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  • 1.
    Carlander, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Johansson, Kenth
    Lasarettet Västervik.
    Lindström, Sivert
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of cell biology.
    Keita, Åsa
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery.
    Jiang, Chonghe
    Linköping University, Department of Biomedicine and Surgery, Division of cell biology. Linköping University, Faculty of Health Sciences.
    Nordborg, C
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Comparison of experimental nerve injury caused by ultrasonically activated scalpel and electrosurgery2005In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 92, no 6, p. 772-777Article in journal (Refereed)
    Abstract [en]

    Background: Iatrogenic nerve injury caused by heat from dissection instruments is a significant problem in many areas of surgery. The aim of the present study was to compare the risk of nerve injury for three different dissection instruments: monopolar and bipolar electrosurgery (ES) and an ultrasonically activated (US) instrument. Methods: The biceps femoris muscle was cut in a standard manner just adjacent to the sciatic nerve using monopolar ES, bipolar ES or US shears. A total of 73 functional experiments were conducted in which the nerve was isolated, divided proximally, and stimulated supramaximally in 37 anaesthetized rats. The electromyographic (EMG) potential was recorded distally before and after each experiment. Nerve dysfunction was defined as more than 10 per cent loss of the evoked EMG potential. Fifty-nine nerves were examined histologically after dissection with the different instruments. The extent of heat damage was determined in four nerves that were divided with ES bipolar scissors and five that were divided with US shears. Results: Reduction in the EMG potential was significantly more frequent in the monopolar ES group than in the US group. Morphological examination also showed significantly less nerve damage in the US group. Conclusion: US instruments may be safer than ES for dissection close to nerves. Copyright © 2005 British Journal of Surgery Society Ltd.

  • 2.
    Carlsson, Anders H.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Yakymenko, Olena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Olivier, Isabelle
    External - unknown .
    Håkansson, Fathima
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Postma, Emily
    External - unknown .
    Keita, Asa V.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Soderholm, Johan D.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Faecalibacterium prausnitzii supernatant improves intestinal barrier function in mice DSS colitis2013In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 48, no 10, p. 1136-1144Article in journal (Refereed)
    Abstract [en]

    Objective. The intestinal microbiota plays a substantial role in the pathogenesis of inflammatory bowel disease (IBD). Faecalibacterium prausnitzii (FP) is underrepresented in IBD patients and have been suggested to have anti-inflammatory effects in mice. Increased intestinal permeability is common in IBD but the relationship between FP and intestinal barrier function has not been investigated. Our aim was to study treatment with FP supernatant on intestinal barrier function in a dextran sodium sulfate (DSS) colitis mice model. Material and methods. C57BL/6 mice received 3% DSS in tap water ad libitum during five days to induce colitis. From day 3 the mice received a daily gavage with FP supernatant or broth during seven days. Ileum and colon were mounted in Ussing chambers for permeability studies with Cr-51-EDTA and Escherichia coli K-12. Colon was saved for Western blot analyses of tight junction proteins. Results. DSS-treated mice showed significant weight loss and colon shortening. Gavage with FP supernatant resulted in a quicker recovery after DSS treatment and less extensive colonic shortening. Ileal mucosa of DSS mice showed a significant increase in Cr-51-EDTA-passage compared to controls. Cr-51-EDTA passage was significantly decreased in mice receiving FP supernatant. No significant differences were observed in passage of E. coli K12. Western blots showed a trend to increased claudin-1 and claudin-2 expressions in DSS mice. Conclusions. Supernatant of FP enhances the intestinal barrier function by affecting paracellular permeability, and may thereby attenuate the severity of DSS-induced colitis in mice. These findings suggest a potential role of FP in the treatment of IBD.

  • 3.
    Christerson, Utrika
    et al.
    University of Kalmar.
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Gustafson-Svard, Christina
    University of Kalmar.
    Increased expression of protease-activated receptor-2 in mucosal mast cells in Crohns ileitis2009In: JOURNAL OF CROHNS and COLITIS, ISSN 1873-9946, Vol. 3, no 2, p. 100-108Article in journal (Refereed)
    Abstract [en]

    Background and aims: Activation of protease-activated receptor-2 (PAR-2) may stimulate various events of importance in inflammatory processes, including release of inflammatory mast cell mediators. PAR-2 is frequently up-regulated during inflammatory conditions, but it is not known if the expression is altered in Crohns disease. The aim of the present study was to investigate the ileal mucosal PAR-2 expression in Crohns ileitis, with particular emphasis on the expression in ileal mucosal mast cells. Methods: Surgical specimens from the distal ileum were collected from patients with Crohns ileitis and patients with colonic cancer as controls. The overall expression of PAR-2 was investigated by Western blot, and the presence of PAR-2 expressing mucosal mast cells by immunohistochemistry and cell counting. The effect of tumor necrosis factor-alpha (TNF-alpha) on the PAR-2 expression in a human mast cell tine (HMC-1) was investigated by RT-PCR and immunocytochemistry. Results: In Crohns specimens, the fraction of PAR-2-expressing mucosal. mast cells was increased about 2.5 times (P andlt; 0.001; n = 14) compared with specimens from control patients (n = 6). No difference was found between inflamed (n = 6) and uninflamed Crohns specimens (P andgt; 0.05; n = 8). Exposure to TNF-alpha for 48 h up-regulated PAR-2 mRNA and protein expression in the HMC-1 cell line. Conclusion: PAR-2 is up-regulated on ileal mucosal mast cells in Crohns ileitis, possibly due to the action of inflammatory cytokines, such as TNF-alpha. This may contribute to perpetuating the inflammatory process in the intestinal mucosa in Crohns ileitis.

  • 4.
    Christerson, Utrika
    et al.
    Kalmar University .
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Gustafson-Svard, Christina
    Kalmar University .
    Potential role of protease-activated receptor-2-stimulated activation of cytosolic phospholipase A(2) in intestinal myofibroblast proliferation: Implications for stricture formation in Crohns disease2009In: JOURNAL OF CROHNS and COLITIS, ISSN 1873-9946, Vol. 3, no 1, p. 15-24Article in journal (Refereed)
    Abstract [en]

    Background and aims: Myofibroblast hyperplasia contributes to muscularis mucosae thickening and stricture formation in Crohns disease (CD). Protease-activated receptor-2 (PAR-2) and cytosolic phospholipase A(2) (cPLA(2)) are known regulators of cell growth, but their significance in intestinal myofibroblast proliferation remain to be elucidated. The principle aims of the present study were to investigate if PAR-2 is expressed in the expanded muscularis mucosa in ileal CD specimens, if inflammatory cytokines may stimulate PAR-2 expression in intestinal myofibroblasts, and if PAR-2 and cPLA(2). may regulate intestinal myofibroblast growth.

    Methods: Immunohistochemistry was used for detection of PAR-2 in ileal CD specimens. Studies on PAR-2 expression, PLA(2) activation and cell growth were performed in a human intestinal myofibroblast cell tine, CCD-18Co. PAR-2 expression was investigated by RT-PCR and immunocytochemistry. PLA(2) activity was analyzed by quantification of released C-14-arachidonic acid (C-14-AA). Cell growth was examined by H-3-thymidine incorporation and cell counting.

    Results: The thickened muscularis mucosae of the CD specimens showed strong PAR-2 expression. In cultured myofibroblasts, tumor necrosis factor-alpha (TNF-alpha) up-regulated PAR-2 mRNA and protein, and potentiated PAR-2-stimutated C-14-AA release by two known PAR-2 activators, trypsin and SLIGRL-NH2. The release of C-14-AA was dependent on cPLA(2). Trypsin stimulated the proliferation of serum-starved cells, and inhibition of cPLA(2) reduced normal cell growth and abolished the growth-promoting effect of trypsin.

    Conclusions: The results suggest that PAR-2-mediated cPLA(2) activation might be of importance in intestinal myofibroblast proliferation. The results also point to the possibility that PAR-2 upregulation by inflammatory cytokines, like TNF-alpha, may modulate this effect.

  • 5.
    Ermund, Anna
    et al.
    University of Gothenburg, Sweden .
    Gustafsson, Jenny K.
    University of Gothenburg, Sweden .
    Hansson, Gunnar C.
    University of Gothenburg, Sweden .
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Mucus Properties and Goblet Cell Quantification in Mouse, Rat and Human Ileal Peyers Patches2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. 83688-Article in journal (Refereed)
    Abstract [en]

    Peyers patches (PPs) are collections of lymphoid follicles in the small intestine, responsible for scanning the intestinal content for foreign antigens such as soluble molecules, particulate matter as well as intact bacteria and viruses. The immune cells of the patch are separated from the intestinal lumen by a single layer of epithelial cells, the follicle-associated epithelium (FAE). This epithelium covers the dome of the follicle and contains enterocyte-like cells and M cells, which are particularly specialized in taking up antigens from the gut. However, the presence and number of goblet cells as well as the presence of mucus on top of the FAE is controversial. When mouse ileal PPs were mounted in a horizontal Ussing-type chamber, we could observe a continuous mucus layer at mounting and new, easily removable mucus was released from the villi on the patch upon stimulation. Confocal imaging using fluorescent beads revealed a penetrable mucus layer covering the domes. Furthermore, immunostaining of FAE from mice, rats and humans with a specific antibody against the main component of intestinal mucus, the MUC2 mucin, clearly identify mucin-containing goblet cells. Transmission electron micrographs further support the identification of mucus releasing goblet cells on the domes of PPs in these species.

  • 6.
    Ganda Mall, John-Peter
    et al.
    School of Medical Sciences, Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    Casado-Bedmar, Maite
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Winberg, Martin E.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Brummer, Robert J.
    School of Medical Sciences, Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    Schoultz, Ida
    School of Medical Sciences, Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. School of Medical Sciences, Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    A ß-Glucan-Based Dietary Fiber Reduces Mast Cell-Induced Hyperpermeability in Ileum From Patients With Crohns Disease and Control Subjects2018In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 24, no 1, p. 166-178Article in journal (Refereed)
    Abstract [en]

    Administration of ß-glucan has shown immune-enhancing effects. Our aim was to investigate whether ß-glucan could attenuate mast cell (MC)-induced hyperpermeability in follicle-associated epithelium (FAE) and villus epithelium (VE) of patients with Crohns disease (CD) and in noninflammatory bowel disease (IBD)-controls. Further, we studied mechanisms of ß-glucan uptake and effects on MCs in vitro.

  • 7. Gullberg, Elisabet
    et al.
    Keita, Åsa
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery.
    Salim, Sa´ad
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery.
    Andersson, Margaretha
    Caldwell, Karin D
    Söderholm, Johan D
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Artursson, Per
    Identification of cell adhesion molecules in the human follicle-associated epithelium that improve nanoparticle uptake into the Peyer's patches2006In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 319, no 2, p. 632-639Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to identify cell adhesion molecules that could serve as targets of the human follicle-associated epithelium (FAE) overlying Peyer's patches and to assess nanoparticle uptake levels across this epithelium. We first studied the expression of the mouse M-cell marker β1- integrin and used a model of human FAE derived from intestinal epithelial Caco-2 cells and Raji B-cells to identify additional potential targets by cDNA array. The protein expression of potential targets in the model FAE and in human ileal FAE tissues was quantified by immunofluorescence. Integrin targeting was studied by investigating the transport of Arg-Gly-Asp (RGD)-coated (integrin-binding), Arg-Gly-Glu (RGE)-coated (nonintegrin-binding), and uncoated nanoparticles across ileal specimens mounted in Ussing chambers. Both β1- integrin and the cell adhesion molecule CD9 were more abundantly expressed in the model and human FAE compared with the Caco-2 control cells or villus epithelium (VE). Uncoated nanoparticles were not taken up across either FAE or VE. General integrin targeting with RGD improved the nanoparticle transport dramatically across the FAE and to a lower extent across the VE. Compared with RGE, RGD improved transport 4-fold across the FAE. There was no difference in the transport of RGD- and RGE-coated nanoparticles across the VE. In conclusion, β1-integrin and CD9 were identified as targets in human FAE. The difference in RGD- and RGE-mediated transport across the FAE, but not the VE, suggests that a specific integrin interaction was the dominating mechanism for improved nanoparticle uptake across the FAE., whereas charge interaction contributed substantially to the improved VE uptake. Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics.

  • 8.
    Keita, Asa V.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Stertman, Linda
    Uppsala University.
    Sun, Yi-Qian
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    Larhed, Agneta
    Uppsala University.
    Sjoholm, Ingvar
    Uppsala University.
    Söderholm, Johan D
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Effects of chronic stress on the immune response to oral human serum albumin-conjugated starch microparticles in rats2007In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 183, no 01-Feb, p. 33-42Article in journal (Refereed)
    Abstract [en]

    Uptake of antigens and bacteria over the follicle-associated epithelium (FAE) is increased after chronic psychological stress. We investigated whether stress affects the immune response to particle-conjugated antigens taken up via the FAE. Rats were submitted to two 10-day periods of water avoidance stress and orally immunized during these periods. Stressed immunized rats displayed altered cell populations and a Th1-skewed immune response within the lymphoid follicles, together with enhanced delayed-type hypersensitivity. We conclude that chronic stress affects the cell-mediated immune response after oral immunization, which may have implications for the understanding of allergic and autoimmune diseases and development of oral vaccines. (c) 2006 Elsevier B.V. All rights reserved.

  • 9.
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Barrier function of the Follicle-Associated Epithelium in Stress and Crohn's disease2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The earliest observable signs of Crohn’s disease are microscopic erosions in the follicle-associated epithelium (FAE) covering the Peyer’s patches. The FAE, which contains M cells, is specialised in sampling of luminal content and delivery to underlying immune cells. This sampling is crucial for induction of protective immune responses, but it also provides a route of entry for microorganisms into the mucosa. Crohn’s disease is associated with an increased immune response to bacteria, and the disease course can be altered by stress.

    The overall aim of this thesis was to study the effects of stress on the FAE and elucidate the role of FAE in the development of intestinal inflammation, specifically Crohn’s disease.

    Initially, rats were submitted to acute and chronic water avoidance stress to study the effects of psychological stress on the FAE. Stressed rats showed enhanced antigen and bacterial passage, and the passage was higher in FAE than in regular villus epithelium (VE). Further, stress gave rise to ultrastructural changes. Subsequent experiments revealed the stress-induced increase in permeability to be regulated by corticotropin-releasing hormone and mast cells. Furthermore, vasoactive intestinal peptide (VIP) mimicked the stress effects on permeability, and the VIP effects were inhibited by a mast cell stabiliser.

    Human studies of ileal mucosa from patients with non-inflammatory disease and healthy controls showed a higher antigen and bacterial passage in FAE than in VE. In patients with Crohn’s disease, the bacterial passage across the FAE was significantly increased compared to non-inflammatory and inflammatory controls (ulcerative colitis). Furthermore, there was an enhanced uptake of bacteria into dendritic cells, and augmented TNF-α release in Crohn’s disease mucosa.

    Taken together this thesis shows that stress can modulate the uptake of luminal antigens and bacteria via the FAE, through mechanisms involving CRH and mast cells. It further shows that human ileal FAE is functionally distinct from VE, and that Crohn’s disease patients exhibit enhanced FAE permeability compared to inflammatory and non-inflammatory controls.

    This thesis presents novel insights into regulation of the FAE barrier, as well as into the pathophysiology of Crohn’s disease by demonstrating a previously unrecognised defect of the FAE barrier function in ileal Crohn’s disease.

    List of papers
    1. Increased antigen and bacterial uptake in follicle-associated epithelium induced by chronic psychological stress in rats
    Open this publication in new window or tab >>Increased antigen and bacterial uptake in follicle-associated epithelium induced by chronic psychological stress in rats
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    2004 (English)In: Gut, ISSN 0017-5749, Vol. 53, no 4, p. 494-500Article in journal (Refereed) Published
    Abstract [en]

    Background: Chronic stress affects the course of inflammatory bowel disease and experimental colitis, and may also initiate intestinal inflammation in rats.

    Aim: To investigate the effects of stress on the M cell containing follicle associated epithelium, specialised in antigen uptake.

    Subjects and methods: Wistar rats were submitted to acute water avoidance stress for one hour or chronic water avoidance stress for 1 hour/day for 10 consecutive days. Permeability to 51Cr-EDTA, horseradish peroxidase, and chemically killed Escherichia coli K-12 was studied in both villus and follicle associated epithelium in Ussing chambers. Segments were further examined by light, electron, and confocal microscopy.

    Results: Acute stress increased horseradish peroxidase flux in villus as well as in follicle associated epithelium. Chronic stress further increased permeability to horseradish peroxidase in villus and follicle associated epithelium, in the latter by almost fourfold. Moreover, chronic stress induced over 30 times increased E coli passage in follicle associated epithelium whereas there was no significant increase in villus epithelium. Bacterial uptake was confirmed by confocal microscopy showing fluorescent bacteria penetrating and passing through the epithelial surface.

    Conclusions: These results show that the barrier function of follicle associated epithelium can be modulated, and that chronic stress enhances the uptake of luminal antigens and bacteria via the follicle associated epithelium. This can increase antigen exposure in Peyer’s patches thereby having implications in the initiation of proinflammatory immune responses within the intestinal mucosa.

    Keywords
    follicle associated epithelium, M cell, Peyer’s patch, inflammatory bowel disease, stress
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14562 (URN)10.1136/gut.2003.028506 (DOI)
    Available from: 2007-07-03 Created: 2007-07-03 Last updated: 2009-08-21
    2. Characterization of antigen and bacterial transport in the follicle-associated epithelium of human ileum
    Open this publication in new window or tab >>Characterization of antigen and bacterial transport in the follicle-associated epithelium of human ileum
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    2006 (English)In: Laboratory investigation, ISSN 0023-6837, Vol. 86, no 5, p. 504-516Article in journal (Refereed) Published
    Abstract [en]

    The follicle-associated epithelium (FAE), covering Peyer's patches, provides a route of entry for antigens and microorganisms. Animal studies showed enhanced antigen and bacterial uptake in FAE, but no study on barrier function of human FAE has been reported. Our aim was to characterize the normal barrier properties of human FAE. Specimens of normal ileum were taken from 30 patients with noninflammatory colonic disease. Villus epithelium (VE) and FAE were identified and mounted in Ussing chambers. Permeability to 51Cr-EDTA, transmucosal flux of the protein antigen, horseradish peroxidase (HRP), and transport of fluorescent Escherichia coli (chemically killed K-12 and live HB101) were measured. Uptake mechanisms were studied by confocal- and transmission electron microscopy, and by using pharmacological inhibitors in an in vitro coculture model of FAE and in human ileal FAE. HRP flux was substantially higher in FAE than in VE, and was reduced by an amiloride analog. Electron microscopy showed HRP-containing endosomes. Transport of E. coli K-12 and HB101 was also augmented in FAE and was confirmed by confocal microscopy. In vitro coculture experiments and electron microscopy revealed actin-dependent, mainly transcellular, uptake of E. coli K-12 into FAE. 51Cr-EDTA permeability was equal in FAE and VE. Augmented HRP flux and bacterial uptake but similar paracellular permeability, suggest functional variations of transcellular transport in the FAE. We show for the first time that FAE of human ileum is functionally distinct from regular VE, rendering the FAE more prone to bacterial–epithelial cell interactions and delivery of antigens to the mucosal immune system.

    Keywords
    E. coli, horseradish peroxidase, M cell, permeability, Peyer's patches
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14563 (URN)10.1038/labinvest.3700397 (DOI)
    Available from: 2007-07-03 Created: 2007-07-03
    3. Increased uptake of non-pathogenic E. coli via the follicle-associated epithelium in ileal Crohn’s disease
    Open this publication in new window or tab >>Increased uptake of non-pathogenic E. coli via the follicle-associated epithelium in ileal Crohn’s disease
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    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:liu:diva-14564 (URN)
    Available from: 2007-07-03 Created: 2007-07-03 Last updated: 2010-01-13
    4. Stress-induced barrier disruption of the follicle-associated epithelium involves corticotropin-releasing hormone, vasoactive intestinal peptide and mast cells
    Open this publication in new window or tab >>Stress-induced barrier disruption of the follicle-associated epithelium involves corticotropin-releasing hormone, vasoactive intestinal peptide and mast cells
    2010 (English)In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 22, no 7, p. 770-e222Article in journal (Refereed) Published
    Abstract [en]

    Background The follicle-associated epithelium (FAE) is specialized in uptake and sampling of luminal antigens and bacteria. We previously showed that stress increased FAE permeability in rats. An increased uptake may alter antigen exposure in Peyers patches leading to intestinal disease. The aim of this study was to elucidate mechanisms involved in the acute stress-induced increase in FAE permeability. Methods Rats were pretreated i.p. with corticotropin-releasing hormone receptor (CRH-R) antagonist, neurokinin receptor 1 (NK-1R) antagonist, atropine, the mast cell stabilizer doxantrazole (DOX), or NaCl, and submitted to 1-h acute water avoidance stress. FAE tissues were mounted in Ussing chambers for measurements of permeability to 51Cr-EDTA, horseradish peroxidase (HRP) and chemically killed Escherichia coli K-12. Further, FAE segments were exposed in vitro in chambers to CRH, substance P (SP), carbachol, and DOX. Neurotransmitter- and receptor distribution was studied by immunohistochemistry. Key Results Stress-induced increases in uptake across FAE of HRP and E. coli were reduced by DOX, CRH-R antagonist and atropine, whereas the NK-1R antagonist decreased 51Cr-EDTA permeability. Exposure to CRH and carbachol increased HRP and E. coli passage, whereas SP increased bacterial and 51Cr-EDTA permeability. DOX counteracted all of these effects. Immunohistochemistry revealed CRH, acetylcholine, SP, and their receptors on mast cells within the Peyers patches, subepithelial dome, and adjacent villi. Conclusions & Inferences Corticotropin-releasing hormone and acetylcholine signaling affect mainly transcellular permeability while SP seems more selective toward the paracellular pathways. Our findings may be of importance for the understanding of the pathogenesis of stress-related intestinal disorders.

    Keywords
    inflammatory bowel disease; neurotrans-mitter; permeability; Peyers patches; Ussing chamber
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-14565 (URN)10.1111/j.1365-2982.2010.01471.x (DOI)000278525200009 ()
    Available from: 2007-07-03 Created: 2007-07-03 Last updated: 2017-12-13
  • 10.
    Keita, Åsa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Carlsson, A H.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Cigehn, M
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ericson, Ann-Charlott
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Mckay, D M:
    University of Calgary, Canada .
    Söderholm, Johan D.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Vasoactive intestinal polypeptide regulates barrier function via mast cells in human intestinal follicle-associated epithelium and during stress in rats2013In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 25, no 6, p. e406-e417Article in journal (Refereed)
    Abstract [en]

    Background Vasoactive intestinal polypeptide (VIP) has been implicated as a regulator of intestinal barrier function and inflammation. Our aim was to elucidate the role of VIP in follicle-associated epithelium (FAE) and villus epithelium (VE) permeability following stress in rats and on human intestinal barrier function. Methods Rats were injected intraperitoneally (i.p.) with VIP receptor-antagonists (anti-VPACs), a mast cell stabilizer, doxantrazole (DOX), or NaCl, and submitted to acute water avoidance stress. Ileal segments were mounted in Ussing chambers to assess 51chromium-edta (51Cr-edta) and Escherichia (E.) coli (strain K-12) permeability. Rat ileal and human ileal and colonic segments were exposed to VIP +/- anti-VPACs or DOX. An in vitro co-culture model of human FAE was used to study epithelial-VIP effects. VIP/VPACs distribution was assessed by microscopy. Key Results Stress increased 51Cr-edta and E.coli permeability in VE and FAE. The increases were abolished by i.p. injection of DOX or anti-VPACs. Ileal VIP-exposure ex vivo increased bacterial passage and this was reduced by DOX. In human FAE ex vivo, VIP treatment doubled bacterial uptake, which was normalized by DOX or anti-VPACs. No barrier effects were observed in human colonic tissue. VPACs were found in rat and human ileal follicles, with partial mast cell co-localization. The co-culture model confirmed VIPmast cellepithelial interactions in the regulation of barrier function. Conclusions andamp; Inferences Stress affects the FAE barrier by mechanisms involving VIP and VPACs on mucosal mast cells. We suggest a regulatory role for VIP in the control of ileal permeability that may be relevant to bacterialepithelial interactions in stress-related intestinal disorders.

  • 11.
    Keita, Åsa
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Salim, Sa´ad
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    Jiang, T.
    Department of Clinical and Experimental Medicine Linköping University.
    Yang, P-C
    Intestinal Disease Research Program McMaster University, Hamilton, Canada.
    Franzén, Lennart
    Aleris Medilab Täby.
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology.
    Magnusson, Karl-Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    Söderholm, Johan D
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Increased uptake of non-pathogenic E. coli via the follicle-associated epithelium in longstanding ileal Crohn's disease2008In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 215, no 2, p. 135-144Article in journal (Refereed)
    Abstract [en]

    In Crohn's disease (CD), inflammation is driven by luminal commensal micro-organisms, however, mechanisms of early phases of inflammation need further clarification. The earliest observable lesions of recurrent CD are microscopic erosions at the specialized follicle-associated epithelium (FAE), which lines the Peyer's patches. Therefore, our aim was to investigate the mucosal barrier to non-pathogenic bacteria in FAE of CD. The FAE of macroscopically normal ileum from patients with longstanding CD, ulcerative colitis, and controls was studied in Ussing chambers regarding electrophysiology and permeability to 51Cr-EDTA, horseradish peroxidase, and non-pathogenic E. coli strains. Transepithelial passage routes and uptake into dendritic cells were studied by confocal and electron microscopy. FAE of CD showed increased numbers of adherent bacteria, after E. coli exposure in Ussing chambers, as well as spontaneously in non-exposed archival surgical tissues. Further, we found increased uptake of fluorescent E. coli K-12 and HB101 across FAE of CD, but not in ulcerative colitis. Microscopy demonstrated intercellular and transcellular uptake of E. coli in CD, but only transcellular in controls. FAE exposed to E. coli demonstrated changes in conductance and 51Cr-EDTA permeability, suggesting that bacteria affected the paracellular pathway in CD mucosa. Following bacterial uptake, CD mucosa also demonstrated an increased percentage of E. coli co-localizing with dendritic cells, and augmented tissue release of TNF-α. Our data present novel insights into the pathophysiology of CD by demonstrating a previously unrecognized defect of FAE barrier to bacteria in ileal CD, leading to increased load of commensal bacteria to the inductive sites of mucosal immunity. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • 12.
    Keita, Åsa V
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Gullberg, Elisabet
    Department of Pharmacy, Uppsala University, BMC, Uppsala, Sweden.
    Ericson, Ann-Charlott
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Salim, Sa’ad Y
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Wallon, Conny
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Kald, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Artursson, Per
    Department of Pharmacy, Uppsala University, BMC, Uppsala, Sweden.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Characterization of antigen and bacterial transport in the follicle-associated epithelium of human ileum2006In: Laboratory investigation, ISSN 0023-6837, Vol. 86, no 5, p. 504-516Article in journal (Refereed)
    Abstract [en]

    The follicle-associated epithelium (FAE), covering Peyer's patches, provides a route of entry for antigens and microorganisms. Animal studies showed enhanced antigen and bacterial uptake in FAE, but no study on barrier function of human FAE has been reported. Our aim was to characterize the normal barrier properties of human FAE. Specimens of normal ileum were taken from 30 patients with noninflammatory colonic disease. Villus epithelium (VE) and FAE were identified and mounted in Ussing chambers. Permeability to 51Cr-EDTA, transmucosal flux of the protein antigen, horseradish peroxidase (HRP), and transport of fluorescent Escherichia coli (chemically killed K-12 and live HB101) were measured. Uptake mechanisms were studied by confocal- and transmission electron microscopy, and by using pharmacological inhibitors in an in vitro coculture model of FAE and in human ileal FAE. HRP flux was substantially higher in FAE than in VE, and was reduced by an amiloride analog. Electron microscopy showed HRP-containing endosomes. Transport of E. coli K-12 and HB101 was also augmented in FAE and was confirmed by confocal microscopy. In vitro coculture experiments and electron microscopy revealed actin-dependent, mainly transcellular, uptake of E. coli K-12 into FAE. 51Cr-EDTA permeability was equal in FAE and VE. Augmented HRP flux and bacterial uptake but similar paracellular permeability, suggest functional variations of transcellular transport in the FAE. We show for the first time that FAE of human ileum is functionally distinct from regular VE, rendering the FAE more prone to bacterial–epithelial cell interactions and delivery of antigens to the mucosal immune system.

  • 13.
    Keita, Åsa V.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Söderholm, Johan D.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery UHL.
    Barrier dysfunction and bacterial uptake in the follicle-associated epithelium of ileal Crohns disease2012In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1258, no 1, p. 125-134Article in journal (Refereed)
    Abstract [en]

    The ability to control uptake across the mucosa and protect from harmful substances in the gut lumen is defined as intestinal barrier function. The etiology of Crohns disease is unknown, but genetic, environmental, and immunological factors all contribute. The frontline between these factors lies in the intestinal barrier. The most important inflammation-driving environmental factor in Crohns disease is the microbiota, where Esherichia coli strains have been assigned a key role. The first observable signs of Crohns disease are small aphtoid ulcers over Peyers patches and lymphoid follicles. The overlaying follicle-associated epithelium (FAE) is specialized for luminal sampling and is an entry site for antigens and bacteria. We have demonstrated increased E. coli uptake across the FAE in Crohns disease, which may initiate inflammation. This short review will discuss barrier dysfunction and bacteria in the context of ileal Crohns disease, and how the FAE might be the site of initial inflammation.

  • 14.
    Keita, Åsa V.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    The intestinal barrier and its regulation by neuroimmune factors2010In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 22, no 7, p. 718-733Article, review/survey (Refereed)
    Abstract [en]

    Background The ability to control uptake across the mucosa and protect from damage of harmful substances from the lumen is defined as intestinal barrier function. A disturbed barrier dysfunction has been described in many human diseases and animal models, for example, inflammatory bowel disease, irritable bowel syndrome, and intestinal hypersensitivity. In most diseases and models, alterations are seen both of the paracellular pathway, via the tight junctions, and of the transcellular routes, via different types of endocytosis. Recent studies of pathogenic mechanisms have demonstrated the important role of neuroimmune interaction with the epithelial cells in the regulation of barrier function. Neural impulses from extrinsic vagal and/or sympathetic efferent fibers or intrinsic enteric nerves influence mucosal barrier function via direct effects on epithelial cells or via interaction with immune cells. For example, by nerve-mediated activation by corticotropin-releasing hormone or cholinergic pathways, mucosal mast cells release a range of mediators with effects on transcellular, and/or paracellular permeability (for example, tryptase, TNF-alpha, nerve growth factor, and interleukins). Purpose In this review, we discuss current physiological and pathophysiological aspects of the intestinal barrier and, in particular, its regulation by neuroimmune factors.

  • 15.
    Keita, Åsa V
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthesiology and Surgical Centre, Department of Surgery UHL.
    Ericson, Ann-Charlott
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Stress-induced barrier disruption of the follicle-associated epithelium involves corticotropin-releasing hormone, vasoactive intestinal peptide and mast cells2010In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 22, no 7, p. 770-e222Article in journal (Refereed)
    Abstract [en]

    Background The follicle-associated epithelium (FAE) is specialized in uptake and sampling of luminal antigens and bacteria. We previously showed that stress increased FAE permeability in rats. An increased uptake may alter antigen exposure in Peyers patches leading to intestinal disease. The aim of this study was to elucidate mechanisms involved in the acute stress-induced increase in FAE permeability. Methods Rats were pretreated i.p. with corticotropin-releasing hormone receptor (CRH-R) antagonist, neurokinin receptor 1 (NK-1R) antagonist, atropine, the mast cell stabilizer doxantrazole (DOX), or NaCl, and submitted to 1-h acute water avoidance stress. FAE tissues were mounted in Ussing chambers for measurements of permeability to 51Cr-EDTA, horseradish peroxidase (HRP) and chemically killed Escherichia coli K-12. Further, FAE segments were exposed in vitro in chambers to CRH, substance P (SP), carbachol, and DOX. Neurotransmitter- and receptor distribution was studied by immunohistochemistry. Key Results Stress-induced increases in uptake across FAE of HRP and E. coli were reduced by DOX, CRH-R antagonist and atropine, whereas the NK-1R antagonist decreased 51Cr-EDTA permeability. Exposure to CRH and carbachol increased HRP and E. coli passage, whereas SP increased bacterial and 51Cr-EDTA permeability. DOX counteracted all of these effects. Immunohistochemistry revealed CRH, acetylcholine, SP, and their receptors on mast cells within the Peyers patches, subepithelial dome, and adjacent villi. Conclusions & Inferences Corticotropin-releasing hormone and acetylcholine signaling affect mainly transcellular permeability while SP seems more selective toward the paracellular pathways. Our findings may be of importance for the understanding of the pathogenesis of stress-related intestinal disorders.

  • 16.
    Parsons, Bryony N.
    et al.
    University of Liverpool, England .
    Wigley, Paul
    University of Liverpool, England .
    Simpson, Hannah L.
    University of Liverpool, England .
    Williams, Jonathan M.
    University of Liverpool, England .
    Humphrey, Suzie
    University of Liverpool, England .
    Salisbury, Anne-Marie
    University of Liverpool, England .
    Watson, Alastair J. M.
    University of Liverpool, England University of E Anglia, England .
    Fry, Stephen C.
    University of Edinburgh, Scotland .
    O'Brien, David
    Provexis Plc, Scotland .
    Roberts, Carol L.
    University of Liverpool, England Provexis Plc, Scotland .
    O'Kennedy, Niamh
    Provexis Plc, Scotland .
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Rhodes, Jonathan M.
    University of Liverpool, England .
    Campbell, Barry J.
    University of Liverpool, England .
    Dietary Supplementation with Soluble Plantain Non-Starch Polysaccharides Inhibits Intestinal Invasion of Salmonella Typhimurium in the Chicken2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. 87658-Article in journal (Refereed)
    Abstract [en]

    Soluble fibres (non-starch polysaccharides, NSP) from edible plants but particularly plantain banana (Musa spp.), have been shown in vitro and ex vivo to prevent various enteric pathogens from adhering to, or translocating across, the human intestinal epithelium, a property that we have termed contrabiotic. Here we report that dietary plantain fibre prevents invasion of the chicken intestinal mucosa by Salmonella. In vivo experiments were performed with chicks fed from hatch on a pellet diet containing soluble plantain NSP (0 to 200 mg/d) and orally infected with S. Typhimurium 4/74 at 8 d of age. Birds were sacrificed 3, 6 and 10 d post-infection. Bacteria were enumerated from liver, spleen and caecal contents. In vitro studies were performed using chicken caecal crypts and porcine intestinal epithelial cells infected with Salmonella enterica serovars following pre-treatment separately with soluble plantain NSP and acidic or neutral polysaccharide fractions of plantain NSP, each compared with saline vehicle. Bacterial adherence and invasion were assessed by gentamicin protection assay. In vivo dietary supplementation with plantain NSP 50 mg/d reduced invasion by S. Typhimurium, as reflected by viable bacterial counts from splenic tissue, by 98.9% (95% CI, 98.1-99.7; Pless than0.0001). In vitro studies confirmed that plantain NSP (5-10 mg/ml) inhibited adhesion of S. Typhimurium 4/74 to a porcine epithelial cell-line (73% mean inhibition (95% CI, 64-81); Pless than0.001) and to primary chick caecal crypts (82% mean inhibition (95% CI, 75-90); Pless than0.001). Adherence inhibition was shown to be mediated via an effect on the epithelial cells and Ussing chamber experiments with ex-vivo human ileal mucosa showed that this effect was associated with increased short circuit current but no change in electrical resistance. The inhibitory activity of plantain NSP lay mainly within the acidic/pectic (homogalacturonan-rich) component. Supplementation of chick feed with plantain NSP was well tolerated and shows promise as a simple approach for reducing invasive salmonellosis.

  • 17.
    Roberts, Carol L
    et al.
    University of Liverpool.
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Duncan, Sylvia H
    University of Aberdeen.
    O'Kennedy, Niamh
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Dabrosin Söderholm, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Rhodes, Jonathan M
    University of Liverpool.
    Campbell, Barry J
    University of Liverpool.
    Translocation of Crohns disease Escherichia coli across M-cells: contrasting effects of soluble plant fibres and emulsifiers2010In: GUT, ISSN 0017-5749, Vol. 59, no 10, p. 1331-1339Article in journal (Refereed)
    Abstract [en]

    Background Crohns disease is common in developed nations where the typical diet is low in fibre and high in processed food. Primary lesions overlie Peyers patches and colonic lymphoid follicles where bacterial invasion through M-cells occurs. We have assessed the effect of soluble non-starch polysaccharide (NSP) and food emulsifiers on translocation of Escherichia coli across M-cells. Methods To assess effects of soluble plant fibres and food emulsifiers on translocation of mucosa-associated E coli isolates from Crohns disease patients and from non-Crohns controls, we used M-cell monolayers, generated by co-culture of Caco2-cl1 and Raji B cells, and human Peyers patches mounted in Ussing chambers. Results E coli translocation increased across M-cells compared to parent Caco2-cl1 monocultures; 15.8-fold (IQR 6.2-32.0) for Crohns disease E coli (N=8) and 6.7-fold (IQR 3.7-21.0) for control isolates (N=5). Electronmicroscopy confirmed E coli within M-cells. Plantain and broccoli NSP markedly reduced E coli translocation across M-cells at 5 mg/ml (range 45.3-82.6% inhibition, pandlt;0.01); apple and leek NSP had no significant effect. Polysorbate-80, 0.01% vol/vol, increased E coli translocation through Caco2-cl1 monolayers 59-fold (pandlt;0.05) and, at higher concentrations, increased translocation across M-cells. Similarly, E coli translocation across human Peyers patches was reduced 45+/-7% by soluble plantain NSP (5 mg/ml) and increased 2-fold by polysorbate-80 (0.1% vol/vol). Conclusions Translocation of E coli across M-cells is reduced by soluble plant fibres, particularly plantain and broccoli, but increased by the emulsifier Polysorbate-80. These effects occur at relevant concentrations and may contribute to the impact of dietary factors on Crohns disease pathogenesis.

  • 18. Roberts, Carol L.
    et al.
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Parsons, Bryony N.
    University of Liverpool, England .
    Prorok-Hamon, Maelle
    University of Liverpool, England .
    Knight, Paul
    University of Liverpool, England .
    Winstanley, Craig
    University of Liverpool, England .
    O´Kennedy, Niamh
    Provexis Plc, Aberdeen, UK.
    Söderholm, Johan D.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Rhodes, Jonathan M.
    University of Liverpool, England .
    Campbell, Barry J.
    University of Liverpool, England .
    Soluble plantain fibre blocks adhesion and M-cell translocation of intestinal pathogens2013In: Journal of Nutritional Biochemistry, ISSN 0955-2863, E-ISSN 1873-4847, Vol. 24, no 1, p. 97-103Article in journal (Refereed)
    Abstract [en]

    Dietary fibres may have prebiotic effects mediated by promotion of beneficial bacteria. This study explores the possibility that soluble plant fibre may also improve health by inhibiting epithelial adhesion and translocation by pathogenic bacteria. We have focussed on soluble non-starch polysaccharide (NSP) from plantain bananas (Musa spp.) which previous studies showed to be particularly effective at blocking Escherichia coli epithelial adherence. In vitro and ex vivo studies assessed the ability of plantain NSP to inhibit epithelial cell adhesion and invasion of various bacterial pathogens, and to inhibit their translocation through microfold (M)-cells and human Peyers patches mounted in Ussing chambers. Plantain NSP showed dose-related inhibition of epithelial adhesion and M-cell translocation by a range of pathogens. At 5 mg/ml, a concentration readily achievable in the gut lumen, plantain NSP inhibited adhesion to Caco2 cells by Salmonella Typhimurium (85.0 +/- 8.2%, Pandlt;.01), Shigella sonnei (46.6 +/- 29.3%. Pandlt;.01), enterotoxigenic E.coli (56.1 +/- 23.7%, Pandlt;.05) and Clostridium difficile (67.6 +/- 12.3%, Pandlt;.001), but did not inhibit adhesion by enteropathogenic E.coli. Plantain NSP also inhibited invasion of Caco2 cells by S. Typhimurium (80.2 +/- 9.7%) and Sh. sonnei (46.7 +/- 13.4%); Pandlt;.01. Plantain NSP, 5 mg/ml, also inhibited translocation of S. Typhimurium and Sh. sonnei across M-cells by 73.3 +/- 5.2% and 46.4 +/- 7.7% respectively (Pandlt;.05). Similarly, S. Typhimurium translocation across Peyers patches was reduced 65.9 +/- 8.1% by plantain NSP (Pandlt;.01). Soluble plantain fibre can block epithelial adhesion and M-cell translocation of intestinal pathogens. This represents an important novel mechanism by which soluble dietary fibres can promote intestinal health and prevent infective diarrhoea. Crown Copyright

  • 19.
    Salim, Sa'ad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Silva, Manuel A
    McMaster University.
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Andersson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Perdue, Mary H
    McMaster University.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    CD83(+)CCR7(-) Dendritic Cells Accumulate in the Subepithelial Dome and Internalize Translocated Escherichia coli HB101 in the Peyers Patches of Heal Crohns Disease2009In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 174, no 1, p. 82-90Article in journal (Refereed)
    Abstract [en]

    Recurrent Crohns disease originates with small erosions in the follicle-associated epithelium overlying the Peyers patches. Animal studies have illustrated mucosal immune regulation by dendritic cells located in the subepithelial dome. The aim of this study was to characterize the dendritic cells at this specific site in patients with Crohns disease. Heal tissues were obtained after surgery performed on Crohns patients; ileal samples from noninflammatory bowel disease and ulcerative colitis served as standard and inflammatory controls, respectively. Flow cytometry of isolated intestinal mononuclear cells showed a larger subset of dendritic cells in Crohns samples compared with controls. This finding was corroborated by confocal microscopy, showing enhanced infiltrates of cells positive for the dendritic cell markers, DC-SIGN(+) and CD83(+), in the subepithelial dome. Moreover, the CD83(+) cells in Crohns tissues showed reduced expression of the lymph node migratory receptor, CCR7, possibly contributing to the high numbers of dendritic cells. After exposure to nonpathogenic Escherichia coli in Ussing chambers, dendritic cells in the subepithelial dome of Crohns disease demonstrated increased co-localization with translocated bacteria. Immunohistochemical results revealed that DC-SIGN(+) cells in Crohns tissues were found to express toll-like receptor 4 and produce tumor necrosis factor-a. In conclusion, nonmigrating dendritic cells that accumulate in the subepithelial dome and internalize nonpathogenic bacteria may be important for the onset and perpetuation of mucosal inflammation in Crohns disease.

  • 20.
    Trulsson, Lena
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery.
    Velin, Åsa
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery.
    Herder, Anders
    Söderkvist, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Cell biology.
    Rüter, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Smeds, Staffan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Telomerase activity in surgical specimens and fine-needle aspiration biopsies from hyperplastic and neoplastic human thyroid tissues2003In: American Journal of Surgery, ISSN 0002-9610, E-ISSN 1879-1883, Vol. 186, no 1, p. 83-88Article in journal (Refereed)
    Abstract [en]

    Background: Telomerase activity (TA) indicates malignancy, but activated lymphocytes also express TA. Correlation between TA in thyroid tissues and fine-needle aspiration (FNA) samples and knowledge about TA in adjacent tissue are of importance. Methods: The telomeric repeat amplification protocol assay followed by enzyme-linked immunosorbent assay detection was performed on 78 thyroid cases including 53 suspected malignancies, preoperative and perioperative FNA specimens, and adjacent tissue. Results: Benign lesions in cancer-suspected cases were TA negative. Eight of 13 papillary (62%) and 4 of 5 follicular (80%) tumors were TA positive (TA+). Lower TA was observed in conventional papillary cancer than in follicular, tall cell variant of papillary and anaplastic cancers. Adjacent tissues with lymphocyte infiltration were TA+ in 9 of 17 cases (53%). Nine of 65 adjacent tissues (14%) were TA+. Three of 6 preoperative and 9 of 11 perioperative FNA samples from malignant tumors corresponded to the tissue TA. Conclusions: High TA may reflect more severe thyroid cancer. Telomerase activity in FNA biopsies does not add reliable diagnostic information, and presence of lymphocytes can give false-positive results.

  • 21.
    Vanheel, Hanne
    et al.
    Katholieke University of Leuven, Belgium .
    Vicario, Maria
    University of Autonoma Barcelona, Spain Centre Invest Biomed Red Enfermedades Hepat and Digest, Spain .
    Vanuytsel, Tim
    Katholieke University of Leuven, Belgium .
    Van Oudenhove, Lukas
    Katholieke University of Leuven, Belgium .
    Martinez, Cristina
    University of Autonoma Barcelona, Spain .
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Pardon, Nicolas
    Katholieke University of Leuven, Belgium .
    Santos, Javier
    University of Autonoma Barcelona, Spain Centre Invest Biomed Red Enfermedades Hepat and Digest, Spain .
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Tack, Jan
    Katholieke University of Leuven, Belgium .
    Farre, Ricard
    Katholieke University of Leuven, Belgium Centre Invest Biomed Red Enfermedades Hepat and Digest, Spain .
    Impaired duodenal mucosal integrity and low-grade inflammation in functional dyspepsia2014In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 63, no 2, p. 262-271Article in journal (Refereed)
    Abstract [en]

    Objective Functional dyspepsia (FD) is an extremely common functional gastrointestinal disorder, the pathophysiology of which is poorly understood. We hypothesised that impaired intestinal barrier function is involved in the onset and persistence of this disorder by inducing low-grade inflammation. Therefore, our aim was to evaluate duodenal mucosal integrity and low-grade inflammation in patients with FD. Design Duodenal biopsy specimens were obtained from 15 patients with FD fulfilling the Rome III criteria and 15 age- and gender-matched healthy volunteers. Transepithelial electrical resistance (TEER) and paracellular permeability were measured in Ussing chambers. Expression of cell-to-cell adhesion proteins was evaluated by real-time PCR, western blot and/or immunofluorescence. Numbers of mast cells, eosinophils and intraepithelial lymphocytes were assessed by immunohistochemistry. Results Patients with FD displayed lower TEER and increased paracellular passage compared with healthy controls, which is indicative of impaired mucosal integrity. In addition, abnormal expression of cell-to-cell adhesion proteins at the level of tight junctions, adherens junctions and desmosomes was shown. Furthermore, patients were characterised by the presence of low-grade inflammation, as demonstrated by increased infiltration of mucosal mast cells and eosinophils. A significant association between the expression level of several cell-to-cell adhesion proteins, the extent of increased permeability and the severity of low-grade inflammation was found. Conclusions These findings challenge the classical paradigm that patients with FD show no structural changes in the gastrointestinal tract. We suggest that impaired intestinal barrier function is a pathophysiological mechanism in FD. Thus, restoration of intestinal barrier integrity may be a potential therapeutic target for treating patients with FD.

  • 22.
    Velin Keita, Åsa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Ericson, Ann-Charlott
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Braaf, Ylva
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Wallon, Conny
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Increased antigen and bacterial uptake in follicle-associated epithelium induced by chronic psychological stress in rats2004In: Gut, ISSN 0017-5749, Vol. 53, no 4, p. 494-500Article in journal (Refereed)
    Abstract [en]

    Background: Chronic stress affects the course of inflammatory bowel disease and experimental colitis, and may also initiate intestinal inflammation in rats.

    Aim: To investigate the effects of stress on the M cell containing follicle associated epithelium, specialised in antigen uptake.

    Subjects and methods: Wistar rats were submitted to acute water avoidance stress for one hour or chronic water avoidance stress for 1 hour/day for 10 consecutive days. Permeability to 51Cr-EDTA, horseradish peroxidase, and chemically killed Escherichia coli K-12 was studied in both villus and follicle associated epithelium in Ussing chambers. Segments were further examined by light, electron, and confocal microscopy.

    Results: Acute stress increased horseradish peroxidase flux in villus as well as in follicle associated epithelium. Chronic stress further increased permeability to horseradish peroxidase in villus and follicle associated epithelium, in the latter by almost fourfold. Moreover, chronic stress induced over 30 times increased E coli passage in follicle associated epithelium whereas there was no significant increase in villus epithelium. Bacterial uptake was confirmed by confocal microscopy showing fluorescent bacteria penetrating and passing through the epithelial surface.

    Conclusions: These results show that the barrier function of follicle associated epithelium can be modulated, and that chronic stress enhances the uptake of luminal antigens and bacteria via the follicle associated epithelium. This can increase antigen exposure in Peyer’s patches thereby having implications in the initiation of proinflammatory immune responses within the intestinal mucosa.

  • 23.
    Velin, Åsa
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery.
    Ander, Stefan
    Johansson, Kenth
    Trulsson, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery.
    Smeds, Staffan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC - Medicin och kirurgicentrum, GE: endokir.
    Inverse relation between mRNA synthesis and secretion of parathyroid hormone in athymic mice grafted with human parathyroid tissue2001In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 109, no 3, p. 235-240Article in journal (Refereed)
    Abstract [en]

    Parathyroid hormone (PTH) mRNA in original and transplanted human adenomatous parathyroid tissue and human serum intact PTH (S-iPTH) was measured in athymic mice at 4, 7, 14, and 28 days after transplantation. Parathyroid tissue was obtained during surgery for hyperparathyroidism and implanted subcutaneously. PTH mRNA detection was done with RT-PCR followed by membrane blot and hybridisation and S-iPTH was analysed using a human specific immunoradiometric method. At 4 days, PTH mRNA was 79.6 ▒ 5.3% (mean ▒ SE) of that in original tissue whereas S-iPTH was only 5.4 ng/l. At 28 days, PTH mRNA was significantly reduced to 60.7▒4.1% whereas S-iPTH was increased to 192 ng/l. The reduced PTH mRNA expression in the transplants at 28 days may be explained by an inhibited DNA transcription. The presence of human S-iPTH in transplanted mice at 4 days may be due to cell disintegration and diffusion. The gradual increase in S-iPH during the experimental period probably reflects increased transplant cell volume and improved graft revascularisation.

  • 24.
    Velin, Åsa
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery.
    Herder, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular and Immunological Pathology.
    Johansson, Kenth
    Trulsson, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery.
    Smeds, Staffan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC - Medicin och kirurgicentrum, GE: endokir.
    Telomerase is not activated in human hyperplastic and adenomatous parathyroid tissue2001In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 145, no 2, p. 161-164Article in journal (Refereed)
    Abstract [en]

    Background: Telomerase is a specific enzyme that appears to have a key role in cellular senescence and the progression of neoplastic tissue. High telomerase activity has been found in several cancers, but not in most normal and benign tissue. Little is known about the influence of telomerase on the abnormal growth associated with hyperparathyroidism. Objective: To analyse telomerase activity in parathyroid tissue obtained from 29 patients undergoing surgery for primary hyperparathyroidism. Design: Tissue for telomerase activity measurements was collected from six hyperplastic, 20 adenomatous and 22 normal parathyroid glands. Methods: The highly sensitive PCR-based telomeric repeat amplification protocol, TRAP, combined with ELISA, was used to detect telomerase activity in tissue extracts containing 3.0 ╡g protein. Result: Telomerase was not activated in any of the analysed tissue by 3 ╡g protein. Reassay of 12 samples containing 6.0 ╡g protein verified these negative TRAP results. Conclusion: Our findings indicate that telomerase is not a part of the mechanism promoting parathyroid proliferation and the underlying conditions remain to be determined.

  • 25.
    Wallon, Conny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Yang, P.
    Intestinal Disease Research Programme, McMaster University, Hamilton, Canada.
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Ericson, Ann-Charlott
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    McKay, D. M.
    Department of Physiology and Biophysics, University of Calgary, Canada.
    Sherman, P. M.
    Departments of Paediatrics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
    Perdue, M. H.
    Intestinal Disease Research Programme, McMaster University, Hamilton, Canada.
    Söderholm, Johan D.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Corticotropin releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro2008In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 57, no 1, p. 50-58Article in journal (Refereed)
    Abstract [en]

    Objective: Persistent stress and life events affect the course of ulcerativecolitis and irritable bowel syndrome by largely unknown mechanisms.Corticotropin-releasing hormone (CRH) has been implicated asan important mediator of stress-induced abnormalities in intestinalmucosal function in animal models, but to date no studies inhuman colon have been reported. The aim was to examine the effectsof CRH on mucosal barrier function in the human colon and toelucidate the mechanisms involved in CRH-induced hyper-permeability.

    Design: Biopsies from 39 volunteers were assessed for macromolecularpermeability (horseradish peroxidise (HRP), 51Cr-EDTA), andelectrophysiology after CRH challenge in Ussing chambers. Thebiopsies were examined by electron and confocal microscopy forHRP and CRH receptor localisation, respectively. Moreover, CRHreceptor mRNA and protein expression were examined in the humanmast cell line, HMC-1.

    Results: Mucosal permeability to HRP was increased by CRH (2.8±0.5pmol/cm2/h) compared to vehicle exposure (1.5±0.4 pmol/cm2/h),p = 0.032, whereas permeability to 51Cr-EDTA and transmucosalelectrical resistance were unchanged. The increased permeabilityto HRP was abolished by -helical CRH (9-41) (1.3±0.6pmol/cm2/h) and the mast cell stabiliser, lodoxamide (1.6±0.6pmol/cm2/h). Electron microscopy showed transcellular passageof HRP through colonocytes. CRH receptor subtypes R1 and R2were detected in the HMC-1 cell line and in lamina propria mastcells in human colon.

    Conclusions: Our results suggest that CRH mediates transcellular uptake ofHRP in human colonic mucosa via CRH receptor subtypes R1 andR2 on subepithelial mast cells. CRH-induced macromolecular uptakein human colon mucosa may have implications for stress-relatedintestinal disorders.

  • 26.
    Wang, Arthur
    et al.
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Keita, Åsa V.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Phan, Van
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    McKay, Catherine M.
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Schoultz, Ida
    Nutrition-Gut-Brain Interactions Research Centre, the Faculty of Medicine, Örebro University, Örebro, Sweden.
    Lee, Joshua
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Murphy, Michael P.
    MRC-Mitochondrial Biology Unit, Cambridge, United Kingdom.
    Fernando, Maria
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Ronaghan, Natalie
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Balce, Dale
    Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada.
    Yates, Robin
    Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada.
    Dicay, Michael
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Beck, Paul L.
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
    MacNaughton, Wallace K.
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Söderholm, Johan D.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Mckay, Derek M.
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Targeting Mitochondria-Derived Reactive Oxygen Species to Reduce Epithelial Barrier Dysfunction and Colitis2014In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 184, no 9, p. 2516-2527Article in journal (Refereed)
    Abstract [en]

    Epithelial permeability is often increased in inflammatory bowel diseases. We hypothesized that perturbed mitochondrial function would cause barrier dysfunction and hence epithelial mitochondria could be targeted to treat intestinal inflammation. Mitochondrial dysfunction was induced in human colon-derived epithelial cell lines or colonic biopsy specimens using dinitrophenol, and barrier function was assessed by transepithelial flux of Escherichia coil with or without mitochondria-targeted antioxidant (MTA) cotreatment. The impact of mitochondria-targeted antioxidants on gut permeability and dextran sodium sulfate (DSS)-induced colitis in mice was tested. Mitochondrial superoxide evoked by dinitrophenol elicited significant internalization and transtocation of E. coil across epithelia and control colonic biopsy specimens, which was more striking in Crohns disease biopsy specimens; the mitochondria-targeted antioxidant, MitoTEMPO, inhibited these barrier defects. Increased gut permeability and reduced epithelial mitochondrial voltage-dependent anion channel expression were observed 3 days after DSS. These changes and the severity of DSS-colitis were reduced by MitoTEMPO treatment. In vitro DSS-stimulated IL-8 production by epithelia was reduced by MitoTEMPO. Metabolic stress evokes significant penetration of commensal bacteria across the epithelium, which is mediated by mitochondria-derived superoxide acting as a signaling, not a cytotoxic, molecule. MitoTEMPO inhibited this barrier dysfunction and suppressed colitis in DSS-colitis, likely via enhancing barrier function and inhibiting proinflammatory cytokine production. These novel findings support consideration of MTAs in the maintenance of epithelial barrier function and the management of inflammatory bowel diseases.

  • 27.
    Yakymenko, Olena
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Schoultz, Ida
    Department of Medical Sciences, Faculty of Health and Medicine, Örebro University, Örebro, Sweden.
    Gullberg, Elisabet
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Almer, Sven
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden / GastroCentrum, Karolinska University Hospital, Stockholm, Sweden.
    Wallon, Conny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Wang, Arthur
    Gastrointestinal Research Group, Cumming School of Medicine, University of Calgary, Calgary, Canada..
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Campbell, Barry J.
    Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, UK.
    McKay, Derek M.
    Gastrointestinal Research Group, Cumming School of Medicine, University of Calgary, Calgary, Canada.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Infliximab restores colonic barrier to adherent-invasive E. coli in Crohn's disease via effects on epithelial lipid rafts2018In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 53, no 6, p. 677-684Article in journal (Refereed)
    Abstract [en]

    Objective: Infliximab is important in the therapeutic arsenal of Crohn’s disease (CD). However, its effect on mucosal barrier function is not fully understood. Adherent-invasive Escherichia coli (AIEC) are important in CD pathophysiology, but the transmucosal uptake routes are partly unknown. We investigated effects of infliximab on uptake of colon-specific AIEC HM427 across CD colonic mucosa.

    Materials and methods: Endoscopic biopsies from non-inflamed colon of seven patients with CD, before and after two infliximab infusions, and eight non-inflammation controls, were mounted in Ussing chambers. Paracellular permeability (51Cr-EDTA) and transmucosal passage of GFP-expressing HM427 were studied. Mechanisms of HM427 transepithelial transport were investigated in Caco-2 monolayers treated with TNF, in the presence of infliximab and/or endocytosis inhibitors.

    Results: Before infliximab treatment, colonic passage of HM427 [CD: 2475 CFU (450–3000); controls 1163(225–1950)] and 51Cr-EDTA permeability were increased in CD (p < .05), but were restored to control levels by infliximab (CD: 150 (18.8–1069)). In TNF-exposed Caco-2 monolayers HM427 transport and lipid rafts/HM427 co-localization was decreased by infliximab. The lipid raft inhibitor methyl-β-cyclodextrin decreased HM427 transport.

    Conclusion: Infliximab restored the colonic barrier to AIEC in CD; an effect partially mediated by blocking lipid rafts in epithelial cells. This ability likely contributes to infliximab’s clinical efficacy in colonic CD.

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