 Cell Monolayers.

    PubMed

    Shin, Hee Soon; Jung, Sun Young; Back, Su Yeon; Do, Jeong-Ryong; Shon, Dong-Hwa

    2015-01-01

    Fructus Arctii is used as a traditional herbal medicine to treat inflammatory diseases in oriental countries. This study aimed to investigate effect of F. Arctii extract on intestinal barrier function in human intestinal epithelial Caco-2 cells and to reveal the active component of F. Arctii. We measured transepithelial electrical resistance (TEER) value (as an index of barrier function) and ovalbumin (OVA) permeation (as an index of permeability) to observe the changes of intestinal barrier function. The treatment of F. Arctii increased TEER value and decreased OVA influx on Caco-2 cell monolayers. Furthermore, we found that arctigenin as an active component of F. Arctii increased TEER value and reduced permeability of OVA from apical to the basolateral side but not arctiin. In the present study, we revealed that F. Arctii could enhance intestinal barrier function, and its active component was an arctigenin on the functionality. We expect that the arctigenin from F. Arctii could contribute to prevention of inflammatory, allergic, and infectious diseases by reinforcing intestinal barrier function.

  17. Arctigenin from Fructus Arctii (Seed of Burdock) Reinforces Intestinal Barrier Function in Caco-2 Cell Monolayers

    PubMed Central

    Shin, Hee Soon; Jung, Sun Young; Back, Su Yeon; Do, Jeong-Ryong; Shon, Dong-Hwa

    2015-01-01

    Fructus Arctii is used as a traditional herbal medicine to treat inflammatory diseases in oriental countries. This study aimed to investigate effect of F. Arctii extract on intestinal barrier function in human intestinal epithelial Caco-2 cells and to reveal the active component of F. Arctii. We measured transepithelial electrical resistance (TEER) value (as an index of barrier function) and ovalbumin (OVA) permeation (as an index of permeability) to observe the changes of intestinal barrier function. The treatment of F. Arctii increased TEER value and decreased OVA influx on Caco-2 cell monolayers. Furthermore, we found that arctigenin as an active component of F. Arctii increased TEER value and reduced permeability of OVA from apical to the basolateral side but not arctiin. In the present study, we revealed that F. Arctii could enhance intestinal barrier function, and its active component was an arctigenin on the functionality. We expect that the arctigenin from F. Arctii could contribute to prevention of inflammatory, allergic, and infectious diseases by reinforcing intestinal barrier function. PMID:26550018

  18. Permeability of rhynchophylline across human intestinal cell in vitro

    PubMed Central

    Ma, Bo; Wang, Jing; Sun, Jing; Li, Ming; Xu, Huibo; Sun, Guibo; Sun, Xiaobo

    2014-01-01

    Rhynchophylline (Rhy) is the major component of Uncaria species, which is used in Chinese traditional medicine for the treatment of central nervous system disorders. However, its oral bioavailability has not been known. This study aims to investigate the intestinal permeability and related mechanisms of Rhy using cultured human epithelial Caco-2 cells. The cytotoxicity of Rhy on Caco-2 cells was evaluated with MTT assay. The effect of Rhy on the integrity of Caco-2 cell monolayer was assayed with transepithelial electrical resistance. The permeability of Rhy across cell monolayer was assayed by measuring Rhy quantity in received side with HPLC. The effect of Rhy on the expression of P-glycoprotein and MDR1 was detected with Western blot and flow cytometry, respectively. In the concentration of Rhy, which did not produce toxicity on cell viability and integrity of Caco-2 cell monolayer, Rhy crossed the monolayer with velocity 2.76~5.57×10^-6 cm/sec and 10.68~15.66×10^-6 cm/sec from apical to basolateral side and from basolateral to apical side, respectively. The permeability of Rhy was increased by verapamil, a P-glycoprotein inhibitor, or rhodamine123, a P-glycoprotein substrate. Rhy revealed an induction effect on P-glycoprotein expression in Caco-2 cells. These results demonstrate the low permeability of Rhy in intro, and suggest that P-glycoprotein may underlie the mechanism. PMID:24966905

  19. Adenosine A2B receptor modulates intestinal barrier function under hypoxic and ischemia/reperfusion conditions

    PubMed Central

    Yang, Yang; Qiu, Yuan; Wang, Wensheng; Xiao, Weidong; Liang, Hongyin; Zhang, Chaojun; Yang, Hanwenbo; Teitelbaum, Daniel H; Sun, Li-Hua; Yang, Hua

    2014-01-01

    Background: Intestinal barrier function failure from ischemia/reperfusion (I/R) and acute hypoxia has been implicated as a critical determinant in the predisposition to intestinal inflammation and a number of inflammatory disorders. Here, we identified the role of Adenosine A2B receptor (A2BAR) in the regulation of intestinal barrier function under I/R and acute hypoxic conditions. Methods: C57BL/6J mice were used, and were randomized into three groups: Sham, I/R, IR+PSB1115 (a specific A2BAR antagonist) groups. After surgery, the small bowel was harvested for immunohistochemical staining, RNA and protein content, and intestinal permeability analyses. Using an epithelial cell culture model, we investigated the influence of hypoxia on the epithelial function, and the role of A2BAR in the expressions of tight junction and epithelial permeability. The expressions of Claudin-1, occludin and ZO-1 were detected by RT-PCR and Western-Blot. Epithelial barrier function was assessed with transepithelial resistance (TER). Results and conclusions: The A2BAR antagonist, PSB1115, significantly increased tight junction protein expression after intestinal I/R or acute hypoxia conditions. PSB1115 also attenuated the disrupted distribution of TJ proteins. Furthermore, inhibition of A2BAR attenuated the decrease in TER induced by I/R or acute hypoxic conditions, and maintained intestinal barrier function. Antagonism of A2BAR activity improves intestinal epithelial structure and barrier function in a mouse model of intestinal I/R and a cell model of acute hypoxia. These findings support a potentially destructive role for A2BAR under intestinal I/R and acute hypoxic conditions. PMID:24966910

  20. Effects of skin surface temperature on epidermal permeability barrier homeostasis.

    PubMed

    Denda, Mitsuhiro; Sokabe, Takaaki; Fukumi-Tominaga, Tomoko; Tominaga, Makoto

    2007-03-01

    Members of the transient receptor potential (TRP) family are temperature sensors, and TRPV1, V3, and V4 are expressed in epidermal keratinocytes. To evaluate the influence of these receptors on epidermal permeability barrier homeostasis, we kept both hairless mouse skin and human skin at various temperatures immediately after tape stripping. At temperatures from 36 to 40 degrees C, barrier recovery was accelerated in both cases compared with the area at 34 degrees C. At 34 or 42 degrees C, barrier recovery was delayed compared with the un-occluded area. 4Alpha-phorbol 12,13-didecanone, an activator of TRPV4, accelerated barrier recovery, whereas ruthenium red, a blocker of TRPV4, delayed barrier recovery. Capsaicin, an activator of TRPV1, delayed barrier recovery, whereas capsazepin, an antagonist of TRPV1, blocked this delay. 2-Aminoethoxydiphenyl borate and camphor, TRPV3 activators, did not affect the barrier recovery rate. As TRPV4 is activated at about 35 degrees C and above, whereas TRPV1 is activated at about 42 degrees C and above, these results suggest that both TRPV1 and TRPV4 play important roles in skin permeability barrier homeostasis. Previous reports suggest the existence of a water flux sensor in the epidermis, and as TRPV4 is known to be activated by osmotic pressure, our results indicate that it might be this sensor.

  1. MICROBIAL CHARACTERIZATION OF MANURE BASED PERMEABLE REACTIVE BARRIER

    EPA Science Inventory

    The implementation of permeable reactive barriers (PRB) provides a viable option for the remediation of contaminants of environmental significance such as dissolved metals (i.e., chromium), chlorinated solvents, and nitrate/ammonia. The designs of PRBs are usually based on the a...

  2. PERMEABLE REACTIVE BARRIERS FOR REMEDIATION OF INORGANIC CONTAMINANTS

    EPA Science Inventory

    The permeable reactive barrier (PRB) technology is an in-situ approach for groundwater remediation that couples subsurface flow management with a passive chemical or biochemical treatment zone. The development and application of the PRB technology has progressed over the last de...

  3. MICROBIAL CHARACTERIZATION OF MANURE BASED PERMEABLE REACTIVE BARRIER

    EPA Science Inventory

    The implementation of permeable reactive barriers (PRB) provides a viable option for the remediation of contaminants of environmental significance such as dissolved metals (i.e., chromium), chlorinated solvents, and nitrate/ammonia. The designs of PRBs are usually based on the a...

  4. COLLECTION OF DESIGN DATA: SITE CHARACTERIZATION FOR PERMEABLE REACTIVE BARRIERS

    EPA Science Inventory

    Permeable reactive barriers (PRBs) for the restoration of contaminated ground water are no longer innovative. PRBs have evolved from innovative to accepted, standard practice, for the containment and treatment of a variety of contaminants in ground water. Like any remedial tech...

  5. LONG-TERM PERFORMANCE OF PERMEABLE REACTIVE BARRIERS: LESSONS LEARNED

    EPA Science Inventory

    This presentation will provide an overview of research efforts at EPA on the application, monitoring, and performance of Permeable Reactive Barriers (PRBs) for groundwater restoration. Over the past 10 years, research projects conducted by research staff at EPA's National Risk M...

  6. Permeable Reactive Barriers for Treatment of Cr6

    EPA Science Inventory

    Several options are available for treatment of hexavalent chromium (Cr(VI)) in groundwater using the permeable reactive barrier (PRB) approach. They include conventional trench-and-fill systems, chemical redox curtains, and organic carbon redox curtains. Each of these PRB syste...

  7. COLLECTION OF DESIGN DATA: SITE CHARACTERIZATION FOR PERMEABLE REACTIVE BARRIERS

    EPA Science Inventory

    Permeable reactive barriers (PRBs) for the restoration of contaminated ground water are no longer innovative. PRBs have evolved from innovative to accepted, standard practice, for the containment and treatment of a variety of contaminants in ground water. Like any remedial tech...

  8. PERMEABLE REACTIVE BARRIERS FOR REMEDIATION OF INORGANIC CONTAMINANTS

    EPA Science Inventory

    The permeable reactive barrier (PRB) technology is an in-situ approach for groundwater remediation that couples subsurface flow management with a passive chemical or biochemical treatment zone. The development and application of the PRB technology has progressed over the last de...

  9. Permeable Reactive Barriers for Treatment of Cr6

    EPA Science Inventory

    Several options are available for treatment of hexavalent chromium (Cr(VI)) in groundwater using the permeable reactive barrier (PRB) approach. They include conventional trench-and-fill systems, chemical redox curtains, and organic carbon redox curtains. Each of these PRB syste...

  10. Lipid rafts are disrupted in mildly inflamed intestinal microenvironments without overt disruption of the epithelial barrier.

    PubMed

    Bowie, Rachel V; Donatello, Simona; Lyes, Clíona; Owens, Mark B; Babina, Irina S; Hudson, Lance; Walsh, Shaun V; O'Donoghue, Diarmuid P; Amu, Sylvie; Barry, Sean P; Fallon, Padraic G; Hopkins, Ann M

    2012-04-15

    Intestinal epithelial barrier disruption is a feature of inflammatory bowel disease (IBD), but whether barrier disruption precedes or merely accompanies inflammation remains controversial. Tight junction (TJ) adhesion complexes control epithelial barrier integrity. Since some TJ proteins reside in cholesterol-enriched regions of the cell membrane termed lipid rafts, we sought to elucidate the relationship between rafts and intestinal epithelial barrier function. Lipid rafts were isolated from Caco-2 intestinal epithelial cells primed with the proinflammatory cytokine interferon-γ (IFN-γ) or treated with methyl-β-cyclodextrin as a positive control for raft disruption. Rafts were also isolated from the ilea of mice in which colitis had been induced in conjunction with in vivo intestinal permeability measurements, and lastly from intestinal biopsies of ulcerative colitis (UC) patients with predominantly mild or quiescent disease. Raft distribution was analyzed by measuring activity of the raft-associated enzyme alkaline phosphatase and by performing Western blot analysis for flotillin-1. Epithelial barrier integrity was estimated by measuring transepithelial resistance in cytokine-treated cells or in vivo permeability to fluorescent dextran in colitic mice. Raft and nonraft fractions were analyzed by Western blotting for the TJ proteins occludin and zonula occludens-1 (ZO-1). Our results revealed that lipid rafts were disrupted in IFN-γ-treated cells, in the ilea of mice with subclinical colitis, and in UC patients with quiescent inflammation. This was not associated with a clear pattern of occludin or ZO-1 relocalization from raft to nonraft fractions. Significantly, a time-course study in colitic mice revealed that disruption of lipid rafts preceded the onset of increased intestinal permeability. Our data suggest for the first time that lipid raft disruption occurs early in the inflammatory cascade in murine and human colitis and, we speculate, may contribute to

  11. The Effect of DA-6034 on Intestinal Permeability in an Indomethacin-Induced Small Intestinal Injury Model

    PubMed Central

    Kwak, Dong Shin; Lee, Oh Young; Lee, Kang Nyeong; Jun, Dae Won; Lee, Hang Lak; Yoon, Byung Chul; Choi, Ho Soon

    2016-01-01

    Background/Aims DA-6034 has anti-inflammatory activities and exhibits cytoprotective effects in acute gastric injury models. However, explanations for the protective effects of DA-6034 on intestinal permeability are limited. This study sought to investigate the effect of DA-6034 on intestinal permeability in an indomethacin-induced small intestinal injury model and its protective effect against small intestinal injury. Methods Rats in the treatment group received DA-6034 from days 0 to 2 and indomethacin from days 1 to 2. Rats in the control group received indomethacin from days 1 to 2. On the fourth day, the small intestines were examined to compare the severity of inflammation. Intestinal permeability was evaluated by using fluorescein isothiocyanate-labeled dextran. Western blotting was performed to confirm the association between DA-6034 and the extracellular signal-regulated kinase (ERK) pathway. Results The inflammation scores in the treatment group were lower than those in the control group, but the difference was statistically insignificant. Hemorrhagic lesions in the treatment group were broader than those in the control group, but the difference was statistically insignificant. Intestinal permeability was lower in the treatment group than in the control group. DA-6034 enhanced extracellular signal-regulated kinase expression, and intestinal permeability was negatively correlated with ERK expression. Conclusions DA-6034 may decrease intestinal permeability in an indomethacin-induced intestinal injury model via the ERK pathway. PMID:27114435

  12. Maintenance of superior mesenteric arterial perfusion prevents increased intestinal mucosal permeability in endotoxic pigs

    SciTech Connect

    Fink, M.P.; Kaups, K.L.; Wang, H.L.; Rothschild, H.R. )

    1991-08-01

    Lipopolysaccharide increases intestinal mucosal permeability to hydrophilic compounds such as chromium 51-labeled edetate (51Cr-EDTA). The authors sought to determine whether this phenomenon is partly mediated by lipopolysaccharide-induced mesenteric hypoperfusion. They assessed permeability in an isolated segment of ileum by measuring plasma-to-lumen clearances (C) for two probes, 51Cr-EDTA and urea, and expressing the results as a ratio (CEDTA/CUREA). In control pigs (n = 6) resuscitated with Ringer's lactate (RL), mucosal permeability was unchanged during the 210-minute period of observation. In pigs (n = 7) infused with lipopolysaccharide (50 micrograms/kg) and similarly resuscitated with RL, mesenteric perfusion (Qsma) decreased significantly and permeability increased progressively and significantly. When endotoxic pigs (n = 6) were resuscitated with a regimen (RL plus hetastarch plus dobutamine) that preserved normal Qsma, lipopolysaccharide-induced mucosal hyperpermeability was prevented. Resuscitation of endotoxic pigs (n = 6) with RL plus hetastarch provided intermediate protection against both mesenteric hypoperfusion and increased permeability. These data suggest that diminished Qsma contributes to impaired ileal mucosal barrier function in experimental endotoxicosis.

  13. Endocannabinoids modulate human blood-brain barrier permeability in vitro.

    PubMed

    Hind, William H; Tufarelli, Cristina; Neophytou, Maria; Anderson, Susan I; England, Timothy J; O'Sullivan, Saoirse E

    2015-06-01

    Endocannabinoids alter permeability at various epithelial barriers, and cannabinoid receptors and endocannabinoid levels are elevated by stroke, with potential neuroprotective effects. We therefore explored the role of endocannabinoids in modulating blood-brain barrier (BBB) permeability in normal conditions and in an ischaemia/reperfusion model. Human brain microvascular endothelial cell and astrocyte co-cultures modelled the BBB. Ischaemia was modelled by oxygen-glucose deprivation (OGD) and permeability was measured by transepithelial electrical resistance. Endocannabinoids or endocannabinoid-like compounds were assessed for their ability to modulate baseline permeability or OGD-induced hyperpermeability. Target sites of action were investigated using receptor antagonists and subsequently identified with real-time PCR. Anandamide (10 μM) and oleoylethanolamide (OEA, 10 μM) decreased BBB permeability (i.e. increased resistance). This was mediated by cannabinoid CB2 receptors, transient receptor potential vanilloid 1 (TRPV1) channels, calcitonin gene-regulated peptide (CGRP) receptor (anandamide only) and PPARα (OEA only). Application of OEA, palmitoylethanolamide (both PPARα mediated) or virodhamine (all 10 μM) decreased the OGD-induced increase in permeability during reperfusion. 2-Arachidonoyl glycerol, noladin ether and oleamide did not affect BBB permeability in normal or OGD conditions. N-arachidonoyl-dopamine increased permeability through a cytotoxic mechanism. PPARα and γ, CB1 receptors, TRPV1 channels and CGRP receptors were expressed in both cell types, but mRNA for CB2 receptors was only present in astrocytes. The endocannabinoids may play an important modulatory role in normal BBB physiology, and also afford protection to the BBB during ischaemic stroke, through a number of target sites. © 2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

  14. Monitoring of Zero-Valent Iron Permeable Reactive Barriers: Electrical Properties and Barrier Aging

    NASA Astrophysics Data System (ADS)

    Labrecque, D. J.; Adkins, P. L.; Slater, L. D.; Versteeg, R.; Sharpe, R.

    2007-12-01

    An innovative method of groundwater remediation invented in the 1990"s, Permeable Reactive Barriers, use sand-sized grains of scrap iron placed in trenches or injected under pressure to remediate a number of organic and inorganic contaminants. Monitoring the aging of these barriers becomes increasingly important as many of these barriers approach their predicted life spans. In-situ resistivity and induced polarization studies have been conducted at six barriers at four different sites: Monticello, Utah; the Denver Federal Center; Kansas City, Missouri; and East Helena, Montana. As some barriers tend to age dramatically faster than others, for this study we consider low permeability barriers as of greater age, as "old" barriers tend to loose permeability rather than exhaust reactive materials. One complicating factor is that two of the barriers studied appear to have issues related to installation. One site, the former Asarco Smelter Site near East Helena, Montana, has been instrumented with an autonomous monitoring system allowing continuous monitoring of the evolution of a relatively new (less than three years old) barrier. The barrier showed surprisingly rapid evolution over the first year of monitoring with changes in both resistivity and chargeability of tens of percent per month. In general, the electrical properties of all of the barriers studied follow a pattern. New barriers are fairly resistive with in-situ conductivity only a few times background (outside the barrier) values. Older barriers get increasingly conductive, with failed barriers showing values of over 100 S/m. The induced polarization response is more complicated. Chargeability values increase over time for young barriers, are largest for healthy barriers in the middle of their lifespan, and decrease as the barrier ages.

  15. Simulation of solute transport across low-permeability barrier walls

    USGS Publications Warehouse

    Harte, P.T.; Konikow, L.F.; Hornberger, G.Z.

    2006-01-01

    Low-permeability, non-reactive barrier walls are often used to contain contaminants in an aquifer. Rates of solute transport through such barriers are typically many orders of magnitude slower than rates through the aquifer. Nevertheless, the success of remedial actions may be sensitive to these low rates of transport. Two numerical simulation methods for representing low-permeability barriers in a finite-difference groundwater-flow and transport model were tested. In the first method, the hydraulic properties of the barrier were represented directly on grid cells and in the second method, the intercell hydraulic-conductance values were adjusted to approximate the reduction in horizontal flow, allowing use of a coarser and computationally efficient grid. The alternative methods were tested and evaluated on the basis of hypothetical test problems and a field case involving tetrachloroethylene (PCE) contamination at a Superfund site in New Hampshire. For all cases, advective transport across the barrier was negligible, but preexisting numerical approaches to calculate dispersion yielded dispersive fluxes that were greater than expected. A transport model (MODFLOW-GWT) was modified to (1) allow different dispersive and diffusive properties to be assigned to the barrier than the adjacent aquifer and (2) more accurately calculate dispersion from concentration gradients and solute fluxes near barriers. The new approach yields reasonable and accurate concentrations for the test cases. ?? 2006.

  16. Simulation of solute transport across low-permeability barrier walls

    NASA Astrophysics Data System (ADS)

    Harte, Philip T.; Konikow, Leonard F.; Hornberger, George Z.

    2006-05-01

    Low-permeability, non-reactive barrier walls are often used to contain contaminants in an aquifer. Rates of solute transport through such barriers are typically many orders of magnitude slower than rates through the aquifer. Nevertheless, the success of remedial actions may be sensitive to these low rates of transport. Two numerical simulation methods for representing low-permeability barriers in a finite-difference groundwater-flow and transport model were tested. In the first method, the hydraulic properties of the barrier were represented directly on grid cells and in the second method, the intercell hydraulic-conductance values were adjusted to approximate the reduction in horizontal flow, allowing use of a coarser and computationally efficient grid. The alternative methods were tested and evaluated on the basis of hypothetical test problems and a field case involving tetrachloroethylene (PCE) contamination at a Superfund site in New Hampshire. For all cases, advective transport across the barrier was negligible, but preexisting numerical approaches to calculate dispersion yielded dispersive fluxes that were greater than expected. A transport model (MODFLOW-GWT) was modified to (1) allow different dispersive and diffusive properties to be assigned to the barrier than the adjacent aquifer and (2) more accurately calculate dispersion from concentration gradients and solute fluxes near barriers. The new approach yields reasonable and accurate concentrations for the test cases.

  17. The selective permeability barrier in the nuclear pore complex

    PubMed Central

    Li, Christina; Goryaynov, Alexander; Yang, Weidong

    2016-01-01

    ABSTRACT The nuclear pore complex (NPC) mediates the shuttle transport of macromolecules between the nucleus and cytoplasm in eukaryotic cells. The permeability barrier formed by intrinsically disordered phenylalanine-glycine-rich nucleoporins (FG-Nups) in the NPC functions as the critical selective control for nucleocytoplasmic transport. Signal-independent small molecules (< 40 kDa) passively diffuse through the pore, but passage of large cargo molecules is inhibited unless they are chaperoned by nuclear transport receptors (NTRs). NTRs are capable of interacting with FG-Nups and guide the cargos to cross the barrier by facilitated diffusion. The native conformation of the FG-Nups permeability barrier and the competition among multiple NTRs interacting with this barrier in the native NPCs are the 2 core questions still being highly debated in the field. Recently, we applied high-speed super-resolution fluorescence microscopy to map out the natural structure of the FG-Nups barrier and determined the competition among multiple NTRs as they interact with the barrier in the native NPCs. In this extra-view article, we will review the current understanding in the configuration and function of FG-Nups barrier and highlight the new evidence obtained recently to answer the core questions in nucleocytoplasmic transport. PMID:27673359

  18. Lactic Acid Bacteria Protects Caenorhabditis elegans from Toxicity of Graphene Oxide by Maintaining Normal Intestinal Permeability under different Genetic Backgrounds

    NASA Astrophysics Data System (ADS)

    Zhao, Yunli; Yu, Xiaoming; Jia, Ruhan; Yang, Ruilong; Rui, Qi; Wang, Dayong

    2015-11-01

    Lactic acid bacteria (LAB) is safe and useful for food and feed fermentation. We employed Caenorhabditis elegans to investigate the possible beneficial effect of LAB (Lactobacillus bulgaricus) pretreatment against toxicity of graphene oxide (GO) and the underlying mechanisms. LAB prevented GO toxicity on the functions of both primary and secondary targeted organs in wild-type nematodes. LAB blocked translocation of GO into secondary targeted organs through intestinal barrier by maintaining normal intestinal permeability in wild-type nematodes. Moreover, LAB prevented GO damage on the functions of both primary and secondary targeted organs in exposed nematodes with mutations of susceptible genes (sod-2, sod-3, gas-1, and aak-2) to GO toxicity by sustaining normal intestinal permeability. LAB also sustained the normal defecation behavior in both wild-type nematodes and nematodes with mutations of susceptible genes. Therefore, the beneficial role of LAB against GO toxicity under different genetic backgrounds may be due to the combinational effects on intestinal permeability and defecation behavior. Moreover, the beneficial effects of LAB against GO toxicity was dependent on the function of ACS-22, homologous to mammalian FATP4 to mammalian FATP4. Our study provides highlight on establishment of pharmacological strategy to protect intestinal barrier from toxicity of GO.

  19. Lactic Acid Bacteria Protects Caenorhabditis elegans from Toxicity of Graphene Oxide by Maintaining Normal Intestinal Permeability under different Genetic Backgrounds

    PubMed Central

    Zhao, Yunli; Yu, Xiaoming; Jia, Ruhan; Yang, Ruilong; Rui, Qi; Wang, Dayong

    2015-01-01

    Lactic acid bacteria (LAB) is safe and useful for food and feed fermentation. We employed Caenorhabditis elegans to investigate the possible beneficial effect of LAB (Lactobacillus bulgaricus) pretreatment against toxicity of graphene oxide (GO) and the underlying mechanisms. LAB prevented GO toxicity on the functions of both primary and secondary targeted organs in wild-type nematodes. LAB blocked translocation of GO into secondary targeted organs through intestinal barrier by maintaining normal intestinal permeability in wild-type nematodes. Moreover, LAB prevented GO damage on the functions of both primary and secondary targeted organs in exposed nematodes with mutations of susceptible genes (sod-2, sod-3, gas-1, and aak-2) to GO toxicity by sustaining normal intestinal permeability. LAB also sustained the normal defecation behavior in both wild-type nematodes and nematodes with mutations of susceptible genes. Therefore, the beneficial role of LAB against GO toxicity under different genetic backgrounds may be due to the combinational effects on intestinal permeability and defecation behavior. Moreover, the beneficial effects of LAB against GO toxicity was dependent on the function of ACS-22, homologous to mammalian FATP4 to mammalian FATP4. Our study provides highlight on establishment of pharmacological strategy to protect intestinal barrier from toxicity of GO. PMID:26611622

  20. Lactic Acid Bacteria Protects Caenorhabditis elegans from Toxicity of Graphene Oxide by Maintaining Normal Intestinal Permeability under different Genetic Backgrounds.

    PubMed

    Zhao, Yunli; Yu, Xiaoming; Jia, Ruhan; Yang, Ruilong; Rui, Qi; Wang, Dayong

    2015-11-27

    Lactic acid bacteria (LAB) is safe and useful for food and feed fermentation. We employed Caenorhabditis elegans to investigate the possible beneficial effect of LAB (Lactobacillus bulgaricus) pretreatment against toxicity of graphene oxide (GO) and the underlying mechanisms. LAB prevented GO toxicity on the functions of both primary and secondary targeted organs in wild-type nematodes. LAB blocked translocation of GO into secondary targeted organs through intestinal barrier by maintaining normal intestinal permeability in wild-type nematodes. Moreover, LAB prevented GO damage on the functions of both primary and secondary targeted organs in exposed nematodes with mutations of susceptible genes (sod-2, sod-3, gas-1, and aak-2) to GO toxicity by sustaining normal intestinal permeability. LAB also sustained the normal defecation behavior in both wild-type nematodes and nematodes with mutations of susceptible genes. Therefore, the beneficial role of LAB against GO toxicity under different genetic backgrounds may be due to the combinational effects on intestinal permeability and defecation behavior. Moreover, the beneficial effects of LAB against GO toxicity was dependent on the function of ACS-22, homologous to mammalian FATP4 to mammalian FATP4. Our study provides highlight on establishment of pharmacological strategy to protect intestinal barrier from toxicity of GO.

  1. Blood-brain barrier permeability imaging using perfusion computed tomography

    PubMed Central

    Avsenik, Jernej; Bisdas, Sotirios; Popovic, Katarina Surlan

    2015-01-01

    Background. The blood-brain barrier represents the selective diffusion barrier at the level of the cerebral microvascular endothelium. Other functions of blood-brain barrier include transport, signaling and osmoregulation. Endothelial cells interact with surrounding astrocytes, pericytes and neurons. These interactions are crucial to the development, structural integrity and function of the cerebral microvascular endothelium. Dysfunctional blood-brain barrier has been associated with pathologies such as acute stroke, tumors, inflammatory and neurodegenerative diseases. Conclusions. Blood-brain barrier permeability can be evaluated in vivo by perfusion computed tomography - an efficient diagnostic method that involves the sequential acquisition of tomographic images during the intravenous administration of iodinated contrast material. The major clinical applications of perfusion computed tomography are in acute stroke and in brain tumor imaging. PMID:26029020

  2. Studies with inulin-type fructans on intestinal infections, permeability, and inflammation.

    PubMed

    Guarner, Francisco

    2007-11-01

    Symbiosis between host and gut bacteria can be optimized by prebiotics. Inulin-type fructans have been shown to improve the microbial balance of the intestinal ecosystem by stimulating the growth of bifidobacteria and lactobacilli. These changes have been associated with several health benefits, including the prevention of gastrointestinal and systemic infections in animal models and human studies. Inulin-type fructans induce changes of the intestinal mucosa characterized by higher villi, deeper crypts, increased number of goblet cells, and a thicker mucus layer on the colonic epithelium. Bacterial antagonism and competition of bifidobacteria and lactobacilli with pathogens, as well as the trophic effects on the intestinal epithelium, may explain the protective role of inulin against enteric infections. In contrast, studies with rats fed a low-calcium diet suggested a negative effect of prebiotics on intestinal barrier function. However, the adverse effect was clearly ascribed to the strong reduction of dietary calcium, as it could be reversed by oral administration of calcium. The adverse effect of a low-calcium diet on intestinal permeability has not been observed in humans. Inulin and oligofructose are now being tested in human studies aimed at prevention of bacterial translocation in critical health conditions. Mixtures of probiotics and prebiotics including inulin or oligofructose significantly reduced the rate of postoperative infections in liver transplant patients. Finally, inulin and oligofructose have proven useful to prevent mucosal inflammatory disorders in animal models and in patients with inflammatory bowel disease.

  3. Actin-interacting protein 1 controls assembly and permeability of intestinal epithelial apical junctions

    PubMed Central

    Baranwal, Somesh

    2015-01-01

    Adherens junctions (AJs) and tight junctions (TJs) are crucial regulators of the integrity and restitution of the intestinal epithelial barrier. The structure and function of epithelial junctions depend on their association with the cortical actin cytoskeleton that, in polarized epithelial cells, is represented by a prominent perijunctional actomyosin belt. The assembly and stability of the perijunctional cytoskeleton is controlled by constant turnover (disassembly and reassembly) of actin filaments. Actin-interacting protein (Aip) 1 is an emerging regulator of the actin cytoskeleton, playing a critical role in filament disassembly. In this study, we examined the roles of Aip1 in regulating the structure and remodeling of AJs and TJs in human intestinal epithelium. Aip1 was enriched at apical junctions in polarized human intestinal epithelial cells and normal mouse colonic mucosa. Knockdown of Aip1 by RNA interference increased the paracellular permeability of epithelial cell monolayers, decreased recruitment of AJ/TJ proteins to steady-state intercellular contacts, and attenuated junctional reassembly in a calcium-switch model. The observed defects of AJ/TJ structure and functions were accompanied by abnormal organization and dynamics of the perijunctional F-actin cytoskeleton. Moreover, loss of Aip1 impaired the apico-basal polarity of intestinal epithelial cell monolayers and inhibited formation of polarized epithelial cysts in 3-D Matrigel. Our findings demonstrate a previously unanticipated role of Aip1 in regulating the structure and remodeling of intestinal epithelial junctions and early steps of epithelial morphogenesis. PMID:25792565

  4. Chlorogenic Acid Decreases Intestinal Permeability and Increases Expression of Intestinal Tight Junction Proteins in Weaned Rats Challenged with LPS

    PubMed Central

    Ruan, Zheng; Liu, Shiqiang; Zhou, Yan; Mi, Shumei; Liu, Gang; Wu, Xin; Yao, Kang; Assaad, Houssein; Deng, Zeyuan; Hou, Yongqing; Wu, Guoyao; Yin, Yulong

    2014-01-01

    Chlorogenic acid, a natural phenolic acid present in fruits and plants, provides beneficial effects for human health. The objectives of this study were to investigate whether chlorogenic acid (CHA) could improve the intestinal barrier integrity for weaned rats with lipopolysaccharide (LPS) challenge. Thirty-two weaned male Sprague Dawley rats (21±1 d of age; 62.26±2.73 g) were selected and randomly allotted to four treatments, including weaned rat control, LPS-challenged and chlorogenic acid (CHA) supplemented group (orally 20 mg/kg and 50 mg/kg body). Dietary supplementation with CHA decreased (P<0.05) the concentrations of urea and albumin in the serum, compared to the LPS-challenged group. The levels of IFN-γ and TNF-α were lower (P<0.05) in the jejunal and colon of weaned rats receiving CHA supplementation, in comparison with the control group. CHA supplementation increased (P<0.05) villus height and the ratio of villus height to crypt depth in the jejunal and ileal mucosae under condictions of LPS challenge. CHA supplementation decreased (P<0.05) intestinal permeability, which was indicated by the ratio of lactulose to mannitol and serum DAO activity, when compared to weaned rats with LPS challenge. Immunohistochemical analysis of tight junction proteins revealed that ZO-1 and occludin protein abundances in the jejunum and colon were increased (P<0.05) by CHA supplementation. Additionally, results of immunoblot analysis revealed that the amount of occludin in the colon was also increased (P<0.05) in CHA-supplemented rats. In conclusion, CHA decreases intestinal permeability and increases intestinal expression of tight junction proteins in weaned rats challenged with LPS. PMID:24887396

  5. Chlorogenic acid decreases intestinal permeability and increases expression of intestinal tight junction proteins in weaned rats challenged with LPS.

    PubMed

    Ruan, Zheng; Liu, Shiqiang; Zhou, Yan; Mi, Shumei; Liu, Gang; Wu, Xin; Yao, Kang; Assaad, Houssein; Deng, Zeyuan; Hou, Yongqing; Wu, Guoyao; Yin, Yulong

    2014-01-01

    Chlorogenic acid, a natural phenolic acid present in fruits and plants, provides beneficial effects for human health. The objectives of this study were to investigate whether chlorogenic acid (CHA) could improve the intestinal barrier integrity for weaned rats with lipopolysaccharide (LPS) challenge. Thirty-two weaned male Sprague Dawley rats (21 ± 1 d of age; 62.26 ± 2.73 g) were selected and randomly allotted to four treatments, including weaned rat control, LPS-challenged and chlorogenic acid (CHA) supplemented group (orally 20 mg/kg and 50 mg/kg body). Dietary supplementation with CHA decreased (P<0.05) the concentrations of urea and albumin in the serum, compared to the LPS-challenged group. The levels of IFN-γ and TNF-α were lower (P<0.05) in the jejunal and colon of weaned rats receiving CHA supplementation, in comparison with the control group. CHA supplementation increased (P<0.05) villus height and the ratio of villus height to crypt depth in the jejunal and ileal mucosae under condictions of LPS challenge. CHA supplementation decreased (P<0.05) intestinal permeability, which was indicated by the ratio of lactulose to mannitol and serum DAO activity, when compared to weaned rats with LPS challenge. Immunohistochemical analysis of tight junction proteins revealed that ZO-1 and occludin protein abundances in the jejunum and colon were increased (P<0.05) by CHA supplementation. Additionally, results of immunoblot analysis revealed that the amount of occludin in the colon was also increased (P<0.05) in CHA-supplemented rats. In conclusion, CHA decreases intestinal permeability and increases intestinal expression of tight junction proteins in weaned rats challenged with LPS.

  6. Protection of the membrane permeability barrier by annexins.

    PubMed

    Creutz, Carl E; Hira, Jaspreet K; Gee, Virginia E; Eaton, James M

    2012-12-18

    Biological membranes are exposed to a number of chemical and physical stresses that may alter the structure of the lipid bilayer in such a way that the permeability barrier to hydrophilic molecules and ions is degraded. These stresses include amphiphilic molecules involved in metabolism and signaling, highly charged polyamines, membrane-permeating peptides, and mechanical and osmotic stresses. As annexins are known to bind to lipid headgroups in the presence of calcium and increase the order of the bilayer lipids, this study addressed whether this activity of annexins provides a potential benefit to the membrane by protecting the bilayer against disruptions of this nature or can promote restoration of the permeability barrier after damage by such agents. The release of carboxyfluorescein from large unilamellar vesicles composed of lipids characteristically present in the inner leaflet of cell membranes (phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, and cholesterol) was used to measure membrane permeability. It was determined that in the presence of calcium, annexin A5 reduced the level of baseline leakage from vesicles and reduced or reversed damage due to arachidonic acid, lysophosphatidic acid, lysophosphatidylcholine, diacylglycerol, monoacylglycerol, spermidine, amyloid-β, amylin, and osmotic shock. Annexin A6 was also able to provide membrane protection in many but not all of these cases. In a cell, it is likely annexins would move to sites of breakdown of the permeability barrier because of the calcium-dependent promotion of the binding of annexins to membranes at sites of calcium entry. Because of the fundamental importance to life of maintaining the permeability barrier of the cell membrane, it is proposed here that this property of annexins may represent a critical, primordial activity that explains their great evolutionary conservation and abundant expression in most cells.

  7. Melt Focusing Along Permeability Barriers in Various Tectonic Settings

    NASA Astrophysics Data System (ADS)

    Montesi, L. G.; Hebert, L. B.

    2012-12-01

    The lithosphere, cold and rigid, acts as a barrier to the migration of melt from sources in the convecting mantle to the surface. In mid-ocean ridge settings in particular, the contrast between the width of the melt production zone at depths, reaching tens to hundreds of kilometer from the ridge axis, and the zone of crustal accretion, only one or two kilometers wide, points to the presence of an efficient focusing mechanism. The development of a zone impermeable to melt, or permeability barrier, at the base of the thermal boundary layer, and transport of melt in a high porosity channel at the base of this barrier provides a reasonable explanation for this focusing. Applied to various segmented and non-segmented mid-ocean ridges like the ultraslow Southwest Indian Ridge and the ultrafast East Pacific Rise at the Siqueiros transform, this process predicts along-strike variations in crustal thickness that compare favorably with observations. Although the concept of permeability barriers has been discussed mainly in the context of mid-ocean ridges, it may apply to other locations where melting in the upper mantle occurs. Permeability barriers form when ascending melt cools and crystallizes as it enters the thermal boundary layer at the base of the lithosphere. Such a setup is present at subduction zones as melts ascending from the mantle wedge interact with the overriding plate. Convection in the wedge introduces thermal gradients that may focus melt roughly to a point above the transition from a coupled to decoupled slab interface. This location is close to where volcanic arcs are observed. Above mantle plumes, a permeability barrier may develop coincident with the lithosphere-asthenosphere boundary, allowing low-degree melts to stall and form a low-velocity layer that has been observed seismically. To date, the hypothesis of a permeability barrier has been thoroughly tested only in the context of mid-ocean ridges. Whether crystallization would be rapid enough in

  8. Striatal blood-brain barrier permeability in Parkinson's disease.

    PubMed

    Gray, Madison T; Woulfe, John M

    2015-05-01

    In vivo studies have shown that blood-brain barrier (BBB) dysfunction is involved in the course of Parkinson's disease (PD). However, these have lacked either anatomic definition or the ability to recognize minute changes in BBB integrity. Here, using histologic markers of serum protein, iron, and erythrocyte extravasation, we have shown significantly increased permeability of the BBB in the postcommissural putamen of PD patients. The dense innervation of the striatum by PD-affected regions allows for exploitation of this permeability for therapeutic goals. These results are also discussed in the context of the retrograde trans-synaptic hypothesis of PD spread.

  9. Impaired Intestinal Permeability Contributes to Ongoing Bowel Symptoms in Patients With Inflammatory Bowel Disease and Mucosal Healing.

    PubMed

    Chang, Jeff; Leong, Rupert W; Wasinger, Valerie C; Ip, Matthew; Yang, Michael; Phan, Tri Giang

    2017-09-01

    Many patients with inflammatory bowel diseases (IBD) have ongoing bowel symptoms of diarrhea or abdominal pain despite mucosal healing. We investigated whether impaired intestinal permeability contributes to these symptoms. We performed a prospective study of intestinal permeability, measured by endoscopic confocal laser endomicroscopy in 110 consecutive subjects (31 with ulcerative colitis [UC], 57 with Crohn's disease [CD], and 22 healthy individuals [controls]) in Sydney, Australia from May 2009 and September 2015. Symptomatic CD was defined by a CD Activity Index score of 150 or more and symptomatic UC by a partial Mayo score of 2 or more. Mucosal healing was defined as CD Endoscopic Index of Severity of 0 in CD or Mayo endoscopic sub-score of 0-1 for patients with UC. Intestinal permeability was quantified by the Confocal Leak Score (CLS; range: 0=no impaired permeability to 100=complete loss of barrier function). The primary endpoint was intestinal permeability in patients with symptomatic IBD in mucosal healing vs patients with asymptomatic IBD in mucosal healing. We determined the sensitivity and specificity of CLS in determining symptoms based on receiver operating characteristic analysis. Ongoing bowel symptoms were present in 16.3% of patients with IBD and mucosal healing (15.4% of patients with CD, 17.4% with UC). Patients with symptomatic IBD had a significantly higher median CLS (19.0) than patients with asymptomatic IBD (7.3; P < .001) or controls (5.9, P < .001). There were no significant differences between patients with IBD in remission vs controls (P = .261). Median CLS was significantly higher in patients with symptomatic than asymptomatic CD (17.7 vs 8.1; P = .009) and patients with symptomatic than asymptomatic UC (22.2 vs 6.9; P = .021). A CLS of 13.1 or more identified ongoing bowel symptoms in patients with IBD and mucosal healing with 95.2% sensitivity and 97.6% specificity; the receiver operating characteristic area under curve value

  10. Intestinal fatty acid-binding protein and gut permeability responses to exercise.

    PubMed

    March, Daniel S; Marchbank, Tania; Playford, Raymond J; Jones, Arwel W; Thatcher, Rhys; Davison, Glen

    2017-05-01

    Intestinal cell damage due to physiological stressors (e.g. heat, oxidative, hypoperfusion/ischaemic) may contribute to increased intestinal permeability. The aim of this study was to assess changes in plasma intestinal fatty acid-binding protein (I-FABP) in response to exercise (with bovine colostrum supplementation, Col, positive control) and compare this to intestinal barrier integrity/permeability (5 h urinary lactulose/rhamnose ratio, L/R). In a double-blind, placebo-controlled, crossover design, 18 males completed two experimental arms (14 days of 20 g/day supplementation with Col or placebo, Plac). For each arm participants performed two baseline (resting) intestinal permeability assessments (L/R) pre-supplementation and one post-exercise following supplementation. Blood samples were collected pre- and post-exercise to determine I-FABP concentration. Two-way repeated measures ANOVA revealed an arm × time interaction for L/R and I-FABP (P < 0.001). Post hoc analyses showed urinary L/R increased post-exercise in Plac (273% of pre, P < 0.001) and Col (148% of pre, P < 0.001) with post-exercise values significantly lower with Col (P < 0.001). Plasma I-FABP increased post-exercise in Plac (191% of pre-exercise, P = 0.002) but not in the Col arm (107%, P = 0.862) with post-exercise values significantly lower with Col (P = 0.013). Correlations between the increase in I-FABP and L/R were evident for visit one (P = 0.044) but not visit two (P = 0.200) although overall plots/patterns do appear similar for each. These findings suggest that exercise-induced intestinal cellular damage/injury is partly implicated in changes in permeability but other factors must also contribute.

  11. Sodium alginate decreases the permeability of intestinal mucus.

    PubMed

    Mackie, Alan R; Macierzanka, Adam; Aarak, Kristi; Rigby, Neil M; Parker, Roger; Channell, Guy A; Harding, Stephen E; Bajka, Balazs H

    2016-01-01

    In the small intestine the nature of the environment leads to a highly heterogeneous mucus layer primarily composed of the MUC2 mucin. We set out to investigate whether the soluble dietary fibre sodium alginate could alter the permeability of the mucus layer. The alginate was shown to freely diffuse into the mucus and to have minimal effect on the bulk rheology when added at concentrations below 0.1%. Despite this lack of interaction between the mucin and alginate, the addition of alginate had a marked effect on the diffusion of 500 nm probe particles, which decreased as a function of increasing alginate concentration. Finally, we passed a protein stabilised emulsion through a simulation of oral, gastric and small intestinal digestion. We subsequently showed that the addition of 0.1% alginate to porcine intestinal mucus decreased the diffusion of fluorescently labelled lipid present in the emulsion digesta. This reduction may be sufficient to reduce problems associated with high rates of lipid absorption such as hyperlipidaemia.

  12. Sodium alginate decreases the permeability of intestinal mucus

    PubMed Central

    Mackie, Alan R.; Macierzanka, Adam; Aarak, Kristi; Rigby, Neil M.; Parker, Roger; Channell, Guy A.; Harding, Stephen E.; Bajka, Balazs H.

    2016-01-01

    In the small intestine the nature of the environment leads to a highly heterogeneous mucus layer primarily composed of the MUC2 mucin. We set out to investigate whether the soluble dietary fibre sodium alginate could alter the permeability of the mucus layer. The alginate was shown to freely diffuse into the mucus and to have minimal effect on the bulk rheology when added at concentrations below 0.1%. Despite this lack of interaction between the mucin and alginate, the addition of alginate had a marked effect on the diffusion of 500 nm probe particles, which decreased as a function of increasing alginate concentration. Finally, we passed a protein stabilised emulsion through a simulation of oral, gastric and small intestinal digestion. We subsequently showed that the addition of 0.1% alginate to porcine intestinal mucus decreased the diffusion of fluorescently labelled lipid present in the emulsion digesta. This reduction may be sufficient to reduce problems associated with high rates of lipid absorption such as hyperlipidaemia. PMID:26726279

  13. Epidermal Permeability Barrier Defects and Barrier Repair Therapy in Atopic Dermatitis

    PubMed Central

    Lee, Hae-Jin

    2014-01-01

    Atopic dermatitis (AD) is a multifactorial inflammatory skin disease perpetuated by gene-environmental interactions and which is characterized by genetic barrier defects and allergic inflammation. Recent studies demonstrate an important role for the epidermal permeability barrier in AD that is closely related to chronic immune activation in the skin during systemic allergic reactions. Moreover, acquired stressors (e.g., Staphylococcus aureus infection) to the skin barrier may also initiate inflammation in AD. Many studies involving patients with AD revealed that defective skin barriers combined with abnormal immune responses might contribute to the pathophysiology of AD, supporting the outside-inside hypothesis. In this review, we discuss the recent advances in human and animal models, focusing on the defects of the epidermal permeability barrier, its immunologic role and barrier repair therapy in AD. PMID:24991450

  14. Eicosapentaenoic Acid Enhances Heat Stress-Impaired Intestinal Epithelial Barrier Function in Caco-2 Cells

    PubMed Central

    Xiao, Guizhen; Tang, Liqun; Yuan, Fangfang; Zhu, Wei; Zhang, Shaoheng; Liu, Zhifeng; Geng, Yan; Qiu, Xiaowen

    2013-01-01

    Objective Dysfunction of the intestinal epithelial tight junction (TJ) barrier is known to have an important etiologic role in the pathophysiology of heat stroke. N-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), play a role in maintaining and protecting the TJ structure and function. This study is aimed at investigating whether n-3 PUFAs could alleviate heat stress-induced dysfunction of intestinal tight junction. Methods Human intestinal epithelial Caco-2 cells were pre-incubated with EPA, DHA or arachidonic acid (AA) and then exposed to heat stress. Transepithelial electrical resistance (TEER) and Horseradish Peroxidase (HRP) permeability were measured to analyze barrier integrity. Levels of TJ proteins, including occludin, ZO-1 and claudin-2, were analyzed by Western blot and localized by immunofluorescence microscopy. Messenger RNA levels were determined by quantitative real time polymerase chain reaction (Q-PCR). TJ morphology was observed by transmission electron microscopy. Results EPA effectively attenuated the decrease in TEER and impairment of intestinal permeability in HRP flux induced by heat exposure. EPA significantly elevated the expression of occludin and ZO-1, while DHA was less effective and AA was not at all effective. The distortion and redistribution of TJ proteins, and disruption of morphology were also effectively prevented by pretreatment with EPA. Conclusion This study indicates for the first time that EPA is more potent than DHA in protecting against heat-induced permeability dysfunction and epithelial barrier damage of tight junction. PMID:24066055

  15. A novel dual-flow bioreactor simulates increased fluorescein permeability in epithelial tissue barriers.

    PubMed

    Giusti, Serena; Sbrana, Tommaso; La Marca, Margherita; Di Patria, Valentina; Martinucci, Valentina; Tirella, Annalisa; Domenici, Claudio; Ahluwalia, Arti

    2014-09-01

    Permeability studies across epithelial barriers are of primary importance in drug delivery as well as in toxicology. However, traditional in vitro models do not adequately mimic the dynamic environment of physiological barriers. Here, we describe a novel two-chamber modular bioreactor for dynamic in vitro studies of epithelial cells. The fluid dynamic environment of the bioreactor was characterized using computational fluid dynamic models and measurements of pressure gradients for different combinations of flow rates in the apical and basal chambers. Cell culture experiments were then performed with fully differentiated Caco-2 cells as a model of the intestinal epithelium, comparing the effect of media flow applied in the bioreactor with traditional static transwells. The flow increases barrier integrity and tight junction expression of Caco-2 cells with respect to the static controls. Fluorescein permeability increased threefold in the dynamic system, indicating that the stimulus induced by flow increases transport across the barrier, closely mimicking the in vivo situation. The results are of interest for studying the influence of mechanical stimuli on cells, and underline the importance of developing more physiologically relevant in vitro tissue models. The bioreactor can be used to study drug delivery, chemical, or nanomaterial toxicity and to engineer barrier tissues.

  16. Epidermal Permeability Barrier (EPB) measurement in mammalian skin

    PubMed Central

    Indra, Arup Kumar; Leid, Mark

    2012-01-01

    A defective skin epidermal permeability barrier (EPB) is responsible for a high mortality rate in premature infants, and is an important risk factor in inflammatory skin diseases such as eczema. We report here fast and accurate methods for measurement of EPB in animal models or in human patients using simple techniques that monitor diffusion of dyes (X-Gal or Lucifer Yellow) through the upper epidermis and measure transepidermal water loss (TEWL) resulting from a defective skin barrier. Accurate diagnosis and early detection of EPB defects in human patients are critical for effective treatment of certain classes of inflammatory skin diseases. PMID:21874444

  17. Selective permeability barrier to urea in shark rectal gland.

    PubMed

    Zeidel, Joshua D; Mathai, John C; Campbell, John D; Ruiz, Wily G; Apodaca, Gerard L; Riordan, John; Zeidel, Mark L

    2005-07-01

    Elasmobranchs such as the dogfish shark Squalus acanthius achieve osmotic homeostasis by maintaining urea concentrations in the 300- to 400-mM range, thus offsetting to some degree ambient marine osmolalities of 900-1,000 mosmol/kgH(2)O. These creatures also maintain salt balance without losing urea by secreting a NaCl-rich (500 mM) and urea-poor (18 mM) fluid from the rectal gland that is isotonic with the plasma. The composition of the rectal gland fluid suggests that its epithelial cells are permeable to water and not to urea. Because previous work showed that lipid bilayers that permit water flux do not block flux of urea, we reasoned that the plasma membranes of rectal gland epithelial cells must either have aquaporin water channels or must have some selective barrier to urea flux. We therefore isolated apical and basolateral membranes from shark rectal glands and determined their permeabilities to water and urea. Apical membrane fractions were markedly enriched for Na-K-2Cl cotransporter, whereas basolateral membrane fractions were enriched for Na-K-ATPase. Basolateral membrane osmotic water permeability (P(f)) averaged 4.3 +/- 1.3 x 10(-3) cm/s, whereas urea permeability averaged 4.2 +/- 0.8 x 10(-7) cm/s. The activation energy for water flow averaged 16.4 kcal/mol. Apical membrane P(f) averaged 7.5 +/- 1.6 x 10(-4) cm/s, and urea permeability averaged 2.2 +/- 0.4 x 10(-7) cm/s, with an average activation energy for water flow of 18.6 kcal/mol. The relatively low water permeabilities and high activation energies argue strongly against water flux via aquaporins. Comparison of membrane water and urea permeabilities with those of artificial liposomes and other isolated biological membranes indicates that the basolateral membrane urea permeability is fivefold lower than would be anticipated for its water permeability. These results indicate that the rectal gland maintains a selective barrier to urea in its basolateral membranes.

  18. A promising camptothecin derivative: Semisynthesis, antitumor activity and intestinal permeability.

    PubMed

    Rodríguez-Berna, Guillermo; Mangas-Sanjuán, Víctor; Gonzalez-Alvarez, Marta; Gonzalez-Alvarez, Isabel; García-Giménez, José Luis; Díaz Cabañas, María José; Bermejo, Marival; Corma, Avelino

    2014-08-18

    Oral administration of camptothecin (CPT) derivatives and other antitumoral agents is being actively developed in order to improve the quality of life of patients with cancer. Though several lipophilic derivatives of CPT have shown interesting oral bioavailability in preclinical and clinical studies, only Topotecan has been approved for this route of administration. Semisynthesis, antitumor activity, biological inhibition mechanism, and in situ intestinal permeability of 9, 10-[1,3]-Dioxinocamptothecin (CDiox), an unexplored CPT derivative, have been studied in this paper. The hexacyclic analog was as effective as Topotecan and CPT in different tumor cell lines, showing an expected similar apoptosis cell mechanism and high ability to inhibit DNA synthesis in HeLa, Caco-2, A375 and MDA-MB-231 cell lines. Furthermore, in vitro and in situ pharmacokinetics transport values obtained for CDiox displayed more favorable absorption profile than CPT and Topotecan.

  19. Changes in intestinal tight junction permeability associated with industrial food additives explain the rising incidence of autoimmune disease.

    PubMed

    Lerner, Aaron; Matthias, Torsten

    2015-06-01

    The incidence of autoimmune diseases is increasing along with the expansion of industrial food processing and food additive consumption. The intestinal epithelial barrier, with its intercellular tight junction, controls the equilibrium between tolerance and immunity to non-self-antigens. As a result, particular attention is being placed on the role of tight junction dysfunction in the pathogenesis of AD. Tight junction leakage is enhanced by many luminal components, commonly used industrial food additives being some of them. Glucose, salt, emulsifiers, organic solvents, gluten, microbial transglutaminase, and nanoparticles are extensively and increasingly used by the food industry, claim the manufacturers, to improve the qualities of food. However, all of the aforementioned additives increase intestinal permeability by breaching the integrity of tight junction paracellular transfer. In fact, tight junction dysfunction is common in multiple autoimmune diseases and the central part played by the tight junction in autoimmune diseases pathogenesis is extensively described. 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. Future research on food additives exposure-intestinal permeability-autoimmunity interplay will enhance our knowledge of the common mechanisms associated with autoimmune progression. Copyright © 2015. Published by Elsevier B.V.

  20. High-fat enteral nutrition reduces intestinal mucosal barrier damage after peritoneal air exposure.

    PubMed

    Tan, Shan-Jun; Yu, Chao; Yu, Zhen; Lin, Zhi-Liang; Wu, Guo-Hao; Yu, Wen-Kui; Li, Jie-Shou; Li, Ning

    2016-05-01

    Peritoneal air exposure is needed in open abdominal surgery, but long-time exposure could induce intestinal mucosal barrier dysfunction followed by many postoperative complications. High-fat enteral nutrition can ameliorate intestinal injury and improve intestinal function in many gastrointestinal diseases. In the present study, we investigated the effect of high-fat enteral nutrition on intestinal mucosal barrier after peritoneal air exposure and the underlying mechanism. Male adult rats were administrated saline, low-fat or high-fat enteral nutrition via gavage before and after peritoneal air exposure for 3 h. Rats undergoing anesthesia without laparotomy received saline as control. Twenty four hours after surgery, samples were collected to assess intestinal mucosal barrier changes in serum D-lactate levels, intestinal permeability, intestinal tight junction protein ZO-1 and occludin levels, and intestinal histopathology. The levels of malondialdehyde and the activity of superoxide dismutase in the ileum tissue were also measured to assess the status of intestinal oxidative stress. High-fat enteral nutrition significantly decreased the serum D-lactate level and increased the intestinal tight junction protein ZO-1 level when compared to the group treated with low-fat enteral nutrition (P < 0.05). Meanwhile, histopathologic findings showed that the intestinal mucosal injury assessed by the Chiu's score and the intestinal epithelial tight junction were also improved much more in the high-fat enteral nutrition-treated group (P < 0.05). In addition, the intestinal malondialdehyde level was lower, and the intestinal superoxide dismutase activity was higher in the high-fat enteral nutrition-treated group than that in the low-fat enteral nutrition-treated group (P < 0.05). These results suggest that high-fat enteral nutrition could reduce intestinal mucosal barrier damage after peritoneal air exposure, and the underlying mechanism may be associated with its antioxidative

  1. Permeability Profiles and Intestinal Toxicity Assessment of Hydrochlorothiazide and Its Inclusion Complex with β-Cyclodextrin Loaded into Chitosan Nanoparticles.

    PubMed

    Onnainty, R; Schenfeld, E M; Petiti, J P; Longhi, M R; Torres, A; Quevedo, M A; Granero, G E

    2016-11-07

    Here, a novel drug delivery system was developed for the hydrochlorothiazide (HCT):β-cyclodextrin (βCD) inclusion complex loaded into chitosan (CS) nanoparticles (NPs) [CS/HCT:βCD NPs]. It was found, for the first time, that exposure of the intestinal mucosa to free HCT resulted in an increased and abnormal intestinal permeability associated with several injuries to the intestinal epithelium. Nevertheless, the HCT delivery system obtained ameliorated the damage of the intestinal epithelium induced by HCT. Furthermore, we found that the corresponding permeability profiles for both the free HCT and the CS/HCT:βCD NPs were exponential and lineal, respectively. We propose that the increased intestinal uptake and severe tissue injury of HCT to the intestinal epithelium could be directly related to possible effects of this drug on the ionoregulatory Na(+/)K(+)-ATPase channel. Thus, it is postulated that the CS/HCT:βCD NPs may increase the gastrointestinal retention of the HCT, which would provide increased adherence to the mucus barrier that lines the intestinal epithelium; consequently, this would act as a slow HCT release delivery system and maintain lower drug levels of luminal gut in comparison with the administration of free HCT, leading to less severe local injury.

  2. Potential benefits of pro- and prebiotics on intestinal mucosal immunity and intestinal barrier in short bowel syndrome.

    PubMed

    Stoidis, Christos N; Misiakos, Evangelos P; Patapis, Paul; Fotiadis, Constantine I; Spyropoulos, Basileios G

    2011-06-01

    The mechanism of impaired gut barrier function in patients with short bowel syndrome (SBS) is poorly understood and includes decreased intestinal motility leading to bacterial overgrowth, a reduction in gut-associated lymphoid tissue following the loss of intestinal length, inhibition of mucosal immunity of the small intestine by intravenous total parental nutrition, and changes in intestinal permeability to macromolecules. Novel therapeutic strategies (i.e. nutritive and surgical) have been introduced in order to prevent the establishment or improve the outcome of this prevalent disease. Pre- and probiotics as a nutritive supplement are already known to be very active in the intestinal tract (mainly in the colon) by maintaining a healthy gut microflora and influencing metabolic, trophic and protective mechanisms, such as the production of SCFA which influence epithelial cell metabolism, turnover and apoptosis. Probiotics have been recommended for patients suffering from SBS in order to decrease bacterial overgrowth and prevent bacterial translocation, two major mechanisms in the pathogenesis of SBS. The present review discusses the research available in the international literature, clinical and experimental, regarding probiotic supplementation for this complicated group of patients based on the clinical spectrum and pathophysiological aspects of the syndrome. The clinical data that were collected for the purposes of the present review suggest that it is difficult to correctly characterise probiotics as a preventive or therapeutic measure. It is very challenging after all to examine the relationship of the bacterial flora, the intestinal barrier and the probiotics as, according to the latest knowledge, demonstrate an interesting interaction.

  3. Control of BTEX migration using a biologically enhanced permeable barrier

    SciTech Connect

    Borden, R.C.; Goin, R.T.; Kao, C.M.

    1997-06-01

    A permeable barrier system, consisting of a line of closely spaced wells, was installed perpendicular to ground water flow to control the migration of a dissolved hydrocarbon plume. The wells were charged with concrete briquets that release oxygen and nitrate at a controlled rate, enhancing aerobic biodegradation in the downgradient aquifer. Laboratory batch reactor experiments were conducted to identify concrete mixtures that slowly released oxygen over an extended time period. A full-scale permeable barrier system using ORC was constructed at a gasoline-spill site. During the first 242 days of operation, total BTEX decreased from 17 to 3.4 mg/L and dissolved oxygen increased from 0.4 to 1.8 mg/L during transport through the barrier. Over time, BTEX treatment efficiencies declined, indicating the barrier system had become less effective in releasing oxygen and nutrients to the highly contaminated portion of the aquifer. Point dilution tests and sediment analyses performed at the conclusion of the project indicated that the aquifer in the vicinity of the remediation wells had been clogged by precipitation with iron minerals.

  4. Interleukin-23 Increases Intestinal Epithelial Cell Permeability In Vitro.

    PubMed

    Heinzerling, Nathan P; Donohoe, Deborah; Fredrich, Katherine; Gourlay, David M; Liedel, Jennifer L

    2016-06-01

    Background Breast milk has a heterogeneous composition that differs between mothers and changes throughout the first weeks after birth. The proinflammatory cytokine IL-23 has a highly variable expression in human breast milk. We hypothesize that IL-23 found in human breast milk is biologically active and promotes epithelial barrier dysfunction. Methods The immature rat small intestinal epithelial cell line, IEC-18, was grown on cell inserts or standard cell culture plates. Confluent cultures were exposed to human breast milk with high or low levels of IL-23 and barrier function was measured using a flux of fluorescein isothiocyanate-dextran (FD-70). In addition, protein and mRNA expression of occludin and ZO-1 were measured and immunofluorescence used to stain occludin and ZO-1. Results Exposure to breast milk with high levels of IL-23 caused an increase flux of FD-70 compared with both controls and breast milk with low levels of IL-23. The protein expression of ZO-1 but not occludin was decreased by exposure to high levels of IL-23. These results correlate with immunofluorescent staining of ZO-1 and occludin which show decreased staining of occludin in both the groups exposed to breast milk with high and low IL-23. Conversely, cells exposed to high IL-23 breast milk had little peripheral staining of ZO-1 compared with controls and low IL-23 breast milk. Conclusion IL-23 in human breast milk is biologically active and negatively affects the barrier function of intestinal epithelial cells through the degradation of tight junction proteins. Georg Thieme Verlag KG Stuttgart · New York.

  5. Intestinal barrier function and absorption in pigs after weaning: a review.

    PubMed

    Wijtten, Peter J A; van der Meulen, Jan; Verstegen, Martin W A

    2011-04-01

    Under commercial conditions, weaning of piglets is associated with social, environmental and dietary stress. Consequently, small-intestinal barrier and absorptive functions deteriorate within a short time after weaning. Most studies that have assessed small-intestinal permeability in pigs after weaning used either Ussing chambers or orally administered marker probes. Paracellular barrier function and active absorption decrease when pigs are weaned at 3 weeks of age or earlier. However, when weaned at 4 weeks of age or later, the barrier function is less affected, and active absorption is not affected or is increased. Weaning stress is a critical factor in relation to the compromised paracellular barrier function after weaning. Adequate feed intake levels after weaning prevent the loss of the intestinal barrier function. Transcellular transport of macromolecules and passive transcellular absorption decrease after weaning. This may reflect a natural intestinal maturation process that is enhanced by the weaning process and prevents the pig from an antigen overload. It seems that passive and active absorption after weaning adapt accurately to the new environment when pigs are weaned after 3 weeks of age. However, when weaned at 3 weeks of age or earlier, the decrease in active absorption indicates that pigs are unable to sufficiently adapt to the new environment. To improve weaning strategies, future studies should distinguish whether the effect of feed intake on barrier function can be directed to a lack of a specific nutrient, i.e. energy or protein.

  6. Effects of glutamine on intestinal permeability and bacterial translocation in TPN-rats with endotoxemia.

    PubMed

    Ding, Lian-An; Li, Jie-Show

    2003-06-01

    To evaluate the protective effect and mechanism of glutamine on the intestinal barrier function in total parenteral nutrition (TPN) rats with trauma or endotoxemia. To perform prospective, randomized and controlled animal experimentation of rats with surgical trauma, TPN and endotoxemia, thirty-four male, adult Sprague Dawley rats were divided into four groups: control group (n=8), TPN group (n=9), trauma and endotoxemia group (LPS, n=8) and trauma plus endotoxemia supplemented with glutamine in TPN solution group (Gln.group, n=9). All groups except the control group were given TPN solutions in 7-day experimental period. For Gln group, 1 000 mg/kg/d of glutamine was added to TPN solution during day 1-6. On the 7(th) day all the animals were gavaged with lactulose (66 mg) and mannitol (50 mg) in 2 ml of normal saline. Then 24 h urine with preservative was collected and kept at -20 degrees. On day 8, under intra-peritoneal anesthesia using 100 mg/kg ketamin, the intestine, liver, mesenteric lymph nodes and blood were taken for examination. The body weight of LPS group decreased most among the four groups. The structure of small intestinal mucosa in TPN group, LPS group and Gln group showed impairments of different degrees, and the damage of small intestinal mucosa in Gln group was remarkably alleviated. The concentrations of interleukins in small intestine mucosa were lower (for IL-4 and IL-6) or the lowest (IL-10) in Gln group. The IgA level in the blood plasma and the mucosa of Gln group was the highest among all of the groups. The urine lactulose/mannitol test showed that the intestinal permeability in LPS group was lower than that in TPN group (P<0.001), but there was no difference between LPS group and Gln group. The rate of bacterial translocation in Gln group was lower than that in LPS group (P<0.02). Prophylactic treatment with glutamine could minimize the increments of intestinal permeability and bacterial translocation caused by trauma and endotoxemia in

  7. Effects of glutamine on intestinal permeability and bacterial translocation in TPN-rats with endotoxemia

    PubMed Central

    Ding, Lian-An; Li, Jie-Show

    2003-01-01

    AIM: To evaluate the protective effect and mechanism of glutamine on the intestinal barrier function in total parenteral nutrition (TPN) rats with trauma or endotoxemia. METHODS: To perform prospective, randomized and controlled animal experimentation of rats with surgical trauma, TPN and endotoxemia, thirty-four male, adult Sprague Dawley rats were divided into four groups: control group (n = 8), TPN group (n = 9), trauma and endotoxemia group (LPS, n = 8) and trauma plus endotoxemia supplemented with glutamine in TPN solution group (Gln.group, n = 9). All groups except the control group were given TPN solutions in 7-day experimental period. For Gln group, 1000 mg/kg/d of glutamine was added to TPN solution during day 1-6. On the 7th day all the animals were gavaged with lactulose (66 mg) and mannitol (50 mg) in 2 mL of normal saline. Then 24 h urine with preservative was collected and kept at -20 °C. On day 8, under intra-peritoneal anesthesia using 100 mg/kg ketamin, the intestine, liver, mesenteric lymph nodes and blood were taken for examination. RESULTS: The body weight of LPS group decreased most among the four groups. The structure of small intestinal mucosa in TPN group, LPS group and Gln group showed impairments of different degrees, and the damage of small intestinal mucosa in Gln group was remarkably alleviated. The concentrations of interleukins in small intestine mucosa were lower (for IL-4 and IL-6) or the lowest (IL-10) in Gln group. The IgA level in the blood plasma and the mucosa of Gln group was the highest among all of the groups. The urine lactulose/mannitol test showed that the intestinal permeability in LPS group was lower than that in TPN group (P < 0.001), but there was no difference between LPS group and Gln group. The rate of bacterial translocation in Gln group was lower than that in LPS group (P < 0.02). CONCLUSION: Prophylactic treatment with glutamine could minimize the increments of intestinal permeability and bacterial

  8. Blood-brain barrier tight junction permeability and ischemic stroke.

    PubMed

    Sandoval, Karin E; Witt, Ken A

    2008-11-01

    The blood-brain barrier (BBB) is formed by the endothelial cells of cerebral microvessels, providing a dynamic interface between the peripheral circulation and the central nervous system. The tight junctions (TJs) between the endothelial cells serve to restrict blood-borne substances from entering the brain. Under ischemic stroke conditions decreased BBB TJ integrity results in increased paracellular permeability, directly contributing to cerebral vasogenic edema, hemorrhagic transformation, and increased mortality. This loss of TJ integrity occurs in a phasic manner, which is contingent on several interdependent mechanisms (ionic dysregulation, inflammation, oxidative and nitrosative stress, enzymatic activity, and angiogenesis). Understanding the inter-relation of these mechanisms is critical for the development of new therapies. This review focuses on those aspects of ischemic stroke impacting BBB TJ integrity and the principle regulatory pathways, respective to the phases of paracellular permeability.

  9. IBD Candidate Genes and Intestinal Barrier Regulation

    PubMed Central

    McCole, Declan F.

    2015-01-01

    Technological advances in the large scale analysis of human genetics have generated profound insights into possible genetic contributions to chronic diseases including the inflammatory bowel diseases (IBDs), Crohn’s disease and ulcerative colitis. To date, 163 distinct genetic risk loci have been associated with either Crohn’s disease or ulcerative colitis, with a substantial degree of genetic overlap between these 2 conditions. Although many risk variants show a reproducible correlation with disease, individual gene associations only affect a subset of patients, and the functional contribution(s) of these risk variants to the onset of IBD is largely undetermined. Although studies in twins have demonstrated that the development of IBD is not mediated solely by genetic risk, it is nevertheless important to elucidate the functional consequences of risk variants for gene function in relevant cell types known to regulate key physiological processes that are compromised in IBD. This article will discuss IBD candidate genes that are known to be, or are suspected of being, involved in regulating the intestinal epithelial barrier and several of the physiological processes presided over by this dynamic and versatile layer of cells. This will include assembly and regulation of tight junctions, cell adhesion and polarity, mucus and glycoprotein regulation, bacterial sensing, membrane transport, epithelial differentiation, and restitution. PMID:25215613

  10. IL-9 regulates intestinal barrier function in experimental T cell-mediated colitis

    PubMed Central

    Gerlach, Katharina; McKenzie, Andrew N; Neurath, Markus F; Weigmann, Benno

    2015-01-01

    As previous studies suggested that IL-9 may control intestinal barrier function, we tested the role of IL-9 in experimental T cell-mediated colitis induced by the hapten reagent 2,4,6-trinitrobenzenesulfonic acid (TNBS). The deficiency of IL-9 suppressed TNBS-induced colitis and led to lower numbers of PU.1 expressing T cells in the lamia propria, suggesting a regulatory role for Th9 cells in the experimental TNBS colitis model. Since IL-9 is known to functionally alter intestinal barrier function in colonic inflammation, we assessed the expression of tight junction molecules in intestinal epithelial cells of TNBS-inflamed mice. Therefore we made real-time PCR analyses for tight junction molecules in the inflamed colon from wild-type and IL-9 KO mice, immunofluorescent stainings and investigated the expression of junctional proteins directly in intestinal epithelial cells of TNBS-inflamed mice by Western blot studies. The results demonstrated that sealing proteins like occludin were up regulated in the colon of inflamed IL-9 KO mice. In contrast, the tight junction protein Claudin1 showed lower expression levels when IL-9 is absent. Surprisingly, the pore-forming molecule Claudin2 revealed equal expression in TNBS-treated wild-type and IL-9-deficient animals. These results illustrate the pleiotropic functions of IL-9 in changing intestinal permeability in experimental colitis. Thus, modulation of IL-9 function emerges as a new approach for regulating barrier function in intestinal inflammation. PMID:25838986

  11. Bifidobacterium animalis ssp. lactis CNCM-I2494 Restores Gut Barrier Permeability in Chronically Low-Grade Inflamed Mice.

    PubMed

    Martín, Rebeca; Laval, Laure; Chain, Florian; Miquel, Sylvie; Natividad, Jane; Cherbuy, Claire; Sokol, Harry; Verdu, Elena F; van Hylckama Vlieg, Johan; Bermudez-Humaran, Luis G; Smokvina, Tamara; Langella, Philippe

    2016-01-01

    Growing evidence supports the efficacy of many probiotic strains in the management of gastrointestinal disorders associated with deregulated intestinal barrier function and/or structure. In particular, bifidobacteria have been studied for their efficacy to both prevent and treat a broad spectrum of animal and/or human gut disorders. The aim of the current work was thus to evaluate effects on intestinal barrier function of Bifidobacterium animalis ssp. lactis CNCM-I2494, a strain used in fermented dairy products. A chronic dinitrobenzene sulfonic acid (DNBS)-induced low-grade inflammation model causing gut dysfunction in mice was used in order to study markers of inflammation, intestinal permeability, and immune function in the presence of the bacterial strain. In this chronic low-grade inflammation mice model several parameters pointed out the absence of an over active inflammation process. However, gut permeability, lymphocyte populations, and colonic cytokines were found to be altered. B. animalis ssp. lactis CNCM-I2494 was able to protect barrier functions by restoring intestinal permeability, colonic goblet cell populations, and cytokine levels. Furthermore, tight junction (TJ) proteins levels were also measured by qRT-PCR showing the ability of this strain to specifically normalize the level of several TJ proteins, in particular for claudin-4. Finally, B. lactis strain counterbalanced CD4(+) lymphocyte alterations in both spleen and mesenteric lymphoid nodes. It restores the Th1/Th2 ratio altered by the DNBS challenge (which locally augments CD4(+) Th1 cells) by increasing the Th2 response as measured by the increase in the production of major representative Th2 cytokines (IL-4, IL-5, and IL-10). Altogether, these data suggest that B. animalis ssp. lactis CNCM-I2494 may efficiently prevent disorders associated with increased barrier permeability.

  12. Bifidobacterium animalis ssp. lactis CNCM-I2494 Restores Gut Barrier Permeability in Chronically Low-Grade Inflamed Mice

    PubMed Central

    Martín, Rebeca; Laval, Laure; Chain, Florian; Miquel, Sylvie; Natividad, Jane; Cherbuy, Claire; Sokol, Harry; Verdu, Elena F.; van Hylckama Vlieg, Johan; Bermudez-Humaran, Luis G.; Smokvina, Tamara; Langella, Philippe

    2016-01-01

    Growing evidence supports the efficacy of many probiotic strains in the management of gastrointestinal disorders associated with deregulated intestinal barrier function and/or structure. In particular, bifidobacteria have been studied for their efficacy to both prevent and treat a broad spectrum of animal and/or human gut disorders. The aim of the current work was thus to evaluate effects on intestinal barrier function of Bifidobacterium animalis ssp. lactis CNCM-I2494, a strain used in fermented dairy products. A chronic dinitrobenzene sulfonic acid (DNBS)-induced low-grade inflammation model causing gut dysfunction in mice was used in order to study markers of inflammation, intestinal permeability, and immune function in the presence of the bacterial strain. In this chronic low-grade inflammation mice model several parameters pointed out the absence of an over active inflammation process. However, gut permeability, lymphocyte populations, and colonic cytokines were found to be altered. B. animalis ssp. lactis CNCM-I2494 was able to protect barrier functions by restoring intestinal permeability, colonic goblet cell populations, and cytokine levels. Furthermore, tight junction (TJ) proteins levels were also measured by qRT-PCR showing the ability of this strain to specifically normalize the level of several TJ proteins, in particular for claudin-4. Finally, B. lactis strain counterbalanced CD4+ lymphocyte alterations in both spleen and mesenteric lymphoid nodes. It restores the Th1/Th2 ratio altered by the DNBS challenge (which locally augments CD4+ Th1 cells) by increasing the Th2 response as measured by the increase in the production of major representative Th2 cytokines (IL-4, IL-5, and IL-10). Altogether, these data suggest that B. animalis ssp. lactis CNCM-I2494 may efficiently prevent disorders associated with increased barrier permeability. PMID:27199937

  13. The role of immunomodulators on intestinal barrier homeostasis in experimental models.

    PubMed

    Andrade, Maria Emília Rabelo; Araújo, Raquel Silva; de Barros, Patrícia Aparecida Vieira; Soares, Anne Danieli Nascimento; Abrantes, Fernanda Alves; Generoso, Simone de Vasconcelos; Fernandes, Simone Odília Antunes; Cardoso, Valbert Nascimento

    2015-12-01

    The intestinal epithelium is composed of specialized epithelial cells that form a physical and biochemical barrier to commensal and pathogenic microorganisms. However, dysregulation of the epithelial barrier function can lead to increased intestinal permeability and bacterial translocation across the intestinal mucosa, which contributes to local and systemic immune activation. The increase in these parameters is associated with inflammatory bowel disease, physical exercise under heat stress, intestinal obstruction, ischemia, and mucositis, among other conditions. Lately, there has been growing interest in immunomodulatory nutrients and probiotics that can regulate host immune and inflammatory responses and possibly restore the intestinal barrier. Immunomodulators such as amino acids (glutamine, arginine, tryptophan, and citrulline), fatty acids (short-chain and omega-3 fatty acids and conjugated linoleic acids), and probiotics (Bifidobacterium, Saccharomyces, and Lactobacillus) have been reported in the literature. Here, we review the critical roles of immunomodulatory nutrients in supporting gut barrier integrity and function. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  14. Bacillus subtilis Protects Porcine Intestinal Barrier from Deoxynivalenol via Improved Zonula Occludens-1 Expression

    PubMed Central

    Gu, Min Jeong; Song, Sun Kwang; Park, Sung Moo; Lee, In Kyu; Yun, Cheol-Heui

    2014-01-01

    Intestinal epithelial cells (IECs) forming the barrier for the first-line of protection are interconnected by tight junction (TJ) proteins. TJ alteration results in impaired barrier function, which causes potentially excessive inflammation leading to intestinal disorders. It has been suggested that toll-like receptor (TLR) 2 ligands and some bacteria enhance epithelial barrier function in humans and mice. However, no such study has yet to be claimed in swine. The aim of the present study was to examine whether Bacillus subtilis could improve barrier integrity and protection against deoxynivalenol (DON)-induced barrier disruption in porcine intestinal epithelial cell line (IPEC-J2). We found that B. subtilis decreased permeability of TJ and improved the expression of zonula occludens (ZO)-1 and occludin during the process of forming TJ. In addition, ZO-1 expression of IPEC-J2 cells treated with B. subtilis was up-regulated against DON-induced damage. In conclusion, B. subtilis may have potential to enhance epithelial barrier function and to prevent the cells from DON-induced barrier dysfunction. PMID:25049991

  15. Deoxynivalenol affects in vitro intestinal epithelial cell barrier integrity through inhibition of protein synthesis.

    PubMed

    De Walle, Jacqueline Van; Sergent, Thérèse; Piront, Neil; Toussaint, Olivier; Schneider, Yves-Jacques; Larondelle, Yvan

    2010-06-15

    Deoxynivalenol (DON), one of the most common mycotoxin contaminants of raw and processed cereal food, adversely affects the gastrointestinal tract. Since DON acts as a protein synthesis inhibitor, the constantly renewing intestinal epithelium could be particularly sensitive to DON. We analyzed the toxicological effects of DON on intestinal epithelial protein synthesis and barrier integrity. Differentiated Caco-2 cells, as a widely used model of the human intestinal barrier, were exposed to realistic intestinal concentrations of DON (50, 500 and 5000 ng/ml) during 24h. DON caused a concentration-dependent decrease in total protein content associated with a reduction in the incorporation of [(3)H]-leucine, demonstrating its inhibitory effect on protein synthesis. DON simultaneously increased the paracellular permeability of the monolayer as reflected through a decreased transepithelial electrical resistance associated with an increased paracellular flux of the tracer [(3)H]-mannitol. A concentration-dependent reduction in the expression level of the tight junction constituent claudin-4 was demonstrated by Western blot, which was not due to diminished transcription, increased degradation, or NF-kappaB, ERK or JNK activation, and was also observed for a tight junction independent protein, i.e. intestinal alkaline phosphatase. These results demonstrate a dual toxicological effect of DON on differentiated Caco-2 cells consisting in an inhibition of protein synthesis as well as an increase in monolayer permeability, and moreover suggest a possible link between them through diminished synthesis of the tight junction constituent claudin-4. Copyright 2010 Elsevier Inc. All rights reserved.

  16. Deoxynivalenol affects in vitro intestinal epithelial cell barrier integrity through inhibition of protein synthesis

    SciTech Connect

    Van De Walle, Jacqueline; Sergent, Therese; Piront, Neil; Toussaint, Olivier; Schneider, Yves-Jacques; Larondelle, Yvan

    2010-06-15

    Deoxynivalenol (DON), one of the most common mycotoxin contaminants of raw and processed cereal food, adversely affects the gastrointestinal tract. Since DON acts as a protein synthesis inhibitor, the constantly renewing intestinal epithelium could be particularly sensitive to DON. We analyzed the toxicological effects of DON on intestinal epithelial protein synthesis and barrier integrity. Differentiated Caco-2 cells, as a widely used model of the human intestinal barrier, were exposed to realistic intestinal concentrations of DON (50, 500 and 5000 ng/ml) during 24 h. DON caused a concentration-dependent decrease in total protein content associated with a reduction in the incorporation of [{sup 3}H]-leucine, demonstrating its inhibitory effect on protein synthesis. DON simultaneously increased the paracellular permeability of the monolayer as reflected through a decreased transepithelial electrical resistance associated with an increased paracellular flux of the tracer [{sup 3}H]-mannitol. A concentration-dependent reduction in the expression level of the tight junction constituent claudin-4 was demonstrated by Western blot, which was not due to diminished transcription, increased degradation, or NF-{kappa}B, ERK or JNK activation, and was also observed for a tight junction independent protein, i.e. intestinal alkaline phosphatase. These results demonstrate a dual toxicological effect of DON on differentiated Caco-2 cells consisting in an inhibition of protein synthesis as well as an increase in monolayer permeability, and moreover suggest a possible link between them through diminished synthesis of the tight junction constituent claudin-4.

  17. [Protective effect of ethyl pyruvate on barrier function of intestinal mucosa in dogs with septic shock].

    PubMed

    Kou, Qiu-Ye; Guan, Xiang-Dong

    2008-03-01

    To investigate the effect of ethyl pyruvate on barrier function of intestinal mucosa in dogs with septic shock. Twenty dogs with septic shock induced by lipopolysaccharides(LPS) were randomly divided into two groups. Dogs randomly received placebo (Ringer's solution, control group, n=8) or ethyl pyruvate in lactated Ringer's solution (0.05 g/kg loading dose over 10 mins, thereafter 0.05 g.kg(-1).h(-1) for 12 hours, EP treatment group, n=12). The diamine oxidase(DAO) activity and D-lactate content were detected at the 0, 8 th, 12 th and 24 th hour of septic shock. Animals were sacrificed at the 24 th hour after septic shock and the jejunal tissue was taken for histopathological examination. The levels of plasma DAO and D-lactate were significantly elevated in both groups after septic shock than those before septic shock. The changes in intestinal parameters of hemoperfusion and permeability in EP treatment group were significantly lowered than those in control group. Inflammation of small intestinal mucosa was more severe in control group than that in EP group, and the pathologic score was significantly lower in EP group(2.33+/-0.25) than that in control group(3.39+/-0.38)(P<0.05). Ethyl pyruvate can lessen intestinal permeability and protect intestinal barrier function in dogs with septic shock.

  18. Biorelevant media resistant co-culture model mimicking permeability of human intestine.

    PubMed

    Antoine, Delphine; Pellequer, Yann; Tempesta, Camille; Lorscheidt, Stefan; Kettel, Bernadette; Tamaddon, Lana; Jannin, Vincent; Demarne, Frédéric; Lamprecht, Alf; Béduneau, Arnaud

    2015-03-15

    Cell culture models are currently used to predict absorption pattern of new compounds and formulations in the human gastro-intestinal tract (GIT). One major drawback is the lack of relevant apical incubation fluids allowing mimicking luminal conditions in the GIT. Here, we suggest a culture model compatible with biorelevant media, namely Fasted State Simulated Intestinal Fluid (FaSSIF) and Fed State Simulated Intestinal Fluid (FeSSIF). Co-culture was set up from Caco-2 and mucus-secreting HT29-MTX cells using an original seeding procedure. Viability and cytotoxicity assays were performed following incubation of FeSSIF and FaSSIF with co-culture. Influence of biorelevant fluids on paracellular permeability or transporter proteins were also evaluated. Results were compared with Caco-2 and HT29-MTX monocultures. While Caco-2 viability was strongly affected with FeSSIF, no toxic effect was detected for the co-cultures in terms of viability and lactate dehydrogenase release. The addition of FeSSIF to the basolateral compartment of the co-culture induced cytotoxic effects which suggested the apical mucus barrier being cell protective. In contrast to FeSSIF, FaSSIF induced a slight increase of the paracellular transport and both tested media inhibited partially the P-gp-mediated efflux in the co-culture. Additionally, the absorptive transport of propranolol hydrochloride, a lipophilic β-blocker, was strongly affected by biorelevant fluids. This study demonstrated the compatibility of the Caco-2/HT29-MTX model with some of the current biorelevant media. Combining biorelevant intestinal fluids with features such as mucus secretion, adjustable paracellular and P-gp mediated transports, is a step forward to more realistic in-vitro models of the human intestine. Copyright © 2015. Published by Elsevier B.V.

  19. Effects of acute intra-abdominal hypertension on multiple intestinal barrier functions in rats

    PubMed Central

    Leng, Yuxin; Yi, Min; Fan, Jie; Bai, Yu; Ge, Qinggang; Yao, Gaiqi

    2016-01-01

    Intra-abdominal hypertension (IAH) is a common and serious complication in critically ill patients for which there is no well-defined treatment strategy. Here, we explored the effect of IAH on multiple intestinal barriers and discussed whether the alteration in microflora provides clues to guide the rational therapeutic treatment of intestinal barriers during IAH. Using a rat model, we analysed the expression of tight junction proteins (TJs), mucins, chemotactic factors, and Toll-like receptor 4 (TLR4) by immunohistochemistry. We also analysed the microflora populations using 16S rRNA sequencing. We found that, in addition to enhanced permeability, acute IAH (20 mmHg for 90 min) resulted in significant disturbances to mucosal barriers. Dysbiosis of the intestinal microbiota was also induced, as represented by decreased Firmicutes (relative abundance), increased Proteobacteria and migration of Bacteroidetes from the colon to the jejunum. At the genus level, Lactobacillus species and Peptostreptococcaceae incertae sedis were decreased, whereas levels of lactococci remained unchanged. Our findings outline the characteristics of IAH-induced barrier changes, indicating that intestinal barriers might be treated to alleviate IAH, and the microflora may be an especially relevant target. PMID:26980423

  20. Epithelia: Understanding the Cell Biology of Intestinal Barrier Dysfunction.

    PubMed

    Hu, Daniel J-K; Jasper, Heinrich

    2017-03-06

    Barrier dysfunction in the intestine is a common characteristic of aging organisms. A recent study provides new insight into the cell biology of this phenomenon. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Automated Impedance Tomography for Monitoring Permeable Reactive Barrier Health

    SciTech Connect

    LaBrecque, D J; Adkins, P L

    2009-07-02

    The objective of this research was the development of an autonomous, automated electrical geophysical monitoring system which allows for near real-time assessment of Permeable Reactive Barrier (PRB) health and aging and which provides this assessment through a web-based interface to site operators, owners and regulatory agencies. Field studies were performed at four existing PRB sites; (1) a uranium tailing site near Monticello, Utah, (2) the DOE complex at Kansas City, Missouri, (3) the Denver Federal Center in Denver, Colorado and (4) the Asarco Smelter site in East Helena, Montana. Preliminary surface data over the PRB sites were collected (in December, 2005). After the initial round of data collection, the plan was modified to include studies inside the barriers in order to better understand barrier aging processes. In September 2006 an autonomous data collection system was designed and installed at the EPA PRB and the electrode setups in the barrier were revised and three new vertical electrode arrays were placed in dedicated boreholes which were in direct contact with the PRB material. Final data were collected at the Kansas City, Denver and Monticello, Utah PRB sites in the fall of 2007. At the Asarco Smelter site in East Helena, Montana, nearly continuous data was collected by the autonomous monitoring system from June 2006 to November 2007. This data provided us with a picture of the evolution of the barrier, enabling us to examine barrier changes more precisely and determine whether these changes are due to installation issues or are normal barrier aging. Two rounds of laboratory experiments were carried out during the project. We conducted column experiments to investigate the effect of mineralogy on the electrical signatures resulting from iron corrosion and mineral precipitation in zero valent iron (ZVI) columns. In the second round of laboratory experiments we observed the electrical response from simulation of actual field PRBs at two sites: the

  2. Long-Term Monitoring of Permeable Reactive Barriers - Progress Report

    SciTech Connect

    Liang, L.

    2001-04-12

    The purpose of this project is to conduct collaborative research to evaluate and maximize the effectiveness of permeable reactive barriers (PRBs) with a broad-based working group including representatives from the U.S. Department of Energy (DOE), U.S. Department of Defense (DoD), and the U.S. Environmental Protection Agency (EPA). The Naval Facilities Engineering Service Center (NFESC) and its project partner, Battelle, are leading the DoD effort with funding from DoD's Environmental Security Technology Certification Program (ESTCP) and Strategic Environmental Research and Development Program (SERDP). Oak Ridge National Laboratory (ORNL) is coordinating the DOE effort with support from Subsurface Contaminant Focus Area (SCFA), a research program under DOEs Office of Science and Technology. The National Risk Management Research Laboratory's Subsurface Protection and Remediation Division is leading EPA's effort. The combined effort of these three agencies allows the evaluation of a large number of sites. Documents generated by this joint project will be reviewed by the participating agencies' principal investigators, the Permeable Barriers Group of the Remediation Technologies Development Forum (RTDF), and the Interstate Technology and Regulatory Cooperation (ITRC). The technical objectives of this project are to collect and review existing field data at selected PRB sites, identify data gaps, conduct additional measurements, and provide recommendations to DOE users on suitable long-term monitoring strategies. The specific objectives are to (1) evaluate geochemical and hydraulic performance of PRBs, (2) develop guidelines for hydraulic and geochemical characterization/monitoring, and (3) devise and implement long-term monitoring strategies through the use of hydrological and geochemical models. Accomplishing these objectives will provide valuable information regarding the optimum configuration and lifetime of barriers at specific sites. It will also permit

  3. Ablation of ceramide synthase 2 exacerbates dextran sodium sulphate-induced colitis in mice due to increased intestinal permeability.

    PubMed

    Kim, Ye-Ryung; Volpert, Giora; Shin, Kyong-Oh; Kim, So-Yeon; Shin, Sun-Hye; Lee, Younghay; Sung, Sun Hee; Lee, Yong-Moon; Ahn, Jung-Hyuck; Pewzner-Jung, Yael; Park, Woo-Jae; Futerman, Anthony H; Park, Joo-Won

    2017-07-12

    Ceramides mediate crucial cellular processes including cell death and inflammation and have recently been implicated in inflammatory bowel disease. Ceramides consist of a sphingoid long-chain base to which fatty acids of various length can be attached. We now investigate the effect of alerting the ceramide acyl chain length on a mouse model of colitis. Ceramide synthase (CerS) 2 null mice, which lack very-long acyl chain ceramides with concomitant increase of long chain bases and C16-ceramides, were more susceptible to dextran sodium sulphate-induced colitis, and their survival rate was markedly decreased compared with that of wild-type littermates. Using mixed bone-marrow chimeric mice, we showed that the host environment is primarily responsible for intestinal barrier dysfunction and increased intestinal permeability. In the colon of CerS2 null mice, the expression of junctional adhesion molecule-A was markedly decreased and the phosphorylation of myosin light chain 2 was increased. In vitro experiments using Caco-2 cells also confirmed an important role of CerS2 in maintaining epithelial barrier function; CerS2-knockdown via CRISPR-Cas9 technology impaired barrier function. In vivo myriocin administration, which normalized long-chain bases and C16-ceramides of the colon of CerS2 null mice, increased intestinal permeability as measured by serum FITC-dextran levels, indicating that altered SLs including deficiency of very-long-chain ceramides are critical for epithelial barrier function. In conclusion, deficiency of CerS2 influences intestinal barrier function and the severity of experimental colitis and may represent a potential mechanism for inflammatory bowel disease pathogenesis. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  4. Kiwifruit cysteine protease actinidin compromises the intestinal barrier by disrupting tight junctions.

    PubMed

    Grozdanovic, Milica M; Čavić, Milena; Nešić, Andrijana; Andjelković, Uroš; Akbari, Peyman; Smit, Joost J; Gavrović-Jankulović, Marija

    2016-03-01

    The intestinal epithelium forms a barrier that food allergens must cross in order to induce sensitization. The aim of this study was to evaluate the impact of the plant-derived food cysteine protease--actinidin (Act d1) on the integrity of intestinal epithelium tight junctions (TJs). Effects of Act d1 on the intestinal epithelium were evaluated in Caco-2 monolayers and in a mouse model by measuring transepithelial resistance and in vivo permeability. Integrity of the tight junctions was analyzed by confocal microscopy. Proteolysis of TJ protein occludin was evaluated by mass spectrometry. Actinidin (1 mg/mL) reduced the transepithelial resistance of the cell monolayer by 18.1% (after 1 h) and 25.6% (after 4 h). This loss of barrier function was associated with Act d 1 disruption of the occludin and zonula occludens (ZO)-1 network. The effect on intestinal permeability in vivo was demonstrated by the significantly higher concentration of 40 kDa FITC-dextran (2.33 μg/mL) that passed from the intestine into the serum of Act d1 treated mice in comparison to the control group (0.5 μg/mL). Human occludin was fragmented, and putative Act d1 cleavage sites were identified in extracellular loops of human occludin. Act d1 caused protease-dependent disruption of tight junctions in confluent Caco-2 cells and increased intestinal permeability in mice. In line with the observed effects of food cysteine proteases in occupational allergy, these results suggest that disruption of tight junctions by food cysteine proteases may contribute to the process of sensitization in food allergy. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Treatment of inorganic contaminants using permeable reactive barriers

    NASA Astrophysics Data System (ADS)

    Blowes, David W.; Ptacek, Carol J.; Benner, Shawn G.; McRae, Che W. T.; Bennett, Timothy A.; Puls, Robert W.

    2000-09-01

    Permeable reactive barriers are an emerging alternative to traditional pump and treat systems for groundwater remediation. This technique has progressed rapidly over the past decade from laboratory bench-scale studies to full-scale implementation. Laboratory studies indicate the potential for treatment of a large number of inorganic contaminants, including As, Cd, Cr, Cu, Hg, Fe, Mn, Mo, Ni, Pb, Se, Tc, U, V, NO 3, PO 4 and SO 4. Small-scale field studies have demonstrated treatment of Cd, Cr, Cu, Fe, Ni, Pb, NO 3, PO 4 and SO 4. Permeable reactive barriers composed of zero-valent iron have been used in full-scale installations for the treatment of Cr, U, and Tc. Solid-phase organic carbon in the form of municipal compost has been used to remove dissolved constituents associated with acid-mine drainage, including SO 4, Fe, Ni, Co and Zn. Dissolved nutrients, including NO 3 and PO 4, have been removed from domestic septic-system effluent and agricultural drainage.

  6. Regulation of intestinal epithelial cells transcriptome by enteric glial cells: impact on intestinal epithelial barrier functions.

    PubMed

    Van Landeghem, Laurianne; Mahé, Maxime M; Teusan, Raluca; Léger, Jean; Guisle, Isabelle; Houlgatte, Rémi; Neunlist, Michel

    2009-11-02

    Emerging evidences suggest that enteric glial cells (EGC), a major constituent of the enteric nervous system (ENS), are key regulators of intestinal epithelial barrier (IEB) functions. Indeed EGC inhibit intestinal epithelial cells (IEC) proliferation and increase IEB paracellular permeability. However, the role of EGC on other important barrier functions and the signalling pathways involved in their effects are currently unknown. To achieve this goal, we aimed at identifying the impact of EGC upon IEC transcriptome by performing microarray studies. EGC induced significant changes in gene expression profiling of proliferating IEC after 24 hours of co-culture. 116 genes were identified as differentially expressed (70 up-regulated and 46 down-regulated) in IEC cultured with EGC compared to IEC cultured alone. By performing functional analysis of the 116 identified genes using Ingenuity Pathway Analysis, we showed that EGC induced a significant regulation of genes favoring both cell-to-cell and cell-to-matrix adhesion as well as cell differentiation. Consistently, functional studies showed that EGC induced a significant increase in cell adhesion. EGC also regulated genes involved in cell motility towards an enhancement of cell motility. In addition, EGC profoundly modulated expression of genes involved in cell proliferation and cell survival, although no clear functional trend could be identified. Finally, important genes involved in lipid and protein metabolism of epithelial cells were shown to be differentially regulated by EGC. This study reinforces the emerging concept that EGC have major protective effects upon the IEB. EGC have a profound impact upon IEC transcriptome and induce a shift in IEC phenotype towards increased cell adhesion and cell differentiation. This concept needs to be further validated under both physiological and pathophysiological conditions.

  7. Lipopolysaccharide regulation of intestinal tight junction permeability is mediated by TLR-4 signal transduction pathway activation of FAK and MyD88

    PubMed Central

    Guo, Shuhong; Nighot, Meghali; Al-Sadi, Rana; Alhmoud, Tarik; Nighot, Prashant; Ma, Thomas Y.

    2015-01-01

    Gut-derived bacterial lipopolysaccharides (LPS) play an essential role in inducing intestinal and systemic inflammatory responses and have been implicated as a pathogenic factor of necrotizing enterocolitis (NEC) and inflammatory bowel disease (IBD). The defective intestinal tight junction (TJ) barrier has been shown to be an important factor contributing to the development of intestinal inflammation. LPS, at physiological concentrations, cause an increase in intestinal tight junction permeability (TJP) via a TLR-4 dependent process; however the intracellular mechanisms that mediate LPS regulation of intestinal TJP remain unclear. The aim of this study was to investigate the adaptor proteins and the signaling interactions that mediate LPS modulation of intestinal TJ barrier using an in-vitro and in-vivo model system. LPS caused a TLR-4 dependent activation of membrane-associated adaptor protein FAK in Caco-2 monolayers. LPS caused an activation of both MyD88-dependent and –independent pathways. SiRNA silencing of MyD88 prevented LPS-induced increase in TJP. LPS caused a MyD88-dependent activation of IRAK4. TLR-4, FAK and MyD88 were co-localized. SiRNA silencing of TLR-4 inhibited TLR-4 associated FAK activation; and FAK knockdown prevented MyD88 activation. In-vivo studies also confirmed that LPS-induced increase in mouse intestinal permeability was associated with FAK and MyD88 activation; knockdown of intestinal epithelial FAK prevented LPS-induced increase in intestinal permeability. Additionally, high dose LPS-induced intestinal inflammation was also dependent on TLR-4/FAK/MyD88 signal-transduction axis. Our data show for the first time that LPS-induced increase in intestinal TJP and intestinal inflammation was regulated by TLR-4 dependent activation of FAK-MyD88-IRAK4 signaling pathway. PMID:26466961

  8. Inflammation and the Intestinal Barrier: Leukocyte-Epithelial Cell Interactions, Cell Junction Remodeling, and Mucosal Repair.

    PubMed

    Luissint, Anny-Claude; Parkos, Charles A; Nusrat, Asma

    2016-10-01

    The intestinal tract is lined by a single layer of columnar epithelial cells that forms a dynamic, permeable barrier allowing for selective absorption of nutrients, while restricting access to pathogens and food-borne antigens. Precise regulation of epithelial barrier function is therefore required for maintaining mucosal homeostasis and depends, in part, on barrier-forming elements within the epithelium and a balance between pro- and anti-inflammatory factors in the mucosa. Pathologic states, such as inflammatory bowel disease, are associated with a leaky epithelial barrier, resulting in excessive exposure to microbial antigens, recruitment of leukocytes, release of soluble mediators, and ultimately mucosal damage. An inflammatory microenvironment affects epithelial barrier properties and mucosal homeostasis by altering the structure and function of epithelial intercellular junctions through direct and indirect mechanisms. We review our current understanding of complex interactions between the intestinal epithelium and immune cells, with a focus on pathologic mucosal inflammation and mechanisms of epithelial repair. We discuss leukocyte-epithelial interactions, as well as inflammatory mediators that affect the epithelial barrier and mucosal repair. Increased knowledge of communication networks between the epithelium and immune system will lead to tissue-specific strategies for treating pathologic intestinal inflammation. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

  9. Inflammation and the Intestinal Barrier: Leukocyte–Epithelial Cell Interactions, Cell Junction Remodeling, and Mucosal Repair

    PubMed Central

    Luissint, Anny-Claude; Parkos, Charles A.; Nusrat, Asma

    2017-01-01

    The intestinal tract is lined by a single layer of columnar epithelial cells that forms a dynamic, permeable barrier allowing for selective absorption of nutrients, while restricting access to pathogens and food-borne antigens. Precise regulation of epithelial barrier function is therefore required for maintaining mucosal homeostasis and depends, in part, on barrier-forming elements within the epithelium and a balance between pro- and anti-inflammatory factors in the mucosa. Pathologic states, such as inflammatory bowel disease, are associated with a leaky epithelial barrier, resulting in excessive exposure to microbial antigens, recruitment of leukocytes, release of soluble mediators, and ultimately mucosal damage. An inflammatory microenvironment affects epithelial barrier properties and mucosal homeostasis by altering the structure and function of epithelial intercellular junctions through direct and indirect mechanisms. We review our current understanding of complex interactions between the intestinal epithelium and immune cells, with a focus on pathologic mucosal inflammation and mechanisms of epithelial repair. We discuss leukocyte–epithelial interactions, as well as inflammatory mediators that affect the epithelial barrier and mucosal repair. Increased knowledge of communication networks between the epithelium and immune system will lead to tissue-specific strategies for treating pathologic intestinal inflammation. PMID:27436072

  10. EICOSAPENTAENOIC ACID ENHANCES HEATSTROKE-IMPAIRED INTESTINAL EPITHELIAL BARRIER FUNCTION IN RATS.

    PubMed

    Xiao, Guizhen; Yuan, Fangfang; Geng, Yan; Qiu, Xiaowen; Liu, Zhifeng; Lu, Jiefu; Tang, Liqun; Zhang, Yali; Su, Lei

    2015-10-01

    Dysfunction of the intestinal barrier plays an important role in the pathological process of heatstroke. Omega-3 (or n-3) polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), help protect the intestinal mucosal barrier. This study assessed if pretreating rats with EPA or DHA could alleviate heat stress-induced damage to the intestinal barrier caused by experimental heatstroke. Male Wistar rats were pregavaged with either EPA, DHA, corn oil, or normal saline (all 1 g/kg) for 21 days before the heatstroke experiment (control rats were not exposed to heat). Experimental rats were exposed to an ambient temperature of 37°C and 60% humidity to induce heatstroke, and then they were allowed to recover at room temperature after rapid cooling. Survival time of rats was monitored after heatstroke. Horseradish peroxidase flux from the gut lumen and the level of plasma D-lactate were measured to analyze intestinal permeability at 6 h after heatstroke. Plasma endotoxin levels were determined using a limulus amoebocyte lysate assay. Expressions of the tight junction (TJ) proteins occludin and ZO-1 were analyzed by Western blot and localized by immunofluorescence microscopy. Tight junction protein morphology was observed by transmission electron microscopy. Fatty acids of ileal mucosa were analyzed using gas chromatography-mass selective detector. Eicosapentaenoic acid significantly increased survival time after heatstroke. Eicosapentaenoic acid significantly decreased intestinal permeability and plasma endotoxin levels. Eicosapentaenoic acid effectively attenuated the heatstroke-induced disruption of the intestinal structure and improved the histology score, whereas DHA was less effective, and corn oil was ineffective. Pretreatment with EPA also increased expression of occludin and ZO-1 to effectively prevent TJ disruption. Eicosapentaenoic acid pretreatment enriched itself in the membrane of intestinal cells. Our results

  11. Intestinal barrier dysfunction in cirrhosis: Current concepts in pathophysiology and clinical implications

    PubMed Central

    Tsiaoussis, Georgios I; Assimakopoulos, Stelios F; Tsamandas, Athanassios C; Triantos, Christos K; Thomopoulos, Konstantinos C

    2015-01-01

    The intestinal lumen is a host place for a wide range of microbiota and sets a unique interplay between local immune system, inflammatory cells and intestinal epithelium, forming a physical barrier against microbial invaders and toxins. Bacterial translocation is the migration of viable or nonviable microorganisms or their pathogen-associated molecular patterns, such as lipopolysaccharide, from the gut lumen to the mesenteric lymph nodes, systemic circulation and other normally sterile extraintestinal sites. A series of studies have shown that translocation of bacteria and their products across the intestinal barrier is a commonplace in patients with liver disease. The deterioration of intestinal barrier integrity and the consulting increased intestinal permeability in cirrhotic patients play a pivotal pathophysiological role in the development of severe complications as high rate of infections, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, variceal bleeding, progression of liver injury and hepatocellular carcinoma. Nevertheless, the exact cellular and molecular mechanisms implicated in the phenomenon of microbial translocation in liver cirrhosis have not been fully elucidated yet. PMID:26301048

  12. Impaired function of the intestinal barrier in a novel sub-health rat model

    PubMed Central

    FENG, SISI; LIU, WEIDONG; ZUO, SHENGNAN; XIE, TINGYAN; DENG, HUI; ZHANG, QIUHUAN; ZHONG, BAIYUN

    2016-01-01

    Sub-health is a state featuring a deterioration in physiological function between health and illness, and the sub-health condition has surfaced as life-threatening in humans. The aim of the present study was to establish a sub-health model in rats, and investigate the function of the intestinal barrier in the sub-health rats and rats following intervention. To establish a sub-health model, the rats were subjected to a high-fat and sugar diet, motion restriction and chronic stress. Their serum glucose and triglyceride levels, immune function and adaptability were then measured. The levels of diamine oxidase and D-lactic acid in the plasma were analyzed as markers of the intestinal permeability. The protein and mRNA expression levels of anti-apoptotic YWHAZ in the colonic tissue was detected using immunohistochemical and reverse transcription-quantitative polymerase chain reaction analyses In the present study, the sub-health rat model was successfully established, and sub-health factors increased the intestinal permeability and reduced the expression of YWHAZ. Providing sub-health rats with normal living conditions did not improve the function of the intestinal barrier. In conclusion, the results of the present study demonstrated that intestinal disorders in the sub-health rat model may result from the damage caused by reduce intestinal barrier function as well as the decreased expression levels of YWHAZ. Additionally, rats in the sub-health condition did not recover following subsequent exposure to normal living conditions, suggesting that certain exercises or medical intervention may be necessary to improve sub-health symptoms. PMID:26957295

  13. Development of a biomimetic phospholipid vesicle-based permeation assay for the estimation of intestinal drug permeability.

    PubMed

    Naderkhani, Elenaz; Isaksson, Johan; Ryzhakov, Alexey; Flaten, Gøril Eide

    2014-06-01

    Permeability is a crucial property of orally administered drugs. Therefore, in drug discovery, it is important to employ methods suitable for rapidly and reliably screening the permeability of large numbers of new drug candidates. The phospholipid vesicle-based permeation assay (PVPA), a model consisting of a tight layer of liposomes immobilized on a filter, offers potential advantages unmet by other methods and has been successfully used in permeability testing of novel active substances as well as formulations. In this study, the PVPA was developed into a more robust, biomimetic model by employing a lipid composition matching that of the intestinal permeation barrier and performing the experiments at the more biologically relevant pH 6.2. As expected, positively charged basic compounds demonstrated increased permeability through the negatively charged biomimetic barriers, and the degree of correct classification according to in vivo absorption was comparable between the original PVPA and the biomimetic PVPA. The biomimetic PVPA further proved to be tremendously more robust toward the presence of tensides compared with the original PVPA; this is a promising finding that renders the biomimetic PVPA an enhanced ability to estimate the permeability of poorly soluble compounds. Hence, the PVPA model developed in this study has evolved an important step forward.

  14. Characterisation of the passive permeability barrier of nuclear pore complexes

    PubMed Central

    Mohr, Dagmar; Frey, Steffen; Fischer, Torsten; Güttler, Thomas; Görlich, Dirk

    2009-01-01

    Nuclear pore complexes (NPCs) restrict uncontrolled nucleocytoplasmic fluxes of inert macromolecules but permit facilitated translocation of nuclear transport receptors and their cargo complexes. We probed the passive barrier of NPCs and observed sieve-like properties with a dominating mesh or channel radius of 2.6 nm, which is narrower than proposed earlier. A small fraction of diffusion channels has a wider opening, explaining the very slow passage of larger molecules. The observed dominant passive diameter approximates the distance of adjacent hydrophobic clusters of FG repeats, supporting the model that the barrier is made of FG repeat domains cross-linked with a spacing of an FG repeat unit length. Wheat germ agglutinin and the dominant-negative importin β45-462 fragment were previously regarded as selective inhibitors of facilitated NPC passage. We now observed that they do not distinguish between the passive and the facilitated mode. Instead, their inhibitory effect correlates with the size of the NPC-passing molecule. They have little effect on small species, inhibit the passage of green fluorescent protein-sized objects >10-fold and virtually block the translocation of larger ones. This suggests that passive and facilitated NPC passage proceed through one and the same permeability barrier. PMID:19680228

  15. Intestinal Permeability and Glucagon-Like Peptide-2 in Children with Autism: A Controlled Pilot Study

    ERIC Educational Resources Information Center

    Robertson, Marli A.; Sigalet, David L.; Holst, Jens J.; Meddings, Jon B.; Wood, Julie; Sharkey, Keith A.

    2008-01-01

    We measured small intestinal permeability using a lactulose:mannitol sugar permeability test in a group of children with autism, with current or previous gastrointestinal complaints. Secondly, we examined whether children with autism had an abnormal glucagon-like peptide-2 (GLP-2) response to feeding. Results were compared with sibling controls…

  16. Intestinal Permeability and Glucagon-Like Peptide-2 in Children with Autism: A Controlled Pilot Study

    ERIC Educational Resources Information Center

    Robertson, Marli A.; Sigalet, David L.; Holst, Jens J.; Meddings, Jon B.; Wood, Julie; Sharkey, Keith A.

    2008-01-01

    We measured small intestinal permeability using a lactulose:mannitol sugar permeability test in a group of children with autism, with current or previous gastrointestinal complaints. Secondly, we examined whether children with autism had an abnormal glucagon-like peptide-2 (GLP-2) response to feeding. Results were compared with sibling controls…

  17. Permeapad™ for investigation of passive drug permeability: The effect of surfactants, co-solvents and simulated intestinal fluids (FaSSIF and FeSSIF).

    PubMed

    Bibi, Hanady Ajine; di Cagno, Massimiliano; Holm, Rene; Bauer-Brandl, Annette

    2015-09-30

    The aim of the present work was to investigate the potential of the new and innovative artificial barrier, Permeapad™, when exposed to surfactants and co-solvents, often employed for poorly water soluble compounds. The barrier was in addition also exposed to fasted and fed state simulated intestinal fluids versions 1 and 2 (FaSSIF and FeSSIF), all of which the Permeapad™ barrier was compatible with based upon relative comparison of the permeability of the hydrophilic marker calcein in phosphate buffer. The new barrier therefore holds a huge potential due to its functional stability and robustness. It can be used as a standard tool to investigate permeability of drugs in the presence of different surfactants and co-solvents, from DMSO stock solutions at even high concentrations and for the evaluation of permeability in the presence of biomimetic media (BMM). Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Intestinal permeability of forskolin by in situ single pass perfusion in rats.

    PubMed

    Liu, Zhen-Jun; Jiang, Dong-bo; Tian, Lu-Lu; Yin, Jia-Jun; Huang, Jian-Ming; Weng, Wei-Yu

    2012-05-01

    The intestinal permeability of forskolin was investigated using a single pass intestinal perfusion (SPIP) technique in rats. SPIP was performed in different intestinal segments (duodenum, jejunum, ileum, and colon) with three concentrations of forskolin (11.90, 29.75, and 59.90 µg/mL). The investigations of adsorption and stability were performed to ensure that the disappearance of forskolin from the perfusate was due to intestinal absorption. The results of the SPIP study indicated that forskolin could be absorbed in all segments of the intestine. The effective permeability (P (eff)) of forskolin was in the range of drugs with high intestinal permeability. The P (eff) was highest in the duodenum as compared to other intestinal segments. The decreases of P (eff) in the duodenum and ileum at the highest forskolin concentration suggested a saturable transport process. The addition of verapamil, a P-glycoprotein inhibitor, significantly enhanced the permeability of forskolin across the rat jejunum. The absorbed fraction of dissolved forskolin after oral administration in humans was estimated to be 100 % calculated from rat P (eff). In conclusion, dissolved forskolin can be absorbed readily in the intestine. The low aqueous solubility of forskolin might be a crucial factor for its poor oral bioavailability.

  19. Bone marrow transplantation helps restore the intestinal mucosal barrier after total body irradiation in mice.

    PubMed

    Garg, Sarita; Wang, Wenze; Prabath, Biju G; Boerma, Marjan; Wang, Junru; Zhou, Daohong; Hauer-Jensen, Martin

    2014-03-01

    Bone marrow transplantation (BMT) substantially improves 10-day survival after total body irradiation (TBI), consistent with an effect on intestinal radiation death. Total body irradiation, in addition to injuring the intestinal epithelium, also perturbs the mucosal immune system, the largest immune system in the body. This study focused on how transplanted bone marrow cells (BMCs) help restore mucosal immune cell populations after sublethal TBI (8.0 Gy). We further evaluated whether transplanted BMCs: (a) home to sites of radiation injury using green fluorescent protein labeled bone marrow; and (b) contribute to restoring the mucosal barrier in vivo. As expected, BMT accelerated recovery of peripheral blood (PB) cells. In the intestine, BMT was associated with significant early recovery of mucosal granulocytes (P = 0.005). Bone marrow transplantation did not affect mucosal macrophages or lymphocyte populations at early time points, but enhanced the recovery of these cells from day 14 onward (P = 0.03). Bone marrow transplantation also attenuated radiation-induced increase of intestinal CXCL1 and restored IL-10 levels (P = 0.001). Most importantly, BMT inhibited the post-radiation increase in intestinal permeability after 10 Gy TBI (P = 0.02) and modulated the expression of tight junction proteins (P = 0.01-0.05). Green fluorescent protein-positive leukocytes were observed both in intestinal tissue and in PB. These findings strongly suggest that BMT, in addition to enhancing general hematopoietic and immune system recovery, helps restore the intestinal immune system and enhances intestinal mucosal barrier function. These findings may be important in the development and understanding of strategies to alleviate or treat intestinal radiation toxicity.

  20. Homoharringtonine increases intestinal epithelial permeability by modulating specific claudin isoforms in Caco-2 cell monolayers.

    PubMed

    Watari, Akihiro; Hashegawa, Maki; Yagi, Kiyohito; Kondoh, Masuo

    2015-01-01

    Homoharringtonine (HHT), a natural alkaloid produced by various Cephalotaxus species, has antileukemic activity in acute and chronic myelogenous leukemia. However, HHT can also induce unanticipated effects in the gastrointestinal tract, such as diarrhea and nausea/vomiting, but the mechanism behind these adverse effects has not been clarified. In the present study, we show that HHT affects the epithelial permeability of intestinal Caco-2 cell monolayers. HHT reduced the transepithelial electrical resistance (TER) of Caco-2 cells in a dose- and time-dependent manner. The HHT effect was reversible and no cytotoxicity was observed at the concentrations used. HHT simultaneously increased the paracellular flux of the 4 kDa and 40 kDa FITC-dextrans associated with the TER reduction. Immunoblotting analysis revealed that HHT decreased the protein expression of TJ components such as claudin-3, -5, and -7. However, the transcription levels of these claudins were not repressed by HHT treatment. HHT also disturbed the cellular localization of claudin-1 and -4. These changes coincided with the reduced barrier function. Our findings suggest that HHT enhances the paracellular permeability of Caco-2 cell monolayers by modulating the protein expression and localization of claudin isoforms; these actions might be responsible for the gastrointestinal effects of HHT. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Mucosal pathobiology and molecular signature of epithelial barrier dysfunction in the small intestine in irritable bowel syndrome.

    PubMed

    González-Castro, Ana M; Martínez, Cristina; Salvo-Romero, Eloísa; Fortea, Marina; Pardo-Camacho, Cristina; Pérez-Berezo, Teresa; Alonso-Cotoner, Carmen; Santos, Javier; Vicario, María

    2017-01-01

    Irritable bowel syndrome (IBS) is one of the most prevalent gastrointestinal disorders in developed countries. Its etiology remains unknown; however, a common finding, regardless of IBS subtype, is the presence of altered intestinal barrier. In fact, signaling and location of cell-to-cell adhesion proteins, in connection with increased immune activity, seem abnormal in the intestinal epithelium of IBS patients. Despite that most research is performed on distal segments of the intestine, altered permeability has been reported in both, the small and the large bowel of all IBS subtypes. The small intestine carries out digestion and nutrient absorption and is also the site where the majority of immune responses to luminal antigens takes place. In fact, the upper intestine is more exposed to environmental antigens than the colon and is also a site of symptom generation. Recent studies have revealed small intestinal structural alterations of the epithelial barrier and mucosal immune activation in association with intestinal dysfunction, suggesting the commitment of the intestine as a whole in the pathogenesis of IBS. This review summarizes the most recent findings on mucosal barrier alterations and its relationship to symptoms arising from the small intestine in IBS, including epithelial structural abnormalities, mucosal immune activation, and microbial dysbiosis, further supporting the hypothesis of an organic origin of IBS. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  2. Visualizing Molecular Diffusion through Passive Permeability Barriers in Cells: Conventional and Novel Approaches

    PubMed Central

    Lin, Yu-Chun; Phua, Siew Cheng; Lin, Benjamin; Inoue, Takanari

    2013-01-01

    Diffusion barriers are universal solutions for cells to achieve distinct organizations, compositions, and activities within a limited space. The influence of diffusion barriers on the spatiotemporal dynamics of signaling molecules often determines cellular physiology and functions. Over the years, the passive permeability barriers in various subcellular locales have been characterized using elaborate analytical techniques. In this review, we will summarize the current state of knowledge on the various passive permeability barriers present in mammalian cells. We will conclude with a description of several conventional techniques and one new approach based on chemically-inducible diffusion trap (C-IDT) for probing permeable barriers. PMID:23731778

  3. Lipopolysaccharide Causes an Increase in Intestinal Tight Junction Permeability in Vitro and in Vivo by Inducing Enterocyte Membrane Expression and Localization of TLR-4 and CD14

    PubMed Central

    Guo, Shuhong; Al-Sadi, Rana; Said, Hamid M.; Ma, Thomas Y.

    2014-01-01

    Bacterial-derived lipopolysaccharides (LPS) play an essential role in the inflammatory process of inflammatory bowel disease. A defective intestinal tight junction (TJ) barrier is an important pathogenic factor of inflammatory bowel disease and other inflammatory conditions of the gut. Despite its importance in mediating intestinal inflammation, the physiological effects of LPS on the intestinal epithelial barrier remain unclear. The major aims of this study were to determine the effects of physiologically relevant concentrations of LPS (0 to 1 ng/mL) on intestinal barrier function using an in vitro (filter-grown Caco-2 monolayers) and an in vivo (mouse intestinal perfusion) intestinal epithelial model system. LPS, at physiologically relevant concentrations (0 to 1 ng/mL), in the basolateral compartment produced a time-dependent increase in Caco-2 TJ permeability without inducing cell death. Intraperitoneal injection of LPS (0.1 mg/kg), leading to clinically relevant plasma concentrations, also caused a time-dependent increase in intestinal permeability in vivo. The LPS-induced increase in intestinal TJ permeability was mediated by an increase in enterocyte membrane TLR-4 expression and a TLR-4–dependent increase in membrane colocalization of membrane-associated protein CD14. In conclusion, these studies show for the first time that LPS causes an increase in intestinal permeability via an intracellular mechanism involving TLR-4–dependent up-regulation of CD14 membrane expression. PMID:23201091

  4. Tight Junctions, Intestinal Permeability, and Autoimmunity Celiac Disease and Type 1 Diabetes Paradigms

    PubMed Central

    Visser, Jeroen; Rozing, Jan; Sapone, Anna; Lammers, Karen; Fasano, Alessio

    2010-01-01

    Autoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs. This review is focused on celiac disease (CD), an autoimmune enteropathy, and type 1 diabetes (T1D), a hyperglycosaemia caused by a destructive autoimmune process targeting the insulin-producing pancreatic islet cells. Even if environmental factors and genetic susceptibility are clearly involved in the pathogenesis of autoimmunity, for most autoimmune disorders there is no or little knowledge about the causing agent or genetic makeup underlying the disease. In this respect, CD represents a unique autoimmune disorder because a close genetic association with HLA-DQ2 or HLA-DQ8 haplotypes and, more importantly, the environmental trigger (the gliadin fraction of gluten-containing grains wheat, barley, and rye) are known. Conversely, the trigger for autoimmune destruction of pancreatic ß cells in T1D is unclear. Interestingly, recent data suggest that gliadin is also involved in the pathogenesis of T1D. There is growing evidence that increased intestinal permeability plays a pathogenic role in various autoimmune diseases including CD and T1D. Therefore, we hypothesize that besides genetic and environmental factors, loss of intestinal barrier function is necessary to develop autoimmunity. In this review, each of these components will be briefly reviewed. PMID:19538307

  5. Nitric oxide attenuates hydrogen peroxide-induced barrier disruption and protein tyrosine phosphorylation in monolayers of intestinal epithelial cell.

    PubMed

    Katsube, Takanori; Tsuji, Hideo; Onoda, Makoto

    2007-06-01

    The intestinal epithelium provides a barrier to the transport of harmful luminal molecules into the systemic circulation. A dysfunctional epithelial barrier is closely associated with the pathogenesis of a variety of intestinal and systemic disorders. We investigated here the effects of nitric oxide (NO) and hydrogen peroxide (H(2)O(2)) on the barrier function of a human intestinal epithelial cell line, Caco-2. When treated with H(2)O(2), Caco-2 cell monolayers grown on permeable supports exhibited several remarkable features of barrier dysfunction as follows: a decrease in transepithelial electrical resistance, an increase in paracellular permeability to dextran, and a disruption of the intercellular junctional localization of the scaffolding protein ZO-1. In addition, an induction of tyrosine phosphorylation of numerous cellular proteins including ZO-1, E-cadherin, and beta-catenin, components of tight and adherens junctions, was observed. On the other hand, combined treatment of Caco-2 monolayers with H(2)O(2) and an NO donor (NOC5 or NOC12) relieved the damage to the barrier function and suppressed the protein tyrosine phosphorylation induced by H(2)O(2) alone. These results suggest that NO protects the barrier function of intestinal epithelia from oxidative stress by modulating some intracellular signaling pathways of protein tyrosine phosphorylation in epithelial cells.

  6. Oral Supplementation with Bovine Colostrum Decreases Intestinal Permeability and Stool Concentrations of Zonulin in Athletes.

    PubMed

    Hałasa, Maciej; Maciejewska, Dominika; Baśkiewicz-Hałasa, Magdalena; Machaliński, Bogusław; Safranow, Krzysztof; Stachowska, Ewa

    2017-04-08

    Increased intestinal permeability has been implicated in various pathologies, has various causes, and can develop during vigorous athletic training. Colostrum bovinum is a natural supplement with a wide range of supposed positive health effects, including reduction of intestine permeability. We assessed influence of colostrum supplementation on intestinal permeability related parameters in a group of 16 athletes during peak training for competition. This double-blind placebo-controlled study compared supplementation for 20 days with 500 mg of colostrum bovinum or placebo (whey). Gut permeability status was assayed by differential absorption of lactulose and mannitol (L/M test) and stool zonulin concentration. Baseline L/M tests found that six of the participants (75%) in the colostrum group had increased intestinal permeability. After supplementation, the test values were within the normal range and were significantly lower than at baseline. The colostrum group Δ values produced by comparing the post-intervention and baseline results were also significantly lower than the placebo group Δ values. The differences in stool zonulin concentration were smaller than those in the L/M test, but were significant when the Δ values due to intervention were compared between the colostrum group and the placebo group. Colostrum bovinum supplementation was safe and effective in decreasing of intestinal permeability in this series of athletes at increased risk of its elevation.

  7. Rhodamine 123 permeability through the catfish intestinal wall: Relationship to thermal acclimation and acute temperature change.

    PubMed

    Kleinow, Kevin M; Johnston, Brad D; Holmes, Earnestine P; McCarrol, Matthew E

    2006-11-01

    Temperature is known to influence xenobiotic retention in fish. The effect of acute and acclimatory temperature change upon Rhodamine 123 (Rho123) permeability through an in vitro catfish multi-segment (3) everted sac intestinal wall model was examined in a 9 cell matrix of acclimation and assay temperatures (10, 20 and 30 degrees C). Changes in Rho123 permeability were examined in context with membrane fluidity, xenobiotic solubility and intestinal morphology. When assayed at the acclimation temperature greater Rho123 permeability was noted at warmer acclimation temperatures for the proximal and middle intestinal segments, while the distal segment exhibited little change and apparent compensation across temperatures. Rho123 permeability was increased as assay temperatures were elevated above the acclimation temperature for most comparisons. Cold acclimation significantly increased total intestinal length (43.2%) and proximal intestine weights while total body weights did not differ. Brush border membranes (BBM) increased fluidity with increased assay temperatures, however, composite anisotropy lines were not significantly different between acclimation treatments. In an additive manner, the membrane probe DPH exhibited increased solubility in BBM with increases in acclimation and assay temperatures. Compositely, these results suggest that acclimation and acute temperature change may differentially influence xenobiotic permeability among intestinal segments with interacting mechanisms.

  8. Postnatal ecdysis establishes the permeability barrier in snake skin: new insights into barrier lipid structures.

    PubMed

    Tu, M C; Lillywhite, H B; Menon, J G; Menon, G K

    2002-10-01

    A competent barrier to transepidermal water loss (TEWL) is essential for terrestrial life. In various vertebrates, epidermal water barriers composed of lipids prevent excessive TEWL, which varies inversely with habitat aridity. Little is known, however, about the mechanisms and regulation of permeability relative to natal transition from the 'aqueous' environments of gestation to the 'aerial' environments of terrestrial neonates. We investigated newly hatched California king snakes Lampropeltis getula to test the hypothesis that the first ecdysis is important for establishing the barrier to TEWL. We found that skin resistance to TEWL increases twofold following the first postnatal ecdysis, corresponding with a roughly twofold increase in thickness and deposition of lamellar lipids in the mesos layer, the site of the skin permeability barrier in snakes. In addition, novel observations on lipid inclusions within the alpha layer of epidermis suggest that this layer has functional similarities with avian epidermis. It appears that emergence of the integument from embryonic fluids, and its subsequent pan-body replacement following contact with air, are essential for completion of barrier competence in the newborn. These conditions provide a potentially useful model for investigations on the mechanism of barrier formation. We also found that hatchling snakes are transiently endothermic, with skin temperatures elevated by approximately 0.6 degrees C above ambient air temperature during the period of barrier formation. Behaviourally, hatchlings showed a higher tendency to seek humid microenvironments before the first ecdysis than after. The degree of water movement across the integument might explain the switch from reclusive to dispersive behaviours associated with postnatal ecdysis in snakes.

  9. Wave scattering by a permeable barrier over undulating bed topography

    NASA Astrophysics Data System (ADS)

    Choudhary, A.; Martha, S. C.

    2016-06-01

    The scattering of surface water waves by bottom undulation in the presence of a permeable vertical barrier is investigated for its solution. A mixed boundary value problem (BVP) arises here in a natural way while examining this physical problem. Regular perturbation analysis is employed to determine the solution of the BVP. By utilizing this analysis the given BVP reduces to two different BVPs up to first order. The solution of the zeroth order BVP is obtained with the aid of eigenfunction expansion method in conjunction with least-squares approximation. The first order BVP is solved with the help of the Green's integral theorem and the physical quantities, namely the reflection and transmission coefficients, are obtained in the form of integrals which involve the bottom undulation and the solution of the zeroth order BVP. A particular form of the bottom undulation which closely resembles to some obstacles made by nature due to sedimentation and ripple growth of sand, is considered to evaluate these integrals. The variation of these coefficients is examined for different values of the porous effect parameter, barrier length, number of ripples and ripple amplitude.

  10. Directed site exploration for permeable reactive barrier design

    USGS Publications Warehouse

    Lee, J.; Graettinger, A.J.; Moylan, J.; Reeves, H.W.

    2009-01-01

    Permeable reactive barriers (PRBs) are being employed for in situ site remediation of groundwater that is typically flowing under natural gradients. Site characterization is of critical importance to the success of a PRB. A design-specific site exploration approach called quantitatively directed exploration (QDE) is presented. The QDE approach employs three spatially related matrices: (1) covariance of input parameters, (2) sensitivity of model outputs, and (3) covariance of model outputs to identify the most important location to explore based on a specific design. Sampling at the location that most reduces overall site uncertainty produces a higher probability of success of a particular design. The QDE approach is demonstrated on the Kansas City Plant, Kansas City, MO, a case study where a PRB was installed and failed. It is shown that additional quantitatively directed site exploration during the design phase could have prevented the remedial failure that was caused by missing a geologic body having high hydraulic conductivity at the south end of the barrier. The most contributing input parameter approach using head uncertainty clearly indicated where the next sampling should be made toward the high hydraulic conductivity zone. This case study demonstrates the need to include the specific design as well as site characterization uncertainty when choosing the sampling locations. ?? 2008 Elsevier B.V.

  11. Human in vivo regional intestinal permeability: quantitation using site-specific drug absorption data.

    PubMed

    Sjögren, Erik; Dahlgren, David; Roos, Carl; Lennernäs, Hans

    2015-06-01

    Application of information on regional intestinal permeability has been identified as a key aspect of successful pharmaceutical product development. This study presents the results and evaluation of an approach for the indirect estimation of site-specific in vivo intestinal effective permeability (Peff) in humans. Plasma concentration-time profiles from 15 clinical studies that administered drug solutions to specific intestinal regions were collected and analyzed. The intestinal absorption rate for each drug was acquired by deconvolution, using historical intravenous data as reference, and used with the intestinal surface area and the dose remaining in the lumen to estimate the Peff. Forty-three new Peff values were estimated (15 from the proximal small intestine, 11 from the distal small intestine, and 17 from the large intestine) for 14 active pharmaceutical ingredients representing a wide range of biopharmaceutical properties. A good correlation (r(2) = 0.96, slope = 1.24, intercept = 0.030) was established between these indirect jejunal Peff estimates and jejunal Peff measurements determined directly using the single-pass perfusion double balloon technique. On average, Peff estimates from the distal small intestine and large intestine were 90% and 40%, respectively, of those from the proximal small intestine. These results support the use of the evaluated deconvolution method for indirectly estimating regional intestinal Peff in humans. This study presents the first comprehensive data set of estimated human regional intestinal permeability values for a range of drugs. These biopharmaceutical data can be used to improve the accuracy of gastrointestinal absorption predictions used in drug development decision-making.

  12. Cellular uptake and transcytosis of lipid-based nanoparticles across the intestinal barrier: Relevance for oral drug delivery.

    PubMed

    Neves, Ana Rute; Queiroz, Joana Fontes; Costa Lima, Sofia A; Figueiredo, Francisco; Fernandes, Rui; Reis, Salette

    2016-02-01

    Oral administration is the preferred route for drug delivery and nanosystems represent a promising tool for protection and transport of hardly soluble, chemically unstable and poorly permeable drugs through the intestinal barrier. In the present work, we have studied lipid nanoparticles cellular uptake, internalization pathways and transcytosis routes through Caco-2 cell monolayers. Both lipid nanosystems presented similar size (∼180nm) and surface charge (-30mV). Nanostructured lipid carriers showed a higher cellular uptake and permeability across the barrier, but solid lipid nanoparticles could enter cells faster than the former. The internalization of lipid nanoparticles occurs mainly through a clathrin-mediated endocytosis mechanism, although caveolae-mediated endocytosis is also involved in the uptake. Both lipid nanoparticles were able to cross the intestinal barrier by a preferential transcellular route. This work contributed to a better knowledge of the developed nanosystems for the oral delivery of a wide spectrum of drugs.

  13. Subacute stress and chronic stress interact to decrease intestinal barrier function in rats.

    PubMed

    Lauffer, Adriana; Vanuytsel, Tim; Vanormelingen, Christophe; Vanheel, Hanne; Salim Rasoel, Shadea; Tóth, Joran; Tack, Jan; Fornari, Fernando; Farré, Ricard

    2016-01-01

    Psychological stress increases intestinal permeability, potentially leading to low-grade inflammation and symptoms in functional gastrointestinal disorders. We assessed the effect of subacute, chronic and combined stress on intestinal barrier function and mast cell density. Male Wistar rats were allocated to four experimental groups (n = 8/group): 1/sham; 2/subacute stress (isolation and limited movement for 24 h); 3/chronic crowding stress for 14 days and 4/combined subacute and chronic stress. Jejunum and colon were collected to measure: transepithelial electrical resistance (TEER; a measure of epithelial barrier function); gene expression of tight junction molecules; mast cell density. Plasma corticosterone concentration was increased in all three stress conditions versus sham, with highest concentrations in the combined stress condition. TEER in the jejunum was decreased in all stress conditions, but was significantly lower in the combined stress condition than in the other groups. TEER in the jejunum correlated negatively with corticosterone concentration. Increased expression of claudin 1, 5 and 8, occludin and zonula occludens 1 mRNAs was detected after subacute stress in the jejunum. In contrast, colonic TEER was decreased only after combined stress, and the expression of tight junction molecules was unaltered. Increased mast cell density was observed in the chronic and combined stress condition in the colon only. In conclusion, our data show that chronic stress sensitizes the gastrointestinal tract to the effects of subacute stress on intestinal barrier function; different underlying cellular and molecular alterations are indicated in the small intestine versus the colon.

  14. Modulation of intestinal barrier by intestinal microbiota: pathological and therapeutic implications.

    PubMed

    Natividad, Jane M M; Verdu, Elena F

    2013-03-01

    Mammals and their intestinal microbiota peacefully coexist in a mutualistic relationship. Commensal bacteria play an active role in shaping and modulating physiological processes in the host, which include, but are not restricted to, the immune system and the intestinal barrier. Both play a crucial role in containing intestinal bacteria and other potentially noxious luminal antigens within the lumen and mucosal compartment. Although mutualism defines the relationship between the host and the intestinal microbiota, disruptions in this equilibrium may promote disease. Thus, alterations in gut microbiota (dysbiosis) have been linked to the recent increased expression of obesity, allergy, autoimmunity, functional and inflammatory disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). In this article, we review the evidence supporting a role of gut microbiota in regulating intestinal barrier function. We discuss the hypothesis that microbial factors can modulate the barrier in ways that can prevent or promote gastrointestinal disease. A better understanding of the role of the intestinal microbiota in maintaining a functional intestinal barrier may help develop targeted strategies to prevent and treat disease.

  15. ECONOMICS ANALYSIS OF THE IMPLEMENTATION OF PERMEABLE REACTIVE BARRIERS FOR REMEDIATION OF CONTAMINATED GROUND WATER

    EPA Science Inventory

    This report presents an analysis of the cost of using permeable reactive barriers to remediate contaminated ground water. When possible, these costs are compared with the cost of pump-and-treat technology for similar situations. Permeable reactive barriers are no longer perceiv...

  16. Surface altered zeolites as permeable barriers for in situ treatment of contaminated groundwater

    SciTech Connect

    1996-11-01

    The authors characterized surfactant-modified zeolite (SMZ) for its ability to sorb organic and inorganic contaminants from water. The ultimate objective is to use SMZ as a permeable barrier to prevent migration of contaminants in groundwater. This report summarizes results under Phase 1 of a three-phase project leading to a full-scale field demonstration of SMZ permeable- barrier technology.

  17. ECONOMICS ANALYSIS OF THE IMPLEMENTATION OF PERMEABLE REACTIVE BARRIERS FOR REMEDIATION OF CONTAMINATED GROUND WATER

    EPA Science Inventory

    This report presents an analysis of the cost of using permeable reactive barriers to remediate contaminated ground water. When possible, these costs are compared with the cost of pump-and-treat technology for similar situations. Permeable reactive barriers are no longer perceiv...

  18. SURFACE-ALTERED ZEOLITES AS PERMEABLE BARRIERS FOR IN SITU TREATMENT OF CONTAMINATED GROUNDWATER

    SciTech Connect

    Robert S. Bowman; Zhaohui Li; Stephen J. Roy; Todd Burt; Timothy L. Johnson; Richard L. Johnson

    1999-08-30

    The overall objective of this effort is to develop and test a zeolite-based permeable barrier system for containing and remediating contaminated groundwater. The projected product is an engineered and tested permeable barrier system that can be adopted by the commercial sector.

  19. Increased intestinal permeability and tight junction disruption by altered expression and localization of occludin in a murine graft versus host disease model

    PubMed Central

    2011-01-01

    Background Hematopoietic stem cell transplantation is increasingly performed for hematologic diseases. As a major side effect, acute graft versus host disease (GvHD) with serious gastrointestinal symptoms including diarrhea, gastrointestinal bleeding and high mortality can be observed. Because surveillance and biopsies of human gastrointestinal GvHD are difficult to perform, rare information of the alterations of the gastrointestinal barrier exists resulting in a need for systematic animal models. Methods To investigate the effects of GvHD on the intestinal barrier of the small intestine we utilized an established acute semi allogenic GvHD in C57BL/6 and B6D2F1 mice. Results By assessing the differential uptake of lactulose and mannitol in the jejunum, we observed an increased paracellular permeability as a likely mechanism for disturbed intestinal barrier function. Electron microscopy, immunohistochemistry and PCR analysis indicated profound changes of the tight-junction complex, characterized by downregulation of the tight junction protein occludin without any changes in ZO-1. Furthermore TNF-α expression was significantly upregulated. Conclusions This analysis in a murine model of GvHD of the small intestine demonstrates serious impairment of intestinal barrier function in the jejunum, with an increased permeability and morphological changes through downregulation and localization shift of the tight junction protein occludin. PMID:21977944

  20. Effect of Gliadin on Permeability of Intestinal Biopsy Explants from Celiac Disease Patients and Patients with Non-Celiac Gluten Sensitivity

    PubMed Central

    Hollon, Justin; Leonard Puppa, Elaine; Greenwald, Bruce; Goldberg, Eric; Guerrerio, Anthony; Fasano, Alessio

    2015-01-01

    Background: Intestinal exposure to gliadin leads to zonulin upregulation and consequent disassembly of intercellular tight junctions and increased intestinal permeability. We aimed to study response to gliadin exposure, in terms of barrier function and cytokine secretion, using intestinal biopsies obtained from four groups: celiac patients with active disease (ACD), celiac patients in remission (RCD), non-celiac patients with gluten sensitivity (GS) and non-celiac controls (NC). Methods: Ex-vivo human duodenal biopsies were mounted in microsnapwells and luminally incubated with either gliadin or media alone. Changes in transepithelial electrical resistance were monitored over 120 min. Media was subsequently collected and cytokines quantified. Results: Intestinal explants from all groups (ACD (n = 6), RCD (n = 6), GS (n = 6), and NC (n = 5)) demonstrated a greater increase in permeability when exposed to gliadin vs. media alone. The increase in permeability in the ACD group was greater than in the RCD and NC groups. There was a greater increase in permeability in the GS group compared to the RCD group. There was no difference in permeability between the ACD and GS groups, between the RCD and NC groups, or between the NC and GS groups. IL-10 was significantly greater in the media of the NC group compared to the RCD and GS groups. Conclusions: Increased intestinal permeability after gliadin exposure occurs in all individuals. Following gliadin exposure, both patients with gluten sensitivity and those with active celiac disease demonstrate a greater increase in intestinal permeability than celiacs in disease remission. A higher concentration of IL-10 was measured in the media exposed to control explants compared to celiac disease in remission or gluten sensitivity. PMID:25734566

  1. Effect of gliadin on permeability of intestinal biopsy explants from celiac disease patients and patients with non-celiac gluten sensitivity.

    PubMed

    Hollon, Justin; Puppa, Elaine Leonard; Greenwald, Bruce; Goldberg, Eric; Guerrerio, Anthony; Fasano, Alessio

    2015-02-27

    Intestinal exposure to gliadin leads to zonulin upregulation and consequent disassembly of intercellular tight junctions and increased intestinal permeability. We aimed to study response to gliadin exposure, in terms of barrier function and cytokine secretion, using intestinal biopsies obtained from four groups: celiac patients with active disease (ACD), celiac patients in remission (RCD), non-celiac patients with gluten sensitivity (GS) and non-celiac controls (NC). Ex-vivo human duodenal biopsies were mounted in microsnapwells and luminally incubated with either gliadin or media alone. Changes in transepithelial electrical resistance were monitored over 120 min. Media was subsequently collected and cytokines quantified. Intestinal explants from all groups (ACD (n = 6), RCD (n = 6), GS (n = 6), and NC (n = 5)) demonstrated a greater increase in permeability when exposed to gliadin vs. media alone. The increase in permeability in the ACD group was greater than in the RCD and NC groups. There was a greater increase in permeability in the GS group compared to the RCD group. There was no difference in permeability between the ACD and GS groups, between the RCD and NC groups, or between the NC and GS groups. IL-10 was significantly greater in the media of the NC group compared to the RCD and GS groups. Increased intestinal permeability after gliadin exposure occurs in all individuals. Following gliadin exposure, both patients with gluten sensitivity and those with active celiac disease demonstrate a greater increase in intestinal permeability than celiacs in disease remission. A higher concentration of IL-10 was measured in the media exposed to control explants compared to celiac disease in remission or gluten sensitivity.

  2. Rebeccamycin Attenuates TNF-α-Induced Intestinal Epithelial Barrier Dysfunction by Inhibiting Myosin Light Chain Kinase Production.

    PubMed

    Watari, Akihiro; Sakamoto, Yuta; Hisaie, Kota; Iwamoto, Kazuki; Fueta, Miho; Yagi, Kiyohito; Kondoh, Masuo

    2017-01-01

    Although proinflammatory cytokine-induced disruption of intestinal epithelial barrier integrity is associated with intestinal inflammatory disease, effective treatment for barrier dysfunction is lacking. Previously, we demonstrated that rebeccamycin alleviates epithelial barrier dysfunction induced by inflammatory cytokines in Caco-2 cell monolayers; however, the underlying mechanism remained unclear. Here, we investigated the mechanism by which rebeccamycin protects the epithelial barrier function of Caco-2 cells exposed to TNF-α. To confirm the epithelial barrier function of Caco-2 cell monolayers, transepithelial electrical resistance (TER) and paracellular permeability were measured. Production levels and localization of tight junction (TJ) proteins were analyzed by immunoblot and immunofluorescence, respectively. Phosphorylated myosin light chain (pMLC) and MLC kinase (MLCK) mRNA expression levels were determined by immunoblot and quantitative RT-PCR, respectively. Rebeccamycin attenuated the TNF-α-induced reduction in TER and increase in paracellular permeability. Rebeccamycin increased claudin-5 expression, but not claudin-1, -2, -4, occludin or ZO-1 expression, and prevented the TNF-α-induced changes in ZO-1 and occludin localization. Rebeccamycin suppressed the TNF-α-induced increase in MLCK mRNA expression, thus suppressing MLC phosphorylation. The rebeccamycin-mediated reduction in MLCK production and protection of epithelial barrier function were alleviated by Chk1 inhibition. Rebeccamycin attenuates TNF-α-induced disruption of intestinal epithelial barrier integrity by inducing claudin-5 expression and suppressing MLCK production via Chk1 activation. © 2017 The Author(s)Published by S. Karger AG, Basel.

  3. Intestinal permeability measurements: general aspects and possible pitfalls.

    PubMed

    Salles Teixeira, Tatiana Fiche; Boroni Moreira, Ana Paula; Silva Souza, Nilian Carla; Frias, Rafael; Gouveia Peluzio, Maria do Carmo

    2014-02-01

    Introducción: Alteraciones funcionales de la barrera intestinal se han relacionado con una variedad de enfermedades intestinales y también con enfermedades no intestinales. Las pruebas de permeabilidad intestinal son consideradas herramientas útiles para evaluar la gravedad de la enfermedad para el posterior seguimiento de los pacientes después de una intervención terapéutica. Objetivo: El objeto de esta revisión ha sido destacar los posibles factores que pueden estar asociados a una mayor permeabilidad intestinal y revisar condiciones clínicas que han sido asociadas en individuos de diferentes edades. También revisar ciertos aspectos metodológicos de las pruebas de permeabilidad intestinal. Resultados y discusión: Las uniones estrechas entre los enterocitos son las principales estructuras encargadas de la regulación de la barrera intestinal. Una alteración de éstas, resulta en una deficiencia en la permeabilidad intestinal y una mayor penetración de las sustancias marcadoras de permeabilidad intestinal. La lactulosa y el manitol son las sustancias marcadoras más utilizadas. La inocuidad y facilidad de los test de permeabilidad han sido de ayuda para explorar y ampliar el conocimiento de muchas condiciones clínicas en las que la disfunción de la barrera intestinal ha sido un sello distintivo. Muchos factores pueden influir en los resultados de los test de permeabilidad. Sin embargo, los investigadores y los clínicos han de tratar de eludir los posibles inconvenientes de las pruebas de permeabilidad intestinal para poder producir evidencias más consistentes. El uso de otras sustancias marcadoras de la fisiología intestinal también puede contribuir a comprender mejor el papel de la barrera intestinal en diferentes enfermedades.

  4. Zeolite in horizontal permeable reactive barriers for artificial groundwater recharge

    NASA Astrophysics Data System (ADS)

    Leal, María; Martínez-Hernández, Virtudes; Lillo, Javier; Meffe, Raffaella; de Bustamante, Irene

    2013-04-01

    The Spanish Water Reuse Royal Decree 1620/2007 considers groundwater recharge as a feasible use of reclaimed water. To achieve the water quality established in the above-mentioned legislation, a tertiary wastewater treatment is required. In this context, the infiltration of effluents generated by secondary wastewater treatments through a Horizontal Permeable Reactive Barrier (HPRB) may represent a suitable regeneration technology. Some nutrients (phosphate and ammonium) and some Pharmaceutical and Personal Care Products (PPCPs) are not fully removed in conventional wastewater treatment plants. To avoid groundwater contamination when effluents of wastewater treatments plants are used in artificial recharge activities, these contaminants have to be removed. Due to its sorption capacities, zeolite is among the most used reactive materials in Permeable Reactive Barrier (PRB). Therefore, the main goal of this study is to evaluate the zeolite retention effectiveness of nutrients and PPCPs occurring in treated wastewater. Batch sorption experiments using synthetic wastewater (SWW) and zeolite were performed. A 1:4 zeolite/SWW ratio was selected due to the high sorption capacity of the reactive material.The assays were carried out by triplicate. All the bottles containing the SWW-zeolite mixture were placed on a mechanical shaker during 24 hours at 140 rpm and 25 °C. Ammonium and phosphate, as main nutrients, and a group of PPCPs were selected as compounds to be tested during the experiments. Nutrients were analyzed by ion chromatography. For PPCPs determination, Solid Phase Extraction (SPE) was applied before their analysis by liquid chromatography-mass spectrometry time of flight (LC-MS/ TOF). The experimental data were fitted to linearized Langmuir and Freundlich isotherm equations to obtain sorption parameters. In general, Freundlich model shows a greater capability of reproducing experimental data. To our knowledge, sorption of the investigated compounds on zeolite

  5. An improved prediction of the human in vivo intestinal permeability and BCS class of drugs using the in vitro permeability ratio obtained for rat intestine using an Ussing chamber system.

    PubMed

    Li, Hong; Jin, Hyo-Eon; Shim, Won-Sik; Shim, Chang-Koo

    2013-10-01

    The Biopharmaceutics Classification System (BCS) was developed to facilitate estimation of the in vivo pharmacokinetic performance of drugs from human intestinal permeability and solubility. However, the measurement of human in vivo intestinal permeability, unlike that of solubility, is problematic and inefficient. Thus, rat in vitro intestinal permeability results obtained via the Ussing chamber technique are often used instead. However, these data could be unreliable due to difficulty in maintaining the viability of the dissected intestinal membrane in the Ussing chamber. Therefore, a more efficient method to obtain a reliable in vitro permeability is mandatory. Here, we propose a new approach by introducing a novel factor called the permeability ratio (PR). Basically, PR is a rat in vitro intestinal permeability obtained from the Ussing chamber, which is then corrected by the permeability of lucifer yellow, a paracellular permeability marker. To prove the validity of the method, 12 model drugs representing different BCS classes were tested, and the correlation with human in vivo intestinal permeability was high. More importantly, the new method perfectly classified all 12 model drugs. The results indicate that PR is a reliable factor with high correlation to human in vivo intestinal permeability, which can further be used to accurately predict the BCS classification.

  6. Boswellia serrata Preserves Intestinal Epithelial Barrier from Oxidative and Inflammatory Damage.

    PubMed

    Catanzaro, Daniela; Rancan, Serena; Orso, Genny; Dall'Acqua, Stefano; Brun, Paola; Giron, Maria Cecilia; Carrara, Maria; Castagliuolo, Ignazio; Ragazzi, Eugenio; Caparrotta, Laura; Montopoli, Monica

    2015-01-01

    Aminosalicylates, corticosteroids and immunosuppressants are currently the therapeutic choices in inflammatory bowel diseases (IBD), however, with limited remission and often serious side effects. Meanwhile complementary and alternative medicine (CAM) use is increasing, particularly herbal medicine. Boswellia serrata is a traditional Ayurvedic remedy with anti-inflammatory properties, of interest for its usefulness in IBDs. The mechanism of this pharmacological potential of Boswellia serrata was investigated in colonic epithelial cell monolayers exposed to H2O2 or INF-γ+TNF-α, chosen as in vitro experimental model of intestinal inflammation. The barrier function was evaluated by the transepithelial electrical resistance (TEER) and paracellular permeability assay, and by the tight junction proteins (zonula occludens-1, ZO-1 and occludin) immunofluorescence. The expression of phosphorylated NF-κB and reactive oxygen species (ROS) generation were determined by immunoblot and cytofluorimetric assay, respectively. Boswellia serrata oleo-gum extract (BSE) and its pure derivative acetyl-11-keto-β-boswellic acid (AKBA), were tested at 0.1-10 μg/ml and 0.027 μg/ml, respectively. BSE and AKBA safety was demonstrated by no alteration of intestinal cell viability and barrier function and integrity biomarkers. H2O2 or INF-γ+TNF-α treatment of Caco-2 cell monolayers significantly reduced TEER, increased paracellular permeability and caused the disassembly of tight junction proteins occludin and ZO-1. BSE and AKBA pretreatment significantly prevented functional and morphological alterations and also the NF-κB phosphorylation induced by the inflammatory stimuli. At the same concentrations BSE and AKBA counteracted the increase of ROS caused by H2O2 exposure. Data showed the positive correlation of the antioxidant activity with the mechanism involved in the physiologic maintenance of the integrity and function of the intestinal epithelium. This study elucidates the

  7. Boswellia serrata Preserves Intestinal Epithelial Barrier from Oxidative and Inflammatory Damage

    PubMed Central

    Catanzaro, Daniela; Rancan, Serena; Orso, Genny; Dall’Acqua, Stefano; Brun, Paola; Giron, Maria Cecilia; Carrara, Maria; Castagliuolo, Ignazio; Ragazzi, Eugenio; Caparrotta, Laura; Montopoli, Monica

    2015-01-01

    Aminosalicylates, corticosteroids and immunosuppressants are currently the therapeutic choices in inflammatory bowel diseases (IBD), however, with limited remission and often serious side effects. Meanwhile complementary and alternative medicine (CAM) use is increasing, particularly herbal medicine. Boswellia serrata is a traditional Ayurvedic remedy with anti-inflammatory properties, of interest for its usefulness in IBDs. The mechanism of this pharmacological potential of Boswellia serrata was investigated in colonic epithelial cell monolayers exposed to H2O2 or INF-γ+TNF-α, chosen as in vitro experimental model of intestinal inflammation. The barrier function was evaluated by the transepithelial electrical resistance (TEER) and paracellular permeability assay, and by the tight junction proteins (zonula occludens-1, ZO-1 and occludin) immunofluorescence. The expression of phosphorylated NF-κB and reactive oxygen species (ROS) generation were determined by immunoblot and cytofluorimetric assay, respectively. Boswellia serrata oleo-gum extract (BSE) and its pure derivative acetyl-11-keto-β-boswellic acid (AKBA), were tested at 0.1-10 μg/ml and 0.027μg/ml, respectively. BSE and AKBA safety was demonstrated by no alteration of intestinal cell viability and barrier function and integrity biomarkers. H2O2 or INF-γ+TNF-α treatment of Caco-2 cell monolayers significantly reduced TEER, increased paracellular permeability and caused the disassembly of tight junction proteins occludin and ZO-1. BSE and AKBA pretreatment significantly prevented functional and morphological alterations and also the NF-κB phosphorylation induced by the inflammatory stimuli. At the same concentrations BSE and AKBA counteracted the increase of ROS caused by H2O2 exposure. Data showed the positive correlation of the antioxidant activity with the mechanism involved in the physiologic maintenance of the integrity and function of the intestinal epithelium. This study elucidates the

  8. Rotavirus Infection Increases Intestinal Motility but Not Permeability at the Onset of Diarrhea

    PubMed Central

    Istrate, Claudia; Hagbom, Marie; Vikström, Elena; Magnusson, Karl-Eric

    2014-01-01

    ABSTRACT The disease mechanisms associated with onset and secondary effects of rotavirus (RV) diarrhea remain to be determined and may not be identical. In this study, we investigated whether onset of RV diarrhea is associated with increased intestinal permeability and/or motility. To study the transit time, fluorescent fluorescein isothiocyanate (FITC)-dextran was given to RV-infected adult and infant mice. Intestinal motility was also studied with an opioid receptor agonist (loperamide) and a muscarinic receptor antagonist (atropine). To investigate whether RV increases permeability at the onset of diarrhea, fluorescent 4- and 10-kDa dextran doses were given to infected and noninfected mice, and fluorescence intensity was measured subsequently in serum. RV increased transit time in infant mice. Increased motility was detected at 24 h postinfection (h p.i.) and persisted up to 72 h p.i in pups. Both loperamide and atropine decreased intestinal motility and attenuated diarrhea. Analysis of passage of fluorescent dextran from the intestine into serum indicated unaffected intestinal permeability at the onset of diarrhea (24 to 48 h p.i.). We show that RV-induced diarrhea is associated with increased intestinal motility via an activation of the myenteric nerve plexus, which in turn stimulates muscarinic receptors on intestinal smooth muscles. IMPORTANCE We show that RV-infected mice have increased intestinal motility at the onset of diarrhea, and that this is not associated with increased intestinal permeability. These new observations will contribute to a better understanding of the mechanisms involved in RV diarrhea. PMID:24371070

  9. Oral Administration of Probiotics Inhibits Absorption of the Heavy Metal Cadmium by Protecting the Intestinal Barrier.

    PubMed

    Zhai, Qixiao; Tian, Fengwei; Zhao, Jianxin; Zhang, Hao; Narbad, Arjan; Chen, Wei

    2016-07-15

    The heavy metal cadmium (Cd) is an environmental pollutant that causes adverse health effects in humans and animals. Our previous work demonstrated that oral administration of probiotics can significantly inhibit Cd absorption in the intestines of mice, but further evidence is needed to gain insights into the related protection mode. The goal of this study was to evaluate whether probiotics can inhibit Cd absorption through routes other than the Cd binding, with a focus on gut barrier protection. In the in vitro assay, both the intervention and therapy treatments of Lactobacillus plantarum CCFM8610 alleviated Cd-induced cytotoxicity in the human intestinal cell line HT-29 and protected the disruption of tight junctions in the cell monolayers. In a mouse model, probiotics with either good Cd-binding or antioxidative ability increased fecal Cd levels and decreased Cd accumulation in the tissue of Cd-exposed mice. Compared with the Cd-only group, cotreatment with probiotics also reversed the disruption of tight junctions, alleviated inflammation, and decreased the intestinal permeability of mice. L. plantarum CCFM8610, a strain with both good Cd binding and antioxidative abilities, exhibited significantly better protection than the other two strains. These results suggest that along with initial intestinal Cd sequestration, probiotics can inhibit Cd absorption by protecting the intestinal barrier, and the protection is related to the alleviation of Cd-induced oxidative stress. A probiotic with both good Cd-binding and antioxidative capacities can be used as a daily supplement for the prevention of oral Cd exposure. The heavy metal cadmium (Cd) is an environmental pollutant that causes adverse health effects in humans and animals. For the general population, food and drinking water are the main sources of Cd exposure due to the biomagnification of Cd within the food chain; therefore, the intestinal tract is the first organ that is susceptible to Cd contamination

  10. Oral Administration of Probiotics Inhibits Absorption of the Heavy Metal Cadmium by Protecting the Intestinal Barrier

    PubMed Central

    Zhai, Qixiao; Tian, Fengwei; Zhao, Jianxin; Zhang, Hao; Narbad, Arjan

    2016-01-01

    ABSTRACT The heavy metal cadmium (Cd) is an environmental pollutant that causes adverse health effects in humans and animals. Our previous work demonstrated that oral administration of probiotics can significantly inhibit Cd absorption in the intestines of mice, but further evidence is needed to gain insights into the related protection mode. The goal of this study was to evaluate whether probiotics can inhibit Cd absorption through routes other than the Cd binding, with a focus on gut barrier protection. In the in vitro assay, both the intervention and therapy treatments of Lactobacillus plantarum CCFM8610 alleviated Cd-induced cytotoxicity in the human intestinal cell line HT-29 and protected the disruption of tight junctions in the cell monolayers. In a mouse model, probiotics with either good Cd-binding or antioxidative ability increased fecal Cd levels and decreased Cd accumulation in the tissue of Cd-exposed mice. Compared with the Cd-only group, cotreatment with probiotics also reversed the disruption of tight junctions, alleviated inflammation, and decreased the intestinal permeability of mice. L. plantarum CCFM8610, a strain with both good Cd binding and antioxidative abilities, exhibited significantly better protection than the other two strains. These results suggest that along with initial intestinal Cd sequestration, probiotics can inhibit Cd absorption by protecting the intestinal barrier, and the protection is related to the alleviation of Cd-induced oxidative stress. A probiotic with both good Cd-binding and antioxidative capacities can be used as a daily supplement for the prevention of oral Cd exposure. IMPORTANCE The heavy metal cadmium (Cd) is an environmental pollutant that causes adverse health effects in humans and animals. For the general population, food and drinking water are the main sources of Cd exposure due to the biomagnification of Cd within the food chain; therefore, the intestinal tract is the first organ that is susceptible to Cd

  11. [Removal of nitrate from groundwater using permeable reactive barrier].

    PubMed

    Li, Xiu-Li; Yang, Jun-Jun; Lu, Xiao-Xia; Zhang, Shu; Hou, Zhen

    2013-03-01

    To provide a cost-effective method for the remediation of nitrate-polluted groundwater, column experiments were performed to study the removal of nitrate by permeable reactive barrier filled with fermented mulch and sand (biowall), and the mechanisms and influence factors were explored. The experimental results showed that the environmental condition in the simulated biowall became highly reduced after three days of operation (oxidation-reduction potential was below - 100 mV), which was favorable for the reduction of nitrate. During the 15 days of operation, the removal rate of nitrate nitrogen (NO3(-) -N) by the simulated biowall was 80%-90% (NO3(-)-N was reduced from 20 mg x L(-1) in the inlet water to 1.6 mg x L(-1) in the outlet water); the concentration of nitrite nitrogen (NO2(-) -N) in the outlet water was below 2.5 mg x L(-1); the concentration of ammonium nitrogen (NH4(+) -N) was low in the first two days but increased to about 12 mg x L(-1) since day three. The major mechanisms involved in the removal of nitrate nitrogen were adsorption and biodegradation. When increasing the water flow velocity in the simulated biowall, the removal rate of NO3(-) -N was reduced and the concentration of NH4(+) -N in the outlet water was significantly reduced. A simulated zeolite wall was set up following the simulated biowall and 98% of the NH4(+) -N could be removed from the water.

  12. Clathrin inhibitor Pitstop-2 disrupts the nuclear pore complex permeability barrier

    PubMed Central

    Liashkovich, Ivan; Pasrednik, Dzmitry; Prystopiuk, Valeria; Rosso, Gonzalo; Oberleithner, Hans; Shahin, Victor

    2015-01-01

    Existence of a selective nucleocytoplasmic permeability barrier is attributed to Phenylalanine-Glycine rich proteins (FG-nups) within the central channel of the nuclear pore complex (NPC). Limited understanding of the FG-nup structural arrangement hinders development of strategies directed at disrupting the NPC permeability barrier. In this report we explore an alternative approach to enhancing the NPC permeability for exogenous macromolecules. We demonstrate that the recently discovered inhibitor of clathrin coat assembly Pitstop-2 compromises the NPC permeability barrier in a rapid and effective manner. Treatment with Pitstop-2 causes a collapse of the NPC permeability barrier and a reduction of Importin β binding accompanied by alteration of the NPC ultrastructure. Interestingly, the effects are induced by the same chemical agent that is capable of inhibiting clathrin-mediated endocytosis. To our knowledge, this is the first functional indication of the previously postulated evolutionary relation between clathrin and NPC scaffold proteins. PMID:25944393

  13. TNF-α Modulation of Intestinal Tight Junction Permeability Is Mediated by NIK/IKK-α Axis Activation of the Canonical NF-κB Pathway

    PubMed Central

    Al-Sadi, Rana; Guo, Shuhong; Ye, Dongmei; Rawat, Manmeet; Ma, Thomas Y.

    2017-01-01

    Tumor necrosis factor (TNF)-α, a key mediator of intestinal inflammation, causes an increase in intestinal epithelial tight junction (TJ) permeability by activating myosin light chain kinase (MLCK; official name MYLK3) gene. However, the precise signaling cascades that mediate the TNF-α–induced activation of MLCK gene and increase in TJ permeability remain unclear. Our aims were to delineate the upstream signaling mechanisms that regulate the TNF-α modulation of intestinal TJ barrier function with the use of in vitro and in vivo intestinal epithelial model systems. TNF-α caused a rapid activation of both canonical and noncanonical NF-κB pathway. NF-κB–inducing kinase (NIK) and mitogen-activated protein kinase kinase-1 (MEKK-1) were activated in response to TNF-α. NIK mediated the TNF-α activation of inhibitory κB kinase (IKK)-α, and MEKK1 mediated the activation of IKK complex, including IKK-β. NIK/IKK-α axis regulated the activation of both NF-κB p50/p65 and RelB/p52 pathways. Surprisingly, the siRNA induced knockdown of NIK, but not MEKK-1, prevented the TNF-α activation of both NF-κB p50/p65 and RelB/p52 and the increase in intestinal TJ permeability. Moreover, NIK/IKK-α/NF-κB p50/p65 axis mediated the TNF-α–induced MLCK gene activation and the subsequent MLCK increase in intestinal TJ permeability. In conclusion, our data show that NIK/IKK-α/regulates the activation of NF-κB p50/p65 and plays an integral role in the TNF-α–induced activation of MLCK gene and increase in intestinal TJ permeability. PMID:26948423

  14. A somatic permeability barrier around the germline is essential for Drosophila spermatogenesis.

    PubMed

    Fairchild, Michael J; Smendziuk, Christopher M; Tanentzapf, Guy

    2015-01-15

    Interactions between the soma and germline are essential for gametogenesis. In the Drosophila testis, differentiating germ cells are encapsulated by two somatic cells that surround the germline throughout spermatogenesis. chickadee (chic), the fly ortholog of Profilin, mediates soma-germline interactions. Knockdown of Chic in the soma results in sterility and severely disrupted spermatogenesis due to defective encapsulation. To study this defect further, we developed a permeability assay to analyze whether the germline is isolated from the surrounding environment by the soma. We find that germline encapsulation by the soma is, by itself, insufficient for the formation of a permeability barrier, but that such a barrier gradually develops during early spermatogenesis. Thus, germline stem cells, gonialblasts and early spermatogonia are not isolated from the outside environment. By late spermatocyte stages, however, a permeability barrier is formed by the soma. Furthermore, we find that, concomitant with formation of the permeability barrier, septate junction markers are expressed in the soma and localize to junctional sites connecting the two somatic cells that surround the germline. Importantly, knockdown of septate junction components also disrupts the permeability barrier. Finally, we show that germline differentiation is delayed when the permeability barrier is compromised. We propose that the permeability barrier around the germline serves an important regulatory function during spermatogenesis by shaping the signaling events that take place between the soma and the germline.

  15. Stress does not increase blood–brain barrier permeability in mice

    PubMed Central

    Roszkowski, Martin

    2016-01-01

    Several studies have reported that exposure to acute psychophysiological stressors can lead to an increase in blood–brain barrier permeability, but these findings remain controversial and disputed. We thoroughly examined this issue by assessing the effect of several well-established paradigms of acute stress and chronic stress on blood–brain barrier permeability in several brain areas of adult mice. Using cerebral extraction ratio for the small molecule tracer sodium fluorescein (NaF, 376 Da) as a sensitive measure of blood–brain barrier permeability, we find that neither acute swim nor restraint stress lead to increased cerebral extraction ratio. Daily 6-h restraint stress for 21 days, a model for the severe detrimental impact of chronic stress on brain function, also does not alter cerebral extraction ratio. In contrast, we find that cold forced swim and cold restraint stress both lead to a transient, pronounced decrease of cerebral extraction ratio in hippocampus and cortex, suggesting that body temperature can be an important confounding factor in studies of blood–brain barrier permeability. To additionally assess if stress could change blood–brain barrier permeability for macromolecules, we measured cerebral extraction ratio for fluorescein isothiocyanate-dextran (70 kDa). We find that neither acute restraint nor cold swim stress affected blood–brain barrier permeability for macromolecules, thus corroborating our findings that various stressors do not increase blood–brain barrier permeability. PMID:27146513

  16. Design of vancomycin RS-100 nanoparticles in order to increase the intestinal permeability

    PubMed Central

    Loveymi, Badir Delf; Jelvehgari, Mitra; Zakeri-Milani, Parvin; Valizadeh, Hadi

    2012-01-01

    Purpose: The purpose of this work was to preparation of vancomycin (VCM) biodegradable nanoparticles to improve the intestinal permeability, using water-in-oil-in-water (W/O/W) multiple emulsion method. Methods: The vancomycin-loaded nanoparticles were created using double-emulsion solvent evaporation method. Using Eudragit RS100 as a coating material. The prepared nanoparticles were identifyed for their micromeritic and crystallographic properties, drug loading, particle size, drug release, Zeta potential, effective permeability (Peff) and oral fractional absorption. Intestinal permeability of VCM nanoparticles was figured out, in different concentrations using SPIP technique in rats. Results: Particle sizes were between 362 and 499 nm for different compositions of VCM-RS-100 nanoparticles. Entrapment efficiency expansed between 63%-94.76%. The highest entrapment efficiency 94.76% was obtained when the ratio of drug to polymer was 1:3. The in vitro release studies were accomplished in pH 7.4. The results showed that physicochemical properties were impressed by drug to polymer ratio. The FT-IR, XRPD and DSC results ruled out any chemical interaction betweenthe drug and RS-100. Effective intestinal permeability values of VCM nanoparticles in concentrations of 200, 300 and 400 μg/ml were higher than that of solutions at the same concentrations. Oral fractional absorption was achieved between 0.419-0.767. Conclusion: Our findings suggest that RS-100 nanoparticles could provide a delivery system for VCM, with enhanced intestinal permeability. PMID:24312770

  17. Design of vancomycin RS-100 nanoparticles in order to increase the intestinal permeability.

    PubMed

    Loveymi, Badir Delf; Jelvehgari, Mitra; Zakeri-Milani, Parvin; Valizadeh, Hadi

    2012-01-01

    The purpose of this work was to preparation of vancomycin (VCM) biodegradable nanoparticles to improve the intestinal permeability, using water-in-oil-in-water (W/O/W) multiple emulsion method. The vancomycin-loaded nanoparticles were created using double-emulsion solvent evaporation method. Using Eudragit RS100 as a coating material. The prepared nanoparticles were identifyed for their micromeritic and crystallographic properties, drug loading, particle size, drug release, Zeta potential, effective permeability (Peff) and oral fractional absorption. Intestinal permeability of VCM nanoparticles was figured out, in different concentrations using SPIP technique in rats. Particle sizes were between 362 and 499 nm for different compositions of VCM-RS-100 nanoparticles. Entrapment efficiency expansed between 63%-94.76%. The highest entrapment efficiency 94.76% was obtained when the ratio of drug to polymer was 1:3. The in vitro release studies were accomplished in pH 7.4. The results showed that physicochemical properties were impressed by drug to polymer ratio. The FT-IR, XRPD and DSC results ruled out any chemical interaction betweenthe drug and RS-100. Effective intestinal permeability values of VCM nanoparticles in concentrations of 200, 300 and 400 μg/ml were higher than that of solutions at the same concentrations. Oral fractional absorption was achieved between 0.419-0.767. Our findings suggest that RS-100 nanoparticles could provide a delivery system for VCM, with enhanced intestinal permeability.

  18. Construction of low permeability soil-bentonite barrier caps and liners for landfills

    SciTech Connect

    Webber, T.; Williams, M.

    1995-12-31

    A low permeability soil barrier layer is the usual regulatory requirement for both caps and liner systems on modern municipal, industrial, and hazardous waste landfills. This soil layer is either used as the sole barrier or as the soil component of a composite liner system. This paper presents construction experience for blending on site soils with sodium bentonite to produce a thick, low permeability soil barrier layer. The paper begins with a description of the components and construction of the barrier layer and discusses how soil-bentonite barrier layers meet or exceed the regulatory performance criteria for both State and Federal agencies.

  19. Self-Microemulsifying Drug Delivery System: Formulation and Study Intestinal Permeability of Ibuprofen in Rats

    PubMed Central

    Subudhi, Bharat Bhushan; Mandal, Surjyanarayan

    2013-01-01

    The study was aimed at developing a self-microemulsifying drug delivery system (SMEDDS) of Ibuprofen for investigating its intestinal transport behavior using the single-pass intestinal perfusion (SPIP) method in rat. Methods. Ibuprofen loaded SMEDDS (ISMEDDS) was developed and was characterized. The permeability behavior of Ibuprofen over three different concentrations (20, 30, and 40 µg/mL) was studied in each isolated region of rat intestine by SPIP method at a flow rate of 0.2 mL/min. The human intestinal permeability was predicted using the Lawrence compartment absorption and transit (CAT) model since effective permeability coefficients (Peff) values for rat are highly correlated with those of human, and comparative intestinal permeability of Ibuprofen was carried out with plain drug suspension (PDS) and marketed formulation (MF). Results. The developed ISMEDDS was stable, emulsified upon mild agitation with 44.4 nm ± 2.13 and 98.86% ± 1.21 as globule size and drug content, respectively. Higher Peff in colon with no significant Peff difference in jejunum, duodenum, and ileum was observed. The estimated human absorption of Ibuprofen for the SMEDDS was higher than that for PDS and MF (P < 0.01). Conclusion. Developed ISMEDDS would possibly be advantageous in terms of minimized side effect, increased bioavailability, and hence the patient compliance. PMID:26555973

  20. Involvement of intestinal permeability in the oral absorption of clarithromycin and telithromycin.

    PubMed

    Togami, Kohei; Hayashi, Yoshiaki; Chono, Sumio; Morimoto, Kazuhiro

    2014-09-01

    The involvement of intestinal permeability in the oral absorption of clarithromycin (CAM), a macrolide antibiotic, and telithromycin (TEL), a ketolide antibiotic, in the presence of efflux transporters was examined. In order independently to examine the intestinal and hepatic availability, CAM and TEL (10 mg/kg) were administered orally, intraportally and intravenously to rats. The intestinal and hepatic availability was calculated from the area under the plasma concentration-time curve (AUC) after administration of CAM and TEL via different routes. The intestinal availabilities of CAM and TEL were lower than their hepatic availabilities. The intestinal availability after oral administration of CAM and TEL increased by 1.3- and 1.6-fold, respectively, after concomitant oral administration of verapamil as a P-glycoprotein (P-gp) inhibitor. Further, an in vitro transport experiment was performed using Caco-2 cell monolayers as a model of intestinal epithelial cells. The apical-to-basolateral transport of CAM and TEL through the Caco-2 cell monolayers was lower than their basolateral-to-apical transport. Verapamil and bromosulfophthalein as a multidrug resistance-associated proteins (MRPs) inhibitor significantly increased the apical-to-basolateral transport of CAM and TEL. Thus, the results suggest that oral absorption of CAM and TEL is dependent on intestinal permeability that may be limited by P-gp and MRPs on the intestinal epithelial cells.

  1. Mechanism of IL-1β Modulation of Intestinal Epithelial Barrier Involves p38 Kinase and Activating Transcription Factor-2 Activation

    PubMed Central

    Al-Sadi, Rana; Guo, Shuhong; Ye, Dongmei; Dokladny, Karol; Alhmoud, Tarik; Ereifej, Lisa; Said, Hamid M.

    2013-01-01

    The defective intestinal epithelial tight junction (TJ) barrier has been postulated to be an important pathogenic factor contributing to intestinal inflammation. It has been shown that the proinflammatory cytokine IL-1β causes an increase in intestinal permeability; however, the signaling pathways and the molecular mechanisms involved remain unclear. The major purpose of this study was to investigate the role of the p38 kinase pathway and the molecular processes involved. In these studies, the in vitro intestinal epithelial model system (Caco-2 monolayers) was used to delineate the cellular and molecular mechanisms, and a complementary in vivo mouse model system (intestinal perfusion) was used to assess the in vivo relevance of the in vitro findings. Our data indicated that the IL-1β increase in Caco-2 TJ permeability correlated with an activation of p38 kinase. The activation of p38 kinase caused phosphorylation and activation of p38 kinase substrate, activating transcription factor (ATF)-2. The activated ATF-2 translocated to the nucleus where it attached to its binding motif on the myosin L chain kinase (MLCK) promoter region, leading to the activation of MLCK promoter activity and gene transcription. Small interfering RNA induced silencing of ATF-2, or mutation of the ATF-2 binding motif prevented the activation of MLCK promoter and MLCK mRNA transcription. Additionally, in vivo intestinal perfusion studies also indicated that the IL-1β increase in mouse intestinal permeability required p38 kinase–dependent activation of ATF-2. In conclusion, these studies show that the IL-1β–induced increase in intestinal TJ permeability in vitro and in vivo was regulated by p38 kinase activation of ATF-2 and by ATF-2 regulation of MLCK gene activity. PMID:23656735

  2. Cold exposure increases intestinal paracellular permeability to nutrients in the mouse.

    PubMed

    Price, Edwin R; Ruff, Lisa J; Guerra, Alberto; Karasov, William H

    2013-11-01

    In situations of increased energy demand and food intake, animals can often acclimate within several days. The intestine generally responds to elevated digestive demand by increasing in size. However, there is likely a limit to how quickly the intestine can grow to meet the new demand. We investigated the immediate and longer-term changes to intestinal properties of the mouse when suddenly exposed to 4°C. We hypothesized that paracellular permeability to nutrients would increase as part of an immediate response to elevated absorptive demand. We measured absorption of l-arabinose, intestinal size and gene expression of several tight junction proteins (claudin-2, claudin-4, claudin-15 and ZO-1) at three time points: pre-exposure, and after 1 day and 2 weeks of cold exposure. Cold exposure increased food intake by 62% after 2 weeks but intake was not significantly increased after 1 day. Intestinal wet mass was elevated after 1 day and throughout the experiment. Absorption of arabinose rose by 20% after 1 day in the cold and was 33% higher after 2 weeks. Expression of claudin-2 increased after 1 day of cold exposure, but there were no changes in expression of any claudin genes when normalized to ZO-1 expression. Our results indicate that intestinal mass can respond rapidly to increased energy demand and that increased paracellular permeability is also part of that response. Increased paracellular permeability may be a consequence of enterocyte hyperplasia, resulting in more tight junctions across which molecules can absorb.

  3. Inhalation of methane preserves the epithelial barrier during ischemia and reperfusion in the rat small intestine.

    PubMed

    Mészáros, András T; Büki, Tamás; Fazekas, Borbála; Tuboly, Eszter; Horváth, Kitti; Poles, Marietta Z; Szűcs, Szilárd; Varga, Gabriella; Kaszaki, József; Boros, Mihály

    2017-06-01

    Methane is part of the gaseous environment of the intestinal lumen. The purpose of this study was to elucidate the bioactivity of exogenous methane on the intestinal barrier function in an antigen-independent model of acute inflammation. Anesthetized rats underwent sham operation or 45-min occlusion of the superior mesenteric artery. A normoxic methane (2.2%)-air mixture was inhaled for 15 min at the end of ischemia and at the beginning of a 60-min or 180-min reperfusion. The integrity of the epithelial barrier of the ileum was assessed by determining the lumen-to-blood clearance of fluorescent dextran, while microvascular permeability changes were detected by the Evans blue technique. Tissue levels of superoxide, nitrotyrosine, myeloperoxidase, and endothelin-1 were measured, the superficial mucosal damage was visualized and quantified, and the serosal microcirculation and mesenteric flow was recorded. Erythrocyte deformability and aggregation were tested in vitro. Reperfusion significantly increased epithelial permeability, worsened macro- and microcirculation, increased the production of proinflammatory mediators, and resulted in a rapid loss of the epithelium. Exogenous normoxic methane inhalation maintained the superficial mucosal structure, decreased epithelial permeability, and improved local microcirculation, with a decrease in reactive oxygen and nitrogen species generation. Both the deformability and aggregation of erythrocytes improved with incubation of methane. Normoxic methane decreases the signs of oxidative and nitrosative stress, improves tissue microcirculation, and thus appears to modulate the ischemia-reperfusion-induced epithelial permeability changes. These findings suggest that the administration of exogenous methane may be a useful strategy for maintaining the integrity of the mucosa sustaining an oxido-reductive attack. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Alterations of intestinal barrier and microbiota in chronic kidney disease.

    PubMed

    Sabatino, Alice; Regolisti, Giuseppe; Brusasco, Irene; Cabassi, Aderville; Morabito, Santo; Fiaccadori, Enrico

    2015-06-01

    Recent studies have highlighted the close relationship between the kidney and the gastrointestinal (GI) tract--frequently referred to as the kidney--gut axis--in patients with chronic kidney disease (CKD). In this regard, two important pathophysiological concepts have evolved: (i) production and accumulation of toxic end-products derived from increased bacterial fermentation of protein and other nitrogen-containing substances in the GI tract, (ii) translocation of endotoxins and live bacteria from gut lumen into the bloodstream, due to damage of the intestinal epithelial barrier and quantitative/qualitative alterations of the intestinal microbiota associated with the uraemic milieu. In both cases, these gut-centred alterations may have relevant systemic consequences in CKD patients, since they are able to trigger chronic inflammation, increase cardiovascular risk and worsen uraemic toxicity. The present review is thus focused on the kidney-gut axis in CKD, with special attention to the alterations of the intestinal barrier and the local microbiota (i.e. the collection of microorganisms living in a symbiotic coexistence with their host in the intestinal lumen) and their relationships to inflammation and uraemic toxicity in CKD. Moreover, we will summarize the most important clinical data suggesting the potential for nutritional modulation of gut-related inflammation and intestinal production of noxious by-products contributing to uraemic toxicity in CKD patients.

  5. High-fat-induced intestinal permeability dysfunction associated with altered fecal bile acids

    PubMed Central

    Stenman, Lotta K; Holma, Reetta; Korpela, Riitta

    2012-01-01

    AIM: To investigate whether high-fat-feeding is associated with increased intestinal permeability via alterations in bile acid metabolism. METHODS: Male C57Bl/6J mice were fed on a high-fat (n = 26) or low-fat diet (n = 24) for 15 wk. Intestinal permeability was measured from duodenum, jejunum, ileum and colon in an Ussing chamber system using 4 kDa FITC-labeled dextran as an indicator. Fecal bile acids were analyzed with gas chromatography. Segments of jejunum and colon were analyzed for the expression of farnesoid X receptor (FXR) and tumor necrosis factor (TNF). RESULTS: Intestinal permeability was significantly increased by high-fat feeding in jejunum (median 0.334 for control vs 0.393 for high-fat, P = 0.03) and colon (0.335 for control vs 0.433 for high-fat, P = 0.01), but not in duodenum or ileum. The concentration of nearly all identified bile acids was significantly increased by high-fat feeding (P < 0.001). The proportion of ursodeoxycholic acid (UDCA) in all bile acids was decreased (1.4% ± 0.1% in high-fat vs 2.8% ± 0.3% in controls, P < 0.01) and correlated inversely with intestinal permeability (r = -0.72, P = 0.01). High-fat feeding also increased jejunal FXR expression, as well as TNF expression along the intestine, especially in the colon. CONCLUSION: High-fat-feeding increased intestinal permeability, perhaps by a mechanism related to bile acid metabolism, namely a decreased proportion of fecal UDCA and increased FXR expression. PMID:22408351

  6. Enhancement of intestinal permeability utilizing solid lipid nanoparticles increases γ-tocotrienol oral bioavailability.

    PubMed

    Abuasal, Bilal S; Lucas, Courtney; Peyton, Breanne; Alayoubi, Alaadin; Nazzal, Sami; Sylvester, Paul W; Kaddoumi, Amal

    2012-05-01

    γ-Tocotrienol (γ-T3), a member of the vitamin E family, has been reported to possess an anticancer activity. γ-T3 is a lipophilic compound with low oral bioavailability. Previous studies showed that γ-T3 has low intestinal permeability. Thus, we have hypothesized that enhancing γ-T3 intestinal permeability will increase its oral bioavailability. Solid lipid nanoparticles (SLN) were tested as a model formulation to enhance γ-T3 permeability and bioavailability. γ-T3 intestinal permeability was compared using in situ rat intestinal perfusion, followed by in vivo relative oral bioavailability studies. In addition, in vitro cellular uptake of γ-T3 from SLN was compared to mixed micelles (MM) in a time and concentration-dependent studies. To elucidate the uptake mechanism(s) of γ-T3 from SLN and MM the contribution of NPC1L1 carrier-mediated uptake, endocytosis and passive permeability were investigated. In situ studies demonstrated SLN has tenfold higher permeability than MM. Subsequent in vivo studies showed γ-T3 relative oral bioavailability from SLN is threefold higher. Consistent with in situ results, in vitro concentration dependent studies revealed γ-T3 uptake from SLN was twofold higher than MM. In vitro mechanistic characterization showed that while endocytosis contributes to γ-T3 uptake from both formulations, the reduced contribution of NPC1L1 to the transport of γ-T3, and passive diffusion enhancement of γ-T3 are primary explanations for its enhanced uptake from SLN. In conclusion, SLN successfully enhanced γ-T3 oral bioavailability subsequent to enhanced passive permeability.

  7. Stress-induced breakdown of intestinal barrier function in the rat: reversal by wood creosote.

    PubMed

    Kuge, Tomoo; Greenwood-Van Meerveld, Beverley; Sokabe, Masahiro

    2006-07-24

    Our previous studies demonstrated that wood creosote (Seirogan) inhibits intestinal secretion and normalizes the transport of electrolytes and water in rats subjected to restraint stress. The goal of the present study was to examine whether wood creosote has a protective effect against stress-induced breakdown of intestinal barrier function. F-344 rats were subjected to 90-min water avoidance stress (WAS) with wood creosote (30 mg/kg) or vehicle administered intragastrically 30 min prior to WAS. Sham stressed rats received wood creosote or vehicle treatment but did not experience the WAS. All rats were euthanized at the end of the WAS or sham-stress and the jejunum and colon were isolated. Epithelial transport was studied in modified Ussing chambers. Spontaneous secretion was assessed by electrophysiological measurement of the short circuit current (I(sc)) while electrical conductance (G) was calculated from the potential difference (PD) and I(sc) using Ohm's law. Intestinal permeability was defined by the mucosal-to-serosal flux of horseradish peroxidase (HRP). WAS significantly elevated basal I(sc) and G and increased epithelial permeability to HRP in the jejunum but not in the colon. Wood creosote resulted in a significant reduction of the stress-induced increase in I(sc), G and the mucosal-to-serosal flux of HRP compared to the vehicle-treated group. Wood creosote caused no significant effects in sham-stressed rats. The results suggest that oral administration of wood creosote may prevent stress-induced diarrhea by preventing aversive effects on small intestinal secretion and barrier function.

  8. Epigenetic control of intestinal barrier function and inflammation in zebrafish

    PubMed Central

    Marjoram, Lindsay; Alvers, Ashley; Deerhake, M. Elizabeth; Bagwell, Jennifer; Mankiewicz, Jamie; Cocchiaro, Jordan L.; Beerman, Rebecca W.; Willer, Jason; Sumigray, Kaelyn D.; Katsanis, Nicholas; Rawls, John F.; Goll, Mary G.; Bagnat, Michel

    2015-01-01

    The intestinal epithelium forms a barrier protecting the organism from microbes and other proinflammatory stimuli. The integrity of this barrier and the proper response to infection requires precise regulation of powerful immune homing signals such as tumor necrosis factor (TNF). Dysregulation of TNF leads to inflammatory bowel diseases (IBD), but the mechanism controlling the expression of this potent cytokine and the events that trigger the onset of chronic inflammation are unknown. Here, we show that loss of function of the epigenetic regulator ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1) in zebrafish leads to a reduction in tnfa promoter methylation and the induction of tnfa expression in intestinal epithelial cells (IECs). The increase in IEC tnfa levels is microbe-dependent and results in IEC shedding and apoptosis, immune cell recruitment, and barrier dysfunction, consistent with chronic inflammation. Importantly, tnfa knockdown in uhrf1 mutants restores IEC morphology, reduces cell shedding, and improves barrier function. We propose that loss of epigenetic repression and TNF induction in the intestinal epithelium can lead to IBD onset. PMID:25730872

  9. Topical apigenin improves epidermal permeability barrier homoeostasis in normal murine skin by divergent mechanisms.

    PubMed

    Hou, Maihua; Sun, Richard; Hupe, Melanie; Kim, Peggy L; Park, Kyungho; Crumrine, Debra; Lin, Tzu-Kai; Santiago, Juan Luis; Mauro, Theodora M; Elias, Peter M; Man, Mao-Qiang

    2013-03-01

    The beneficial effects of certain herbal medicines on cutaneous function have been appreciated for centuries. Among these agents, chrysanthemum extract, apigenin, has been used for skin care, particularly in China, for millennia. However, the underlying mechanisms by which apigenin benefits the skin are not known. In this study, we first determined whether topical apigenin positively influences permeability barrier homoeostasis, and then the basis thereof. Hairless mice were treated topically with either 0.1% apigenin or vehicle alone twice daily for 9 days. At the end of the treatments, permeability barrier function was assessed with either an electrolytic water analyzer or a Tewameter. Our results show that topical apigenin significantly enhanced permeability barrier homoeostasis after tape stripping, although basal permeability barrier function remained unchanged. Improved barrier function correlated with enhanced filaggrin expression and lamellar body production, which was paralleled by elevated mRNA levels for the epidermal ABCA12. The mRNA levels for key lipid synthetic enzymes also were upregulated by apigenin. Finally, both cathelicidin-related peptide and mouse beta-defensin 3 immunostaining were increased by apigenin. We conclude that topical apigenin improves epidermal permeability barrier function by stimulating epidermal differentiation, lipid synthesis and secretion, as well as cutaneous antimicrobial peptide production. Apigenin could be useful for the prevention and treatment of skin disorders characterized by permeability barrier dysfunction, associated with reduced filaggrin levels and impaired antimicrobial defenses, such as atopic dermatitis. © 2013 John Wiley & Sons A/S.

  10. Heavy Cigarette Smokers in a Chinese Population Display a Compromised Permeability Barrier

    PubMed Central

    Xin, Shujun; Ye, Li; Lv, Chengzhi; Elias, Peter M.

    2016-01-01

    Cigarette smoking is associated with various cutaneous disorders with defective permeability. Yet, whether cigarette smoking influences epidermal permeability barrier function is largely unknown. Here, we measured skin biophysical properties, including permeability barrier homeostasis, stratum corneum (SC) integrity, SC hydration, skin surface pH, and skin melanin/erythema index, in cigarette smokers. A total of 99 male volunteers were enrolled in this study. Smokers were categorized as light-to-moderate (<20 cigarettes/day) or heavy smokers (≥20 cigarettes/day). An MPA5 was used to measure SC hydration and skin melanin/erythema index on the dorsal hand, forehead, and cheek. Basal transepidermal water loss (TEWL) and barrier recovery rates were assessed on the forearm. A Skin-pH-Meter pH900 was used to measure skin surface pH. Our results showed that heavy cigarette smokers exhibited delayed barrier recovery after acute abrogation (1.02% ± 13.06 versus 16.48% ± 6.07), and barrier recovery rates correlated negatively with the number of daily cigarettes consumption (p = 0.0087). Changes in biophysical parameters in cigarette smokers varied with body sites. In conclusion, heavy cigarette smokers display compromised permeability barrier homeostasis, which could contribute, in part, to the increased prevalence of certain cutaneous disorders characterized by defective permeability. Thus, improving epidermal permeability barrier should be considered for heavy cigarette smokers. PMID:27437403

  11. Is an intestinal permeability test a valid marker for slight dietary transgressions in adolescents with coeliac disease?

    PubMed Central

    Fernández-Calle, P; Codoceo, R; Polanco, I; Gómez-Cerezo, J; Orsi, M; Tenias, J M

    1993-01-01

    Adolescents with coeliac disease often fail to adhere to a strict gluten free diet. The effectiveness of intestinal permeability to sugars as a marker of slight dietary transgressions by such adolescents was assessed. Severe dietary transgressions were excluded from the study. Subjects were divided into two groups according to whether they committed slight dietary transgressions or adhered to a strict gluten free diet. A reference group of preadolescents with coeliac disease was also included in the study. Intestinal permeability and antigliadin antibody tests were performed on all patients. The diagnostic marker of intestinal permeability was excellent in the reference group. Neither the intestinal permeability test nor antigliadin antibody tests, however, succeeded in discriminating between the two groups of adolescents considered in this study. In conclusion the intestinal permeability test is not a valid marker for slight dietary transgression in such patients. PMID:8314509

  12. The biopharmaceutics of successful controlled release drug product: Segmental-dependent permeability of glipizide vs. metoprolol throughout the intestinal tract.

    PubMed

    Zur, Moran; Cohen, Noa; Agbaria, Riad; Dahan, Arik

    2015-07-15

    The purpose of this work was to study the challenges and prospects of regional-dependent absorption in a controlled-release scenario, through the oral biopharmaceutics of the sulfonylurea antidiabetic drug glipizide. The BCS solubility class of glipizide was determined, and its physicochemical properties and intestinal permeability were thoroughly investigated, both in-vitro (PAMPA and Caco-2) and in-vivo in rats. Metoprolol was used as the low/high permeability class boundary marker. Glipizide was found to be a low-solubility compound. All intestinal permeability experimental methods revealed similar trend; a mirror image small intestinal permeability with opposite regional/pH-dependency was obtained, a downward trend for glipizide, and an upward trend for metoprolol. Yet the lowest permeability of glipizide (terminal Ileum) was comparable to the lowest permeability of metoprolol (proximal jejunum). At the colon, similar permeability was evident for glipizide and metoprolol, that was higher than metoprolol's jejunal permeability. We present an analysis that identifies metoprolol's jejunal permeability as the low/high permeability class benchmark anywhere throughout the intestinal tract; we show that the permeability of both glipizide and metoprolol matches/exceeds this threshold throughout the entire intestinal tract, accounting for their success as controlled-release dosage form. This represents a key biopharmaceutical characteristic for a successful controlled-release dosage form.

  13. Spray-dried porcine plasma influences intestinal barrier function, inflammation, and diarrhea in weaned pigs.

    PubMed

    Peace, Ralph Michael; Campbell, Joy; Polo, Javier; Crenshaw, Joe; Russell, Louis; Moeser, Adam

    2011-07-01

    The objective of this study was to evaluate the effects of dietary inclusion levels of spray-dried porcine plasma (SDPP) on postweaning (PW) intestinal barrier function, mucosal inflammation, and clinical indices of gut health in pigs. Ex vivo Ussing chamber studies were conducted to measure Ileal and colonic barrier function in terms of transepithelial electrical resistance and paracellular flux of (3)H-mannitol and (14)C-inulin. Intestinal inflammation was assessed by histological analysis and mucosal levels of proinflammatory cytokines. Dietary inclusion of 2.5 and 5% SDPP reduced colonic paracellular permeability of (14)C-inulin compared with controls (0% SDPP) on d 7 PW. Both 2.5 and 5% dietary SDPP reduced ileal (3)H-mannitol and (14)C-inulin permeability on d 14 PW. The 5% SDPP diet reduced colonic short-circuit current, an index of net electrogenic ion transport, and fecal scores when measured on d 7 and 14 PW compared with the control and 2.5% SDPP groups (P < 0.05). Histological analysis revealed fewer lamina propria cells in ileum and colon from pigs fed diets containing 2.5 and 5% SDPP on d 7 and 14 PW. Levels of the proinflammatory cytokine TNFα were reduced in the colon but not ileum from pigs fed the 5% SDPP on d 7 and 14 PW compared with controls (P < 0.05). IFNγ levels were lower than in controls in both of the SDPP-fed groups in the ileum and colon on d 7 but not on d 14 PW. Overall, this study demonstrated that dietary inclusion of SDPP had beneficial effects on intestinal barrier function, inflammation, and diarrhea in weaned pigs.

  14. The "perfect storm" for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity.

    PubMed

    Vaarala, Outi; Atkinson, Mark A; Neu, Josef

    2008-10-01

    It is often stated that type 1 diabetes results from a complex interplay between varying degrees of genetic susceptibility and environmental factors. While agreeing with this principal, our desire is that this Perspectives article will highlight another complex interplay potentially associated with this disease involving facets related to the gut, one where individual factors that, upon their interaction with each another, form a "perfect storm" critical to the development of type 1 diabetes. This trio of factors includes an aberrant intestinal microbiota, a "leaky" intestinal mucosal barrier, and altered intestinal immune responsiveness. Studies examining the microecology of the gastrointestinal tract have identified specific microorganisms whose presence appears related (either quantitatively or qualitatively) to disease; in type 1 diabetes, a role for microflora in the pathogenesis of disease has recently been suggested. Increased intestinal permeability has also been observed in animal models of type 1 diabetes as well as in humans with or at increased-risk for the disease. Finally, an altered mucosal immune system has been associated with the disease and is likely a major contributor to the failure to form tolerance, resulting in the autoimmunity that underlies type 1 diabetes. Herein, we discuss the complex interplay between these factors and raise testable hypotheses that form a fertile area for future investigations as to the role of the gut in the pathogenesis and prevention of type 1 diabetes.

  15. Iron Hydroxy Carbonate Formation in Zerovalent Iron Permeable Reactive Barriers: Characterization and Evaluation of Phase Stability

    EPA Science Inventory

    Predicting the long-term potential of permeable reactive barriers for treating contaminated groundwater relies on understanding the endpoints of biogeochemical reactions between influent groundwater and the reactive medium. Iron hydroxy carbonate (chukanovite) is frequently obs...

  16. Performance Assessment of a Permeable Reactive Barrier for Ground Water Remediation Fifteen Years After Installation

    EPA Science Inventory

    The fifteen-year performance of a granular iron, permeable reactive barrier (PRB; Elizabeth City, North Carolina) is reviewed with respect to contaminanttreatment (hexavalent chromium and trichloroethylene) and hydraulic performance. Due to in-situ treatment of the chromium sourc...

  17. COST ANALYSIS OF PERMEABLE REACTIVE BARRIERS FOR REMEDIATION OF GROUND WATER

    EPA Science Inventory

    ABSTRACT

    Permeable reactive barriers (PRB's) are an emerging, alternative in-situ approach for remediating contaminated groundwater that combine subsurface fluid flow management with a passive chemical treatment zone. PRB's are a potentially more cost effective treatment...

  18. PERFORMANCE OF PERMEABLE REACTIVE BARRIER AT U.S. COAST GUARD SITE, ELIZABETH CITY, NC

    EPA Science Inventory

    Permeable reactive barriers are innovative and cost-effective remedial technologies and are becoming more desirable methods for in-situ passive remediation of ground water contaminated with chlorinated hydrocarbons and redox-sensitive metals. As contaminated water passes through ...

  19. Performance Assessment of a Permeable Reactive Barrier for Ground Water Remediation Fifteen Years After Installation

    EPA Science Inventory

    The fifteen-year performance of a granular iron, permeable reactive barrier (PRB; Elizabeth City, North Carolina) is reviewed with respect to contaminanttreatment (hexavalent chromium and trichloroethylene) and hydraulic performance. Due to in-situ treatment of the chromium sourc...

  20. PERMEABLE REACTIVE BARRIERS FOR IN-SITU TREATMENT OF ARSENIC-CONTAMINATED GROUNDWATER

    EPA Science Inventory

    Laboratory and field research has shown that permeable reactive barriers (PRBs) containing a variety of materials can treat arsenic (As) contaminated groundwater. Sites where these PRBs are located include a mine tailings facility, fertilizer and chemical manufacturing sites, a...

  1. BIFUNCTIONAL ALUMINUN: A PERMEABLE BARRIER MATERIAL FOR THE DEGRADATION OF MTBE

    EPA Science Inventory

    Bifunctional aluminum is an innovative remedial material for the treatment of gasoline oxygenates in permeable reactive barriers (PRBs). PRBs represent a promising environmental technology for remediation of groundwater contamination. Although zero-valent metals (ZVM) have been...

  2. COST ANALYSIS OF PERMEABLE REACTIVE BARRIERS FOR REMEDIATION OF GROUND WATER

    EPA Science Inventory

    ABSTRACT

    Permeable reactive barriers (PRB's) are an emerging, alternative in-situ approach for remediating contaminated groundwater that combine subsurface fluid flow management with a passive chemical treatment zone. PRB's are a potentially more cost effective treatment...

  3. PERFORMANCE OF PERMEABLE REACTIVE BARRIER AT U.S. COAST GUARD SITE, ELIZABETH CITY, NC

    EPA Science Inventory

    Permeable reactive barriers are innovative and cost-effective remedial technologies and are becoming more desirable methods for in-situ passive remediation of ground water contaminated with chlorinated hydrocarbons and redox-sensitive metals. As contaminated water passes through ...

  4. PERFORMANCE MONITORING OF PERMEABLE REACTIVE BARRIERS TO REMEDIATE CONTAMINATED GROUND WATER

    EPA Science Inventory

    Permeable reactive barriers (PRB's) are an emerging, alternative in-situ approach for remediating groundwater contamination that combine subsurface fluid flow management with a passive chemical treatment zone. Removal of contaminants from the groundwater plume is achieved by alt...

  5. LONG-TERM PERFORMANCE ASSESSMENT OF PERMEABLE REACTIVE BARRIERS TO REMEDIATE CONTAMINATED GROUND WATER

    EPA Science Inventory

    Permeable reactive barriers (PRBs) are an emerging, alternative in-situ approach for remediating groundwater contamination that combine subsurface fluid flow management with a passive chemical treatment zone. The few pilot and commercial installations which have been implemented ...

  6. PERMEABLE REACTIVE BARRIERS FOR IN-SITU TREATMENT OF ARSENIC-CONTAMINATED GROUNDWATER

    EPA Science Inventory

    Laboratory and field research has shown that permeable reactive barriers (PRBs) containing a variety of materials can treat arsenic (As) contaminated groundwater. Sites where these PRBs are located include a mine tailings facility, fertilizer and chemical manufacturing sites, a...

  7. BIFUNCTIONAL ALUMINUN: A PERMEABLE BARRIER MATERIAL FOR THE DEGRADATION OF MTBE

    EPA Science Inventory

    Bifunctional aluminum is an innovative remedial material for the treatment of gasoline oxygenates in permeable reactive barriers (PRBs). PRBs represent a promising environmental technology for remediation of groundwater contamination. Although zero-valent metals (ZVM) have been...

  8. Iron Hydroxy Carbonate Formation in Zerovalent Iron Permeable Reactive Barriers: Characterization and Evaluation of Phase Stability

    EPA Science Inventory

    Predicting the long-term potential of permeable reactive barriers for treating contaminated groundwater relies on understanding the endpoints of biogeochemical reactions between influent groundwater and the reactive medium. Iron hydroxy carbonate (chukanovite) is frequently obs...

  9. LONG-TERM PERFORMANCE ASSESSMENT OF PERMEABLE REACTIVE BARRIERS TO REMEDIATE CONTAMINATED GROUND WATER

    EPA Science Inventory

    Permeable reactive barriers (PRBs) are an emerging, alternative in-situ approach for remediating groundwater contamination that combine subsurface fluid flow management with a passive chemical treatment zone. The few pilot and commercial installations which have been implemented ...

  10. Permeable Barrier Materials for Strontium Immobilization: - UFA Determination of Hydraulic Conductivity. - Column Sorption Experiments

    DTIC Science & Technology

    1996-01-01

    Meadows clinoptilolite was also tested since it is currently being considered for use as a permeable barrier at N-Springs. 14. SUBJECT TERMS 15. NUMBER OF...permeability of reactive barrier); Soda Springs phosphate rock; and fish debris. Ash Meadows Clinoptilolite was also tested since it is currently being...follows: bone char > quartz sand > NC apatite >> fish debris:sand = Ash Meadows clinoptilolite:sand >> clinoptilolite >> hydroxyapatite > Soda Springs

  11. Simultaneous gas-chromatographic urinary measurement of sugar probes to assess intestinal permeability: use of time course analysis to optimize its use to assess regional gut permeability

    PubMed Central

    Shaikh, Maliha; Rajan, Kumar; Forsyth, Christopher B.; Voigt, Robin M.; Keshavarzian, Ali

    2015-01-01

    Background Measurement of intestinal permeability is important in several diseases but currently several methods are employed. We sought to: (1) develop a new GC based method to measure urinary mannitol, lactulose and sucralose to assess regional and total gut permeability; (2) analyze the kinetics of these sugars in the urine to determine which ratio is useful to represent intestinal permeability; and (3) determine whether age, gender, race and BMI impact these values. Methods Subjects drank a cocktail of sucrose, lactulose, mannitol and sucralose and these sugars were measured in the urine at 5, 12 and 24 h with gas chromatography. Results Urinary mannitol exhibited significantly different kinetics than lactulose and sucralose which were similar to each other and varied little over the 24 h. No permeability differences were observed for renal function, age, race, sex, or BMI. Conclusions Our data do not support the use of the widely used L/M ratio as an accurate estimate of intestinal permeability. Our data support the use of: The sucralose/lactulose (S/M) ratio to measure: small intestine permeability (first 5 h); small and large intestine (first 12 hours), and total gut permeability (24 h). This was also found to be true in a Parkinson’s disease model. PMID:25591964

  12. Prophylactic tributyrin treatment mitigates chronic-binge ethanol-induced intestinal barrier and liver injury.

    PubMed

    Cresci, Gail A; Glueck, Bryan; McMullen, Megan R; Xin, Wei; Allende, Daniella; Nagy, Laura E

    2017-09-01

    Impaired gut-liver axis is a potential factor contributing to alcoholic liver disease. Ethanol depletes intestinal integrity and causes gut dysbiosis. Butyrate, a fermentation byproduct of gut microbiota, is altered negatively following chronic ethanol exposure. This study aimed to determine whether prophylactic tributyrin could protect the intestinal barrier and liver in mice during combined chronic-binge ethanol exposure. C57BL/6J mice exposed to 5% v/v ethanol-containing diet for 10 days received a single ethanol gavage (5 g/kg) 9 h before euthanasia. Control mice were isocalorically pair-fed maltose dextrin for ethanol. Diets were supplemented (5 mM) with tributyrin or glycerol. Intestine and liver disease activity was assessed histologically. Protein and mRNA expression of tight junction (TJ) proteins, toll-like receptors, and tumor necrosis factor-alpha were assessed. Caco-2 monolayers with or without ethanol exposure and/or sodium butyrate were used to test butyrate's direct effects on intestinal integrity. Chronic-binge ethanol feeding impaired intestinal TJ protein co-localization staining; however, tributyrin co-treatment mitigated these effects. Ethanol depleted TJ and transepithelial electrical resistance in Caco-2 monolayers, but butyrate co-treatment reduced these effects. Hepatic toll-like receptor mRNA expression and tumor necrosis factor-alpha protein expression was induced by ethanol; however, the response was significantly dampened in mice co-treated with tributyrin. Tributyrin altered localization of both neutrophils and single hepatocyte death: Leukocytes and apoptotic hepatocytes localized predominantly around the portal tract in ethanol-only treated mice, whereas localization predominated around the central vein in ethanol-tributyrin mice. Prophylactic tributyrin supplementation mitigated effects of combined chronic-binge ethanol exposure on disruption of intestinal TJ localization and intestinal permeability and liver injury. © 2017

  13. Oleoylethanolamine and palmitoylethanolamine modulate intestinal permeability in vitro via TRPV1 and PPARα.

    PubMed

    Karwad, Mustafa A; Macpherson, Tara; Wang, Bo; Theophilidou, Elena; Sarmad, Sarir; Barrett, David A; Larvin, Michael; Wright, Karen L; Lund, Jonathan N; O'Sullivan, Saoirse E

    2017-02-01

    Cannabinoids modulate intestinal permeability through cannabinoid receptor 1 (CB1). The endocannabinoid-like compounds oleoylethanolamine (OEA) and palmitoylethanolamine (PEA) play an important role in digestive regulation, and we hypothesized they would also modulate intestinal permeability. Transepithelial electrical resistance (TEER) was measured in human Caco-2 cells to assess permeability after application of OEA and PEA and relevant antagonists. Cells treated with OEA and PEA were stained for cytoskeletal F-actin changes and lysed for immunoassay. OEA and PEA were measured by liquid chromatography-tandem mass spectrometry. OEA (applied apically, logEC50 -5.4) and PEA (basolaterally, logEC50 -4.9; apically logEC50 -5.3) increased Caco-2 resistance by 20-30% via transient receptor potential vanilloid (TRPV)-1 and peroxisome proliferator-activated receptor (PPAR)-α. Preventing their degradation (by inhibiting fatty acid amide hydrolase) enhanced the effects of OEA and PEA. OEA and PEA induced cytoskeletal changes and activated focal adhesion kinase and ERKs 1/2, and decreased Src kinases and aquaporins 3 and 4. In Caco-2 cells treated with IFNγ and TNFα, OEA (via TRPV1) and PEA (via PPARα) prevented or reversed the cytokine-induced increased permeability compared to vehicle (0.1% ethanol). PEA (basolateral) also reversed increased permeability when added 48 or 72 h after cytokines (P < 0.001, via PPARα). Cellular and secreted levels of OEA and PEA (P < 0.001-0.001) were increased in response to inflammatory mediators. OEA and PEA have endogenous roles and potential therapeutic applications in conditions of intestinal hyperpermeability and inflammation.-Karwad, M. A., Macpherson, T., Wang, B., Theophilidou, E., Sarmad, S., Barrett, D. A., Larvin, M., Wright, K. L., Lund, J. N., O'Sullivan, S. E. Oleoylethanolamine and palmitoylethanolamine modulate intestinal permeability in vitro via TRPV1 and PPARα. © FASEB.

  14. Comparison study of ferrofluid and powder iron oxide nanoparticle permeability across the blood–brain barrier

    PubMed Central

    Hoff, Dan; Sheikh, Lubna; Bhattacharya, Soumya; Nayar, Suprabha; Webster, Thomas J

    2013-01-01

    In the present study, the permeability of 11 different iron oxide nanoparticle (IONP) samples (eight fluids and three powders) was determined using an in vitro blood–brain barrier model. Importantly, the results showed that the ferrofluid formulations were statistically more permeable than the IONP powder formulations at the blood–brain barrier, suggesting a role for the presently studied in situ synthesized ferrofluid formulations using poly(vinyl) alcohol, bovine serum albumin, collagen, glutamic acid, graphene, and their combinations as materials which can cross the blood–brain barrier to deliver drugs or have other neurological therapeutic efficacy. Conversely, the results showed the least permeability across the blood–brain barrier for the IONP with collagen formulation, suggesting a role as a magnetic resonance imaging contrast agent but limiting IONP passage across the blood–brain barrier. Further analysis of the data yielded several trends of note, with little correlation between permeability and fluid zeta potential, but a larger correlation between permeability and fluid particle size (with the smaller particle sizes having larger permeability). Such results lay the foundation for simple modification of iron oxide nanoparticle formulations to either promote or inhibit passage across the blood–brain barrier, and deserve further investigation for a wide range of applications. PMID:23426527

  15. Comparison study of ferrofluid and powder iron oxide nanoparticle permeability across the blood-brain barrier.

    PubMed

    Hoff, Dan; Sheikh, Lubna; Bhattacharya, Soumya; Nayar, Suprabha; Webster, Thomas J

    2013-01-01

    In the present study, the permeability of 11 different iron oxide nanoparticle (IONP) samples (eight fluids and three powders) was determined using an in vitro blood-brain barrier model. Importantly, the results showed that the ferrofluid formulations were statistically more permeable than the IONP powder formulations at the blood-brain barrier, suggesting a role for the presently studied in situ synthesized ferrofluid formulations using poly(vinyl) alcohol, bovine serum albumin, collagen, glutamic acid, graphene, and their combinations as materials which can cross the blood-brain barrier to deliver drugs or have other neurological therapeutic efficacy. Conversely, the results showed the least permeability across the blood-brain barrier for the IONP with collagen formulation, suggesting a role as a magnetic resonance imaging contrast agent but limiting IONP passage across the blood-brain barrier. Further analysis of the data yielded several trends of note, with little correlation between permeability and fluid zeta potential, but a larger correlation between permeability and fluid particle size (with the smaller particle sizes having larger permeability). Such results lay the foundation for simple modification of iron oxide nanoparticle formulations to either promote or inhibit passage across the blood-brain barrier, and deserve further investigation for a wide range of applications.

  16. cis-Peptide Bonds: A Key for Intestinal Permeability of Peptides? .

    PubMed

    Marelli, Udaya Kiran; Ovadia, Oded; Frank, Andreas Oliver; Chatterjee, Jayanta; Gilon, Chaim; Hoffman, Amnon; Kessler, Horst

    2015-10-19

    Recent structural studies on libraries of cyclic hexapeptides led to the identification of common backbone conformations that may be instrumental to the oral availability of peptides. Furthermore, the observation of differential Caco-2 permeabilities of enantiomeric pairs of some of these peptides strongly supports the concept of conformational specificity driven uptake and also suggests a pivotal role of carrier-mediated pathways for peptide transport, especially for scaffolds of polar nature. This work presents investigations on the Caco-2 and PAMPA permeability profiles of 13 selected N-methylated cyclic pentaalanine peptides derived from the basic cyclo(-D-Ala-Ala4 -) template. These molecules generally showed moderate to low transport in intestinal epithelia with a few of them exhibiting a Caco-2 permeability equal to or slightly higher than that of mannitol, a marker for paracellular permeability. We identified that the majority of the permeable cyclic penta- and hexapeptides possess an N-methylated cis-peptide bond, a structural feature that is also present in the orally available peptides cyclosporine A and the tri-N-methylated analogue of the Veber-Hirschmann peptide. Based on these observations it appears that the presence of N-methylated cis-peptide bonds at certain locations may promote the intestinal permeability of peptides through a suitable conformational preorganization. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Dimethyl fumarate reduces the risk of mycotoxins via improving intestinal barrier and microbiota

    PubMed Central

    Ma, Ning; Wu, Yi; Xie, Fei; Du, Kexin; Wang, Yuan; Shi, Linxin; Ji, Linbao; Liu, Tianyi; Ma, Xi

    2017-01-01

    The effects of dimethyl fumarate (DMF) on mycotoxins and animal growth performance are well documented. However, its mechanism of anti-mildew effects is still unknown. The current study investigated how DMF detoxified the mycotoxin and improved the growth performance using BALB/c mice model, especially its effects on intestinal barrier function and gut micro-ecology. Our study also compared with the ultraviolet radiation (UR) treatment, a traditional anti-mildew control (TC). The results indicated that the DMF treatment had a lower contents of mycotoxin, better growth performance and improved mucosal morphology (P < 0.05), accompanied with the decreased intestinal permeability and the tighter gut barrier. Moreover, the efficiency of DMF was better than TC (P < 0.05). 16S rRNA gene sequence analysis revealed that the richness and diversity of bacteria was increased in DMF treatment. The most abundant OTUs belonged to Firmicutes and Bacteroidetes, and their changes in DMF were more moderate than the TC group, suggesting a more stable micro-ecology and the positive impact of DMF on the biodiversity of intestine. Specifically, the increased abundance of bacteria producing short-chain fatty acids (SCFAs), such as Gemella, Roseburia, Bacillus and Bacteroides in DMF group and prebiotics such as Lactobacillus in TC group, suggested a more healthier microbial composition and distribution. These findings supported that DMF had significant effects on animal's growth performance and intestinal barrier function by modulating the pathway of nutrient absorption and increasing the diversity and balance of gut microbes, which also illuminate that DMF is more efficient than traditional anti-mildew method. PMID:28574825

  18. Intestinal Barrier Maturation in Very Low Birthweight Infants: Relationship to Feeding and Antibiotic Exposure.

    PubMed

    Saleem, Bushra; Okogbule-Wonodi, Adora C; Fasano, Alessio; Magder, Laurence S; Ravel, Jacques; Kapoor, Shiv; Viscardi, Rose M

    2017-04-01

    To test the hypothesis that feeding and antibiotic exposures affect intestinal barrier maturation in preterm infants, we serially measured intestinal permeability (IP) biomarkers in infants <33 weeks gestation (gestational age [GA]) during the first 2 weeks of life. Eligible infants <33 weeks GA were enrolled within 4 days of birth in a prospective study of IP biomarkers (NCT01756040). Study participants received the nonmetabolized sugars lactulose/rhamnose enterally on study days 1, 8, and 15 and lactulose/rhamnose were measured in urine by high-performance liquid chromatography. Serum zonulin and fecal alpha-1-anti-trypsin, 2 other IP markers, were measured by semiquantitative Western blot and ELISA, respectively. In a cohort of 43 subjects, the lactulose/rhamnose ratio was increased on day 1 and decreased over 2 weeks, but remained higher in infants born at ≤28 weeks of gestation compared with IP in infants born at >28 weeks of gestation. Exclusive breastmilk feeding was associated with more rapid maturation in intestinal barrier function. A cluster analysis of 35 subjects who had urine samples from all time points revealed 3 IP patterns (cluster 1, normal maturation: n = 20 [57%]); cluster 2, decreased IP during the first week and subsequent substantial increase: n = 5 [14%]); and cluster 3, delayed maturation: n = 10 [29%]). There were trends toward more prolonged antibiotic exposure (P = .092) and delayed initiation of feeding ≥4 days (P = .064) in infants with abnormal IP patterns. Intestinal barrier maturation in preterm infants is GA and postnatal age dependent, and is influenced by feeding with a maturational effect of breastmilk feeding and possibly by antibiotic exposures. ClinicalTrials.gov: NCT01756040. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Dietary grape seed proanthocyanidins (GSPs) improve weaned intestinal microbiota and mucosal barrier using a piglet model

    PubMed Central

    Han, Meng; Song, Peixia; Huang, Chang; Rezaei, Arash; Farrar, Shabnam; Brown, Michael A.; Ma, Xi

    2016-01-01

    Proanthocyanidins have been suggested as an effective antibiotic alternative, however their mechanisms are still unknown. The present study investigated the effects of grape seed proanthocyanidins on gut microbiota and mucosal barrier using a weaned piglet model in comparison with colistin. Piglets weaned at 28 day were randomly assigned to four groups treated with a control ration, or supplemented with 250 mg/kg proanthocyanidins, kitasamycin/colistin, or 250 mg/kg proanthocyanidins and half-dose antibiotics, respectively. On day 28, the gut chyme and tissue samples were collected to test intestinal microbiota and barrier function, respectively. Proanthocyanidins treated piglets had better growth performance and reduced diarrhea incidence (P < 0.05), accompanied with decreased intestinal permeability and improved mucosal morphology. Gene sequencing analysis of 16S rRNA revealed that dietary proanthocyanidins improved the microbial diversity in ileal and colonic digesta, and the most abundant OTUs belong to Firmicutes and Bacteroidetes spp. Proanthocyanidins treatment decreased the abundance of Lactobacillaceae, and increased the abundance of Clostridiaceae in both ileal and colonic lumen, which suggests that proanthocyanidins treatment changed the bacterial composition and distribution. Administration of proanthocyanidins increased the concentration of propionic acid and butyric acid in the ileum and colon, which may activate the expression of GPR41. In addition, dietary proanthocyanidins improved the antioxidant indices in serum and intestinal mucosa, accompanied with increasing expression of barrier occludin. Our findings indicated that proanthocyanidins with half-dose colistin was equivalent to the antibiotic treatment and assisted weaned animals in resisting intestinal oxidative stress by increasing diversity and improving balance of gut microbes. PMID:27880936

  20. Changes in intestinal permeability and nutritional status after cytotoxic therapy in patients with cancer.

    PubMed

    Souza, Nilian C S; Simões, Belinda P; Júnior, Alceu A J; Chiarello, Paula G

    2014-01-01

    Damage to intestinal mucosa may impair nutritional status and increase the demand for nutrients involved in intestinal cell proliferation (retinol and folate). It is still unclear if cytotoxic therapy affects serum concentrations of these nutrients in patients with cancer and if this would be associated with disturbances of intestinal mucosa. Intestinal permeability, serum folate, and retinol and nutritional status of 22 patients with hematologic malignancies and 17 healthy volunteers [control group (CG)] were assessed before (T0) and after cytotoxic therapy (T1). Ingestion of lactulose and mannitol was used to assess intestinal permeability. Anthropometric, body composition, phase angle (PA), and biochemical analysis (albumin, retinol, and folate) were also performed. Lactulose/mannitol ratio (0.026 ± 0.014 vs. 0.052 ± 0.037) and lactulose excretion (0.27 ± 0.18% vs. 0.53 ± 0.6%) increased at T1. PA decreased (7.2 ± 1.9° vs. 6.2 ± 0.9°). Serum folate and albumin (20.7 ± 9.5 nmol/L, 37.7 ± 5.5 g/L) were lower than CG (39.2 ± 16.4 nmol/L, 42.9 ± 5.2 g/L) but did not change at T1 (17.5 ± 7.0 nmol/L, 35.9 ± 4.5 g/L). Serum retinol did not differ from CG and did not change at T1 (1.83 ± 0.30 μmol/L vs. 1.69 ± 0.3 μmol/L; CG: 1.86 ± 0.20 μmol/L). Abnormal intestinal permeability, low serum folate levels, and its possible relationship with intestinal alterations, and reduced PA, may be associated with poor nutritional status in cancer patients.

  1. Evaluation of physicochemical properties and intestinal permeability of six dietary polyphenols in human intestinal colon adenocarcinoma Caco-2 cells.

    PubMed

    Rastogi, Himanshu; Jana, Snehasis

    2016-02-01

    Phenolic compounds are common ingredients in many dietary supplements and functional foods. However, data concerning physicochemical properties and permeability of polyphenols on the intestinal epithelial cells are scarce. The aims of this study were to determine the experimental partition coefficient (Log P), and parallel artificial membrane permeability assay (PAMPA), to characterize the bi-directional transport of six phenolic compounds viz. caffeic acid, chrysin, gallic acid, quercetin, resveratrol and rutin in Caco-2 cells. The experimental Log P values of six polyphenols were correlated (R (2) = 0.92) well with the calculated Log P values. The apparent permeability (P app) range of all polyphenols in PAMPA for the apical (AP) to basolateral (BL) was 1.18 ± 0.05 × 10(-6) to 5.90 ± 0.16 × 10(-6) cm/s. The apparent Caco-2 permeability (P app) range for the AP-BL was 0.96 ± 0.03 × 10(-6) to 3.80 ± 0.45 × 10(-6) cm/s. The efflux ratio of P app (BL → AP) to P app (AP → BL) for all phenolics was <2, suggesting greater permeability in the absorptive direction. Six compounds exhibited strong correlations between Log P and PAMPA/Caco-2 cell monolayer permeation data. Dietary six polyphenols were poorly absorbed through PAMPA and Caco-2 cells, and their transepithelial transports were mainly by passive diffusion.

  2. Yersinia pseudotuberculosis disrupts intestinal barrier integrity through hematopoietic TLR-2 signaling

    PubMed Central

    Jung, Camille; Meinzer, Ulrich; Montcuquet, Nicolas; Thachil, Elodie; Château, Danielle; Thiébaut, Raphaële; Roy, Maryline; Alnabhani, Ziad; Berrebi, Dominique; Dussaillant, Monique; Pedruzzi, Eric; Thenet, Sophie; Cerf-Bensussan, Nadine; Hugot, Jean-Pierre; Barreau, Frederick

    2012-01-01

    Intestinal barrier function requires intricate cooperation between intestinal epithelial cells and immune cells. Enteropathogens are able to invade the intestinal lymphoid tissue known as Peyer’s patches (PPs) and disrupt the integrity of the intestinal barrier. However, the underlying molecular mechanisms of this process are poorly understood. In mice infected with Yersinia pseudotuberculosis, we found that PP barrier dysfunction is dependent on the Yersinia virulence plasmid and the expression of TLR-2 by hematopoietic cells, but not by intestinal epithelial cells. Upon TLR-2 stimulation, Y. pseudotuberculosis–infected monocytes activated caspase-1 and produced IL-1β. In turn, IL-1β increased NF-κB and myosin light chain kinase activation in intestinal epithelial cells, thus disrupting the intestinal barrier by opening the tight junctions. Therefore, Y. pseudotuberculosis subverts intestinal barrier function by altering the interplay between immune and epithelial cells during infection. PMID:22565313

  3. Long noncoding RNA SPRY4-IT1 regulates intestinal epithelial barrier function by modulating the expression levels of tight junction proteins

    PubMed Central

    Xiao, Lan; Rao, Jaladanki N.; Cao, Shan; Liu, Lan; Chung, Hee Kyoung; Zhang, Yun; Zhang, Jennifer; Liu, Yulan; Gorospe, Myriam; Wang, Jian-Ying

    2016-01-01

    Epithelial cells line the intestinal mucosa and form an important barrier to a wide array of noxious substances in the lumen. Disruption of the barrier integrity occurs commonly in various pathologies. Long noncoding RNAs (lncRNAs) control diverse biological processes, but little is known about the role of lncRNAs in regulation of the gut permeability. Here we show that the lncRNA SPRY4-IT1 regulates the intestinal epithelial barrier function by altering expression of tight junction (TJ) proteins. SPRY4-IT1 silencing led to dysfunction of the epithelial barrier in cultured cells by decreasing the stability of mRNAs encoding TJ proteins claudin-1, claudin-3, occludin, and JAM-1 and repressing their translation. In contrast, increasing the levels of SPRY4-IT1 in the intestinal mucosa protected the gut barrier in mice exposed to septic stress by increasing the abundance of TJ proteins. SPRY4-IT1 directly interacted with TJ mRNAs, and this process was enhanced through the association with the RNA-binding protein HuR. Of interest, the intestinal mucosa from patients with increased gut permeability exhibited a decrease in the levels of SPRY4-IT1. These findings highlight a novel role for SPRY4-IT1 in controlling the intestinal epithelial barrier and define a mechanism by which SPRY4-IT1 modulates TJ expression by altering the stability and translation of TJ mRNAs. PMID:26680741

  4. Long noncoding RNA SPRY4-IT1 regulates intestinal epithelial barrier function by modulating the expression levels of tight junction proteins.

    PubMed

    Xiao, Lan; Rao, Jaladanki N; Cao, Shan; Liu, Lan; Chung, Hee Kyoung; Zhang, Yun; Zhang, Jennifer; Liu, Yulan; Gorospe, Myriam; Wang, Jian-Ying

    2016-02-15

    Epithelial cells line the intestinal mucosa and form an important barrier to a wide array of noxious substances in the lumen. Disruption of the barrier integrity occurs commonly in various pathologies. Long noncoding RNAs (lncRNAs) control diverse biological processes, but little is known about the role of lncRNAs in regulation of the gut permeability. Here we show that the lncRNA SPRY4-IT1 regulates the intestinal epithelial barrier function by altering expression of tight junction (TJ) proteins. SPRY4-IT1 silencing led to dysfunction of the epithelial barrier in cultured cells by decreasing the stability of mRNAs encoding TJ proteins claudin-1, claudin-3, occludin, and JAM-1 and repressing their translation. In contrast, increasing the levels of SPRY4-IT1 in the intestinal mucosa protected the gut barrier in mice exposed to septic stress by increasing the abundance of TJ proteins. SPRY4-IT1 directly interacted with TJ mRNAs, and this process was enhanced through the association with the RNA-binding protein HuR. Of interest, the intestinal mucosa from patients with increased gut permeability exhibited a decrease in the levels of SPRY4-IT1. These findings highlight a novel role for SPRY4-IT1 in controlling the intestinal epithelial barrier and define a mechanism by which SPRY4-IT1 modulates TJ expression by altering the stability and translation of TJ mRNAs.

  5. REMEDIATION OF TCE-CONTAMINATED GROUNDWATER BY A PERMEABLE REACTIVE BARRIER FILLED WITH PLANT MULCH (BIOWALL)

    EPA Science Inventory

    A pilot-scale permeable reactive barrier filled with plant mulch was installed at Altus Air Force Base (in Oklahoma, USA) to treat trichloroethylene (TCE) contamination in ground water emanating from a landfill. The barrier was constructed in June 2002. It was 139 meters long, 7 ...

  6. REMEDIATION OF TCE-CONTAMINATED GROUNDWATER BY A PERMEABLE REACTIVE BARRIER FILLED WITH PLANT MULCH (BIOWALL)

    EPA Science Inventory

    A pilot-scale permeable reactive barrier filled with plant mulch was installed at Altus Air Force Base (in Oklahoma, USA) to treat trichloroethylene (TCE) contamination in ground water emanating from a landfill. The barrier was constructed in June 2002. It was 139 meters long, 7 ...

  7. Combat-training increases intestinal permeability, immune activation and gastrointestinal symptoms in soldiers.

    PubMed

    Li, X; Kan, E M; Lu, J; Cao, Y; Wong, R K; Keshavarzian, A; Wilder-Smith, C H

    2013-04-01

    Gastrointestinal (GI) symptoms are common in soldiers in combat or high-pressure operational situations and often lead to compromised performance. Underlying mechanisms are unclear, but neuroendocrine dysregulation, immune activation and increased intestinal permeability may be involved in stress-related GI dysfunction. To study the effects of prolonged, intense, mixed psychological and physical stress on intestinal permeability, systemic inflammatory and stress markers in soldiers during high-intensity combat-training. In 37 male army medical rapid response troops, GI symptoms, stress markers, segmental intestinal permeability using the 4-sugar test (sucrose, lactulose, mannitol and sucralose) and immune activation were assessed during the 4th week of an intense combat-training and a rest period. Combat-training elicited higher stress, anxiety and depression scores (all P < 0.01) as well as greater incidence and severity of GI symptoms [irritable bowel syndrome symptom severity score (IBS-SSS), P < 0.05] compared with rest. The IBS-SSS correlated with depression (r = 0.41, P < 0.01) and stress (r = 0.40, P < 0.01) ratings. Serum levels of cortisol, interleukin-6, and tumour necrosis factor-α, and segmental GI permeability increased during combat-training compared with rest (all P < 0.05). The lactulose:mannitol ratio was higher in soldiers with GI symptoms (IBS-SSS ≥75) during combat-training than those without (IBS-SSS <75) (P < 0.05). Prolonged combat-training not only induces the expected increases in stress, anxiety and depression, but also GI symptoms, pro-inflammatory immune activation and increased intestinal permeability. Identification of subgroups of individuals at high-risk of GI compromise and of long-term deleterious effects of operational stress as well as the development of protective measures will be the focus of future studies. © 2013 Blackwell Publishing Ltd.

  8. Gas chromatographic method for detection of urinary sucralose: application to the assessment of intestinal permeability.

    PubMed

    Farhadi, Ashkan; Keshavarzian, Ali; Holmes, Earle W; Fields, Jeremy; Zhang, Lei; Banan, Ali

    2003-01-25

    We developed a capillary column gas chromatography (CCGC) method for the measurement of urinary sucralose (S) and three other sugar probes including, sucrose, lactulose (L) and mannitol (M) for use in in vivo studies of intestinal permeability. We compared the capillary method with a packed column gas chromatography (PCGC) method. We also investigated a possible role for sucralose as a probe for the measurement of whole gut permeability. Sample preparation was rapid and simple. The above four sugars were detected precisely, without interference. We measured intestinal permeability using 5- and 24-h urine collections in 14 healthy volunteers. The metabolism of sugars was evaluated by incubating the intestinal bacteria with an iso-osmolar mixture of mannitol, lactulose and sucralose at 37 degrees C for 19 h. Sugar concentrations and the pH of the mixture were monitored. The use of the CCGC method improved the detection of sucralose as compared to PCGC. The average coefficient of variation decreased from 15% to 4%. It also increased the sensitivity of detection by 200-2000-fold. The GC assay was linear between sucralose concentrations of 0.2 and 40 g/l (r=1.000). Intestinal bacteria metabolized lactulose and acidified the media but did not metabolize sucralose or mannitol. The new method for the measurement of urinary sucralose permits the simultaneous quantitation of sucrose, mannitol and lactulose, and is rapid, simple, sensitive, accurate and reproducible. Because neither S nor M is metabolized by intestinal bacteria, and because only a tiny fraction of either sugar is absorbed, this pair of sugar probes appears to be available for absorption throughout the GI tract. Thus, the 24-h urinary concentrations of S and M, or the urinary S/M ratio following an oral dose of a sugar mixture, might be good markers for whole gut permeability.

  9. Heat Stress Reduces Intestinal Barrier Integrity and Favors Intestinal Glucose Transport in Growing Pigs

    PubMed Central

    Pearce, Sarah C.; Mani, Venkatesh; Boddicker, Rebecca L.; Johnson, Jay S.; Weber, Thomas E.; Ross, Jason W.; Rhoads, Robert P.; Baumgard, Lance H.; Gabler, Nicholas K.

    2013-01-01

    Excessive heat exposure reduces intestinal integrity and post-absorptive energetics that can inhibit wellbeing and be fatal. Therefore, our objectives were to examine how acute heat stress (HS) alters intestinal integrity and metabolism in growing pigs. Animals were exposed to either thermal neutral (TN, 21°C; 35–50% humidity; n = 8) or HS conditions (35°C; 24–43% humidity; n = 8) for 24 h. Compared to TN, rectal temperatures in HS pigs increased by 1.6°C and respiration rates by 2-fold (P<0.05). As expected, HS decreased feed intake by 53% (P<0.05) and body weight (P<0.05) compared to TN pigs. Ileum heat shock protein 70 expression increased (P<0.05), while intestinal integrity was compromised in the HS pigs (ileum and colon TER decreased; P<0.05). Furthermore, HS increased serum endotoxin concentrations (P = 0.05). Intestinal permeability was accompanied by an increase in protein expression of myosin light chain kinase (P<0.05) and casein kinase II-α (P = 0.06). Protein expression of tight junction (TJ) proteins in the ileum revealed claudin 3 and occludin expression to be increased overall due to HS (P<0.05), while there were no differences in claudin 1 expression. Intestinal glucose transport and blood glucose were elevated due to HS (P<0.05). This was supported by increased ileum Na+/K+ ATPase activity in HS pigs. SGLT-1 protein expression was unaltered; however, HS increased ileal GLUT-2 protein expression (P = 0.06). Altogether, these data indicate that HS reduce intestinal integrity and increase intestinal stress and glucose transport. PMID:23936392

  10. Human and simulated intestinal fluids as solvent systems to explore food effects on intestinal solubility and permeability.

    PubMed

    Stappaerts, Jef; Wuyts, Benjamin; Tack, Jan; Annaert, Pieter; Augustijns, Patrick

    2014-10-15

    The mixed micelles and vesicles present in the intraluminal environment of the postprandial state exhibit suitable solubilizing capacities for lipophilic drugs. This increase in solubility, however, is accompanied by a decrease in the free fraction caused by micellar entrapment of these lipophilic compounds. In this study, both simulated and aspirated human intestinal fluids of fasted and fed state conditions were used to evaluate the influence of food on the intestinal disposition of a series of structurally related β-blockers, with varying logP values. Using the in situ intestinal perfusion technique with mesenteric blood sampling in rats, it was demonstrated that fed state conditions significantly decreased the absorptive flux of the more lipophilic compounds metoprolol, propranolol and carvedilol, whereas the influence on the flux of the hydrophilic β-blocker atenolol was limited. The solubility of BCS class II compound carvedilol was found to increase significantly in simulated and aspirated media of the fed state. Intestinal perfusions using intestinal media saturated with carvedilol, revealed a higher flux in the fasted state compared to the fed state, despite the higher solubility in the fed state. This study underscores the importance of addressing the complex nature of the behavior of compounds in the intraluminal environment in fasted and fed state conditions. Moreover, our data point out the value of studying the effect of food on both solubility and permeability using biorelevant experimental conditions. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. NMDA- and endothelin-1-induced increases in blood-brain barrier permeability quantitated with Lucifer yellow.

    PubMed

    Miller, R D; Monsul, N T; Vender, J R; Lehmann, J C

    1996-03-01

    At 48 h following intrastriatal injection of N-methyl-D-aspartate (NMDA; 100 nmol/microliter) or endothelin-1 (ET-1; 143 pmol/microliter), significant increases in brain penetration of the highly polar, fluorescent tracer Lucifer yellow were observed. The competitive NMDA receptor antagonist selfotel (CGS-19755; 30 nmol/microliter, i.c.) significantly reduced the NMDA-induced increases in blood-brain barrier permeability, but not those induced by ET-1. These results suggest that NMDA receptors can mediate increases in blood-brain barrier permeability but do not primarily mediate increases in blood-brain barrier permeability caused by ET-1. This is the first study to our knowledge investigating the relationship between excitotoxicity and disruption of the blood-brain barrier, a major pathophysiological event in stroke and traumatic brain injury.

  12. Using FLIM in the study of permeability barrier function of aged and young skin

    NASA Astrophysics Data System (ADS)

    Xu, P.; Choi, E. H.; Man, M. Q.; Crumrine, D.; Mauro, T.; Elias, P.

    2006-02-01

    Aged skin commonly is afflicted by inflammatory skin diseases or xerosis/eczema that can be triggered or exacerbated by impaired epidermal permeability barrier homeostasis. It has been previously described a permeability barrier defect in humans of advanced age (> 75 years), which in a murine analog >18 mos, could be attributed to reduced lipid synthesis synthesis. However, the functional abnormality in moderately aged mice is due not to decreased lipid synthesis, but rather to a specific defect in stratum corneum (SC) acidification causing impaired lipid processing processing. Endogenous Na +/H + antiporter (NHE1) level was found declined in moderately aged mouse epidermis. This acidification defect leads to perturbed permeability barrier homeostasis through more than one pathways, we addressed suboptimal activation of the essential, lipid-processing enzyme, β-glucocerebrosidase (BGC) is linked to elevated SC pH. Finally, the importance of the epidermis acidity is shown by the normalization of barrier function after exogenous acidification of moderately aged skin.

  13. Delivery of Berberine Using Chitosan/Fucoidan-Taurine Conjugate Nanoparticles for Treatment of Defective Intestinal Epithelial Tight Junction Barrier

    PubMed Central

    Wu, Shao-Jung; Don, Trong-Ming; Lin, Cheng-Wei; Mi, Fwu-Long

    2014-01-01

    Bacterial-derived lipopolysaccharides (LPS) can cause defective intestinal barrier function and play an important role in the development of inflammatory bowel disease. In this study, a nanocarrier based on chitosan and fucoidan was developed for oral delivery of berberine (Ber). A sulfonated fucoidan, fucoidan-taurine (FD-Tau) conjugate, was synthesized and characterized by Fourier transform infrared (FTIR) spectroscopy. The FD-Tau conjugate was self-assembled with berberine and chitosan (CS) to form Ber-loaded CS/FD-Tau complex nanoparticles with high drug loading efficiency. Berberine release from the nanoparticles had fast release in simulated intestinal fluid (SIF, pH 7.4), while the release was slow in simulated gastric fluid (SGF, pH 2.0). The effect of the berberine-loaded nanoparticles in protecting intestinal tight-junction barrier function against nitric oxide and inflammatory cytokines released from LPS-stimulated macrophage was evaluated by determining the transepithelial electrical resistance (TEER) and paracellular permeability of a model macromolecule fluorescein isothiocyanate-dextran (FITC-dextran) in a Caco-2 cells/RAW264.7 cells co-culture system. Inhibition of redistribution of tight junction ZO-1 protein by the nanoparticles was visualized using confocal laser scanning microscopy (CLSM). The results suggest that the nanoparticles may be useful for local delivery of berberine to ameliorate LPS-induced intestinal epithelia tight junction disruption, and that the released berberine can restore barrier function in inflammatory and injured intestinal epithelial. PMID:25421323

  14. Changes in intestinal microbiota composition and metabolism coincide with increased intestinal permeability in young adults under prolonged physiologic stress.

    PubMed

    Karl, J Philip; Margolis, Lee M; Madslien, Elisabeth H; Murphy, Nancy E; Castellani, John W; Gundersen, Yngvar; Hoke, Allison V; Levangie, Michael W; Kumar, Raina; Chakraborty, Nabarun; Gautam, Aarti; Hammamieh, Rasha; Martini, Svein; Montain, Scott J; Pasiakos, Stefan M

    2017-03-23

    The magnitude, temporal dynamics, and physiologic effects of intestinal microbiome responses to physiologic stress are poorly characterized. This study used a systems biology approach and multiple-stressor military training environment to determine the effects of physiologic stress on intestinal microbiota composition and metabolic activity, and intestinal permeability (IP). 73 Soldiers were provided three rations/d with or without protein- or carbohydrate-based supplements during a four day cross-country ski march (STRESS). IP was measured before and during STRESS. Blood and stool samples were collected before and after STRESS to measure inflammation, stool microbiota, and stool and plasma global metabolite profiles. IP increased 62%±57% (mean±SD, P<0.001) during STRESS independent of diet group, and was associated with increased inflammation. Intestinal microbiota responses were characterized by increased α-diversity, and changes in the relative abundance of >50% of identified genera, including increased abundances of less dominant taxa at the expense of more dominant taxa such as Bacteroides. Changes in intestinal microbiota composition were linked to 23% of metabolites that were significantly altered in stool after STRESS. Pre-STRESS Actinobacteria relative abundance, and changes in serum IL-6 and stool cysteine concentrations, collectively, accounted for 84% of the variability in the change in IP. Findings demonstrate that a multiple-stressor military training environment induced increases in IP that were associated with alterations in markers of inflammation, and with intestinal microbiota composition and metabolism. Observed associations between IP, the pre-stress microbiota, and microbiota metabolites suggest targeting the intestinal microbiota could provide novel strategies for preserving IP during physiologic stress.

  15. Epithelial Cell Damage Activates Bactericidal/Permeability Increasing-Protein (BPI) Expression in Intestinal Epithelium.

    PubMed

    Balakrishnan, Arjun; Chakravortty, Dipshikha

    2017-01-01

    As the first line of defense against invading pathogen, intestinal epithelium produces various antimicrobial proteins (AMP) that help in clearance of pathogen. Bactericidal/permeability-increasing protein (BPI) is a 55 kDa AMP that is expressed in intestinal epithelium. Dysregulation of BPI in intestinal epithelium is associated with various inflammatory diseases like Crohn's Disease, Ulcerative colitis, and Infectious enteritis's. In this paper, we report a direct correlation between intestinal damage and BPI expression. In Caco-2 cells, we see a significant increase in BPI levels upon membrane damage mediated by S. aureus infection and pore-forming toxins (Streptolysin and Listeriolysin). Cells detect changes in potassium level as a Danger-associated molecular pattern associated with cell damage and induce BPI expression in a p38 dependent manner. These results are further supported by in vivo findings that the BPI expression in murine intestinal epithelium is induced upon infection with bacteria which cause intestinal damage (Salmonella Typhimurium and Shigella flexneri) whereas mutants that do not cause intestinal damage (STM ΔfliC and STM ΔinvC) did not induce BPI expression. Our results suggest that epithelial damage associated with infection act as a signal to induce BPI expression.

  16. Potential of Lactobacillus plantarum CCFM639 in Protecting against Aluminum Toxicity Mediated by Intestinal Barrier Function and Oxidative Stress.

    PubMed

    Yu, Leilei; Zhai, Qixiao; Tian, Fengwei; Liu, Xiaoming; Wang, Gang; Zhao, Jianxin; Zhang, Hao; Narbad, Arjan; Chen, Wei

    2016-12-02

    Aluminum (Al) is a ubiquitous metal that can seriously harm the health of animals and humans. In our previous study, we demonstrated that Lactobacillus plantarum CCFM639 can decrease Al burden in the tissues of mice by inhibiting intestinal Al absorption. The main aim of the present research was to investigate whether the protection by the strain is also associated with enhancement of the intestinal barrier, alleviation of oxidative stress and modulation of the inflammatory response. In an in vitro cell model, two protection modes (intervention and therapy) were examined and the results indicated that L. plantarum CCFM639 alleviated Al-induced cytotoxicity. In a mouse model, L. plantarum CCFM639 treatment was found to significantly alleviate oxidative stress in the intestinal tract, regulate the function of the intestinal mucosal immune system, restore the integrity of tight junction proteins and maintain intestinal permeability. These results suggest that in addition to Al sequestration, L. plantarum CCFM639 can also inhibit Al absorption by protecting the intestinal barrier, alleviating Al-induced oxidative stress and inflammatory response. Therefore, L. plantarum CCFM639 has the potential to be a dietary supplement ingredient that provides protection against Al-induced gut injury.

  17. Potential of Lactobacillus plantarum CCFM639 in Protecting against Aluminum Toxicity Mediated by Intestinal Barrier Function and Oxidative Stress

    PubMed Central

    Yu, Leilei; Zhai, Qixiao; Tian, Fengwei; Liu, Xiaoming; Wang, Gang; Zhao, Jianxin; Zhang, Hao; Narbad, Arjan; Chen, Wei

    2016-01-01

    Aluminum (Al) is a ubiquitous metal that can seriously harm the health of animals and humans. In our previous study, we demonstrated that Lactobacillus plantarum CCFM639 can decrease Al burden in the tissues of mice by inhibiting intestinal Al absorption. The main aim of the present research was to investigate whether the protection by the strain is also associated with enhancement of the intestinal barrier, alleviation of oxidative stress and modulation of the inflammatory response. In an in vitro cell model, two protection modes (intervention and therapy) were examined and the results indicated that L. plantarum CCFM639 alleviated Al-induced cytotoxicity. In a mouse model, L. plantarum CCFM639 treatment was found to significantly alleviate oxidative stress in the intestinal tract, regulate the function of the intestinal mucosal immune system, restore the integrity of tight junction proteins and maintain intestinal permeability. These results suggest that in addition to Al sequestration, L. plantarum CCFM639 can also inhibit Al absorption by protecting the intestinal barrier, alleviating Al-induced oxidative stress and inflammatory response. Therefore, L. plantarum CCFM639 has the potential to be a dietary supplement ingredient that provides protection against Al-induced gut injury. PMID:27918411

  18. Neutrophil priming by hypoxic preconditioning protects against epithelial barrier damage and enteric bacterial translocation in intestinal ischemia/reperfusion.

    PubMed

    Lu, Yen-Zhen; Wu, Chi-Chin; Huang, Yi-Chen; Huang, Ching-Ying; Yang, Chung-Yi; Lee, Tsung-Chun; Chen, Chau-Fong; Yu, Linda Chia-Hui

    2012-05-01

    Intestinal ischemia/reperfusion (I/R) induces mucosal barrier dysfunction and bacterial translocation (BT). Neutrophil-derived oxidative free radicals have been incriminated in the pathogenesis of ischemic injury in various organs, but their role in the bacteria-containing intestinal tract is debatable. Primed neutrophils are characterized by a faster and higher respiratory burst activity associated with more robust bactericidal effects on exposure to a second stimulus. Hypoxic preconditioning (HPC) attenuates ischemic injury in brain, heart, lung and kidney; no reports were found in the gut. Our aim is to investigate whether neutrophil priming by HPC protects against intestinal I/R-induced barrier damage and bacterial influx. Rats were raised in normoxia (NM) or kept in a hypobaric hypoxic chamber (380 Torr) 17 h/day for 3 weeks for HPC, followed by sham operation or intestinal I/R. Gut permeability was determined by using an ex vivo macromolecular flux assay and an in vivo magnetic resonance imaging-based method. Liver and spleen homogenates were plated for bacterial culturing. Rats raised in HPC showed diminished levels of BT, and partially improved mucosal histopathology and epithelial barrier function compared with the NM groups after intestinal I/R. Augmented cytokine-induced neutrophil chemoattractant (CINC)-1 and -3 levels and myeloperoxidase activity correlated with enhanced infiltration of neutrophils in intestines of HPC-I/R compared with NM-I/R rats. HPC alone caused blood neutrophil priming, as shown by elevated production of superoxide and hydrogen peroxide on stimulation, increased membrane translocation of cytosolic p47(phox) and p67(phox), as well as augmented bacterial-killing and phagocytotic activities. Neutrophil depletion reversed the mucosal protection by HPC, and aggravated intestinal leakiness and BT following I/R. In conclusion, neutrophil priming by HPC protects against I/R-induced BT via direct antimicrobial activity by oxidative

  19. Characterization of a major permeability barrier in the zebrafish embryo.

    PubMed

    Hagedorn, M; Kleinhans, F W; Artemov, D; Pilatus, U

    1998-11-01

    Fish embryos represent a class of multicompartmental biological systems that have not been successfully cryopreserved, primarily because of the lack of understanding of how water and cryoprotectants permeate the compartments. We are using the zebrafish embryo as a model to understand these kinetics. Zebrafish embryos have two major compartments, the blastoderm and the yolk, which is surrounded by the multinucleated yolk syncytial layer (YSL). We determined the water and cryoprotectant permeability in these compartments using two methods. First, we measured shrink/swell dynamics in optical volumetric experiments. Zebrafish embryos shrank over time and did not re-expand while immersed in dimethyl sulfoxide (DMSO) or propylene glycol. Second, we measured DMSO uptake with diffusion-weighted nuclear magnetic resonance spectroscopy. DMSO uptake was rapid during the first few minutes, then gradual thereafter. We used one- and two-compartment models to analyze the data and to determine the permeability parameters. We found that the two-compartment model provided a better fit to the data. On the basis of this model and in the presence of DMSO, the yolk and blastoderm had very similar water permeabilities (i.e., 0.01 and 0. 005 micron x min-1atm-1, respectively), but they had different DMSO permeabilities separated by three orders of magnitude (i.e., permeability of the yolk predicted that the yolk/YSL compartment should be more susceptible to cryodamage. To test this, the yolk, blastoderm, and YSL were examined at the ultrastructural level after vitrification. Only the YSL incurred significant damage after freezing and thawing (p

  20. Intestinal permeability and orocaecal transit time in elderly patients with Parkinson's disease.

    PubMed Central

    Davies, K. N.; King, D.; Billington, D.; Barrett, J. A.

    1996-01-01

    The aetiology of weight loss in patients with Parkinson's disease is likely to be multifactorial. We studied 15 patients with Parkinson's disease and 15 age- and sex-matched controls and looked for evidence of malabsorption due to small bowel bacterial overgrowth or alteration of intestinal permeability. There was a marked increase in orocaecal transit time in the patients with Parkinson's disease, although lactulose hydrogen breath testing did not show evidence of small bowel bacterial contamination. Intestinal permeability measured by the differential sugar absorption test was also deranged. There was reduced absorption of mannitol in patients with Parkinson's disease while lactulose absorption was similar in both groups, suggesting decreased non-mediated uptake across the enterocyte brush border membrane in patients with Parkinson's disease. PMID:8731708

  1. Plasma albumin concentrations and intestinal permeability in Bangladeshi children infected with Ascaris lumbricoides.

    PubMed

    Northrop, C A; Lunn, P G; Wainwright, M; Evans, J

    1987-01-01

    Plasma albumin concentration and intestinal permeability have been investigated in Bangladeshi children before and 9-14 d after successful treatment for ascariasis. Children infected with A. lumbricoides had lower plasma albumin concentrations than counterparts not harbouring this worm and values increased with successful treatment. Intestinal permeability tests indicated that the children had impaired gastrointestinal function and some loss of mucosal integrity; these factors had not improved 9-14 d after A. lumbricoides expulsion. The lowered nitrogen nutritional status implied by the reduced plasma albumin values in infected children, and the improvement following treatment, are in keeping with previous reports that A. lumbricoides impairs protein digestion or absorption. This may be the basis of the better growth rates of dewormed children in this area.

  2. [Alteration of intestinal permeability: the missing link between gut microbiota modifications and inflammation in obesity?].

    PubMed

    Genser, Laurent; Poitou, Christine; Brot-Laroche, Édith; Rousset, Monique; Vaillant, Jean-Christophe; Clément, Karine; Thenet, Sophie; Leturque, Armelle

    2016-05-01

    The increasing incidence of obesity and associated metabolic complications is a worldwide public health issue. The role of the gut in the pathophysiology of obesity, with an important part for microbiota, is becoming obvious. In rodent models of diet-induced obesity, the modifications of gut microbiota are associated with an alteration of the intestinal permeability increasing the passage of food or bacterial antigens, which contribute to low-grade inflammation and insulin resistance. In human obesity, intestinal permeability modification, and its role in the crosstalk between gut microbiota changes and inflammation at systemic and tissular levels, are still poorly documented. Hence, further characterization of the triggering mechanisms of such inflammatory responses in obese subjects could enable the development of personalized intervention strategies that will help to reduce the risk of obesity-associated diseases.

  3. A permeability barrier surrounds taste buds in lingual epithelia.

    PubMed

    Dando, Robin; Pereira, Elizabeth; Kurian, Mani; Barro-Soria, Rene; Chaudhari, Nirupa; Roper, Stephen D

    2015-01-01

    Epithelial tissues are characterized by specialized cell-cell junctions, typically localized to the apical regions of cells. These junctions are formed by interacting membrane proteins and by cytoskeletal and extracellular matrix components. Within the lingual epithelium, tight junctions join the apical tips of the gustatory sensory cells in taste buds. These junctions constitute a selective barrier that limits penetration of chemosensory stimuli into taste buds (Michlig et al. J Comp Neurol 502: 1003-1011, 2007). We tested the ability of chemical compounds to permeate into sensory end organs in the lingual epithelium. Our findings reveal a robust barrier that surrounds the entire body of taste buds, not limited to the apical tight junctions. This barrier prevents penetration of many, but not all, compounds, whether they are applied topically, injected into the parenchyma of the tongue, or circulating in the blood supply, into taste buds. Enzymatic treatments indicate that this barrier likely includes glycosaminoglycans, as it was disrupted by chondroitinase but, less effectively, by proteases. The barrier surrounding taste buds could also be disrupted by brief treatment of lingual tissue samples with DMSO. Brief exposure of lingual slices to DMSO did not affect the ability of taste buds within the slice to respond to chemical stimulation. The existence of a highly impermeable barrier surrounding taste buds and methods to break through this barrier may be relevant to basic research and to clinical treatments of taste.

  4. A permeability barrier surrounds taste buds in lingual epithelia

    PubMed Central

    Dando, Robin; Pereira, Elizabeth; Kurian, Mani; Barro-Soria, Rene; Chaudhari, Nirupa

    2014-01-01

    Epithelial tissues are characterized by specialized cell-cell junctions, typically localized to the apical regions of cells. These junctions are formed by interacting membrane proteins and by cytoskeletal and extracellular matrix components. Within the lingual epithelium, tight junctions join the apical tips of the gustatory sensory cells in taste buds. These junctions constitute a selective barrier that limits penetration of chemosensory stimuli into taste buds (Michlig et al. J Comp Neurol 502: 1003–1011, 2007). We tested the ability of chemical compounds to permeate into sensory end organs in the lingual epithelium. Our findings reveal a robust barrier that surrounds the entire body of taste buds, not limited to the apical tight junctions. This barrier prevents penetration of many, but not all, compounds, whether they are applied topically, injected into the parenchyma of the tongue, or circulating in the blood supply, into taste buds. Enzymatic treatments indicate that this barrier likely includes glycosaminoglycans, as it was disrupted by chondroitinase but, less effectively, by proteases. The barrier surrounding taste buds could also be disrupted by brief treatment of lingual tissue samples with DMSO. Brief exposure of lingual slices to DMSO did not affect the ability of taste buds within the slice to respond to chemical stimulation. The existence of a highly impermeable barrier surrounding taste buds and methods to break through this barrier may be relevant to basic research and to clinical treatments of taste. PMID:25209263

  5. Lactobacillus rhamnosus CNCM I-3690 and the commensal bacterium Faecalibacterium prausnitzii A2-165 exhibit similar protective effects to induced barrier hyper-permeability in mice

    PubMed Central

    Laval, L; Martin, R; Natividad, JN; Chain, F; Miquel, S; de Maredsous, C Desclée; Capronnier, S; Sokol, H; Verdu, EF; van Hylckama Vlieg, JET; Bermúdez-Humarán, LG; Smokvina, T; Langella, P

    2015-01-01

    Impaired gut barrier function has been reported in a wide range of diseases and syndromes and in some functional gastrointestinal disorders. In addition, there is increasing evidence that suggests the gut microbiota tightly regulates gut barrier function and recent studies demonstrate that probiotic bacteria can enhance barrier integrity. Here, we aimed to investigate the effects of Lactobacillus rhamnosus CNCM I-3690 on intestinal barrier function. In vitro results using a Caco-2 monolayer cells stimulated with TNF-α confirmed the anti-inflammatory nature of the strain CNCM I-3690 and pointed out a putative role for the protection of the epithelial function. Next, we tested the protective effects of L. rhamnosus CNCM I-3690 in a mouse model of increased colonic permeability. Most importantly, we compared its performance to that of the well-known beneficial human commensal bacterium Faecalibacterium prauznitzii A2-165. Increased colonic permeability was normalized by both strains to a similar degree. Modulation of apical tight junction proteins expression was then analyzed to decipher the mechanism underlying this effect. We showed that CNCM I-3690 partially restored the function of the intestinal barrier and increased the levels of tight junction proteins Occludin and E-cadherin. The results indicate L. rhamnosus CNCM I-3690 is as effective as the commensal anti-inflammatory bacterium F. prausnitzii to treat functional barrier abnormalities. PMID:25517879

  6. Lactobacillus rhamnosus CNCM I-3690 and the commensal bacterium Faecalibacterium prausnitzii A2-165 exhibit similar protective effects to induced barrier hyper-permeability in mice.

    PubMed

    Laval, L; Martin, R; Natividad, J N; Chain, F; Miquel, S; Desclée de Maredsous, C; Capronnier, S; Sokol, H; Verdu, E F; van Hylckama Vlieg, J E T; Bermúdez-Humarán, L G; Smokvina, T; Langella, P

    2015-01-01

    Impaired gut barrier function has been reported in a wide range of diseases and syndromes and in some functional gastrointestinal disorders. In addition, there is increasing evidence that suggests the gut microbiota tightly regulates gut barrier function and recent studies demonstrate that probiotic bacteria can enhance barrier integrity. Here, we aimed to investigate the effects of Lactobacillus rhamnosus CNCM I-3690 on intestinal barrier function. In vitro results using a Caco-2 monolayer cells stimulated with TNF-α confirmed the anti-inflammatory nature of the strain CNCM I-3690 and pointed out a putative role for the protection of the epithelial function. Next, we tested the protective effects of L. rhamnosus CNCM I-3690 in a mouse model of increased colonic permeability. Most importantly, we compared its performance to that of the well-known beneficial human commensal bacterium Faecalibacterium prauznitzii A2-165. Increased colonic permeability was normalized by both strains to a similar degree. Modulation of apical tight junction proteins expression was then analyzed to decipher the mechanism underlying this effect. We showed that CNCM I-3690 partially restored the function of the intestinal barrier and increased the levels of tight junction proteins Occludin and E-cadherin. The results indicate L. rhamnosus CNCM I-3690 is as effective as the commensal anti-inflammatory bacterium F. prausnitzii to treat functional barrier abnormalities.

  7. Application of Blood-Brain Barrier Permeability Imaging in Global Cerebral Edema.

    PubMed

    Ivanidze, J; Kallas, O N; Gupta, A; Weidman, E; Baradaran, H; Mir, D; Giambrone, A; Segal, A Z; Claassen, J; Sanelli, P C

    2016-09-01

    Blood-brain barrier permeability is not routinely evaluated in the clinical setting. Global cerebral edema occurs after SAH and is associated with BBB disruption. Detection of global cerebral edema using current imaging techniques is challenging. Our purpose was to apply blood-brain barrier permeability imaging in patients with global cerebral edema by using extended CT perfusion. Patients with SAH underwent CTP in the early phase after aneurysmal rupture (days 0-3) and were classified as having global cerebral edema or nonglobal cerebral edema using established noncontrast CT criteria. CTP data were postprocessed into blood-brain barrier permeability quantitative maps of PS (permeability surface-area product), K(trans) (volume transfer constant from blood plasma to extravascular extracellular space), Kep (washout rate constant of the contrast agent from extravascular extracellular space to intravascular space), VE (extravascular extracellular space volume per unit of tissue volume), VP (plasmatic volume per unit of tissue volume), and F (plasma flow) by using Olea Sphere software. Mean values were compared using t tests. Twenty-two patients were included in the analysis. Kep (1.32 versus 1.52, P < .0001), K(trans) (0.15 versus 0.19, P < .0001), VP (0.51 versus 0.57, P = .0007), and F (1176 versus 1329, P = .0001) were decreased in global cerebral edema compared with nonglobal cerebral edema while VE (0.81 versus 0.39, P < .0001) was increased. Extended CTP was used to evaluate blood-brain barrier permeability in patients with SAH with and without global cerebral edema. Kep is an important indicator of altered blood-brain barrier permeability in patients with decreased blood flow, as Kep is flow-independent. Further study of blood-brain barrier permeability is needed to improve diagnosis and monitoring of global cerebral edema. © 2016 by American Journal of Neuroradiology.

  8. Decreased melatonin secretion is associated with increased intestinal permeability and marker of endotoxemia in alcoholics

    PubMed Central

    Gorenz, Annika; Shaikh, Maliha; Desai, Vishal; Forsyth, Christopher; Fogg, Louis; Burgess, Helen J.; Keshavarzian, Ali

    2015-01-01

    Chronic heavy alcohol use is known to cause gut leakiness and alcoholic liver disease (ALD), but only 30% of heavy drinkers develop increased intestinal permeability and ALD. The hypothesis of this study was that disruption of circadian rhythms is a potential risk factor in actively drinking alcoholics for gut leakiness and endotoxemia. We studied 20 subjects with alcohol use disorder (AD) and 17 healthy controls (HC, 6 day workers, 11 night workers). Subjects wore a wrist actiwatch for 7 days and underwent a 24-h dim light phase assessment and urine collection for intestinal permeability. The AD group had significantly less total sleep time and increased fragmentation of sleep (P < 0.05). AD also had significantly lower plasma melatonin levels compared with the HC [mean area under the curve (AUC) 322.78 ± 228.21 vs. 568.75 ± 304.26 pg/ml, P = 0.03]. In the AD group, AUC of melatonin was inversely correlated with small bowel and colonic intestinal permeability (lactulose-to-mannitol ratio, r = −0.39, P = 0.03; urinary sucralose, r = −0.47, P = 0.01). Cosinor analysis of lipopolysaccharide-binding protein (marker of endotoxemia) and lipopolysaccharide every 4 h for 24 h in HC and AD subjects had a midline estimating statistic of rhythm of 5,026.15 ± 409.56 vs. 6,818.02 ± 628.78 ng/ml (P < 0.01) and 0.09 ± 0.03 vs. 0.15 ± 0.19 EU/ml (P < 0.05), respectively. We found plasma melatonin was significantly lower in the AD group, and lower melatonin levels correlated with increased intestinal permeability and a marker of endotoxemia. Our study suggests the suppression of melatonin in AD may promote gut leakiness and endotoxemia. PMID:25907689

  9. The role of intestinal epithelial barrier function in the development of NEC

    PubMed Central

    Halpern, Melissa D; Denning, Patricia W

    2015-01-01

    The intestinal epithelial barrier plays an important role in maintaining host health. Breakdown of intestinal barrier function is known to play a role in many diseases such as infectious enteritis, idiopathic inflammatory bowel disease, and neonatal inflammatory bowel diseases. Recently, increasing research has demonstrated the importance of understanding how intestinal epithelial barrier function develops in the premature neonate in order to develop strategies to promote its maturation. Optimizing intestinal barrier function is thought to be key to preventing neonatal inflammatory bowel diseases such as necrotizing enterocolitis. In this review, we will first summarize the key components of the intestinal epithelial barrier, what is known about its development, and how this may explain NEC pathogenesis. Finally, we will review what therapeutic strategies may be used to promote optimal development of neonatal intestinal barrier function in order to reduce the incidence and severity of NEC. PMID:25927016

  10. Uremic plasma impairs barrier function and depletes the tight junction protein constituents of intestinal epithelium.

    PubMed

    Vaziri, Nosratola D; Goshtasbi, Nisa; Yuan, Jun; Jellbauer, Stefan; Moradi, Hamid; Raffatellu, Manuela; Kalantar-Zadeh, Kamyar

    2012-01-01

    Chronic kidney disease (CKD) causes intestinal barrier dysfunction which by allowing influx of endotoxin and other noxious products contributes to the CKD-associated systemic inflammation and uremic toxicity. We have recently shown that intestinal barrier dysfunction in CKD animals is due to degradation of transcellular (claudin-1 and occludin) and intracellular (ZO1) constituents of epithelial tight junction (TJ). This study determined whether CKD-associated disruption of TJ is mediated by retained uremic toxins/metabolites and, if so, whether they are removed by hemodialysis. The TJ-forming human enterocytes (T84 cells) were seeded on the Transwell plates and utilized when transepithelial electrical resistance (TER) exceeded 1,000 mΩ/cm(2) to ensure full polarization and TJ formation. The cells were then incubated for 24 h in media containing 10% pre- or posthemodialysis plasma from end-stage renal disease (ESRD) patients or healthy individuals. TER was then measured and cells were processed for Western blot and immunohistological analyses. Compared with the control plasma, incubation in media containing predialysis plasma from ESRD patients resulted in a marked drop in TER pointing to increased epithelial permeability. This was accompanied by significant reductions in claudin-1 (85%), occludin (15%), and ZO1 (70%) abundance. The severity of TJ damage and dysfunction was significantly less in cells exposed to the postdialysis in comparison to predialysis plasma. These findings point to the presence of as-yet unidentified product(s) in the uremic plasma capable of depleting epithelial TJ. Exposure to uremic milieu damages the intestinal epithelial TJ and impairs its barrier function, events which are mediated by agents which are partially removed by hemodialysis. Copyright © 2012 S. Karger AG, Basel.

  11. Glycoprotein A33 deficiency: a new mouse model of impaired intestinal epithelial barrier function and inflammatory disease

    PubMed Central

    Williams, Benjamin B.; Tebbutt, Niall C.; Buchert, Michael; Putoczki, Tracy L.; Doggett, Karen; Bao, Shisan; Johnstone, Cameron N.; Masson, Frederick; Hollande, Frederic; Burgess, Antony W.; Scott, Andrew M.; Ernst, Matthias; Heath, Joan K.

    2015-01-01

    ABSTRACT The cells of the intestinal epithelium provide a selectively permeable barrier between the external environment and internal tissues. The integrity of this barrier is maintained by tight junctions, specialised cell-cell contacts that permit the absorption of water and nutrients while excluding microbes, toxins and dietary antigens. Impairment of intestinal barrier function contributes to multiple gastrointestinal disorders, including food hypersensitivity, inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Glycoprotein A33 (GPA33) is an intestinal epithelium-specific cell surface marker and member of the CTX group of transmembrane proteins. Roles in cell-cell adhesion have been demonstrated for multiple CTX family members, suggesting a similar function for GPA33 within the gastrointestinal tract. To test a potential requirement for GPA33 in intestinal barrier function, we generated Gpa33−/− mice and subjected them to experimental regimens designed to produce food hypersensitivity, colitis and CAC. Gpa33−/− mice exhibited impaired intestinal barrier function. This was shown by elevated steady-state immunosurveillance in the colonic mucosa and leakiness to oral TRITC-labelled dextran after short-term exposure to dextran sodium sulphate (DSS) to injure the intestinal epithelium. Gpa33−/− mice also exhibited rapid onset and reduced resolution of DSS-induced colitis, and a striking increase in the number of colitis-associated tumours produced by treatment with the colon-specific mutagen azoxymethane (AOM) followed by two cycles of DSS. In contrast, Gpa33−/− mice treated with AOM alone showed no increase in sporadic tumour formation, indicating that their increased tumour susceptibility is dependent on inflammatory stimuli. Finally, Gpa33−/− mice displayed hypersensitivity to food allergens, a common co-morbidity in humans with IBD. We propose that Gpa33−/− mice provide a valuable model to study the mechanisms linking

  12. Central Role of the Gut Epithelial Barrier in the Pathogenesis of Chronic Intestinal Inflammation: Lessons Learned from Animal Models and Human Genetics

    PubMed Central

    Pastorelli, Luca; De Salvo, Carlo; Mercado, Joseph R.; Vecchi, Maurizio; Pizarro, Theresa T.

    2013-01-01

    The gut mucosa is constantly challenged by a bombardment of foreign antigens and environmental microorganisms. As such, the precise regulation of the intestinal barrier allows the maintenance of mucosal immune homeostasis and prevents the onset of uncontrolled inflammation. In support of this concept, emerging evidence points to defects in components of the epithelial barrier as etiologic factors in the pathogenesis of inflammatory bowel diseases (IBDs). In fact, the integrity of the intestinal barrier relies on different elements, including robust innate immune responses, epithelial paracellular permeability, epithelial cell integrity, as well as the production of mucus. The purpose of this review is to systematically evaluate how alterations in the aforementioned epithelial components can lead to the disruption of intestinal immune homeostasis, and subsequent inflammation. In this regard, the wealth of data from mouse models of intestinal inflammation and human genetics are pivotal in understanding pathogenic pathways, for example, that are initiated from the specific loss of function of a single protein leading to the onset of intestinal disease. On the other hand, several recently proposed therapeutic approaches to treat human IBD are targeted at enhancing different elements of gut barrier function, further supporting a primary role of the epithelium in the pathogenesis of chronic intestinal inflammation and emphasizing the importance of maintaining a healthy and effective intestinal barrier. PMID:24062746

  13. (51Cr)EDTA intestinal permeability in children with cow's milk intolerance

    SciTech Connect

    Schrander, J.J.; Unsalan-Hooyen, R.W.; Forget, P.P.; Jansen, J. )

    1990-02-01

    Making use of ({sup 51}Cr)EDTA as a permeability marker, we measured intestinal permeability in a group of 20 children with proven cow's milk intolerance (CMI), a group of 17 children with similar complaints where CMI was excluded (sick controls), and a group of 12 control children. ({sup 51}Cr)EDTA test results (mean +/- SD) were 6.85 +/- 3.64%, 3.42 +/- 0.94%, and 2.61 +/- 0.67% in the group with CMI, the sick control, and the control group, respectively. When compared to both control groups, patients with cow's milk intolerance (CMI) showed a significantly increased small bowel permeability. We conclude that the ({sup 51}Cr)EDTA test can be helpful for the diagnosis of cow's milk intolerance.

  14. SURFACE-ALTERED ZEOLITES AS PERMEABLE BARRIERS FOR IN SITU TREATMENT OF CONTAMINATED GROUNDWATER

    SciTech Connect

    Robert S. Bowman; Pengfei Zhang; Xian Tao

    2002-03-01

    This report summarizes experiments to develop and test surfactant-modified zeolite/zero-valent iron (SMZ/ZVI) pellets for permeable reactive barriers to treat groundwater contamination. Coating a glass foam core with a mixture of hexadecyltrimethylammonium surfactant, zeolite, and ZVI produced a high hydraulic conductivity, mechanically stable pellet. Laboratory experiments showed that the pellets completely removed soluble chromate from aqueous solution, and reduced perchloroethylene (PCE) concentrations more than pellets that lacked surfactant. Based upon the laboratory results, they predicted a 1-m-wide SMZ/ZVI barrier that would reduce PCE concentrations by four orders of magnitude. Thirteen cubic meters (470 cubic feet) of SMZ/ZVI pellets were manufactured and emplaced in a permeable barrier test facility. A controlled plume of chromate and PCE was allowed to contact the barrier for four weeks. The entire plume was captured by the barrier. No chromate was detected downgradient of the barrier. The PCE broke through the barrier after four weeks, and downgradient concentrations ultimately exceeded 10% of the influent PCE. The less-than-expected PCE reduction was attributed to insufficient surfactant content, the large size, and pH-altering characteristics of the bulk-produced pellets. The pellets developed here can be improved to yield a performance- and cost-competitive permeable barrier material.

  15. Absorption and Effect of Azaspiracid-1 Over the Human Intestinal Barrier.

    PubMed

    Abal, Paula; Louzao, M Carmen; Fraga, María; Vilariño, Natalia; Ferreiro, Sara; Vieytes, Mercedes R; Botana, Luis M

    2017-08-28

    Azaspiracids (AZAs) are marine biotoxins produced by the dinoflagellates genera Azadinium and Amphidoma. These toxins cause azaspiracid poisoning (AZP), characterized by severe gastrointestinal illness in humans after the consumption of bivalve molluscs contaminated with AZAs. The main aim of the present study was to examine the consequences of human exposure to AZA1 by the study of absorption and effects of the toxin on Caco-2 cells, a reliable model of the human intestine. The ability of AZA1 to cross the human intestinal epithelium has been evaluated by the Caco-2 transepithelial permeability assay. The toxin has been detected and quantified using a microsphere-based immunoassay. Cell alterations and ultrastructural effects has been observed with confocal and transmission electron microscopy Results: AZA1 was absorbed by Caco-2 cells in a dose-dependent way without affecting cell viability. However, modifications on occludin distribution detected by confocal microscopy imaging indicated a possible monolayer integrity disruption. Nevertheless, transmission electron microscopy imaging revealed ultrastructural damages at the nucleus and mitochondria with autophagosomes in the cytoplasm, however, tight junctions and microvilli remained unaffected. After the ingestion of molluscs with the AZA1, the toxin will be transported through the human intestinal barrier to blood causing damage on epithelial cells. © 2017 The Author(s). Published by S. Karger AG, Basel.

  16. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers.

    PubMed

    Peng, Luying; Li, Zhong-Rong; Green, Robert S; Holzman, Ian R; Lin, Jing

    2009-09-01

    Butyrate, one of the SCFA, promotes the development of the intestinal barrier. However, the molecular mechanisms underlying the butyrate regulation of the intestinal barrier are unknown. To test the hypothesis that the effect of butyrate on the intestinal barrier is mediated by the regulation of the assembly of tight junctions involving the activation of the AMP-activated protein kinase (AMPK), we determined the effect of butyrate on the intestinal barrier by measuring the transepithelial electrical resistance (TER) and inulin permeability in a Caco-2 cell monolayer model. We further used a calcium switch assay to study the assembly of epithelial tight junctions and determined the effect of butyrate on the assembly of epithelial tight junctions and AMPK activity. We demonstrated that the butyrate treatment increased AMPK activity and accelerated the assembly of tight junctions as shown by the reorganization of tight junction proteins, as well as the development of TER. AMPK activity was also upregulated by butyrate during calcium switch-induced tight junction assembly. Compound C, a specific AMPK inhibitor, inhibited the butyrate-induced activation of AMPK. The facilitating effect of butyrate on the increases in TER in standard culture media, as well as after calcium switch, was abolished by compound C. We conclude that butyrate enhances the intestinal barrier by regulating the assembly of tight junctions. This dynamic process is mediated by the activation of AMPK. These results suggest an intriguing link between SCFA and the intracellular energy sensor for the development of the intestinal barrier.

  17. Butyrate Enhances the Intestinal Barrier by Facilitating Tight Junction Assembly via Activation of AMP-Activated Protein Kinase in Caco-2 Cell Monolayers12

    PubMed Central

    Peng, Luying; Li, Zhong-Rong; Green, Robert S.; Holzman, Ian R.; Lin, Jing

    2009-01-01

    Butyrate, one of the SCFA, promotes the development of the intestinal barrier. However, the molecular mechanisms underlying the butyrate regulation of the intestinal barrier are unknown. To test the hypothesis that the effect of butyrate on the intestinal barrier is mediated by the regulation of the assembly of tight junctions involving the activation of the AMP-activated protein kinase (AMPK), we determined the effect of butyrate on the intestinal barrier by measuring the transepithelial electrical resistance (TER) and inulin permeability in a Caco-2 cell monolayer model. We further used a calcium switch assay to study the assembly of epithelial tight junctions and determined the effect of butyrate on the assembly of epithelial tight junctions and AMPK activity. We demonstrated that the butyrate treatment increased AMPK activity and accelerated the assembly of tight junctions as shown by the reorganization of tight junction proteins, as well as the development of TER. AMPK activity was also upregulated by butyrate during calcium switch-induced tight junction assembly. Compound C, a specific AMPK inhibitor, inhibited the butyrate-induced activation of AMPK. The facilitating effect of butyrate on the increases in TER in standard culture media, as well as after calcium switch, was abolished by compound C. We conclude that butyrate enhances the intestinal barrier by regulating the assembly of tight junctions. This dynamic process is mediated by the activation of AMPK. These results suggest an intriguing link between SCFA and the intracellular energy sensor for the development of the intestinal barrier. PMID:19625695

  18. Permeability of the blood-brain barrier predicts conversion from optic neuritis to multiple sclerosis.

    PubMed

    Cramer, Stig P; Modvig, Signe; Simonsen, Helle J; Frederiksen, Jette L; Larsson, Henrik B W

    2015-09-01

    Optic neuritis is an acute inflammatory condition that is highly associated with multiple sclerosis. Currently, the best predictor of future development of multiple sclerosis is the number of T2 lesions visualized by magnetic resonance imaging. Previous research has found abnormalities in the permeability of the blood-brain barrier in normal-appearing white matter of patients with multiple sclerosis and here, for the first time, we present a study on the capability of blood-brain barrier permeability in predicting conversion from optic neuritis to multiple sclerosis and a direct comparison with cerebrospinal fluid markers of inflammation, cellular trafficking and blood-brain barrier breakdown. To this end, we applied dynamic contrast-enhanced magnetic resonance imaging at 3 T to measure blood-brain barrier permeability in 39 patients with monosymptomatic optic neuritis, all referred for imaging as part of the diagnostic work-up at time of diagnosis. Eighteen healthy controls were included for comparison. Patients had magnetic resonance imaging and lumbar puncture performed within 4 weeks of onset of optic neuritis. Information on multiple sclerosis conversion was acquired from hospital records 2 years after optic neuritis onset. Logistic regression analysis showed that baseline permeability in normal-appearing white matter significantly improved prediction of multiple sclerosis conversion (according to the 2010 revised McDonald diagnostic criteria) within 2 years compared to T2 lesion count alone. There was no correlation between permeability and T2 lesion count. An increase in permeability in normal-appearing white matter of 0.1 ml/100 g/min increased the risk of multiple sclerosis 8.5 times whereas having more than nine T2 lesions increased the risk 52.6 times. Receiver operating characteristic curve analysis of permeability in normal-appearing white matter gave a cut-off of 0.13 ml/100 g/min, which predicted conversion to multiple sclerosis with a sensitivity of

  19. Permeability of the blood–brain barrier predicts conversion from optic neuritis to multiple sclerosis

    PubMed Central

    Modvig, Signe; Simonsen, Helle J.; Frederiksen, Jette L.; Larsson, Henrik B. W.

    2015-01-01

    Optic neuritis is an acute inflammatory condition that is highly associated with multiple sclerosis. Currently, the best predictor of future development of multiple sclerosis is the number of T2 lesions visualized by magnetic resonance imaging. Previous research has found abnormalities in the permeability of the blood–brain barrier in normal-appearing white matter of patients with multiple sclerosis and here, for the first time, we present a study on the capability of blood–brain barrier permeability in predicting conversion from optic neuritis to multiple sclerosis and a direct comparison with cerebrospinal fluid markers of inflammation, cellular trafficking and blood–brain barrier breakdown. To this end, we applied dynamic contrast-enhanced magnetic resonance imaging at 3 T to measure blood–brain barrier permeability in 39 patients with monosymptomatic optic neuritis, all referred for imaging as part of the diagnostic work-up at time of diagnosis. Eighteen healthy controls were included for comparison. Patients had magnetic resonance imaging and lumbar puncture performed within 4 weeks of onset of optic neuritis. Information on multiple sclerosis conversion was acquired from hospital records 2 years after optic neuritis onset. Logistic regression analysis showed that baseline permeability in normal-appearing white matter significantly improved prediction of multiple sclerosis conversion (according to the 2010 revised McDonald diagnostic criteria) within 2 years compared to T2 lesion count alone. There was no correlation between permeability and T2 lesion count. An increase in permeability in normal-appearing white matter of 0.1 ml/100 g/min increased the risk of multiple sclerosis 8.5 times whereas having more than nine T2 lesions increased the risk 52.6 times. Receiver operating characteristic curve analysis of permeability in normal-appearing white matter gave a cut-off of 0.13 ml/100 g/min, which predicted conversion to multiple sclerosis with a

  20. 'You shall not pass!': quantifying barrier permeability and proximity avoidance by animals.

    PubMed

    Beyer, Hawthorne L; Gurarie, Eliezer; Börger, Luca; Panzacchi, Manuela; Basille, Mathieu; Herfindal, Ivar; Van Moorter, Bram; R Lele, Subhash; Matthiopoulos, Jason

    2016-01-01

    Impediments to animal movement are ubiquitous and vary widely in both scale and permeability. It is essential to understand how impediments alter ecological dynamics via their influence on animal behavioural strategies governing space use and, for anthropogenic features such as roads and fences, how to mitigate these effects to effectively manage species and landscapes. Here, we focused primarily on barriers to movement, which we define as features that cannot be circumnavigated but may be crossed. Responses to barriers will be influenced by the movement capabilities of the animal, its proximity to the barriers, and habitat preference. We developed a mechanistic modelling framework for simultaneously quantifying the permeability and proximity effects of barriers on habitat preference and movement. We used simulations based on our model to demonstrate how parameters on movement, habitat preference and barrier permeability can be estimated statistically. We then applied the model to a case study of road effects on wild mountain reindeer summer movements. This framework provided unbiased and precise parameter estimates across a range of strengths of preferences and barrier permeabilities. The quality of permeability estimates, however, was correlated with the number of times the barrier is crossed and the number of locations in proximity to barriers. In the case study we found that reindeer avoided areas near roads and that roads are semi-permeable barriers to movement. There was strong avoidance of roads extending up to c. 1 km for four of five animals, and having to cross roads reduced the probability of movement by 68·6% (range 3·5-99·5%). Human infrastructure has embedded within it the idea of networks: nodes connected by linear features such as roads, rail tracks, pipelines, fences and cables, many of which divide the landscape and limit animal movement. The unintended but potentially profound consequences of infrastructure on animals remain poorly understood

  1. Novel sulpiride-loaded solid lipid nanoparticles with enhanced intestinal permeability

    PubMed Central

    Ibrahim, Waheed M; AlOmrani, Abdullah H; B Yassin, Alaa Eldeen

    2014-01-01

    Background Solid lipid nanoparticles (SLN), novel drug delivery carriers, can be utilized in enhancing both intestinal permeability and dissolution of poorly absorbed drugs. The aim of this work was to enhance the intestinal permeability of sulpiride by loading into SLN. Methods A unique ultrasonic melt-emulsification method with minimum stress conditions was used for the preparation of SLN. The mixture of the drug and the melted lipids was simply dispersed in an aqueous solution of a surfactant at a temperature that was 10°C higher than the melting points of the lipids using probe sonication, and was then simultaneously dispersed in cold water. Several formulation parameters were optimized, including the drug-to-lipid ratio, and the types of lipids and surfactants used. The produced SLN were evaluated for their particle size and shape, surface charge, entrapment efficiency, crystallinity of the drug and lipids, and the drug release profile. The rat everted sac intestine model was utilized to evaluate the change in intestinal permeability of sulpiride by loading into SLN. Results The method adopted allowed successful preparation of SLN with a monodispersed particle size of 147.8–298.8 nm. Both scanning electron microscopic and atomic force microscopic images showed uniform spherical particles and confirmed the sizes determined by the light scattering technique. Combination of triglycerides with stearic acid resulted in a marked increase in zeta potential, entrapment efficiency, and drug loading; however, the particle size was increased. The type of surfactant used was critical for particle size, charge, drug loading, and entrapment efficiency. Generally, the in vitro release profile demonstrated by all formulations showed the common biphasic mode with a varying degree of burst release. The everted sac model showed markedly enhanced sulpiride permeability in the case of the SLN-loaded formulation. The in situ results showed a very good correlation with the in

  2. Acylation of salmon calcitonin modulates in vitro intestinal peptide flux through membrane permeability enhancement.

    PubMed

    Trier, Sofie; Linderoth, Lars; Bjerregaard, Simon; Strauss, Holger M; Rahbek, Ulrik L; Andresen, Thomas L

    2015-10-01

    Acylation of peptide drugs with fatty acid chains has proven beneficial for prolonging systemic circulation, as well as increasing enzymatic stability and interactions with lipid cell membranes. Thus, acylation offers several potential benefits for oral delivery of therapeutic peptides, and we hypothesize that tailoring the acylation may be used to optimize intestinal translocation. This work aims to characterize acylated analogues of the therapeutic peptide salmon calcitonin (sCT), which lowers blood calcium, by systematically increasing acyl chain length at two positions, in order to elucidate its influence on intestinal cell translocation and membrane interaction. We find that acylation drastically increases in vitro intestinal peptide flux and confers a transient permeability enhancing effect on the cell layer. The analogues permeabilize model lipid membranes, indicating that the effect is due to a solubilization of the cell membrane, similar to transcellular oral permeation enhancers. The effect is dependent on pH, with larger effect at lower pH, and is impacted by acylation chain length and position. Compared to the unacylated peptide backbone, N-terminal acylation with a short chain provides 6- or 9-fold increase in peptide translocation at pH 7.4 and 5.5, respectively. Prolonging the chain length appears to hamper translocation, possibly due to self-association or aggregation, although the long chain acylated analogues remain superior to the unacylated peptide. For K(18)-acylation a short chain provides a moderate improvement, whereas medium and long chain analogues are highly efficient, with a 12-fold increase in permeability compared to the unacylated peptide backbone, on par with currently employed oral permeation enhancers. For K(18)-acylation the medium chain acylation appears to be optimal, as elongating the chain causes greater binding to the cell membrane but similar permeability, and we speculate that increasing the chain length further may

  3. Assessment of permeability barriers to macromolecules in the rodent endometrium at the onset of implantation.

    PubMed

    Bany, Brent M; Hamilton, G Scot

    2011-01-01

    In rodents, embryo implantation is an invasive process, which begins with its attachment to the uterine wall and culminates in the formation of the definitive placenta several days later. It is critical that the endometrium provide a supportive environment for the implanting embryo during this process, as the placenta is not yet established. The concept of changing permeability barriers to macromolecules between different extracellular compartments in the rodent uterus at the onset of implantation has been established. This chapter provides protocols that can be used to assess this changing permeability barrier and the associated redistribution of macromolecules during the early phases of implantation in rodents. An increased permeability of the endometrial vasculature to plasma proteins occurs in areas adjacent to the implanting blastocyst. In addition, alterations in the extracellular matrix enhance the accumulation of fluid and extravasated macromolecules. We describe several protocols proven to be effective in studying and quantifying early vascular and extravascular responses to natural and artificial "implantation stimuli." The first three protocols represent qualitative and quantitative methods to assess the early endometrial "vascular permeability" response. On the contrary, the fourth protocol addresses the onset of decidualization and the arising permeability barrier, which restricts the movement of macromolecules through the extracellular space. This barrier is believed to provide transient protection for the implanting embryo against potentially harmful maternal serum proteins. This protocol describes assessment of resistance of the primary decidual zone to the movement of macromolecules across the compartments of the extracellular space.

  4. Effect of anticholinesterase compound phosalone on blood-brain barrier (BBB) permeability.

    PubMed

    Bharavi, K; Reddy, K S

    2005-01-01

    To elucidate the role of acetylcholinesterase (AChE) enzyme in BBB function, phosalone, an organophosphorous compound, was studied using rat brain micro vessels in vitro. Phosalone at 100 mg/kg b. wt. induced convulsions and caused a significant inhibition of AChE resulting in increased permeability as assessed by volume distribution. The anaesthetized phosalone treated group also increased permeability as compared to the control but the values were significantly (P<0.05) lower than phosalone alone treated group. The inhibition of AChE enzyme has altered the barrier function at the dose level at which it caused convulsion and had an added effect on permeability of BBB.

  5. Protective Effects of Ferulic Acid against Heat Stress-Induced Intestinal Epithelial Barrier Dysfunction In Vitro and In Vivo.

    PubMed

    He, Shasha; Liu, Fenghua; Xu, Lei; Yin, Peng; Li, Deyin; Mei, Chen; Jiang, Linshu; Ma, Yunfei; Xu, Jianqin

    2016-01-01

    Heat stress is important in the pathogenesis of intestinal epithelial barrier dysfunction. Ferulic acid (FA), a phenolic acid widely found in fruits and vegetables, can scavenge free radicals and activate cell stress responses. This study is aimed at investigating protective effects of FA on heat stress-induced dysfunction of the intestinal epithelial barrier in vitro and in vivo. Intestinal epithelial (IEC-6) cells were pretreated with FA for 4 h and then exposed to heat stress. Heat stress caused decreased transepithelial electrical resistance (TER) and increased permeability to 4-kDa fluorescein isothiocyanate (FITC)-dextran (FD4). Both effects were inhibited by FA in a dose-dependent manner. FA significantly attenuated the decrease in occludin, ZO-1 and E-cadherin expression observed with heat stress. The distortion and redistribution of occludin, ZO-1 and E-cadherin proteins were also effectively prevented by FA pretreatment. Moreover, heat stress diminished electron-dense material detected in tight junctions (TJs), an effect also alleviated by FA in a dose-dependent manner. In an in vivo heat stress model, FA (50 mg/kg) was administered to male Sprague-Dawley rats for 7 consecutive days prior to exposure to heat stress. FA pretreatment significantly attenuated the effects of heat stress on the small intestine, including the increased FD4 permeability, disrupted tight junctions and microvilli structure, and reduced occludin, ZO-1 and E-cadherin expression. Taken together, our results demonstrate that FA pretreatment is potentially protective against heat stress-induced intestinal epithelial barrier dysfunction.

  6. Rapid and reversible enhancement of blood–brain barrier permeability using lysophosphatidic acid

    PubMed Central

    On, Ngoc H; Savant, Sanjot; Toews, Myron; Miller, Donald W

    2013-01-01

    The present study characterizes the effects of lysophosphatidic acid (LPA) on blood–brain barrier (BBB) permeability focusing specifically on the time of onset, duration, and magnitude of LPA-induced changes in cerebrovascular permeability in the mouse using both magnetic resonance imaging (MRI) and near infrared fluorescence imaging (NIFR). Furthermore, potential application of LPA for enhanced drug delivery to the brain was also examined by measuring the brain accumulation of radiolabeled methotrexate. Exposure of primary cultured brain microvessel endothelial cells (BMECs) to LPA produced concentration-dependent increases in permeability that were completely abolished by clostridium toxin B. Administration of LPA disrupted BBB integrity and enhanced the permeability of small molecular weight marker gadolinium diethylenetriaminepentaacetate (Gd-DTPA) contrast agent, the large molecular weight permeability marker, IRdye800cwPEG, and the P-glycoprotein efflux transporter probe, Rhodamine 800 (R800). The increase in BBB permeability occurred within 3 minutes after LPA injection and barrier integrity was restored within 20 minutes. A decreased response to LPA on large macromolecule BBB permeability was observed after repeated administration. The administration of LPA also resulted in 20-fold enhancement of radiolabeled methotrexate in the brain. These studies indicate that administration of LPA in combination with therapeutic agents may increase drug delivery to the brain. PMID:24045401

  7. Modulation of blood-brain barrier permeability in mice using synthetic E-cadherin peptide.

    PubMed

    On, Ngoc H; Kiptoo, Paul; Siahaan, Teruna J; Miller, Donald W

    2014-03-03

    The present work characterizes the effects of synthetic E-cadherin peptide (HAV) on blood-brain barrier (BBB) integrity using various techniques including magnetic resonance imaging (MRI) and near-infrared fluorescent imaging (NIRF). The permeability of small molecular weight permeability marker gadolinium diethylenetriaminepentaacetate (Gd-DTPA) contrast agent, the large molecular weight permeability marker, IRDye 800CW PEG, and the P-glycoprotein (P-gp) efflux transporter contrast agent, rhodamine 800 (R800), were examined in the presence and absence of HAV peptide. The results consistently demonstrated that systemic iv administration of HAV peptide resulted in a reversible disruption of BBB integrity and enhanced the accumulation of all the dyes examined. The magnitude of increase ranged from 2-fold to 5-fold depending on the size and the properties of the permeability markers. The time frame for BBB disruption with HAV peptide was rapid, occurring within 3-6 min following injection of the peptide. Furthermore, modulation of BBB permeability was reversible with the barrier integrity being restored within 60 min of the injection. The increased BBB permeability observed following HAV peptide administration was not attributable to changes in cerebral blood flow. These studies support the potential use of cadherin peptides to rapidly and reversibly modulate BBB permeability of a variety of therapeutic agents.

  8. Protective Effect of Huoxiang Zhengqi Oral Liquid on Intestinal Mucosal Mechanical Barrier of Rats with Postinfectious Irritable Bowel Syndrome Induced by Acetic Acid

    PubMed Central

    Liu, Yao; Liu, Wei; Peng, Qiu-Xian; Peng, Jiang-Li; Yu, Lin-Zhong; Hu, Jian-Lan

    2014-01-01

    In this study, a rat model with acetic acid-induced PI-IBS was used to study the role of HXZQ oral liquid in repairing the colonic epithelial barrier and reducing intestinal permeability. Pathomorphism of colonic tissue, epithelial ultrastructure, DAO activity in serum, and the protein expression of ZO-1 and occludin were examined to investigate protective effect mechanisms of HXZQ on intestinal mucosa barrier and then present experimental support for its use for prevention and cure of PI-IBS. PMID:25254052

  9. Food derived bioactive peptides and intestinal barrier function.

    PubMed

    Martínez-Augustin, Olga; Rivero-Gutiérrez, Belén; Mascaraque, Cristina; Sánchez de Medina, Fermín

    2014-12-09

    A wide range of food-derived bioactive peptides have been shown to exert health-promoting actions and are therefore considered functional foods or nutraceuticals. Some of these actions are related to the maintenance, reinforcement or repairment of the intestinal barrier function (IBF) whose role is to selectively allow the absorption of water, nutrients and ions while preventing the influx of microorganisms from the intestinal lumen. Alterations in the IBF have been related to many disorders, such as inflammatory bowel disease or metabolic syndrome. Components of IBF are the intestinal epithelium, the mucus layer, secretory immunoglobulin A and cells of the innate and adaptive immune systems. Here we review the effects of food derived bioactive peptides on these IBF components. In vitro and in vivo effects, both in healthy and disease states, have been reviewed. Although limited, the available information indicates a potential for food-derived peptides to modify IBF and to contribute to disease treatment, but further research is needed to better isolate responsible peptides, and to help define their mode of action.

  10. Food Derived Bioactive Peptides and Intestinal Barrier Function

    PubMed Central

    Martínez-Augustin, Olga; Rivero-Gutiérrez, Belén; Mascaraque, Cristina; Sánchez de Medina, Fermín

    2014-01-01

    A wide range of food-derived bioactive peptides have been shown to exert health-promoting actions and are therefore considered functional foods or nutraceuticals. Some of these actions are related to the maintenance, reinforcement or repairment of the intestinal barrier function (IBF) whose role is to selectively allow the absorption of water, nutrients and ions while preventing the influx of microorganisms from the intestinal lumen. Alterations in the IBF have been related to many disorders, such as inflammatory bowel disease or metabolic syndrome. Components of IBF are the intestinal epithelium, the mucus layer, secretory immunoglobulin A and cells of the innate and adaptive immune systems. Here we review the effects of food derived bioactive peptides on these IBF components. In vitro and in vivo effects, both in healthy and disease states, have been reviewed. Although limited, the available information indicates a potential for food-derived peptides to modify IBF and to contribute to disease treatment, but further research is needed to better isolate responsible peptides, and to help define their mode of action. PMID:25501338

  11. The important role of epidermal triacylglycerol metabolism for maintenance of the skin permeability barrier function.

    PubMed

    Radner, Franz P W; Fischer, Judith

    2014-03-01

    Survival in a terrestrial, dry environment necessitates a permeability barrier for regulated permeation of water and electrolytes in the cornified layer of the skin (the stratum corneum) to minimize desiccation of the body. This barrier is formed during cornification and involves a cross-linking of corneocyte proteins as well as an extensive remodeling of lipids. The cleavage of precursor lipids from lamellar bodies by various hydrolytic enzymes generates ceramides, cholesterol, and non-esterified fatty acids for the extracellular lipid lamellae in the stratum corneum. However, the important role of epidermal triacylglycerol (TAG) metabolism during formation of a functional permeability barrier in the skin was only recently discovered. Humans with mutations in the ABHD5/CGI-58 (α/β hydrolase domain containing protein 5, also known as comparative gene identification-58, CGI-58) gene suffer from a defect in TAG catabolism that causes neutral lipid storage disease with ichthyosis. In addition, mice with deficiencies in genes involved in TAG catabolism (Abhd5/Cgi-58 knock-out mice) or TAG synthesis (acyl-CoA:diacylglycerol acyltransferase-2, Dgat2 knock-out mice) also develop severe skin permeability barrier dysfunctions and die soon after birth due to increased dehydration. As a result of these defects in epidermal TAG metabolism, humans and mice lack ω-(O)-acylceramides, which leads to malformation of the cornified lipid envelope of the skin. In healthy skin, this epidermal structure provides an interface for the linkage of lamellar membranes with corneocyte proteins to maintain permeability barrier homeostasis. This review focuses on recent advances in the understanding of biochemical mechanisms involved in epidermal neutral lipid metabolism and the generation of a functional skin permeability barrier. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous

  12. Optimization of the Caco-2 permeability assay to screen drug compounds for intestinal absorption and efflux.

    PubMed

    Press, Barry

    2011-01-01

    In vitro permeability assays are a valuable tool for scientists during lead compound optimization. As a majority of discovery projects are focused on the development of orally bioavailable drugs, correlation of in vitro permeability data to in vivo absorption results is critical for understanding the structural-physicochemical relationship (SPR) of drugs exhibiting low levels of absorption. For more than a decade, the Caco-2 screening assay has remained a popular, in vitro system to test compounds for both intestinal permeability and efflux liability. Despite advances in artificial membrane technology and in silico modeling systems, drug compounds still benefit from testing in cell-based epithelial monolayer assays for lead optimization. This chapter provides technical information for performing and optimizing the Caco-2 assay. In addition, techniques are discussed for dealing with some of the most pressing issues surrounding in vitro permeability assays (i.e., low aqueous solubility of test compounds and low postassay recovery). Insights are offered to help researchers avoid common pitfalls in the interpretation of in vitro permeability data, which can often lead to the perception of misleading results for correlation to in vivo data.

  13. Protective Capacity of Resveratrol, a Natural Polyphenolic Compound, against Deoxynivalenol-Induced Intestinal Barrier Dysfunction and Bacterial Translocation.

    PubMed

    Ling, Ka-Ho; Wan, Murphy Lam Yim; El-Nezami, Hani; Wang, Mingfu

    2016-05-16

    Contamination of food/feedstuffs by mycotoxins is a serious problem worldwide, causing severe economic losses and serious health problems in animals/humans. Deoxynivalenol (DON) is a major mycotoxin contaminant and is known to impair intestinal barrier function. Grapes and red wine are rich in polyphenols, such as resveratrol (RES), which has striking antioxidant and anti-inflammatory activities. RES is a food-derived component; therefore, it may be simultaneously present with DON in the gastrointestinal tract. The aim of this study was to explore in vitro protective effects of RES against DON-induced intestinal damage. The results showed that RES could protect DON-induced bacteria translocation because of enhanced of intestinal barrier function by restoring the DON-induced decrease in transepithelial electrical resistance and increase in paracellular permeability. Further mechanistic studies demonstrated that RES protects against DON-induced barrier dysfunction by promoting the assembly of claudin-4 in the tight junction complex. This is probably mediated through modulation of IL-6 and IL-8 secretion via mitogen-activated protein kinase-dependent pathways. Our results imply that RES can protect against DON-induced intestinal damage and that RES may be used as a novel dietary intervention strategy to reduce DON toxicity in animals/humans.

  14. Probiotic-derived polyphosphate enhances the epithelial barrier function and maintains intestinal homeostasis through integrin-p38 MAPK pathway.

    PubMed

    Segawa, Shuichi; Fujiya, Mikihiro; Konishi, Hiroaki; Ueno, Nobuhiro; Kobayashi, Naoyuki; Shigyo, Tatsuro; Kohgo, Yutaka

    2011-01-01

    Probiotics exhibit beneficial effects on human health, particularly in the maintenance of intestinal homeostasis in a complex manner notwithstanding the diversity of an intestinal flora between individuals. Thus, it is highly probable that some common molecules secreted by probiotic and/or commensal bacteria contribute to the maintenance of intestinal homeostasis and protect the intestinal epithelium from injurious stimuli. To address this question, we aimed to isolate the cytoprotective compound from a lactobacillus strain, Lactobacillus brevis SBC8803 which possess the ability to induce cytoprotective heat shock proteins in mouse small intestine. L. brevis was incubated in MRS broth and the supernatant was passed through with a 0.2-µm filter. Caco2/bbe cells were treated with the culture supernatant, and HSP27 expression was evaluated by Western blotting. HSP27-inducible components were separated by ammonium sulfate precipitation, DEAE anion exchange chromatography, gel filtration, and HPLC. Finally, we identified that the HSP27-inducible fraction was polyphosphate (poly P), a simple repeated structure of phosphates, which is a common product of lactobacilli and other bacteria associated with intestinal microflora without any definitive physiological functions. Then, poly P was synthesized by poly P-synthesizing enzyme polyphosphate kinase. The synthesized poly P significantly induced HSP27 from Caco2/BBE cells. In addition, Poly P suppressed the oxidant-induced intestinal permeability in the mouse small intestine and pharmacological inhibitors of p38 MAPK and integrins counteract its protective effect. Daily intrarectal administration of poly P (10 µg) improved the inflammation grade and survival rate in 4% sodium dextran sulfate-administered mice. This study, for the first time, demonstrated that poly P is the molecule responsible for maintaining intestinal barrier actions which are mediated through the intestinal integrin β1-p38 MAPK.

  15. Probiotic-Derived Polyphosphate Enhances the Epithelial Barrier Function and Maintains Intestinal Homeostasis through Integrin–p38 MAPK Pathway

    PubMed Central

    Segawa, Shuichi; Fujiya, Mikihiro; Konishi, Hiroaki; Ueno, Nobuhiro; Kobayashi, Naoyuki; Shigyo, Tatsuro; Kohgo, Yutaka

    2011-01-01

    Probiotics exhibit beneficial effects on human health, particularly in the maintenance of intestinal homeostasis in a complex manner notwithstanding the diversity of an intestinal flora between individuals. Thus, it is highly probable that some common molecules secreted by probiotic and/or commensal bacteria contribute to the maintenance of intestinal homeostasis and protect the intestinal epithelium from injurious stimuli. To address this question, we aimed to isolate the cytoprotective compound from a lactobacillus strain, Lactobacillus brevis SBC8803 which possess the ability to induce cytoprotective heat shock proteins in mouse small intestine. L. brevis was incubated in MRS broth and the supernatant was passed through with a 0.2-µm filter. Caco2/bbe cells were treated with the culture supernatant, and HSP27 expression was evaluated by Western blotting. HSP27-inducible components were separated by ammonium sulfate precipitation, DEAE anion exchange chromatography, gel filtration, and HPLC. Finally, we identified that the HSP27-inducible fraction was polyphosphate (poly P), a simple repeated structure of phosphates, which is a common product of lactobacilli and other bacteria associated with intestinal microflora without any definitive physiological functions. Then, poly P was synthesized by poly P-synthesizing enzyme polyphosphate kinase. The synthesized poly P significantly induced HSP27 from Caco2/BBE cells. In addition, Poly P suppressed the oxidant-induced intestinal permeability in the mouse small intestine and pharmacological inhibitors of p38 MAPK and integrins counteract its protective effect. Daily intrarectal administration of poly P (10 µg) improved the inflammation grade and survival rate in 4% sodium dextran sulfate-administered mice. This study, for the first time, demonstrated that poly P is the molecule responsible for maintaining intestinal barrier actions which are mediated through the intestinal integrin β1-p38 MAPK. PMID:21858054

  16. Bacillus cereus-induced permeability of the blood-ocular barrier during experimental endophthalmitis.

    PubMed

    Moyer, Andrea L; Ramadan, Raniyah T; Novosad, Billy D; Astley, Roger; Callegan, Michelle C

    2009-08-01

    The purpose of this study was to determine to what extent blood-retinal barrier (BRB) permeability occurred during experimental Bacillus cereus endophthalmitis and whether tight junction alterations were involved in permeability. Mice were intravitreally injected with 100 colony-forming units of B. cereus, and eyes were analyzed at specific times after infection for permeability to fibrin and albumin, quantitation of intraocular plasma constituent leakage, production of inflammatory cytokines, and alterations in tight junction protein localization and expression at the level of the retinal pigment epithelium. B. cereus induced the leakage of albumin and fibrin into the aqueous and vitreous humor by 8 hours after infection. BRB permeability occurred as early as 4 hours and increased 13.30-fold compared with uninfected controls by 8 hours. Production of proinflammatory cytokines IL-6, MIP-1alpha, IL-1beta, and KC increased over the course of infection. In the retina, ZO-1 disruption began by 4 hours and was followed by decreasing occludin and ZO-1 expression at 4 and 8 hours, respectively. Tubulin condensation and RPE65 degradation occurred by 12 hours. A quorum-sensing mutant B. cereus strain caused BRB permeability comparable to that of wild-type B. cereus. Wild-type and mutant B. cereus sterile supernatants induced blood-ocular barrier permeability similarly to that of wild-type infection. These results indicate that BRB permeability occurs during the early stages of experimental B. cereus endophthalmitis, beginning as early as 4 hours after infection. Disruption of tight junctions at the level of the retinal pigment epithelium may contribute to barrier breakdown. Quorum-sensing dependent factors may not significantly contribute to BRB permeability.

  17. Alteration of intestinal barrier function during activity-based anorexia in mice.

    PubMed

    Jésus, Pierre; Ouelaa, Wassila; François, Marie; Riachy, Lina; Guérin, Charlène; Aziz, Moutaz; Do Rego, Jean-Claude; Déchelotte, Pierre; Fetissov, Sergueï O; Coëffier, Moïse

    2014-12-01

    Anorexia nervosa is a severe eating disorder often leading to malnutrition and cachexia, but its pathophysiology is still poorly defined. Chronic food restriction during anorexia nervosa may induce gut barrier dysfunction, which may contribute to disease development and its complications. Here we have characterized intestinal barrier function in mice with activity-based anorexia (ABA), an animal model of anorexia nervosa. Male C57Bl/6 ABA or limited food access (LFA) mice were placed respectively in cages with or without activity wheel. After 5 days of acclimatization, both ABA and LFA mice had progressively limited access to food from 6 h/d at day 6 to 3 h/d at day 9 and until the end of experiment at day 17. A group of pair-fed mice (PF) was also compared to ABA. On day 17, food intake was lower in ABA than LFA mice (2.0 ± 0.18 g vs. 3.0 ± 0.14 g, p < 0.001) and weight loss was more pronounced in ABA and PF compared to LFA mice (23.6 ± 1.6% and 24.7 ± 0.7% vs. 16.5 ± 1.2%; p < 0.05). Colonic histology showed decreased thickness of the muscularis layer in ABA compared to LFA mice (p < 0.05). Colonic permeability was increased in both ABA and PF compared to LFA mice (p < 0.05) but jejunal paracellular permeability was not affected. Expression of claudin-1 in the colon was lower in the ABA than the LFA group (p < 0.05), whereas occludin expression remained unaffected. Increased colonic permeability and histological alterations found in ABA mice suggest that intestinal barrier dysfunction may also occur in anorexia nervosa. The role of these alterations in the pathophysiology of anorexia nervosa should be further evaluated. Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  18. Effects of Soybean Agglutinin on Mechanical Barrier Function and Tight Junction Protein Expression in Intestinal Epithelial Cells from Piglets

    PubMed Central

    Pan, Li; Qin, Guixin; Zhao, Yuan; Wang, Jun; Liu, Feifei; Che, Dongsheng

    2013-01-01

    In this study, we sought to investigate the role of soybean agglutinin (SBA) in mediating membrane permeability and the mechanical barrier function of intestinal epithelial cells. The IPEC-J2 cells were cultured and treated with 0, 0.5, 1.0, 1.5, 2.0, 2.5, or 3.0 mg/mL SBA. Transepithelial electrical resistance (TEER) and alkaline phosphatase (AP) activity were measured to evaluate membrane permeability. The results showed a significant decrease in TEER values (p < 0.05) in a time- and dose-dependent manner, and a pronounced increase in AP activity (p < 0.05). Cell growth and cell morphology were used to evaluate the cell viability. A significant cell growth inhibition (p < 0.05) and alteration of morphology were observed when the concentration of SBA was increased. The results of western blotting showed that the expression levels of occludin and claudin-3 were decreased by 31% and 64% compared to those of the control, respectively (p < 0.05). In addition, immunofluorescence labeling indicated an obvious decrease in staining of these targets and changes in their localizations. In conclusion, SBA increased the membrane permeability, inhibited the cell viability and reduced the levels of tight junction proteins (occludin and claudin-3), leading to a decrease in mechanical barrier function in intestinal epithelial cells. PMID:24189218

  19. Bovine colostrum increases pore-forming claudin-2 protein expression but paradoxically not ion permeability possibly by a change of the intestinal cytokine milieu.

    PubMed

    Bodammer, Peggy; Kerkhoff, Claus; Maletzki, Claudia; Lamprecht, Georg

    2013-01-01

    An impaired intestinal barrier function is involved in the pathogenesis of inflammatory bowel disease (IBD). Several nutritional factors are supposed to be effective in IBD treatment but scientific data about the effects on the intestinal integrity remain scarce. Bovine colostrum was shown to exert beneficial effects in DSS-induced murine colitis, and the present study was undertaken to explore the underlying molecular mechanisms. Western blot revealed increased claudin-2 expression in the distal ileum of healthy mice after feeding with colostrum for 14 days, whereas other tight junction proteins (claudin-3, 4, 10, 15) remained unchanged. The colostrum-induced claudin-2 induction was confirmed in differentiated Caco-2 cells after culture with colostrum for 48 h. Paradoxically, the elevation of claudin-2, which forms a cation-selective pore, was neither accompanied by increased ion permeability nor impaired barrier function. In an in situ perfusion model, 1 h exposure of the colonic mucosa to colostrum induced significantly increased mRNA levels of barrier-strengthening cytokine transforming growth factor-β, while interleukine-2, interleukine-6, interleukine-10, interleukine-13, and tumor-necrosis factor-α remained unchanged. Thus, modulation of the intestinal transforming growth factor-β expression might have compensated the claudin-2 increase and contributed to the observed barrier strengthening effects of colostrum in vivo and in vitro.

  20. Early weaning increases intestinal permeability, alters expression of cytokine and tight junction proteins, and activates mitogen-activated protein kinases in pigs.

    PubMed

    Hu, C H; Xiao, K; Luan, Z S; Song, J

    2013-03-01

    Although weaning stress has been reported to impair intestinal barrier function, the mechanisms have not yet been elucidated. In the present study, the intestinal morphology and permeability and mRNA expressions of tight junction proteins and cytokines in the intestine of piglets during the 2 wk after weaning were assessed. The phosphorylated (activated) ratios of p38, c-Jun NH(2)-terminal kinase (JNK), and extracellular regulated kinases (ERK1/2) were determined to investigate whether mitogen-activated protein kinase (MAPK) signaling pathways are involved in the early weaning process. A shorter villus and deeper crypt were observed on d 3 and 7 postweaning. Although damaged intestinal morphology recovered to preweaning values on d 14 postweaning, the intestinal mucosal barrier, which was reflected by transepithelial electrical resistance (TER) and paracellular flux of dextran (4 kDa) in the Ussing chamber and tight junction protein expression, was not recovered. Compared with the preweaning stage (d 0), jejunal TER and mRNA expressions of occludin and claudin-1 on d 3, 7, and 14 postweaning and Zonula occludens-1 (ZO-1) mRNA on d 3 and 7 postweaning were reduced, and paracellular flux of dextran on d 3, 7, and 14 postweaning was increased. An increase (P < 0.05) of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) mRNA on d 3 and d 7 postweaning and an increase (P < 0.05) of interferon-γ (IFN-γ) mRNA on d 3 postweaning were observed compared with d 0. No significant increase of transforming growth factor β1 (TGF-β1) and interleukin-10 (IL-10) mRNA after weaning was observed. The phosphorylated (activated) ratios of JNK and p38 on d 3 and 7 postweaning and the phosphorylated ratio of ERK1/2 on d 3 postweaning were increased (P < 0.05) compared with d 0. The results indicated that early weaning induced sustained impairment in the intestinal barrier, decreased mRNA expression of tight junction proteins, and upregulated the expression of proinflammatory

  1. Development of a Non-Aqueous Dispersion to Improve Intestinal Epithelial Flux of Poorly Permeable Macromolecules.

    PubMed

    Maher, Sam; Medani, Mekki; Carballeira, Nestor N; Winter, Desmond C; Baird, Alan W; Brayden, David J

    2017-01-01

    Intestinal permeation enhancers (PEs) offer an attractive strategy to enable oral peptide administration. However, optimal presentation of peptide and PE from solid-dosage forms is offset by slow dissolution rates in the small intestine, which reduces the likelihood that the PE can reach the threshold concentration for sufficient permeability enhancement. The purpose of this study was to design a PE-based liquid dispersion that can improve intestinal permeation of macromolecules across Caco-2 monolayers and isolated rat/human intestinal mucosae mounted in Ussing chambers. An enhancer screen in monolayers based on permeability (TEER, Papp [(14)C]-mannitol) and cytotoxicity (MTT assay) initially identified methyl 10-hydroxydecanoate (10-OHC10CH3) as a candidate. 10-OHC10CH3 (20 mM) increased the Papp of fluorescent dextran of 4 kDa (FD4) (167-fold), 10 kDa (FD10) (429-fold), and 40 kDa (FD40) (520-fold) across monolayers. Blends of 10-OHC10CH3 with low molecular weight PEGs (0.2-1 kDa) formed liquid dispersions in which enhancement capacity across monolayers of 10-OHC10CH3 was increased over 10-OHC10CH3 alone in the order PEG200 < PEG400 < PEG600 < PEG1000. Finally, a 1:5 ratio of 10-OHC10CH3 (10-20 mM)/PEG600 (50-100 mM) increased the Papp of [(14)C]-mannitol across rat and human intestinal mucosae. This study highlights the potential future role for non-aqueous, PE-based liquid dispersions in oral delivery of macromolecules.

  2. Intestinal permeability to (/sup 51/Cr)EDTA in children with Crohn's disease and celiac disease

    SciTech Connect

    Turck, D.; Ythier, H.; Maquet, E.; Deveaux, M.; Marchandise, X.; Farriaux, J.P.; Fontaine, G.

    1987-07-01

    (/sup 51/Cr)EDTA was used as a probe molecule to assess intestinal permeability in 7 healthy control adults, 11 control children, 17 children with Crohn's disease, and 6 children with untreated celiac disease. After subjects fasted overnight, 75 kBq/kg (= 2 microCi/kg) /sup 51/Cr-labeled EDTA was given by mouth; 24-h urinary excretion of (/sup 51/Cr)EDTA was measured and expressed as a percentage of the total oral dose. Mean and SD were as follows: control adults 1.47 +/- 0.62, control children 1.59 +/- 0.55, and patients with Crohn's disease or celiac disease 5.35 +/- 1.94. The difference between control children and patients was statistically significant (p less than 0.001). These results show that intestinal permeability to (/sup 51/Cr)EDTA is increased among children with active or inactive Crohn's disease affecting small bowel only or small bowel and colon, and with untreated celiac disease. The (/sup 51/Cr)EDTA permeability test could facilitate the decision to perform more extensive investigations in children suspected of small bowel disease who have atypical or poor clinical and biological symptomatology.

  3. Gastrointestinal Symptoms and Altered Intestinal Permeability Induced by Combat Training Are Associated with Distinct Metabotypic Changes.

    PubMed

    Phua, Lee Cheng; Wilder-Smith, Clive H; Tan, Yee Min; Gopalakrishnan, Theebarina; Wong, Reuben K; Li, Xinhua; Kan, Mary E; Lu, Jia; Keshavarzian, Ali; Chan, Eric Chun Yong

    2015-11-06

    Physical and psychological stress have been shown to modulate multiple aspects of gastrointestinal (GI) physiology, but its molecular basis remains elusive. We therefore characterized the stress-induced metabolic phenotype (metabotype) in soldiers during high-intensity combat training and correlated the metabotype with changes in GI symptoms and permeability. In a prospective, longitudinal study, urinary metabotyping was conducted on 38 male healthy soldiers during combat training and a rest period using gas chromatography-mass spectrometry. The urinary metabotype during combat training was clearly distinct from the rest period (partial least-squares discriminant analysis (PLSDA) Q(2) = 0.581), confirming the presence of a unique stress-induced metabotype. Differential metabolites related to combat stress were further uncovered, including elevated pyroglutamate and fructose, and reduced gut microbial metabolites, namely, hippurate and m-hydroxyphenylacetate (p < 0.05). The extent of pyroglutamate upregulation exhibited a positive correlation with an increase in IBS-SSS in soldiers during combat training (r = 0.5, p < 0.05). Additionally, the rise in fructose levels was positively correlated with an increase in intestinal permeability (r = 0.6, p < 0.005). In summary, protracted and mixed psychological and physical combat-training stress yielded unique metabolic changes that corresponded with the incidence and severity of GI symptoms and alteration in intestinal permeability. Our study provided novel molecular insights into stress-induced GI perturbations, which could be exploited for future biomarker research or development of therapeutic strategies.

  4. Permeability of milk protein antigens across the intestinal epithelium in vitro.

    PubMed

    Marcon-Genty, D; Tomé, D; Dumontier, A M; Kheroua, O; Desjeux, J F

    1989-01-01

    Degradations by proteolytic enzymes and intestinal epithelial permeability represent two major drawbacks to the transfer of food protein antigens to blood. These steps were studied in vitro for the milk protein antigens beta-lactoglobulin (beta-Lg), alpha-Lactalbumin (alpha-La) and beta-casein (beta-cas). Pepsin-trypsin hydrolysis and permeability in isolated rabbit ileum in Ussing chamber were suited by ELISA and radiolabelled-protein measurement. Pepsin-trypsin hydrolysis showed an increasing resistance in the order beta-cas less than alpha-La less than beta-Lg. The rate of absorption of the antigenic proteins by isolated rabbit ileum was in the same order, and the rate of absorption of the whole proteins (degraded and antigenic forms) was significantly higher for beta-Lg than for alpha-La and beta-cas. These results suggest a selective intestinal permeability for milk protein antigens. This selectivity is probably important in the mechanism of food protein sensitization via the oral route.

  5. Effect of eicosapentaenoic acid-derived prostaglandin E3 on intestinal epithelial barrier function.

    PubMed

    Rodríguez-Lagunas, Maria J; Ferrer, Ruth; Moreno, Juan J

    2013-05-01

    Prostaglandins (PG) are inflammatory mediators derived from arachidonic or eicosapentaenoic acid giving rise to the 2-series or the 3-series prostanoids, respectively. Previously, we have observed that PGE2 disrupts epithelial barrier function. Considering the beneficial effect of fish oil consumption in intestinal inflammatory processes, the aim of this study was to assess the role of PGE3 on epithelial barrier function assessed from transepithelial electrical resistance and dextran fluxes in Caco-2 cells. The results indicate that PGE3 increased paracellular permeability (PP) to the same extent as PGE2, through the interaction with EP1 and EP4 receptors and with intracellular Ca(2+) and cAMP as the downstream targets. Moreover, we observed a redistribution of tight junction proteins, occludin and claudin-4. In conclusion, PGE3 is able to increase PP thus leading to reconsider the role of PGE2/PGE3 ratio in the beneficial effects of dietary fish oil supplementation in the disruption of barrier function.

  6. Potential performance of pillared inorgano- organo bentonite for soil mix technology permeable reactive barrier (Invited)

    NASA Astrophysics Data System (ADS)

    Abunada, Z. M.; Al-Tabbaa, A.

    2013-12-01

    Modified bentonite has gained more interest for their effect in contaminant removal and environmental protection. This study is investigating the use of three different modified inorgano-organo bentonite (IOB) in soil mixing permeable reactive barrier. IOB were prepared using pillaring agents and quaternary ammonium cations (QAC) with different loading ratios. The permeabilities of compacted specimens containing IOB with two different soil types (sandy and gravelly soil) were measured for site contaminated groundwater, pure water and TEX compounds to study the potential of soil mix permeable reactive barrier (PRB). The soil permeability decreased by 1-2 order of magnitude once mixed with IOB. It also decreased by about 100 in case of TEX compound and site groundwater. The IOB was tested to remove Toluene, Ethyl-benzene, and o-Xylene (TEX) compound from model contaminated water in both batch and column test. Physical characteristics such as pore volume, porosity and specific structure in addition to level of surfactant loading were determined. Materials removal efficiency varied due to the surfactant loading, soil type and contaminant molecular weight. Sorption isotherm showed that the adsorbates preference increased in the order of T>E>X in all IOB types. Maximum TEX compound sorptive capacity varied also due to soil type with the highest was 86.89% 93.19% and 90.2% for T,E,X respectively on sandy soil. Key words: Inorgano-organo bentonite, permeability, reactive barrier, soil mix, sorption

  7. A framework for understanding semi-permeable barrier effects on migratory ungulates

    USGS Publications Warehouse

    Sawyer, Hall; Kauffman, Matthew J.; Middleton, Arthur D.; Morrison, Thomas A.; Nielson, Ryan M.; Wyckoff, Teal B.

    2013-01-01

    1. Impermeable barriers to migration can greatly constrain the set of possible routes and ranges used by migrating animals. For ungulates, however, many forms of development are semi-permeable, and making informed management decisions about their potential impacts to the persistence of migration routes is difficult because our knowledge of how semi-permeable barriers affect migratory behaviour and function is limited. 2. Here, we propose a general framework to advance the understanding of barrier effects on ungulate migration by emphasizing the need to (i) quantify potential barriers in terms that allow behavioural thresholds to be considered, (ii) identify and measure behavioural responses to semi-permeable barriers and (iii) consider the functional attributes of the migratory landscape (e.g. stopovers) and how the benefits of migration might be reduced by behavioural changes. 3. We used global position system (GPS) data collected from two subpopulations of mule deer Odocoileus hemionus to evaluate how different levels of gas development influenced migratory behaviour, including movement rates and stopover use at the individual level, and intensity of use and width of migration route at the population level. We then characterized the functional landscape of migration routes as either stopover habitat or movement corridors and examined how the observed behavioural changes affected the functionality of the migration route in terms of stopover use. 4. We found migratory behaviour to vary with development intensity. Our results suggest that mule deer can migrate through moderate levels of development without any noticeable effects on migratory behaviour. However, in areas with more intensive development, animals often detoured from established routes, increased their rate of movement and reduced stopover use, while the overall use and width of migration routes decreased. 5. Synthesis and applications. In contrast to impermeable barriers that impede animal movement

  8. Ethanol Impairs Intestinal Barrier Function in Humans through Mitogen Activated Protein Kinase Signaling: A Combined In Vivo and In Vitro Approach

    PubMed Central

    Elamin, Elhaseen; Masclee, Ad; Troost, Freddy; Pieters, Harm-Jan; Keszthelyi, Daniel; Aleksa, Katarina; Dekker, Jan; Jonkers, Daisy

    2014-01-01

    Background Ethanol-induced gut barrier disruption is associated with several gastrointestinal and liver disorders. Aim Since human data on effects of moderate ethanol consumption on intestinal barrier integrity and involved mechanisms are limited, the objectives of this study were to investigate effects of a single moderate ethanol dose on small and large intestinal permeability and to explore the role of mitogen activated protein kinase (MAPK) pathway as a primary signaling mechanism. Methods Intestinal permeability was assessed in 12 healthy volunteers after intraduodenal administration of either placebo or 20 g ethanol in a randomised cross-over trial. Localization of the tight junction (TJ) and gene expression, phosphorylation of the MAPK isoforms p38, ERK and JNK as indicative of activation were analyzed in duodenal biopsies. The role of MAPK was further examined in vitro using Caco-2 monolayers. Results Ethanol increased small and large intestinal permeability, paralleled by redistribution of ZO-1 and occludin, down-regulation of ZO-1 and up-regulation of myosin light chain kinase (MLCK) mRNA expression, and increased MAPK isoforms phosphorylation. In Caco-2 monolayers, ethanol increased permeability, induced redistribution of the junctional proteins and F-actin, and MAPK and MLCK activation, as indicated by phosphorylation of MAPK isoforms and myosin light chain (MLC), respectively, which could be reversed by pretreatment with either MAPK inhibitors or the anti-oxidant L-cysteine. Conclusions Administration of moderate ethanol dosage can increase both small and colon permeability. Furthermore, the data indicate a pivotal role for MAPK and its crosstalk with MLCK in ethanol-induced intestinal barrier disruption. Trial Registration ClinicalTrials.gov NCT00928733 PMID:25226407

  9. LONG-TERM PERFORMANCE OF PERMEABLE REACTIVE BARRIERS TO REMEDIATE CONTAMINATED GROUND WATER

    EPA Science Inventory

    This research brief presents findings over the past four years at two sites where detailed investigations by the U.S. Environmental Protection Agency (U.S. EPA) have focused on the long-term performance of PRBs under a Tri-Agency Permeable Reactive Barrier Initiative (TRI). This ...

  10. EVALUATION OF PERMEABLE REACTIVE BARRIER PERFORMANCE: A TRI-AGENCY INITIATIVE

    EPA Science Inventory

    The permeable reactive barrier (PRB) technology represents a passive option for long-term treatment of ground-water contamination. PRBs are a potentially more cost-effective treatment option for a variety of dissolved contaminants, such as certain types of chlorinated solvents, ...

  11. Blood-Brain Barrier Permeability and Monocyte Infiltration in Experimental Allergic Encephalomyelitis

    ERIC Educational Resources Information Center

    Floris, S.; Blezer, E. L. A.; Schreibelt, G.; Dopp, E.; van der Pol, S. M. A.; Schadee-Eestermans, I. L.; Nicolay, K.; Dijkstra, C. D.; de Vries, H. E.

    2004-01-01

    Enhanced cerebrovascular permeability and cellular infiltration mark the onset of early multiple sclerosis lesions. So far, the precise sequence of these events and their role in lesion formation and disease progression remain unknown. Here we provide quantitative evidence that blood-brain barrier leakage is an early event and precedes massive…

  12. ACCUMULATION RATE OF MICROBIAL BIOMASS AT TWO PERMEABLE REACTIVE BARRIER SITES

    EPA Science Inventory

    Accumulation of mineral precipitates and microbial biomass are key factors that impact the long-term performance of in-situ Permeable Reactive Barriers for treating contaminated groundwater. Both processes can impact remedial performance by decreasing zero-valent iron reactivity...

  13. CHROMIUM REMOVAL PROCESSES DURING GROUNDWATER REMEDIATION BY A ZEROVALENT IRON PERMEABLE REACTIVE BARRIER

    EPA Science Inventory

    Solid-phase associations of chromium were examined in core materials collected from a full-scale, zerovalent iron, permeable reactive barrier (PRB) at the U.S. Coast Guard Support Center located near Elizabeth City (NC). The PRB was installed in 1996 to treat groundwater contami...

  14. SPATIAL DISTRIBUTION OF CARBON AND SULFUR PRECIPITATING WITHIN PERMEABLE REACTIVE BARRIERS: DEVELOPMENT OF ANALYTICAL METHODS

    EPA Science Inventory

    A permeable reactive barrier (PRB) is a wall of porous reactive material placed in the path of a dissolved contaminant plume for the purpose of removing contaminants from ground water. Chemical processes within these reactive materials remove both inorganic and organic contamina...

  15. AMELIORATION OF ACID MINE DRAINAGE USING REACTIVE MIXTURES IN PERMEABLE REACTIVE BARRIERS

    EPA Science Inventory

    The generation and release of acidic drainage from mine wastes is an environmental problem of international scale. The use of zero-valent iron and/or iron mixtures in subsurface Permeable Reactive Barriers (PRB) presents a possible passive alternative for remediating acidic grou...

  16. A Tracer Test to Characterize Treatment of TCE in a Permeable Reactive Barrier

    EPA Science Inventory

    A tracer test was conducted to characterize the flow of ground water surrounding a permeable reactive barrier constructed with plant mulch (a biowall) at the OU-1 site on Altus Air Force Base, Oklahoma. This biowall is intended to intercept and treat ground water contaminated by ...

  17. Nanosized iron based permeable reactive barriers for nitrate removal - Systematic review

    NASA Astrophysics Data System (ADS)

    Araújo, Rui; Castro, Ana C. Meira; Santos Baptista, João; Fiúza, António

    2016-08-01

    It is unquestionable that an effective decision concerning the usage of a certain environmental clean-up technology should be conveniently supported. Significant amount of scientific work focussing on the reduction of nitrate concentration in drinking water by both metallic iron and nanomaterials and their usage in permeable reactive barriers has been worldwide published over the last two decades. This work aims to present in a systematic review of the most relevant research done on the removal of nitrate from groundwater using nanosized iron based permeable reactive barriers. The research was based on scientific papers published between 2004 and June 2014. It was performed using 16 combinations of keywords in 34 databases, according to PRISMA statement guidelines. Independent reviewers validated the selection criteria. From the 4161 records filtered, 45 met the selection criteria and were selected to be included in this review. This study's outcomes show that the permeable reactive barriers are, indeed, a suitable technology for denitrification and with good performance record but the long-term impact of the use of nanosized zero valent iron in this remediation process, in both on the environment and on the human health, is far to be conveniently known. As a consequence, further work is required on this matter, so that nanosized iron based permeable reactive barriers for the removal of nitrate from drinking water can be genuinely considered an eco-efficient technology.

  18. CHROMIUM REMOVAL PROCESSES DURING GROUNDWATER REMEDIATION BY A ZEROVALENT IRON PERMEABLE REACTIVE BARRIER

    EPA Science Inventory

    Solid-phase associations of chromium were examined in core materials collected from a full-scale, zerovalent iron, permeable reactive barrier (PRB) at the U.S. Coast Guard Support Center located near Elizabeth City (NC). The PRB was installed in 1996 to treat groundwater contami...

  19. ACCUMULATION RATE OF MICROBIAL BIOMASS AT TWO PERMEABLE REACTIVE BARRIER SITES

    EPA Science Inventory

    Accumulation of mineral precipitates and microbial biomass are key factors that impact the long-term performance of in-situ Permeable Reactive Barriers for treating contaminated groundwater. Both processes can impact remedial performance by decreasing zero-valent iron reactivity...

  20. A Tracer Test to Characterize Treatment of TCE in a Permeable Reactive Barrier

    EPA Science Inventory

    A tracer test was conducted to characterize the flow of ground water surrounding a permeable reactive barrier constructed with plant mulch (a biowall) at the OU-1 site on Altus Air Force Base, Oklahoma. This biowall is intended to intercept and treat ground water contaminated by ...

  1. LONG-TERM PERFORMANCE OF PERMEABLE REACTIVE BARRIERS: LESSONS LEARNED, FUTURE DIRECTIONS

    EPA Science Inventory

    Recently, a synthesis of research findings by EPA has been prepared and presented in an EPA report titled Capstone Report on the Application, Monitoring, and Performance of Permeable Reactive Barriers for Ground-Water Remediation (EPA/600/R-03/045 a,b). Another report has also be...

  2. GROUND WATER REMEDIATION RESEARCH: PERMEABLE REACTIVE BARRIERS AND SOURCE ZONE REMEDIATION

    EPA Science Inventory

    An overview of ground water remediation research conducted at the Subsurface Protection and Remediation Division is provided. The focus of the overview is on Permeable Reactive Barriers for treatment of organic and inorganic contaminants and remediation of DNAPL source zones.

  3. EVALUATION OF PERMEABLE REACTIVE BARRIER PERFORMANCE: A TRI-AGENCY INITIATIVE

    EPA Science Inventory

    The permeable reactive barrier (PRB) technology represents a passive option for long-term treatment of ground-water contamination. PRBs are a potentially more cost-effective treatment option for a variety of dissolved contaminants, such as certain types of chlorinated solvents, ...

  4. LONG-TERM PERFORMANCE OF PERMEABLE REACTIVE BARRIERS TO REMEDIATE CONTAMINATED GROUND WATER

    EPA Science Inventory

    This research brief presents findings over the past four years at two sites where detailed investigations by the U.S. Environmental Protection Agency (U.S. EPA) have focused on the long-term performance of PRBs under a Tri-Agency Permeable Reactive Barrier Initiative (TRI). This ...

  5. SPATIAL DISTRIBUTION OF CARBON AND SULFUR PRECIPITATING WITHIN PERMEABLE REACTIVE BARRIERS: DEVELOPMENT OF ANALYTICAL METHODS

    EPA Science Inventory

    A permeable reactive barrier (PRB) is a wall of porous reactive material placed in the path of a dissolved contaminant plume for the purpose of removing contaminants from ground water. Chemical processes within these reactive materials remove both inorganic and organic contamina...

  6. LONG-TERM PERFORMANCE OF PERMEABLE REACTIVE BARRIERS: LESSONS LEARNED, FUTURE DIRECTIONS

    EPA Science Inventory

    Recently, a synthesis of research findings by EPA has been prepared and presented in an EPA report titled Capstone Report on the Application, Monitoring, and Performance of Permeable Reactive Barriers for Ground-Water Remediation (EPA/600/R-03/045 a,b). Another report has also be...

  7. LONG-TERM PERFORMANCE MONITORING OF PERMEABLE REACTIVE BARRIERS TO REMEDIATE CONTAMINATED GROUND WATER

    EPA Science Inventory

    Permeable reactive barriers (PRB's) are an alternative in-situ approach for remediating contaminated groundwater that combine subsurface fluid flow management with a passive chemical treatment zone. PRB's are being selected with increased frequency at waste sites (more than 40 f...

  8. Glomerular permeability barrier in the rat. Functional assessment by in vitro methods.

    PubMed Central

    Daniels, B S; Deen, W M; Mayer, G; Meyer, T; Hostetter, T H

    1993-01-01

    The formation of glomerular ultrafiltrate is dependent on the prevailing hemodynamic forces within the glomerular microcirculation and the intrinsic properties of the filtration barrier. However, direct assessment of the permeability barrier is difficult with most available techniques. We used confocal microscopy to image 1-micron thick optical cross-sections of isolated intact glomeruli and glomeruli denuded of cells and quantitated dextran (70,000 mol wt) diffusion from the capillary lumen. Dextran permeance was 11 times greater for the acellular filtration barrier than the intact peripheral capillary. Consideration of the basement membrane and cells as series resistors demonstrated that cells of the filtration barrier contribute 90% of the total resistance to macromolecular permeance. Using a different approach, dextran sieving coefficients for acellular glomeruli consolidated as a multilayer sheet in a filtration cell were similar to those for intact glomeruli in vivo at radii 30-36 A and approximately 50 times greater at a dextran radius of 60 A. The presence of cells significantly reduced hydraulic permeability determined on consolidated intact or acellular glomeruli in an ultrafiltration cell with 50 mmHg applied pressure. The glomerular basement membrane does restrict macromolecular permeability but cells are important determinants of the overall macromolecular and hydraulic permeability of the glomerulus. Images PMID:7688767

  9. GROUND WATER REMEDIATION RESEARCH: PERMEABLE REACTIVE BARRIERS AND SOURCE ZONE REMEDIATION

    EPA Science Inventory

    An overview of ground water remediation research conducted at the Subsurface Protection and Remediation Division is provided. The focus of the overview is on Permeable Reactive Barriers for treatment of organic and inorganic contaminants and remediation of DNAPL source zones.

  10. A clay permeable reactive barrier to remove Cs-137 from groundwater: Column experiments.

    PubMed

    De Pourcq, K; Ayora, C; García-Gutiérrez, M; Missana, T; Carrera, J

    2015-11-01

    Clay minerals are reputed sorbents for Cs-137 and can be used as a low-permeability material to prevent groundwater flow. Therefore, clay barriers are employed to seal Cs-137 polluted areas and nuclear waste repositories. This work is motivated by cases where groundwater flow cannot be impeded. A permeable and reactive barrier to retain Cs-137 was tested. The trapping mechanism is based on the sorption of cesium on illite-containing clay. The permeability of the reactive material is provided by mixing clay on a matrix of wood shavings. Column tests combined with reactive transport modeling were performed to check both reactivity and permeability. Hydraulic conductivity of the mixture (10(-4) m/s) was sufficient to ensure an adequate hydraulic performance of an eventual barrier excavated in most aquifers. A number of column experiments confirmed Cs retention under different flow rates and inflow solutions. A 1D reactive transport model based on a cation-exchange mechanism was built. It was calibrated with batch experiments for high concentrations of NH4+ and K+ (the main competitors of Cs in the exchange positions). The model predicted satisfactorily the results of the column experiments. Once validated, it was used to investigate the performance and duration of a 2 m thick barrier under different scenarios (flow, clay content, Cs-137 and K concentration).

  11. AMELIORATION OF ACID MINE DRAINAGE USING REACTIVE MIXTURES IN PERMEABLE REACTIVE BARRIERS

    EPA Science Inventory

    The generation and release of acidic drainage from mine wastes is an environmental problem of international scale. The use of zero-valent iron and/or iron mixtures in subsurface Permeable Reactive Barriers (PRB) presents a possible passive alternative for remediating acidic grou...

  12. COST ANALYSIS OF PERMEABLE REACTIVE BARRIERS FOR REMEDIATION OF GROUND WATER

    EPA Science Inventory

    The U. S. Environmental Protection Agency's Office of Research and Development and its contractor have evaluated cost data from 22 sites where permeable reactive barriers (PRBs) have been utilized to remediate contaminated ground water resources. Most of the sites evaluated wer...

  13. COST ANALYSIS OF PERMEABLE REACTIVE BARRIERS FOR REMEDIATION OF GROUND WATER

    EPA Science Inventory

    The U. S. Environmental Protection Agency's Office of Research and Development and its contractor have evaluated cost data from 22 sites where permeable reactive barriers (PRBs) have been utilized to remediate contaminated ground water resources. Most of the sites evaluated wer...

  14. Blood-Brain Barrier Permeability and Monocyte Infiltration in Experimental Allergic Encephalomyelitis

    ERIC Educational Resources Information Center

    Floris, S.; Blezer, E. L. A.; Schreibelt, G.; Dopp, E.; van der Pol, S. M. A.; Schadee-Eestermans, I. L.; Nicolay, K.; Dijkstra, C. D.; de Vries, H. E.

    2004-01-01

    Enhanced cerebrovascular permeability and cellular infiltration mark the onset of early multiple sclerosis lesions. So far, the precise sequence of these events and their role in lesion formation and disease progression remain unknown. Here we provide quantitative evidence that blood-brain barrier leakage is an early event and precedes massive…

  15. Mutation of EpCAM leads to intestinal barrier and ion transport dysfunction.

    PubMed

    Kozan, Philip A; McGeough, Matthew D; Peña, Carla A; Mueller, James L; Barrett, Kim E; Marchelletta, Ronald R; Sivagnanam, Mamata

    2015-05-01

    Congenital tufting enteropathy (CTE) is a devastating diarrheal disease seen in infancy that is typically associated with villous changes and the appearance of epithelial tufts. We previously found mutations in epithelial cell adhesion molecule (EpCAM) to be causative in CTE. We developed a knock-down cell model of CTE through transfection of an EpCAM shRNA construct into T84 colonic epithelial cells to elucidate the in vitro role of EpCAM in barrier function and ion transport. Cells with EpCAM deficiency exhibited decreased electrical resistance, increased permeability, and decreased ion transport. Based on mutations in CTE patients, an in vivo mouse model was developed, with tamoxifen-inducible deletion of exon 4 in Epcam resulting in mutant protein with decreased expression. Tamoxifen treatment of Epcam (Δ4/Δ4) mice resulted in pathological features of villous atrophy and epithelial tufts, similar to those in human CTE patients, within 4 days post induction. Epcam (Δ4/Δ4) mice also showed decreased expression of tight junctional proteins, increased permeability, and decreased ion transport in the intestines. Taken together, these findings reveal mechanisms that may underlie disease in CTE. Knock-down EpCAM cell model of congenital tufting enteropathy was developed. In vivo inducible mouse model was developed resulting in mutant EpCAM protein. Cells with EpCAM deficiency demonstrated barrier and ion transport dysfunction. Tamoxifen-treated Epcam (Δ4/Δ4) mice demonstrated pathological features. Epcam (Δ4/Δ4) mice showed improper barrier function and ion transport.

  16. The gut microbiota influences blood-brain barrier permeability in mice.

    PubMed

    Braniste, Viorica; Al-Asmakh, Maha; Kowal, Czeslawa; Anuar, Farhana; Abbaspour, Afrouz; Tóth, Miklós; Korecka, Agata; Bakocevic, Nadja; Ng, Lai Guan; Guan, Ng Lai; Kundu, Parag; Gulyás, Balázs; Halldin, Christer; Hultenby, Kjell; Nilsson, Harriet; Hebert, Hans; Volpe, Bruce T; Diamond, Betty; Pettersson, Sven

    2014-11-19

    Pivotal to brain development and function is an intact blood-brain barrier (BBB), which acts as a gatekeeper to control the passage and exchange of molecules and nutrients between the circulatory system and the brain parenchyma. The BBB also ensures homeostasis of the central nervous system (CNS). We report that germ-free mice, beginning with intrauterine life, displayed increased BBB permeability compared to pathogen-free mice with a normal gut flora. The increased BBB permeability was maintained in germ-free mice after birth and during adulthood and was associated with reduced expression of the tight junction proteins occludin and claudin-5, which are known to regulate barrier function in endothelial tissues. Exposure of germ-free adult mice to a pathogen-free gut microbiota decreased BBB permeability and up-regulated the expression of tight junction proteins. Our results suggest that gut microbiota-BBB communication is initiated during gestation and propagated throughout life.

  17. Oral supplementation with non-absorbable antibiotics or curcumin attenuates western diet-induced atherosclerosis and glucose intolerance in LDLR-/- mice--role of intestinal permeability and macrophage activation.

    PubMed

    Ghosh, Siddhartha S; Bie, Jinghua; Wang, Jing; Ghosh, Shobha

    2014-01-01

    Association between circulating lipopolysaccharide (LPS) and metabolic diseases (such as Type 2 Diabetes and atherosclerosis) has shifted the focus from Western diet-induced changes in gut microbiota per se to release of gut bacteria-derived products into circulation as the possible mechanism for the chronic inflammatory state underlying the development of these diseases. Under physiological conditions, an intact intestinal barrier prevents this release of LPS underscoring the importance of examining and modulating the direct effects of Western diet on intestinal barrier function. In the present study we evaluated two strategies, namely selective gut decontamination and supplementation with oral curcumin, to modulate Western-diet (WD) induced changes in intestinal barrier function and subsequent development of glucose intolerance and atherosclerosis. LDLR-/- mice were fed WD for 16 weeks and either received non-absorbable antibiotics (Neomycin and polymyxin) in drinking water for selective gut decontamination or gavaged daily with curcumin. WD significantly increased intestinal permeability as assessed by in vivo translocation of FITC-dextran and plasma LPS levels. Selective gut decontamination and supplementation with curcumin significantly attenuated the WD-induced increase in plasma LPS levels (3.32 vs 1.90 or 1.51 EU/ml, respectively) and improved intestinal barrier function at multiple levels (restoring intestinal alkaline phosphatase activity and expression of tight junction proteins, ZO-1 and Claudin-1). Consequently, both these interventions significantly reduced WD-induced glucose intolerance and atherosclerosis in LDLR-/- mice. Activation of macrophages by low levels of LPS (50 ng/ml) and its exacerbation by fatty acids is likely the mechanism by which release of trace amounts of LPS into circulation due to disruption of intestinal barrier function induces the development of these diseases. These studies not only establish the important role of intestinal

  18. Oral Supplementation with Non-Absorbable Antibiotics or Curcumin Attenuates Western Diet-Induced Atherosclerosis and Glucose Intolerance in LDLR−/− Mice – Role of Intestinal Permeability and Macrophage Activation

    PubMed Central

    Ghosh, Siddhartha S.; Bie, Jinghua; Wang, Jing; Ghosh, Shobha

    2014-01-01

    Association between circulating lipopolysaccharide (LPS) and metabolic diseases (such as Type 2 Diabetes and atherosclerosis) has shifted the focus from Western diet-induced changes in gut microbiota per se to release of gut bacteria-derived products into circulation as the possible mechanism for the chronic inflammatory state underlying the development of these diseases. Under physiological conditions, an intact intestinal barrier prevents this release of LPS underscoring the importance of examining and modulating the direct effects of Western diet on intestinal barrier function. In the present study we evaluated two strategies, namely selective gut decontamination and supplementation with oral curcumin, to modulate Western-diet (WD) induced changes in intestinal barrier function and subsequent development of glucose intolerance and atherosclerosis. LDLR−/− mice were fed WD for 16 weeks and either received non-absorbable antibiotics (Neomycin and polymyxin) in drinking water for selective gut decontamination or gavaged daily with curcumin. WD significantly increased intestinal permeability as assessed by in vivo translocation of FITC-dextran and plasma LPS levels. Selective gut decontamination and supplementation with curcumin significantly attenuated the WD-induced increase in plasma LPS levels (3.32 vs 1.90 or 1.51 EU/ml, respectively) and improved intestinal barrier function at multiple levels (restoring intestinal alkaline phosphatase activity and expression of tight junction proteins, ZO-1 and Claudin-1). Consequently, both these interventions significantly reduced WD-induced glucose intolerance and atherosclerosis in LDLR−/− mice. Activation of macrophages by low levels of LPS (50 ng/ml) and its exacerbation by fatty acids is likely the mechanism by which release of trace amounts of LPS into circulation due to disruption of intestinal barrier function induces the development of these diseases. These studies not only establish the important role of

  19. Effects of simulated weightlessness on the intestinal mucosal barrier of rats

    NASA Astrophysics Data System (ADS)

    Chen, Ying; Yang, Chun-min; Mao, Gao-ping; Liu, Qing-sen; Guo, Ming-zhou

    2011-07-01

    This study employed a rat tail-suspension model to investigate the effects of simulated weightlessness on the intestinal mucosal barrier. Twenty-four Wistar rats were randomly divided into control (CON), 14-day tail-suspension (SUS-14d), and 21-day tail-suspension (SUS-21d) groups ( n = 8 per group). Expression of occludin and zonula occludins-1 (ZO-1), proteins of the tight junction (TJ), in the intestinal mucosa was measured by immunohistochemical analysis, Western blotting, and mRNA fluorescent quantitation PCR. Plasma concentrations of diamine oxidase (DAO) and D-lactate were determined using an enzymatic spectrophotometric assay. Expression of occludin and ZO-1 was reduced in the SUS-14d and SUS-21d groups as compared to the CON group, with lowest expression observed in the SUS-21d group ( P < 0.01). Examination by transmission electron microscopy (TEM) of the jejunal epithelium revealed increased intercellular space, decreased TJ and desmosome densities, and destruction of microvilli in the SUS-14d and SUS-21d groups. Plasma DAO and D-lactate concentrations in the SUS-21d group were higher than those in SUS-14d group and significantly higher than those in the CON group ( P < 0.01). In all three groups, the expression of occludin and ZO-1 was found to correlate negatively with DAO ( P < 0.01) and D-lactate ( P < 0.01) concentrations. It is concluded that simulated weightless results in down-regulation of expression of TJ proteins in the rat intestinal mucosa. Simulated weightlessness is proposed to increase intestinal permeability through damage to the TJ.

  20. Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism.

    PubMed

    Vanuytsel, Tim; van Wanrooy, Sander; Vanheel, Hanne; Vanormelingen, Christophe; Verschueren, Sofie; Houben, Els; Salim Rasoel, Shadea; Tόth, Joran; Holvoet, Lieselot; Farré, Ricard; Van Oudenhove, Lukas; Boeckxstaens, Guy; Verbeke, Kristin; Tack, Jan

    2014-08-01

    Intestinal permeability and psychological stress have been implicated in the pathophysiology of IBD and IBS. Studies in animals suggest that stress increases permeability via corticotropin-releasing hormone (CRH)-mediated mast cell activation. Our aim was to investigate the effect of stress on intestinal permeability in humans and its underlying mechanisms. Small intestinal permeability was quantified by a 2 h lactulose-mannitol urinary excretion test. In a first study, 23 healthy volunteers were subjected to four different conditions: control; indomethacin; public speech and anticipation of electroshocks. In a second study, five test conditions were investigated in 13 volunteers: control; after pretreatment with disodium cromoglycate (DSCG); administration of CRH; DSCG+CRH and DSCG+public speech. Indomethacin, as a positive comparator (0.071±0.040 vs 0.030±0.022; p<0.0001), and public speech (0.059±0.040; p<0.01), but not the shock protocol increased intestinal permeability. Similarly, salivary cortisol was only increased after public speech. Subgroup analysis demonstrated that the effect of public speech on permeability was only present in subjects with a significant elevation of cortisol. CRH increased the lactulose-mannitol ratio (0.042±0.021 vs 0.028±0.009; p=0.02), which was inhibited by the mast cell stabiliser DSCG. Finally, intestinal permeability was unaltered by public speech with DSCG pretreatment. Acute psychological stress increases small intestinal permeability in humans. Peripheral CRH reproduces the effect of stress and DSCG blocks the effect of both stress and CRH, suggesting the involvement of mast cells. These findings provide new insight into the complex interplay between the central nervous system and GI function in man. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  1. Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis.

    PubMed

    Reiberger, Thomas; Ferlitsch, Arnulf; Payer, Berit A; Mandorfer, Mattias; Heinisch, Birgit B; Hayden, Hubert; Lammert, Frank; Trauner, Michael; Peck-Radosavljevic, Markus; Vogelsang, Harald

    2013-05-01

    We evaluated the gastrointestinal permeability and bacterial translocation in cirrhotic patients with portal hypertension (PHT) prior to and after non-selective betablocker (NSBB) treatment. Hepatic venous pressure gradient (HVPG) was measured prior to and under NSBB treatment. Gastroduodenal and intestinal permeability was assessed by the sucrose-lactulose-mannitol (SLM) test. Anti-gliadin and anti-endomysial antibodies were measured. Levels of LPS-binding protein (LBP) and interleukin-6 (IL-6) were quantified by ELISA, and NOD2 and toll-like receptor 2 (TLR2) polymorphisms were genotyped. Fifty cirrhotics were included (72% male, 18% ascites, 60% alcoholic etiology). Abnormal gastroduodenal and intestinal permeability was found in 72% and 59% of patients, respectively. Patients with severe portal hypertension (HVPG ≥20 mm Hg; n=35) had increased markers of gastroduodenal/intestinal permeability (urine sucrose levels p=0.049; sucrose/mannitol ratios p=0.007; intestinal permeability indices p=0.002), and bacterial translocation (LBP p=0.002; IL-6 p=0.025) than patients with HVPG <20 mm Hg. A substantial portion of patients showed elevated levels of anti-gliadin antibodies (IgA: 60%, IgG: 34%) whereas no anti-endomysial antibodies were detected. A significant correlation of portal pressure (i.e., HVPG) with all markers of gastroduodenal/intestinal permeability and with LBP and IL-6 levels was observed. NOD2 and TLR2 risk variants were associated with abnormal intestinal permeability and elevated markers of bacterial translocation. At follow-up HVPG measurements under NSBB, we found an amelioration of gastroduodenal/intestinal permeability and a decrease of bacterial translocation (LBP - 16% p=0.018; IL-6 - 41% p<0.0001) levels, which was not limited to hemodynamic responders. Abnormal SLM test results and higher LBP/IL-6 levels were associated with a higher risk of variceal bleeding during follow-up but not with mortality. Abnormal gastroduodenal/intestinal

  2. Increased blood-brain barrier permeability on perfusion CT might predict malignant middle cerebral artery infarction.

    PubMed

    Bektas, Hesna; Wu, Tzu-Ching; Kasam, Mallikarjunarao; Harun, Nusrat; Sitton, Clark W; Grotta, James C; Savitz, Sean I

    2010-11-01

    Perfusion CT has been used to assess the extent of blood-brain barrier breakdown. The purpose of this study was to determine the predictive value of blood-brain barrier permeability measured using perfusion CT for development of malignant middle cerebral artery infarction requiring hemicraniectomy (HC). We retrospectively identified patients from our stroke registry who had middle cerebral artery infarction and were evaluated with admission perfusion CT. Blood-brain barrier permeability and cerebral blood volume maps were generated and infarct volumes calculated. Clinical and radiographic characteristics were compared between those who underwent HC versus those who did not undergo HC. One hundred twenty-two patients (12 HC, 110 no HC) were identified. Twelve patients who underwent HC had developed edema, midline shift, or infarct expansion. Infarct permeability area, infarct cerebral blood volume area, and infarct volumes were significantly different (P < 0.018, P < 0.0211, P < 0.0001, P < 0.0014) between HC and no HC groups. Age (P = 0.03) and admission National Institutes of Health Stroke Scale (P = 0.0029) were found to be independent predictors for HC. Using logistic regression modeling, there was an association between increased infarct permeability area and HC. The OR for HC based on a 5-, 10-, 15-, or 20-cm² increase in infarct permeability area were 1.179, 1.390, 1.638, or 1.932, respectively (95% CI, 1.035 to 1.343, 1.071 to 1.804, 1.108 to 2.423, 1.146 to 3.255, respectively). Increased infarct permeability area is associated with an increased likelihood for undergoing HC. Because early HC for malignant middle cerebral artery infarction has been associated with better outcomes, the infarct permeability area on admission perfusion CT might be a useful tool to predict malignant middle cerebral artery infarction and need for HC.

  3. The gut-blood barrier permeability - A new marker in cardiovascular and metabolic diseases?

    PubMed

    Ufnal, Marcin; Pham, Kinga

    2017-01-01

    Recent studies suggest that blood-borne metabolites of gut microbiota, such as trimethylamine N-oxide (TMAO) are involved in the aetiology of cardiovascular diseases and may serve as markers of cardiovascular risk. To enter the bloodstream the microbiota-derived molecules need to pass the gut-blood barrier (GBB). The GBB plays an important role in maintaining organism homeostasis. It is a complex multi-layer system which determines the absorption of nutrients, water and many other substances. The integrity and permeability of the GBB may be impaired in numerous diseases including gastrointestinal, metabolic and cardiovascular diseases. Here, we propose that the evaluation of the GBB permeability may have a significant diagnostic potential in cardiovascular and metabolic diseases. Second, we suggest that the GBB permeability is a variable that confounds diagnostic value of new gut microbiota-derived biomarkers such as TMAO. Therefore, cardiovascular risk assessment requires the evaluation of both TMAO and the GBB permeability.

  4. The effects of hypoglycemic and alcoholic coma on the blood-brain barrier permeability

    PubMed Central

    Yorulmaz, Hatice; Seker, Fatma Burcu; Oztas, Baria

    2011-01-01

    In this investigation, the effects of hypoglycemic coma and alcoholic coma on the blood-brain barrier (BBB) permeability have been compared. Female adult Wistar albino rats weighing 180-230 g were divided into three groups: Control group (n=8), Alcoholic Coma Group (n=18), and Hypoglycemic Coma group (n=12). The animals went into coma approximately 3-4 hours after insulin administration and 3-5 minutes after alcohol administration. Evans blue (4mL/kg) was injected intravenously as BBB tracer. It was observed that the alcoholic coma did not significantly increase the BBB permeability in any of the brain regions when compared to control group. Changes in BBB permeability were significantly increased by the hypoglycemic coma in comparison to the control group values (p<0.01). Our findings suggest that hypoglycemic and alcoholic coma have different effects on the BBB permeability depending on the energy metabolism. PMID:21619558

  5. Botulinum Toxin Complex Increases Paracellular Permeability in Intestinal Epithelial Cells via Activation of p38 Mitogen-Activated Protein Kinase

    PubMed Central

    MIYASHITA, Shin-ichiro; SAGANE, Yoshimasa; INUI, Ken; HAYASHI, Shintaro; MIYATA, Keita; SUZUKI, Tomonori; OHYAMA, Tohru; WATANABE, Toshihiro; NIWA, Koichi

    2013-01-01

    ABSTRACT Clostridium botulinum produces a large toxin complex (L-TC) that increases paracellular permeability in intestinal epithelial cells by a mechanism that remains unclear. Here, we show that mitogen-activated protein kinases (MAPKs) are involved in this permeability increase. Paracellular permeability was measured by FITC-dextran flux through a monolayer of rat intestinal epithelial IEC-6 cells, and MAPK activation was estimated from western blots. L-TC of C. botulinum serotype D strain 4947 increased paracellular dextran flux and activated extracellular signal-regulated kinase (ERK), p38, but not c-Jun N-terminal kinase (JNK) in IEC-6 cells. The permeability increase induced by L-TC was abrogated by the p38 inhibitor SB203580. These results indicate that L-TC increases paracellular permeability by activating p38, but not JNK and ERK. PMID:23884081

  6. Intestinal permeability to (/sup 51/Cr)EDTA in children with cystic fibrosis

    SciTech Connect

    Leclercq-Foucart, J.; Forget, P.; Sodoyez-Goffaux, F.; Zappitelli, A.

    1986-05-01

    Intestinal permeability was investigated in 14 children with cystic fibrosis making use of (/sup 51/Cr)EDTA as probe molecule. Ten normal young adults and 11 children served as controls. After oral administration of (/sup 51/Cr)EDTA, 24 h urine was collected. Urinary radioactivity was calculated and results expressed as percentage of oral dose excreted in 24 h urine. Mean and SEM were as follows: 2.51 +/- 0.21, 2.35 +/- 0.24, and 13.19 +/- 1.72 for control children, normal adults, and cystic fibrosis patients, respectively. The permeability differences between cystic fibrosis patients and either control children or control adults are significant (p less than 0.001).

  7. Antibiotic Treatment Affects Intestinal Permeability and Gut Microbial Composition in Wistar Rats Dependent on Antibiotic Class.

    PubMed

    Tulstrup, Monica Vera-Lise; Christensen, Ellen Gerd; Carvalho, Vera; Linninge, Caroline; Ahrné, Siv; Højberg, Ole; Licht, Tine Rask; Bahl, Martin Iain

    2015-01-01

    Antibiotics are frequently administered orally to treat bacterial infections not necessarily related to the gastrointestinal system. This has adverse effects on the commensal gut microbial community, as it disrupts the intricate balance between specific bacterial groups within this ecosystem, potentially leading to dysbiosis. We hypothesized that modulation of community composition and function induced by antibiotics affects intestinal integrity depending on the antibiotic administered. To address this a total of 60 Wistar rats (housed in pairs with 6 cages per group) were dosed by oral gavage with either amoxicillin (AMX), cefotaxime (CTX), vancomycin (VAN), metronidazole (MTZ), or water (CON) daily for 10-11 days. Bacterial composition, alpha diversity and caecum short chain fatty acid levels were significantly affected by AMX, CTX and VAN, and varied among antibiotic treatments. A general decrease in diversity and an increase in the relative abundance of Proteobacteria was observed for all three antibiotics. Additionally, the relative abundance of Bifidobacteriaceae was increased in the CTX group and both Lactobacillaceae and Verrucomicrobiaceae were increased in the VAN group compared to the CON group. No changes in microbiota composition or function were observed following MTZ treatment. Intestinal permeability to 4 kDa FITC-dextran decreased after CTX and VAN treatment and increased following MTZ treatment. Plasma haptoglobin levels were increased by both AMX and CTX but no changes in expression of host tight junction genes were found in any treatment group. A strong correlation between the level of caecal succinate, the relative abundance of Clostridiaceae 1 family in the caecum, and the level of acute phase protein haptoglobin in blood plasma was observed. In conclusion, antibiotic-induced changes in microbiota may be linked to alterations in intestinal permeability, although the specific interactions remain to be elucidated as changes in permeability did

  8. [The role of intestinal permeability in the pathogenesis of ankylosing spondylitis].

    PubMed

    Liu, Y; Xu, B; Cai, X

    1995-02-01

    By use of low molecular weight polyethlene glycol (PEG400) as tracer, a revised Chedwick method with capillary gas chromatography was used to examine the intestinal permeability in 49 subjects including patients with ankylosing spondylitis (AS) and rheumatoid arthritis (RA) and healthy controls. Recovery percentage, maximal recovery percentage [Rmax(%)] and Rmax(w) were used to find the effect of bowel permeability in the pathogenesis and disease flare up of AS, as well as the role of HLA-B27 for the bowel permeability. The results showed that in AS group, the recovery of first component (242D) was higher and the Rmax(%) was lower than those in the controls. No statistical difference was found with other indexes. The results indicated that bowel permeability is not elevated in AS. The passage of enteral bacteria antigen into the host may not result from the process of nonspecific penetration. We postulate that there may somehow be a process of "active transportation" in the pathogenesis of AS. More studies of the process are necessary to clarify its importance in the early stage of AS.

  9. TNF-α modulation of intestinal epithelial tight junction barrier is regulated by ERK1/2 activation of Elk-1.

    PubMed

    Al-Sadi, Rana; Guo, Shuhong; Ye, Dongmei; Ma, Thomas Y

    2013-12-01

    Tumor necrosis factor (TNF-α) is a proinflammatory cytokine that plays a critical role in the pathogenesis of inflammatory bowel disease. TNF-α causes an increase in intestinal permeability; however, the signaling pathways and the molecular mechanisms involved remain unclear. The major purpose of this study was to investigate the role of MAP kinase pathways (ERK1/2 and p38 kinase) and the molecular processes involved. An in vitro intestinal epithelial model system consisting of Caco-2 monolayers and an in vivo mouse model system were used to delineate the cellular and molecular mechanisms involved in TNF-α effects on tight junction barrier. The TNF-α-induced increase in Caco-2 tight junction permeability was mediated by activation of the ERK1/2 signaling pathway, but not the p38 kinase pathway. Activation of the ERK1/2 pathway led to phosphorylation and activation of the ETS domain-containing transcription factor Elk-1. The activated Elk-1 translocated to the nucleus, where it bound to its binding motif on the myosin light chain kinase (MLCK) promoter region, leading to the activation of MLCK promoter activity and gene transcription. In addition, in vivo intestinal perfusion studies also indicated that the TNF-α-induced increase in mouse intestinal permeability requires ERK1/2-dependent activation of Elk-1. These studies provide novel insight into the cellular and molecular processes that regulate the TNF-α-induced increase in intestinal epithelial tight junction permeability.

  10. MicroRNA 29 Targets Nuclear Factor-κB–Repressing Factor and Claudin 1 to Increase Intestinal Permeability

    PubMed Central

    Zhou, QiQi; Costinean, Stefan; Croce, Carlo M.; Brasier, Alan R.; Merwat, Shehzad; Larson, Scott A.; Basra, Sarpreet; Verne, G. Nicholas

    2014-01-01

    BACKGROUND & AIMS Some patients with irritable bowel syndrome with diarrhea (IBS-D) have intestinal hyperpermeability, which contributes to their diarrhea and abdominal pain. MicroRNA 29 (MIR29) regulates intestinal permeability in patients with IBS-D. We investigated and searched for targets of MIR29 and investigated the effects of disrupting Mir29 in mice. METHODS We investigated expression MIR29A and B in intestinal biopsies collected during endoscopy from patients with IBS (n = 183) and without IBS (controls) (n = 36). Levels were correlated with disease phenotype. We also generated and studied Mir29−/− mice, in which expression of Mir29a and b, but not c, is lost. Colitis was induced by administration of 2,4,6-trinitrobenzenesulfonic acid; intestinal tissues were collected and permeability was assessed. Microarray analysis was performed using tissues from Mir29−/− mice. Changes in levels of target genes were measured in human colonic epithelial cells and small intestinal epithelial cells after knockdown of MIR29 with anti-MIRs. RESULTS Intestinal tissues from patients with IBS-D (but not IBS with constipation or controls) had increased levels of MIR29A and B, but reduced levels of Claudin-1 (CLDN1) and nuclear factor-κB–repressing factor (NKRF). Induction of colitis and water avoidance stress increased levels of Mir29a and Mir29b and intestinal permeability in wild-type mice; these increased intestinal permeability in colons of far fewer Mir29−/− mice. In microarray and knockdown experiments, MIR29A and B were found to reduce levels of NKRF and CLDN1 messenger RNA, and alter levels of other messenger RNAs that regulate intestinal permeability. CONCLUSIONS Based on experiments in knockout mice and analyses of intestinal tissue samples from patients with IBS-D, MIR29 targets and reduces expression of CLDN1 and NKRF to increase intestinal permeability. Strategies to block MIR29 might be developed to restore intestinal permeability in patients with

  11. Redox-active media for permeable reactive barriers

    SciTech Connect

    Sivavec, T.M.; Mackenzie, P.D.; Horney, D.P.; Baghel, S.S.

    1997-12-31

    In this paper, three classes of redox-active media are described and evaluated in terms of their long-term effectiveness in treating TCE-contaminated groundwater in permeable reactive zones. Zero-valent iron, in the form of recycled cast iron filings, the first class, has received considerable attention as a reactive media and has been used in about a dozen pilot- and full-scale subsurface wall installations. Criteria used in selecting commercial sources of granular iron, will be discussed. Two other classes of redox-active media that have not yet seen wide use in pilot- or full-scale installations will also be described: Fe(II) minerals and bimetallic systems. Fe(II) minerals, including magnetite (Fe{sub 3}O{sub 4}), and ferrous sulfide (troilite, FeS), are redox-active and afford TCE reduction rates and product distributions that suggest that they react via a reductive mechanism similar to that which operates in the FeO system. Fe(II) species within the passive oxide layer coating the iron metal may act as electron transfer mediators, with FeO serving as the bulk reductant. Bimetallic systems, the third class of redox-active media, are commonly prepared by plating a second metal onto zero-valent iron (e.g., Ni/Fe and Pd/Fe) and have been shown to accelerate solvent degradation rates relative to untreated iron metal. The long-term effectiveness of this approach, however, has not yet been determined in groundwater treatability tests. The results of a Ni-plated iron column study using site groundwater indicate that a change in reduction mechanism (to catalytic dehydrohalogenation/hydrogenation) accounts for the observed rate enhancement. A significant loss in media reactivity was observed over time, attributable to Ni catalyst deactivation or poisoning. Zero-valent iron systems have not shown similar losses in reactivity in long-term laboratory, pilot or field investigations.

  12. The intestinal permeability of neolignans from the seeds of Myristica fragrans in the Caco-2 cell monolayer model.

    PubMed

    Yang, Xiu-Wei; Huang, Xin; Ma, Lian; Wu, Qi; Xu, Wei

    2010-10-01

    The intestinal permeability and transport of 10 neolignans isolated from MYRISTICA FRAGRANS were studied by using the Caco-2 cell monolayer model. The 10 neolignans were measured by HPLC. Transport parameters and permeability coefficients were then calculated and compared with those of the model compounds, propranolol and atenolol. Among the 10 neolignans, the 8- O-4'-type neolignans demonstrated high permeability while the benzofuran-type neolignans were of poor to moderate permeability. Among them, eight neolignans were transported mainly VIA passive diffusion. These findings indicate that the 8- O-4'-type neolignans are well-absorbed compounds and can be used as oral leading compounds in drug discovery.

  13. Effects of continuous renal replacement therapy on intestinal mucosal barrier function during extracorporeal membrane oxygenation in a porcine model

    PubMed Central

    2014-01-01

    Backgrounds Extracorporeal membrane oxygenation (ECMO) has been recommended for treatment of acute, potentially reversible, life-threatening respiratory failure unresponsive to conventional therapy. Intestinal mucosal barrier dysfunction is one of the most critical pathophysiological disorders during ECMO. This study aimed to determine whether combination with CRRT could alleviate damage of intestinal mucosal barrier function during VV ECMO in a porcine model. Methods Twenty-four piglets were randomly divided into control(C), sham(S), ECMO(E) and ECMO + CRRT(EC) group. The animals were treated with ECMO or ECMO + CRRT for 24 hours. After the experiments, piglets were sacrificed. Jejunum, ileum and colon were harvested for morphologic examination of mucosal injury and ultrastructural distortion. Histological scoring was assessed according to Chiu’s scoring standard. Blood samples were taken from the animals at -1, 2, 6, 12 and 24 h during experiment. Blood, liver, spleen, kidney and mesenteric lymphnode were collected for bacterial culture. Serum concentrations of diamine oxidase (DAO) and intestinal fatty acid binding protein (I-FABP) were tested as markers to assess intestinal epithelial function and permeability. DAO levels were determined by spectrophotometry and I-FABP levels by enzyme linked immunosorbent assay. Results Microscopy findings showed that ECMO-induced intestinal microvillus shedding and edema, morphological distortion of tight junction between intestinal mucous epithelium and loose cell-cell junctions were significantly improved with combination of CRRT. No significance was detected on positive rate of serum bacterial culture. The elevated colonies of bacterial culture in liver and mesenteric lymphnode in E group reduced significantly in EC group (p < 0.05). Compared with E group, EC group showed significantly decreased level of serum DAO and I-FABP (p < 0.05). Conclusions CRRT can alleviate the intestinal mucosal dysfunction

  14. Direct visualization of the arterial wall water permeability barrier using CARS microscopy.

    PubMed

    Lucotte, Bertrand M; Powell, Chloe; Knutson, Jay R; Combs, Christian A; Malide, Daniela; Yu, Zu-Xi; Knepper, Mark; Patel, Keval D; Pielach, Anna; Johnson, Errin; Borysova, Lyudmyla; Dora, Kim A; Balaban, Robert S

    2017-05-02

    The artery wall is equipped with a water permeation barrier that allows blood to flow at high pressure without significant water leak. The precise location of this barrier is unknown despite its importance in vascular function and its contribution to many vascular complications when it is compromised. Herein we map the water permeability in intact arteries, using coherent anti-Stokes Raman scattering (CARS) microscopy and isotopic perfusion experiments. Generation of the CARS signal is optimized for water imaging with broadband excitation. We identify the water permeation barrier as the endothelial basolateral membrane and show that the apical membrane is highly permeable. This is confirmed by the distribution of the AQP1 water channel within endothelial membranes. These results indicate that arterial pressure equilibrates within the endothelium and is transmitted to the supporting basement membrane and internal elastic lamina macromolecules with minimal deformation of the sensitive endothelial cell. Disruption of this pressure transmission could contribute to endothelial cell dysfunction in various pathologies.

  15. Effect of Wild-Type Shigella Species and Attenuated Shigella Vaccine Candidates on Small Intestinal Barrier Function, Antigen Trafficking, and Cytokine Release

    PubMed Central

    Fiorentino, Maria; Levine, Myron M.

    2014-01-01

    Bacterial dysentery due to Shigella species is a major cause of morbidity and mortality worldwide. The pathogenesis of Shigella is based on the bacteria's ability to invade and replicate within the colonic epithelium, resulting in severe intestinal inflammatory response and epithelial destruction. Although the mechanisms of pathogenesis of Shigella in the colon have been extensively studied, little is known on the effect of wild-type Shigella on the small intestine and the role of the host response in the development of the disease. Moreover, to the best of our knowledge no studies have described the effects of apically administered Shigella flexneri 2a and S. dysenteriae 1 vaccine strains on human small intestinal enterocytes. The aim of this study was to assess the coordinated functional and immunological human epithelial responses evoked by strains of Shigella and candidate vaccines on small intestinal enterocytes. To model the interactions of Shigella with the intestinal mucosa, we apically exposed monolayers of human intestinal Caco2 cells to increasing bacterial inocula. We monitored changes in paracellular permeability, examined the organization of tight-junctions and the pro-inflammatory response of epithelial cells. Shigella infection of Caco2 monolayers caused severe mucosal damage, apparent as a drastic increase in paracellular permeability and disruption of tight junctions at the cell-cell boundary. Secretion of pro-inflammatory IL-8 was independent of epithelial barrier dysfunction. Shigella vaccine strains elicited a pro-inflammatory response without affecting the intestinal barrier integrity. Our data show that wild-type Shigella infection causes a severe alteration of the barrier function of a small intestinal cell monolayer (a proxy for mucosa) and might contribute (along with enterotoxins) to the induction of watery diarrhea. Diarrhea may be a mechanism by which the host attempts to eliminate harmful bacteria and transport them from the small to

  16. Chitosan-modified porous silicon microparticles for enhanced permeability of insulin across intestinal cell monolayers.

    PubMed

    Shrestha, Neha; Shahbazi, Mohammad-Ali; Araújo, Francisca; Zhang, Hongbo; Mäkilä, Ermei M; Kauppila, Jussi; Sarmento, Bruno; Salonen, Jarno J; Hirvonen, Jouni T; Santos, Hélder A

    2014-08-01

    Porous silicon (PSi) based particulate systems are emerging as an important drug delivery system due to its advantageous properties such as biocompatibility, biodegradability and ability to tailor the particles' physicochemical properties. Here, annealed thermally hydrocarbonized PSi (AnnTHCPSi) and undecylenic acid modified AnnTHCPSi (AnnUnTHCPSi) microparticles were developed as a PSi-based platform for oral delivery of insulin. Chitosan (CS) was used to modify the AnnUnTHCPSi microparticles to enhance the intestinal permeation of insulin. Surface modification with CS led to significant increase in the interaction of PSi microparticles with Caco-2/HT-29 cell co-culture monolayers. Compared to pure insulin, the CS-conjugated microparticles significantly improved the permeation of insulin across the Caco-2/HT-29 cell monolayers, with ca. 20-fold increase in the amount of insulin permeated and ca. 7-fold increase in the apparent permeability (P(app)) value. Moreover, among all the investigated particles, the CS-conjugated microparticles also showed the highest amount of insulin associated with the mucus layer and the intestinal Caco-2 cells and mucus secreting HT-29 cells. Our results demonstrate that CS-conjugated AnnUnTHCPSi microparticles can efficiently enhance the insulin absorption across intestinal cells, and thus, they are promising microsystems for the oral delivery of proteins and peptides across the intestinal cell membrane. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Intestinal epithelium is more susceptible to cytopathic injury and altered permeability than the lung epithelium in the context of acute sepsis.

    PubMed

    Julian, Mark W; Bao, Shengying; Knoell, Daren L; Fahy, Ruairi J; Shao, Guohong; Crouser, Elliott D

    2011-10-01

    Mitochondrial morphology and function are altered in intestinal epithelia during endotoxemia. However, it is unclear whether mitochondrial abnormalities occur in lung epithelial cells during acute sepsis or whether mitochondrial dysfunction corresponds with altered epithelial barrier function. Thus, we hypothesized that the intestinal epithelium is more susceptible to mitochondrial injury than the lung epithelium during acute sepsis and that mitochondrial dysfunction precedes impaired barrier function. Using a resuscitated feline model of Escherichia coli-induced sepsis, lung and ileal tissues were harvested after 6 h for histological and mitochondrial ultrastructural analyses in septic (n = 6) and time-matched controls (n = 6). Human lung epithelial cells (HLEC) and Caco-2 monolayers (n = 5) were exposed to 'cytomix' (TNFα: 40 ng/ml, IL-1β: 20 ng/ml, IFNγ: 10 ng/ml) for 24-72 h, and measurements of transepithelial electrical resistance (TER), epithelial permeability and mitochondrial membrane potential (ΔΨ) were taken. Lung epithelial morphology, mitochondrial ultrastructure and pulmonary gas exchange were unaltered in septic animals compared to matching controls. While histologically intact, ileal epithelia demonstrated marked mitochondrial ultrastructural damage during sepsis. Caco-2 monolayers treated with cytomix showed a significant decrease in mitochondrial ΔΨ within 24 h, which was associated with a progressive reduction in TER and increased epithelial permeability over the subsequent 48 h. In contrast, mitochondrial ΔΨ and epithelial barrier functions were preserved in HLEC following cytomix. These findings indicate that intestinal epithelium is more susceptible to mitochondrial damage and dysfunction than the lung epithelium in the context of sepsis. Early alterations in mitochondrial function portend subsequent epithelial barrier dysfunction.

  18. Intracellular ascorbate tightens the endothelial permeability barrier through Epac1 and the tubulin cytoskeleton.

    PubMed

    Parker, William H; Rhea, Elizabeth Meredith; Qu, Zhi-Chao; Hecker, Morgan R; May, James M

    2016-10-01

    Vitamin C, or ascorbic acid, both tightens the endothelial permeability barrier in basal cells and also prevents barrier leak induced by inflammatory agents. Barrier tightening by ascorbate in basal endothelial cells requires nitric oxide derived from activation of nitric oxide synthase. Although ascorbate did not affect cyclic AMP levels in our previous study, there remains a question of whether it might activate downstream cyclic AMP-dependent pathways. In this work, we found in both primary and immortalized cultured endothelial cells that ascorbate tightened the endothelial permeability barrier by ∼30%. In human umbilical vein endothelial cells, this occurred at what are likely physiologic intracellular ascorbate concentrations. In so doing, ascorbate decreased measures of oxidative stress and also flattened the cells to increase cell-to-cell contact. Inhibition of downstream cyclic AMP-dependent proteins via protein kinase A did not prevent ascorbate from tightening the endothelial permeability barrier, whereas inhibition of Epac1 did block the ascorbate effect. Although Epac1 was required, its mediator Rap1 was not activated. Furthermore, ascorbate acutely stabilized microtubules during depolymerization induced by colchicine and nocodazole. Over several days in culture, ascorbate also increased the amount of stable acetylated α-tubulin. Microtubule stabilization was further suggested by the finding that ascorbate increased the amount of Epac1 bound to α-tubulin. These results suggest that physiologic ascorbate concentrations tighten the endothelial permeability barrier in unstimulated cells by stabilizing microtubules in a manner downstream of cyclic AMP that might be due both to increasing nitric oxide availability and to scavenging of reactive oxygen or nitrogen species.

  19. Arabinoxylan in wheat is more responsible than cellulose for promoting intestinal barrier function in weaned male piglets.

    PubMed

    Chen, Hong; Wang, Wei; Degroote, Jeroen; Possemiers, Sam; Chen, Daiwen; De Smet, Stefaan; Michiels, Joris

    2015-01-01

    The effect of dietary fiber on intestinal function primarily has been ascribed to its interaction with intestinal bacteria in the hindgut, whereas changes in intestinal bacteria in the host have been considered to depend on fiber composition. The objectives of this study were to determine the contribution of the major fiber components to the health-promoting effects of wheat bran on intestinal mucosal barrier function and to elucidate the involvement of microbiota changes in weaned piglets. Thirty freshly weaned male piglets were assigned to 5 dietary treatment groups (n = 6) according to litter and weight. The piglets consumed synthetic diets ad libitum for 30 d, including a basal control diet (CON) without fiber components, a wheat bran diet (WB) as reference diet (10% wheat bran), and 3 other diets containing amounts of fiber components equivalent to those in the WB, i.e., an arabinoxylan diet (AX), a cellulose diet (CEL), and a combined arabinoxylan and cellulose diet (CB). The groups consuming diets containing arabinoxylans (i.e., the WB, AX, and CB groups) had increased intestinal secretory immunoglobulin A concentrations, goblet cell number and cecal short-chain fatty acid concentrations, and reduced branched-chain fatty acid concentrations and pH values compared with the CON group. In the WB group, the stimulated secretion of Cl(-) was suppressed (60.8% and 47.5% change in short-circuit current caused by theophylline and carbachol, respectively) in the distal small intestine compared with the CON group. The AX and CB groups also had increased intestinal alkaline phosphatase activities and reduced intestinal transcellular permeability (by 77.3% and 67.2%, respectively) compared with the CON group. Meanwhile, in the WB group, cecal Bacteroidetes and Enterobacteriaceae populations were lower, and the growth of Lactobacillus was higher in the AX and CB groups than in the CON group, whereas no positive effect on intestinal barrier function was observed in the

  20. Transforming Growth Factor-β Regulation of Epithelial Tight Junction Proteins Enhances Barrier Function and Blocks Enterohemorrhagic Escherichia coli O157:H7-Induced Increased Permeability

    PubMed Central

    Howe, Kathryn L.; Reardon, Colin; Wang, Arthur; Nazli, Aisha; McKay, Derek M.

    2005-01-01

    Enterohemorrhagic Escherichia coli O157:H7 (EHEC) is an enteric pathogen that causes potentially fatal symptoms after intimate adhesion, modulation of intestinal epithelial signal transduction, and alteration of epithelial function (eg, barrier disruption). Although the epithelial barrier is critical to gut homeostasis, only a few agents, such as transforming growth factor (TGF)-β, can enhance or protect epithelial barrier function. Our aims were to delineate the mechanism(s) behind TGF-β-induced barrier enhancement and to determine whether TGF-β could prevent EHEC-induced barrier disruption. Using monolayers of the human T84 colonic epithelial cell line, we found that TGF-β induced a significant increase in transepithelial electrical resistance (a measure of paracellular permeability) through activation of ERK MAPK and SMAD signaling pathways and up-regulation of the tight junction protein claudin-1. Additionally, TGF-β pretreatment of epithelia blocked the decrease in transepithelial electrical resistance and the increase in transepithelial passage of [3H]-mannitol caused by EHEC infection. EHEC infection was associated with reduced expression of zonula occludens-1, occludin, and claudin-2 (but not claudin-1 or claudin-4); TGF-β pretreatment prevented these changes. These studies provide insight into EHEC pathogenesis by illustrating the mechanisms underlying TGF-β-induced epithelial barrier enhancement and identifying TGF-β as an agent capable of blocking EHEC-induced increases in epithelial permeability via maintenance of claudin-2, occludin, and zonula occludens-1 levels. PMID:16314472

  1. Arsenic-containing hydrocarbons and arsenic-containing fatty acids: Transfer across and presystemic metabolism in the Caco-2 intestinal barrier model.

    PubMed

    Meyer, Sören; Raber, Georg; Ebert, Franziska; Taleshi, Mojtaba S; Francesconi, Kevin A; Schwerdtle, Tanja

    2015-10-01

    Arsenic-containing hydrocarbons (AsHCs) and arsenic-containing fatty acids (AsFAs) represent two classes of arsenolipids occurring naturally in marine food. Toxicological data are yet scarce and an assessment regarding the risk to human health has not been possible. Here, we investigated the transfer and presystemic metabolism of five arsenolipids in an intestinal barrier model. Three AsHCs and two AsFAs were applied to the Caco-2 intestinal barrier model. Thereby, the short-chain AsHCs reached up to 50% permeability. Transport is likely to occur via passive diffusion. The AsFAs showed lower intestinal bioavailability, but respective permeabilities were still two to five times higher as compared to arsenobetaine or arsenosugars. Interestingly, AsFAs were effectively biotransformed while passing the in vitro intestinal barrier, whereas AsHCs were transported to the blood-facing compartment essentially unchanged. AsFAs can be presystemically metabolised and the amount of transferred arsenic is lower than that for AsHCs. In contrast, AsHCs are likely to be highly intestinally bioavailable to humans. Since AsHCs exert strong toxicity in vitro and in vivo, toxicity studies with experimental animals as well as a human exposure assessment are needed to assess the risk to human health related to the presence of AsHCs in seafood. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. [Effect of multicomponent environment on intestinal permeability of puerarin in biopharmaceutics classification system of Chinese materia medica].

    PubMed

    Liu, Yang; Wang, Gang; Dong, Ling; Tang, Ming-Min; Zhu, Mei-Ling; Dong, Hong-Huant; Hou, Cheng-Bo

    2014-12-01

    The evaluation of permeability in biopharmaceutics classification system of Chinese materia medica (CMMBCS) requires multicomponent as a whole in order to conduct research, even in the study of a specific component, should also be put in the multicomponent environment. Based on this principle, the high content components in Gegen Qinlian decoction were used as multicomponent environmental impact factors in the experiment, and the relevant parameters of intestinal permeability about puerarin were measured with using in situ single-pass intestinal perfusion model, to investigate and evaluate the intestinal permeability of puerarin with other high content components. The experimental results showed that different proportions of baicalin, glycyrrhizic acid and berberine had certain influence on intestinal permeability of puerarin, and glycyrrhizic acid could significantly inhibit the intestinal absorption of puerarin, moreover, high concentration of berberine could promote the absorption of puerarin. The research results indicated that the important research ideas of permeability evaluation in biopharmaceutics classification system of Chinese materia medica with fully considering the effects of other ingredients in multicomponent environment.

  3. Use of jet grouting to create a low permeability horizontal barrier below an incinerator ash landfill

    SciTech Connect

    Furth, A.J.; Burke, G.K.; Deutsch, W.L. Jr.

    1997-12-31

    The City of Philadelphia`s Division of Aviation (DOA) has begun construction of a new commuter runway, designated as Runway 8-26, at the Philadelphia International Airport. A portion of this runway will be constructed over a former Superfund site known as the Enterprise Avenue Landfill, which for many years was used to dispose of solid waste incinerator ash and other hazardous materials. The site was clay capped in the 1980`s, but in order for the DOA to use the site, additional remediation was needed to meet US EPA final closure requirements. One component of the closure plan included installation of a low permeability horizontal barrier above a very thin (approximately 0.61 to 0.91 meters) natural clay stratum which underlies an approximately 1020 m{sup 2} area of the landfill footprint so as to insure that a minimum 1.52 meter thick low permeability barrier exists beneath the entire 150,000 m{sup 2} landfill. The new barrier was constructed using jet grouting techniques to achieve remote excavation and replacement of the bottom 0.91 meters of the waste mass with a low permeability grout. The grout was formulated to meet the low permeability, low elastic modulus and compressive strength requirements of the project design. This paper will discuss the advantages of using jet grouting for the work and details the development of the grout mixture, modeling of the grout zone under load, field construction techniques, performance monitoring and verification testing.

  4. Permeability of the blood-brain barrier to a rhenacarborane.

    PubMed

    Hawkins, Patrick M; Jelliss, Paul A; Nonaka, Naoko; Shi, Xiaoming; Banks, William A

    2009-05-01

    The treatment of brain malignancies with boron neutron capture therapy depends on their ability to cross the blood-brain barrier (BBB). An especially promising class of boron-containing compounds is the rhenacarboranes that, if able to cross the BBB, could act as delivery vehicles as well as a source of boron. Here, we examined the ability of the 3-NO-3,3-kappa(2)-(2,2'-N(2)C(10)H(6)(Me)[(CH(2))(7)(131)I]-4,4')-closo-3,1,2-ReC(2)B(9)H(11) (rhenacarborane) labeled with iodine-131 to be taken up into the bloodstream after subcutaneous administration and to cross the BBB. The (131)I-rhenacarborane was quickly absorbed from the injection site and reached a steady state in arterial serum of 2.59%/ml of the administered dose. Between 73 and 95% of the radioactivity in serum 6 h after administration represented intact (131)I-rhenacarborane. Its octanol/buffer partition coefficient was 1.74, showing it to be lipophilic. Tissue/serum ratios for brain, lung, and liver showed classic patterns for a lipid-soluble substance with high levels immediately achieved and rapid redistribution. For brain, a steady state of approximately 0.107% of the administered dose/gram-brain was rapidly reached, and 71% of the radioactivity in brain 6 h after subcutaneous administration represented intact (131)I-rhenacarborane. Steady-state values were 1.53 and 0.89% of the injected dose per gram for lung and liver, respectively. (131)I-Rhenacarborane was quickly effluxed from brain by a nonsaturable system after its injection into the lateral ventricle of the brain. In conclusion, these results show that a rhenacarborane was enzymatically resistant and able to cross the BBB by transmembrane diffusion and accumulate in brain in substantial amounts. This supports their use as therapeutic agents for targeting the central nervous system.

  5. Understanding Measurements of Intestinal Permeability in Healthy Humans with Urine Lactulose and Mannitol Excretion

    PubMed Central

    Camilleri, Michael; Nadeau, Ashley; Lamsam, Jesse; Nord, Sara Linker; Ryks, Michael; Burton, Duane; Sweetser, Seth; Zinsmeister, Alan R.; Singh, Ravinder

    2009-01-01

    Our aim was to understand the information from differential two-sugar excretion (2-SE) in measuring intestinal permeability. In a crossover study in 12 healthy volunteers, we compared urinary excretion ratios of lactulose (L) to mannitol [(M) LMR] after ingestion in liquid formulation (LF) or in delayed-release, methacrylate-coated capsules (CAP). Both formulations were radiolabeled. Urine was collected every 2 hours from 0–8h, and from 8–24h. Two hours after LF, gastric residual was 15.9 ± 6.2 % (SEM), and the percentage in colon was 49.6 ± 7.8 %; in 11/12 participants, liquid had entered colon within 2h. Average CAP arrival time in colon was 5.16 ± 0.46h (mode 6 h). After LF, mannitol was extensively absorbed in the first 8h; lactulose absorption was low thoughout the 24h. After the LF, the LMR (geometric mean, 95% CI/hour) in the 0–2h urine was 0.08 [0.05, 0.11]), which was lower than in 8–24h urine (0.32,[0.16, 0.46]; p<0.05). Urine LMRs at 8–24h were similar after LF or CAP. We concluded that, after LF, sugar excretion in 0–2h urine may reflect both SI and colon permeability. Colonic permeability is reflected by urine sugar excretion between 6 and 24h. CAP delivery reduces mannitol excreted at 0–6h, compared to LF. The 0 to 5 or 6h 2-SE urine likely reflects both SI and colon permeability; the higher LMR in the 8–24h urine relative to 0–2h urine should be interpreted with caution and does not mean that colon is more permeable than SI. PMID:19614866

  6. Alcohol-induced premature permeability in mouse placenta-yolk sac barriers in vivo.

    PubMed

    Haghighi Poodeh, S; Salonurmi, T; Nagy, I; Koivunen, P; Vuoristo, J; Räsänen, J; Sormunen, R; Vainio, S; Savolainen, M J

    2012-10-01

    Acute alcohol exposure induces malformation and malfunction of placenta-yolk sac tissues in rodents, reducing the labyrinth zone in the placenta and altering the permeability and fluidity of the cell membrane. During normal mouse placentation the cells line up in an optimal way to form a hemotrichorial placenta where layers II and III are connected through gap junctions. These act as molecular sieves that limit the passage of large molecules. PlGF is a developmentally regulated protein that controls the passage of molecules in the vasculosyncytial membranes and media of large blood vessels in the placental villi. In addition to the chorioallontoic placenta, rodents also have another type of placenta that consists of Reichert's membrane within the trophoblast cell layer on the maternal side and the parietal endodermal cells on the embryonic site. This forms a separate materno-fetal transport system. We study here whether alcohol affects these two placental barriers, leading to placental malfunction that in turn diminishes the nutrient supply to the embryo. CD-1 mice received two intraperitoneal injections of 3 g/kg ethanol at 4 h intervals at 8.75 days post coitum (dpc). The placentas were collected on 9.5, 11.5 and 14.5 dpc and used for histopathological protein studies. Hemotrichorial cell layer structure interactions through connective tissue and gap junction were analyzed by electron microscopy. The permeability of the feto-maternal barrier was visualized with Evans Blue. VEGF, a permeability inducer, was found to be up-regulated in the mouse placenta after acute alcohol exposure, and permeability was also affected by altered structures in the barriers that separate the feto-maternal blood circulation which destroyed the gap junctions in the hemotrichorial cell layer, reduced the thickness of Reichert's membrane and interfered with with Reichert's trophoblast/Reichert's parietal interaction. These defects together could have caused the permeability malfunction

  7. Epidermal Permeability Barrier Recovery Is Delayed in Vitiligo-Involved Sites

    PubMed Central

    Liu, J.; Man, W.Y.; Lv, C.Z.; Song, S.P.; Shi, Y.J.; Elias, P.M.; Man, M.Q.

    2010-01-01

    Background/Objectives Prior studies have demonstrated that both the skin surface pH and epidermal permeability barrier function vary with skin pigmentation types. Although melanin deficiency is the main feature of vitiligo, alterations in cutaneous biophysical properties in vitiligo have not yet been well defined. In the present study, stratum corneum (SC) hydration, the skin surface pH and epidermal permeability barrier function in vitiligo were evaluated. Methods A total of 30 volunteers with vitiligo comprising 19 males and 11 females aged 13–51 years (mean age: 27.91 ± 2.06 years) were enrolled in this study. The skin surface pH, SC hydration, melanin/erythema index and transepidermal water loss (TEWL) were measured by respective probes connected to a Courage-Khazaka MPA5. SC integrity was determined by measuring the TEWL following each D-Squame application. The barrier recovery rate was assessed at 5 h following barrier disruption by repeated tape stripping. Results In addition to SC hydration, both melanin and erythema index were significantly lower in vitiligo lesions than in contralateral, nonlesional sites, while no difference in skin surface pH between vitiligo-involved and uninvolved areas was observed. In addition, neither the basal TEWL nor SC integrity in the involved areas differed significantly from that in the uninvolved areas. However, barrier recovery in vitiligo-involved sites was significantly delayed in comparison with uninvolved sites (40.83 ± 5.39% vs. 58.30 ± 4.71%; t = 2.441; p < 0.02). Conclusion Barrier recovery following tape stripping of the SC is delayed in vitiligo. Therefore, improvement in epidermal permeability barrier function may be an important unrecognized factor to be considered in treating patients with vitiligo. PMID:20185976

  8. Physicochemical properties and in vitro intestinal permeability properties and intestinal cell toxicity of silica particles, performed in simulated gastrointestinal fluids.

    PubMed

    Sakai-Kato, Kumiko; Hidaka, Masayuki; Un, Keita; Kawanishi, Toru; Okuda, Haruhiro

    2014-03-01

    Amorphous silica particles with the primary dimensions of a few tens of nm, have been widely applied as additives in various fields including medicine and food. Especially, they have been widely applied in powders for making tablets and to coat tablets. However, their behavior and biological effects in the gastrointestinal tracts associated with oral administration remains unknown. Amorphous silica particles with diameters of 50, 100, and 200nm were incubated in the fasted-state and fed-state simulated gastric and intestinal fluids. The sizes, intracellular transport into Caco-2 cells (model cells for intestinal absorption), the Caco-2 monolayer membrane permeability, and the cytotoxicity against Caco-2 cells were then evaluated for the silica particles. Silica particles agglomerated in fed-state simultaneous intestinal fluids. The agglomeration and increased particles size inhibited the particles' absorption into the Caco-2 cells or particles' transport through the Caco-2 cells. The in vitro cytotoxicity of silica particles was not observed when the average size was larger than 100nm, independent of the fluid and the concentration. Our study indicated the effect of diet on the agglomeration of silica particles. The sizes of silica particles affected the particles' absorption into or transport through the Caco-2 cells, and cytotoxicity in vitro, depending on the various biological fluids. The findings obtained from our study may offer valuable information to evaluate the behavior of silica particles in the gastrointestinal tracts or safety of medicines or foods containing these materials as additives. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Induced phytoextraction/soil washing of lead using biodegradable chelate and permeable barriers.

    PubMed

    Kos, Bostjan; Lestan, Domen

    2003-02-01

    Chelate-induced remediation has been proposed as an effective tool for the extraction of lead (Pb) from contaminated soils by plants. However, side-effects, mainly mobilization and leaching of Pb, raise environmental concerns. Biodegradable, synthetic organic chelate ethylenediaminedisuccinic acid (EDDS), and commonly used ethylenedimanetetraacetic acid (EDTA) were used for induced phytoextraction with a test plant Brassica rapa and in situ washing of soil contaminated with 1350 mg/kg of Pb. Horizontal permeable barriers were placed 20 cm deep in soil columns and tested for their ability to prevent leaching of Pb. The reactive materials in the barriers were nutrient enriched vermiculite, peat or agricultural hydrogel, and apatite. EDTA and EDDS addition increased Pb concentrations in the test plant by 158 and 89 times compared to the control, to 817 and 464 mg/kg, respectively. In EDTA treatments, approximately 25% or more of total initial soil Pb was leached in single cycle of chelate addition. In EDDS treatments, 20% of the initial Pb was leached from columns with no barrier, while barriers with vermiculite or hydrogel and apatite decreased leaching by more than 60 times, to 0.35%. 11.6% of total initial Pb was washed from the soil above the barrier with vermiculite and apatite, where almost all leached Pb was accumulated. Results indicate that use of biodegradable chelate EDDS and permeable barriers may lead to environmentally safe induced Pb phytoextraction and in situ washing of Pb.

  10. Trospium chloride is absorbed from two intestinal "absorption windows" with different permeability in healthy subjects.

    PubMed

    Tadken, Tobias; Weiss, Michael; Modess, Christiane; Wegner, Danilo; Roustom, Tarek; Neumeister, Claudia; Schwantes, Ulrich; Schulz, Hans-Ulrich; Weitschies, Werner; Siegmund, Werner

    2016-12-30

    Intestinal P-glycoprotein is regio-selectively expressed and is a high affinity, low capacity efflux carrier for the cationic, poorly permeable trospium. Organic cation transporter 1 (OCT1) provides lower affinity but higher capacity for trospium uptake. To evaluate regional intestinal permeability, absorption profiles after gastric infusion of trospium chloride (30mg/250ml=[I]2) for 6h and after swallowing 30mg immediate-release tablets in fasted and fed healthy subjects, were evaluated using an inverse Gaussian density function to model input rate and mean absorption time (MAT). Trospium chloride was slowly absorbed (MAT ∼10h) after gastric infusion involving two processes with different input rates, peaking at about 3h and 7h. Input rates and MAT were influenced by dosage form and meal. In conclusion, trospium is absorbed from two "windows" located in the jejunum and cecum/ascending colon, whose uptake capacity might result from local abundance and functional interplay of P-glycoprotein and OCT1. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Influence of a high-fat diet on gut microbiota, intestinal permeability and metabolic endotoxaemia.

    PubMed

    Moreira, Ana Paula Boroni; Texeira, Tatiana Fiche Salles; Ferreira, Alessandra Barbosa; Peluzio, Maria do Carmo Gouveia; Alfenas, Rita de Cássia Gonçalves

    2012-09-01

    Lipopolysaccharide (LPS) may play an important role in chronic diseases through the activation of inflammatory responses. The type of diet consumed is of major concern for the prevention and treatment of these diseases. Evidence from animal and human studies has shown that LPS can diffuse from the gut to the circulatory system in response to the intake of high amounts of fat. The method by which LPS move into the circulatory system is either through direct diffusion due to intestinal paracellular permeability or through absorption by enterocytes during chylomicron secretion. Considering the impact of metabolic diseases on public health and the association between these diseases and the levels of LPS in the circulatory system, this review will mainly discuss the current knowledge about high-fat diets and subclinical inflammation. It will also describe the new evidence that correlates gut microbiota, intestinal permeability and alkaline phosphatase activity with increased blood LPS levels and the biological effects of this increase, such as insulin resistance. Although the majority of the studies published so far have assessed the effects of dietary fat, additional studies are necessary to deepen the understanding of how the amount, the quality and the structure of the fat may affect endotoxaemia. The potential of food combinations to reduce the negative effects of fat intake should also be considered in future studies. In these studies, the effects of flavonoids, prebiotics and probiotics on endotoxaemia should be investigated. Thus, it is essential to identify dietetic strategies capable of minimising endotoxaemia and its postprandial inflammatory effects.

  12. Nitric Oxide and Airway Epithelial Barrier Function: Regulation of Tight Junction Proteins and Epithelial Permeability

    PubMed Central

    Olson, Nels; Greul, Anne-Katrin; Hristova, Milena; Bove, Peter F.; Kasahara, David I.; van der Vliet, Albert

    2008-01-01

    Acute airway inflammation is associated with enhanced production of nitric oxide (NO•) and altered airway epithelial barrier function, suggesting a role of NO• or its metabolites in epithelial permeability. While high concentrations of S-nitrosothiols disrupted transepithelial resistance (TER) and increased permeability in 16HBE14o- cells, no significant barrier disruption was observed by NONOates, in spite of altered distribution and expression of some TJ proteins. Barrier disruption of mouse tracheal epithelial (MTE) cell monolayers in response to inflammatory cytokines was independent of NOS2, based on similar effects in MTE cells from NOS2-/- mice and a lack of effect of the NOS2-inhibitor 1400W. Cell pre-incubation with LPS protected MTE cells from TER loss and increased permeability by H2O2, which was independent of NOS2. However, NOS2 was found to contribute to epithelial wound repair and TER recovery after mechanical injury. Overall, our results demonstrate that epithelial NOS2 is not responsible for epithelial barrier dysfunction during inflammation, but may contribute to restoration of epithelial integrity. PMID:19100237

  13. Potential Retinal Benefits of Dietary Polyphenols Based on Their Permeability across the Blood-Retinal Barrier.

    PubMed

    Liu, Yixiang; Liu, Guang-Ming; Cao, Min-Jie; Chen, Qingchou; Sun, Lechang; Ji, Baoping

    2017-04-19

    Whether all dietary polyphenols nourish the eyes via oral supplementation is controversial. Given that passage of dietary polyphenols across the blood-retina barrier (BRB) is the precondition for polyphenols to exhibit ocular benefits, the BRB permeability of polyphenols was assessed in this study. Being common dietary polyphenols in fruits and vegetables, nonanthocyanin flavonoids, anthocyanins, and phenolic acids were investigated. BRB was simulated in vitro by using a differentiated retinal pigment epithelial cell monolayer cultivated on a Transwell culture system. Penetration rate was calculated by quantitatively analyzing the polyphenols in basolateral media. The BRB permeability of different polyphenols obviously (p < 0.05) differed, as follows: phenolic acids > nonanthocyanin flavonoids > anthocyanins. Glycosylation and methylation improved the BRB permeability of nonanthocyanin flavonoids and anthocyanins. However, instability and carbonylation at the C-4 position severely suppressed the BRB permeability of anthocyanins and nonanthocyanin flavonoids. Moreover, a new metabolite was discovered during penetration of anthocyanins into the BRB. However, hydrophilic phenolic acids exhibited better BRB permeability than hydrophobic ones. Data demonstrate that BRB permeability of polyphenols was determined based on structural characteristics, hydrophilicity, stability, and metabolic changes.

  14. Novel RpoS-Dependent Mechanisms Strengthen the Envelope Permeability Barrier during Stationary Phase.

    PubMed

    Mitchell, Angela M; Wang, Wei; Silhavy, Thomas J

    2017-01-15

    Gram-negative bacteria have effective methods of excluding toxic compounds, including a largely impermeable outer membrane (OM) and a range of efflux pumps. Furthermore, when cells become nutrient limited, RpoS enacts a global expression change providing cross-protection against many stresses. Here, we utilized sensitivity to an anionic detergent (sodium dodecyl sulfate [SDS]) to probe changes occurring to the cell's permeability barrier during nutrient limitation. Escherichia coli is resistant to SDS whether cells are actively growing, carbon limited, or nitrogen limited. In actively growing cells, this resistance depends on the AcrAB-TolC efflux pump; however, this pump is not necessary for protection under either carbon-limiting or nitrogen-limiting conditions, suggesting an alternative mechanism(s) of SDS resistance. In carbon-limited cells, RpoS-dependent pathways lessen the permeability of the OM, preventing the necessity for efflux. In nitrogen-limited but not carbon-limited cells, the loss of rpoS can be completely compensated for by the AcrAB-TolC efflux pump. We suggest that this difference simply reflects the fact that nitrogen-limited cells have access to a metabolizable energy (carbon) source that can efficiently power the efflux pump. Using a transposon mutant pool sequencing (Tn-Seq) approach, we identified three genes, sanA, dacA, and yhdP, that are necessary for RpoS-dependent SDS resistance in carbon-limited stationary phase. Using genetic analysis, we determined that these genes are involved in two different envelope-strengthening pathways. These genes have not previously been implicated in stationary-phase stress responses. A third novel RpoS-dependent pathway appears to strengthen the cell's permeability barrier in nitrogen-limited cells. Thus, though cells remain phenotypically SDS resistant, SDS resistance mechanisms differ significantly between growth states. Gram-negative bacteria are intrinsically resistant to detergents and many

  15. Novel RpoS-Dependent Mechanisms Strengthen the Envelope Permeability Barrier during Stationary Phase

    PubMed Central

    Wang, Wei

    2016-01-01

    ABSTRACT Gram-negative bacteria have effective methods of excluding toxic compounds, including a largely impermeable outer membrane (OM) and a range of efflux pumps. Furthermore, when cells become nutrient limited, RpoS enacts a global expression change providing cross-protection against many stresses. Here, we utilized sensitivity to an anionic detergent (sodium dodecyl sulfate [SDS]) to probe changes occurring to the cell's permeability barrier during nutrient limitation. Escherichia coli is resistant to SDS whether cells are actively growing, carbon limited, or nitrogen limited. In actively growing cells, this resistance depends on the AcrAB-TolC efflux pump; however, this pump is not necessary for protection under either carbon-limiting or nitrogen-limiting conditions, suggesting an alternative mechanism(s) of SDS resistance. In carbon-limited cells, RpoS-dependent pathways lessen the permeability of the OM, preventing the necessity for efflux. In nitrogen-limited but not carbon-limited cells, the loss of rpoS can be completely compensated for by the AcrAB-TolC efflux pump. We suggest that this difference simply reflects the fact that nitrogen-limited cells have access to a metabolizable energy (carbon) source that can efficiently power the efflux pump. Using a transposon mutant pool sequencing (Tn-Seq) approach, we identified three genes, sanA, dacA, and yhdP, that are necessary for RpoS-dependent SDS resistance in carbon-limited stationary phase. Using genetic analysis, we determined that these genes are involved in two different envelope-strengthening pathways. These genes have not previously been implicated in stationary-phase stress responses. A third novel RpoS-dependent pathway appears to strengthen the cell's permeability barrier in nitrogen-limited cells. Thus, though cells remain phenotypically SDS resistant, SDS resistance mechanisms differ significantly between growth states. IMPORTANCE Gram-negative bacteria are intrinsically resistant to

  16. Chronic sleep restriction disrupts interendothelial junctions in the hippocampus and increases blood-brain barrier permeability.

    PubMed

    Hurtado-Alvarado, G; Velázquez-Moctezuma, J; Gómez-González, B

    2017-10-01

    Chronic sleep loss in the rat increases blood-brain barrier permeability to Evans blue and FITC-dextrans in almost the whole brain and sleep recovery during short periods restores normal blood-brain barrier permeability. Sleep loss increases vesicle density in hippocampal endothelial cells and decreases tight junction protein expression. However, at the ultrastructural level the effect of chronic sleep loss on interendothelial junctions is unknown. In this study we characterised the ultrastructure of interendothelial junctions in the hippocampus, the expression of tight junction proteins, and quantified blood-brain barrier permeability to fluorescein-sodium after chronic sleep restriction. Male Wistar rats were sleep restricted using the modified multiple platform method during 10 days, with a daily schedule of 20-h sleep deprivation plus 4-h sleep recovery at their home-cages. At the 10th day hippocampal samples were obtained immediately at the end of the 20-h sleep deprivation period, and after 40 and 120 min of sleep recovery. Samples were processed for transmission electron microscopy and western blot. Chronic sleep restriction increased blood-brain barrier permeability to fluorescein-sodium, and decreased interendothelial junction complexity by increasing the frequency of less mature end-to-end and simply overlap junctions, even after sleep recovery, as compared to intact controls. Chronic sleep loss also induced the formation of clefts between narrow zones of adjacent endothelial cell membranes in the hippocampus. The expression of claudin-5 and actin decreased after chronic sleep loss as compared to intact animals. Therefore, it seems that chronic sleep loss disrupts interendothelial junctions that leads to blood-brain barrier hyperpermeability in the hippocampus. © 2017 The Authors Journal of Microscopy © 2017 Royal Microscopical Society.

  17. Calcium solubility, intestinal sojourn time and paracellular permeability codetermine passive calcium absorption in rats.

    PubMed

    Duflos, C; Bellaton, C; Pansu, D; Bronner, F

    1995-09-01

    To investigate the nonsaturable, paracellular pathway of intestinal Ca absorption, the luminal contents of 12-cm segments of the intestine of 8-wk-old male Sprague-Dawley rats were analyzed for pH, sojourn time and soluble and insoluble Ca over a 24-h period. The rats had been fed one of two high Ca diets for 2 wk: 1.5% Ca (diet group 3a) and 3.1% (diet group 5a). The pH of the small intestine increased from < 6.6 to > 8.0 from duodenum to ileum; transit time increased from 2.5 min in the duodenum to 58 min in the distal ileum, with the entire ileum accounting on the average for 74% of the transit time of 3 h. The amount of Ca solubilized throughout the intestine was 32 +/- 3.3 mumol in diet group 3a and 53 +/- 5.3 mumol in diet group 5a, i.e., 2.7% and 2.0% of the total luminal Ca. Because absorption by diet group 3a was 1.45 +/- 0.23 mmol/d and that by diet group 5a was 2.50 +/- 0.18 mmol/d, the amounts absorbed were 45.3 and 47.1 times greater than present in the lumen in soluble form at any one time. Thus, over a 24-h period, an average of 3.2% (46.2/1440) of the soluble Ca present in the lumen at any time was absorbed per min. Calculations involving the gradient between luminal and plasma Ca show that the rate of Ca diffusion from lumen to blood is < 2% of what it would be if the paracellular path were unrestricted. Thus, intestinal sojourn time, Ca solubility and mucosal permeability to Ca are factors that determine the rate of passive Ca absorption.

  18. Leaky gut and mycotoxins: Aflatoxin B1 does not increase gut permeability in broiler chickens

    USDA-ARS?s Scientific Manuscript database

    Previous studies conducted in our laboratory have demonstrated that intestinal barrier function can be adversely affected by diet ingredients or feed restriction, resulting in increased intestinal inflammation-associated permeability. Two experiments were conducted in broilers to evaluate the effect...

  19. Intestinal permeability in relation to birth weight and gestational and postnatal age

    PubMed Central

    van Elburg, R M; Fetter, W; Bunkers, C; Heymans, H

    2003-01-01

    Objective: To determine the relation between intestinal permeability and birth weight, gestational age, postnatal age, and perinatal risk factors in neonates. Study design: Intestinal permeability was measured by the sugar absorption test within two days of birth and three to six days later in preterm and healthy term infants. In the sugar absorption test, the urinary lactulose/mannitol ratio is measured after oral ingestion of a solution (375 mosm) of lactulose and mannitol. Results: A first sugar absorption test was performed in 116 preterm (26–36 weeks gestation) and 16 term infants. A second test was performed in 102 preterm and nine term infants. In the preterm infants, the lactulose/mannitol ratio was not related to gestational age (r = -0.09, p = 0.32) or birth weight (r = 0.07, p = 0.43). The median lactulose/mannitol ratio was higher if measured less than two days after birth than when measured three to six days later (0.427 and 0.182 respectively, p<0.001). The lactulose/mannitol ratio was higher in preterm infants than term infants if measured within the first 2 days of life (0.404 and 0.170 respectively, p < 0.001), but not different three to six days later (0.182 and 0.123 respectively, p = 0.08). In multiple regression analysis of perinatal risk factors, only umbilical arterial pH correlated with the lactulose/mannitol ratio in preterm infants less than 2 days of age (T = -1.98, p = 0.05). Conclusions: In preterm infants (26–36 weeks gestation), intestinal permeability is not related to gestational age or birth weight but is higher during the first 2 days of life than three to six days later. It is higher in preterm infants than in healthy term infants only if measured within two days of birth. This suggests rapid postnatal adaptation of the small intestine in preterm infants. PMID:12496227

  20. Intestinal absorption of the intact peptide carnosine in man, and comparison with intestinal permeability to lactulose.

    PubMed Central

    Gardner, M L; Illingworth, K M; Kelleher, J; Wood, D

    1991-01-01

    1. Healthy humans ingested the dipeptide carnosine (L-beta-alanyl-L-histidine). Their plasma levels and urinary outputs of carnosine and beta-alanine were monitored over the following 5 h. 2. Large amounts of intact carnosine (up to 14% of the ingested dose) were recovered in the urine over the 5 h after ingestion. However, carnosine was undetectable in the plasma unless precautions were taken to inhibit blood carnosinase activity ex vivo during and after blood collection. 3. The amount of carnosine recovered in urine varied substantially between subjects. It correlated negatively with carnosinase enzymic activity in the plasma. Highest carnosinase activities were observed in those subjects who regularly underwent physical training. 4. Urinary recovery of the disaccharide lactulose also varied considerably between subjects, but was substantially lower than that of carnosine. There was no significant correlation between the recoveries of carnosine and lactulose. 5. When lactulose was ingested with a hypertonic solution, the urinary recovery of lactulose was generally increased. When carnosine was ingested with a hypertonic solution, the urinary recovery of carnosine was reduced: hence the paracellular route probably is not dominant for absorption of intact carnosine. 6. Intact carnosine must have crossed the intestine to an extent much greater than hitherto recognized. Rapid post-absorptive hydrolysis is a severe obstacle to quantification of intact peptide absorption. PMID:1910085

  1. Topical application of TRPM8 agonists accelerates skin permeability barrier recovery and reduces epidermal proliferation induced by barrier insult: role of cold-sensitive TRP receptors in epidermal permeability barrier homoeostasis.

    PubMed

    Denda, Mitsuhiro; Tsutsumi, Moe; Denda, Sumiko

    2010-09-01

    TRPA1 and TRPM8 receptors are activated at low temperature (A1: below 17 degrees C and M8: below 22 degrees C). Recently, we observed that low temperature (below 22 degrees C) induced elevation of intracellular calcium in keratinocytes. Moreover, we demonstrated that topical application of TRPA1 agonists accelerated the recovery of epidermal permeability barrier function after disruption. In this study, we examined the effect of topical application of TRPM8 modulators on epidermal permeability barrier homoeostasis. Immunohistochemical study and RT-PCR confirmed the expression of TRPM8 or TRPM8-like protein in epidermal keratinocytes. Topical application of TRPM8 agonists, menthol and WS 12 accelerated barrier recovery after tape stripping. The effect of WS12 was blocked by a non-selective TRP antagonist, Ruthenium Red, and a TRPM8-specific antagonist, BTCT. Topical application of WS12 also reduced epidermal proliferation associated with barrier disruption under low humidity, and this effect was blocked by BTCT. Our results indicate that TRPM8 or a closely related protein in epidermal keratinocytes plays a role in epidermal permeability barrier homoeostasis and epidermal proliferation after barrier insult.

  2. New treatments for restoring impaired epidermal barrier permeability: skin barrier repair creams.

    PubMed

    Draelos, Zoe Diana

    2012-01-01

    Skin health depends on an intact barrier composed of protein-rich corneocytes surrounded by the lamellar intercellular lipids. This barrier provides waterproof protection for the body, preventing infection, regulating electrolyte balance, maintaining body temperature, and providing a mechanism for sensation. Damage to the skin barrier results in skin disease that can be treated by a variety of externally applied substances, such as ceramides, hyaluronic acid, licorice extracts, dimethicone, petrolatum, and paraffin wax. These substances are found in moisturizers that are sold as cosmetics and in prescriptions as 510(k) devices. This contribution examines the formulation and effect of skin barrier creams.

  3. Gut microbiota, intestinal permeability, obesity-induced inflammation, and liver injury.

    PubMed

    Frazier, Thomas H; DiBaise, John K; McClain, Craig J

    2011-09-01

    Obesity and its metabolic complications are major health problems in the United States and worldwide, and increasing evidence implicates the microbiota in these important health issues. Indeed, it appears that the microbiota function much like a metabolic "organ," influencing nutrient acquisition, energy homeostasis, and, ultimately, the control of body weight. Moreover, alterations in gut microbiota, increased intestinal permeability, and metabolic endotoxemia likely play a role in the development of a chronic low-grade inflammatory state in the host that contributes to the development of obesity and associated chronic metabolic diseases such as nonalcoholic fatty liver disease. Supporting these concepts are the observations that increased gut permeability, low-grade endotoxemia, and fatty liver are observed in animal models of obesity caused by either high-fat or high-fructose feeding. Consistent with these observations, germ-free mice are protected from obesity and many forms of liver injury. Last, many agents that affect gut flora/permeability, such as probiotics/prebiotics, also appear to affect obesity and certain forms of liver injury in animal model systems. Here the authors review the role of the gut microbiota and metabolic endotoxemia-induced inflammation in the development of obesity and liver injury, with special reference to the intensive care unit setting.

  4. Intestinal permeability and P-glycoprotein-mediated efflux transport of ticagrelor in Caco-2 monolayer cells.

    PubMed

    Marsousi, Niloufar; Doffey-Lazeyras, Fabienne; Rudaz, Serge; Desmeules, Jules A; Daali, Youssef

    2016-12-01

    Ticagrelor is the unique reversible oral antiplatelet drug commercialized today. During this study, the intestinal permeability of ticagrelor and its potential P-glycoprotein (P-gp)-mediated active transport were assessed. To this end, bidirectional transport of ticagrelor was performed across Caco-2 (human epithelial colorectal adenocarcinoma) monolayer model in the presence and absence of potent P-gp inhibitor valspodar. Ticagrelor presented an apical-basolateral apparent permeability coefficient (Papp ) of 6.0 × 10(-6) cm/s. On the other hand, mean efflux ratio (ER) of 2.71 was observed for ticagrelor describing a higher efflux permeability compared to the influx component. Valspodar showed a significant inhibitory effect on the efflux of ticagrelor suggesting involvement of P-gp in its oral disposition. Co-incubation of the P-gp inhibitor decreased the efflux Papp of ticagrelor from 1.60 × 10(-5) to 1.13 × 10(-5) cm/s and decreased its ER by 70%. Results suggest a modest active transport of ticagrelor by P-gp across the Caco-2 cell monolayer. The co-administration of ticagrelor with a P-gp inhibitor seems altogether unlikely to have an extended impact on pharmacokinetics of ticagrelor and cause bleeding events in patients. © 2016 Société Française de Pharmacologie et de Thérapeutique.

  5. Magnesium sulphate treatment decreases blood-brain barrier permeability during acute hypertension in pregnant rats.

    PubMed

    Euser, Anna G; Bullinger, Lisa; Cipolla, Marilyn J

    2008-02-01

    Eclampsia is associated with increased blood-brain barrier (BBB) permeability and formation of cerebral oedema. Magnesium sulphate is used to treat eclampsia despite an unclear mechanism of action. This study was to determine the effect of magnesium sulphate on in vivo BBB permeability and formation of cerebral oedema during acute hypertension and on brain aquaporin-4 (AQP4) protein expression. An in vivo model of hypertensive encephalopathy was used in late-pregnant (LP) rats following magnesium sulphate treatment, 270 mg kg(-1) i.p. injection every 4 h for 24 h. Permeability of the BBB was determined by in situ brain perfusion of Evan's Blue (EB) and sodium fluorescein (NaFl), and dye clearance determined by fluorescence spectrophotometry. Cerebral oedema was determined following acute hypertension by measuring brain water content. The effect of magnesium treatment on AQP4 expression was determined by Western blot analysis. Acute hypertension with autoregulatory breakthrough increased BBB permeability to EB in both brain regions studied (P < 0.05). Magnesium attenuated BBB permeability to EB during acute hypertension by 41% in the posterior cerebrum (P < 0.05) but had no effect in the anterior cerebrum (P > 0.05). Treatment with magnesium did not change NaFl permeability, cerebral oedema formation or AQP4 expression. In summary, BBB permeability to Evan's Blue was increased by acute hypertension in LP rats, and this was attenuated by treatment with magnesium sulphate. The greatest effect on BBB permeability to EB was in the posterior cerebrum, an area particularly susceptible to oedema formation during eclampsia.