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  • 1.
    Gullberg, Elisabet
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    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.
    Peyer's patches and M cells as potential sites of the inflammatory onset in Crohn's disease2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1072, p. 218-232Article in journal (Refereed)
    Abstract [en]

    Clinical observations suggest that the sites of initial inflammation in ileal Crohn's disease (CD) are the lymphoid follicles, where the aphtoid lesions originate from small erosions of the follicle-associated epithelium (FAE). Lymphoid follicles and Peyer's patches (PPs) consist of a number of B-cell follicles with intervening T cell areas. The T cell follicular area is also populated by dendritic cells (DCs) and macrophages. A single layer of epithelial cells covering each follicle forms a dome between the surrounding villi. This FAE differs from normal villus epithelium in several ways that make the epithelial cells of the FAE more exposed to the luminal contents, more accessible to antigens, and in closer contact with the immune system. The most prominent feature is the presence of specialized M cells, which are optimized for antigen adherence and transport. M cells play an important role in the surveillance of the intestinal lumen, but also provide a route of entry for various pathogens. In this article we review the current knowledge on the epithelial phenotype of the human FAE, and changes of the FAE and M cells in intestinal inflammation, leading to a hypothesis of the role of the FAE and M cells in the pathogenesis of CD.

  • 2.
    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.

  • 3.
    Ragnarsson, Eva Ge
    et al.
    Uppsala University.
    Schoultz, Ida
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    Gullberg, Elisabet
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    Carlsson, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    Tafazoli, Farideh
    Linköping University, Department of health and environment. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology .
    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.
    Artursson, Per
    Uppsala University.
    Yersinia pseudotuberculosis induces transcytosis of nanoparticles across human intestinal villus epithelium via invasin-dependent macropinocytosis2008In: Laboratory Investigation, ISSN 0023-6837, E-ISSN 1530-0307, Vol. 88, no 11, p. 1215-1226Article in journal (Refereed)
    Abstract [en]

    Crohns disease is characterized by a defect in intestinal barrier function, where bacteria are considered the most important inflammation-driving factor. Enteric bacteria, including E. coli and Yersinia spp, affect tight junctions in enterocytes, but little is known about bacterial effects on the transcellular pathway. Our objective was to study the short-term effects of Y. pseudotuberculosis on uptake of nanoparticles across human villus epithelium. Monolayers of human colon epithelium-derived Caco-2 cells and biopsies of normal human ileum were studied after 2 h exposure to Y. pseudotuberculosis expressing (inv+) or lacking (inv-) the bacterial adhesion molecule, invasin. Transepithelial transport of fluorescent nanoparticles (markers of transcytosis) was quantified by flow cytometry, and mechanisms explored by using inhibitors of endocytosis. Epithelial expressions of beta 1-integrin and particle uptake pathways were studied by confocal microscopy. The paracellular pathway was assessed by electrical resistance (TER), mannitol flux, and expression of tight junction proteins occludin and caludin-4 by confocal microscopy. Inv + Y. pseudotuberculosis adhered to the apical surface of epithelial cells and induced transcytosis of exogenous nanoparticles across Caco-2 monolayers (30-fold increase, P < 0.01) and ileal mucosa (268 +/- 47% of control; P < 0.01), whereas inv-bacteria had no effect on transcytosis. The transcytosis was concentration-, particle size-and temperature-dependent, and possibly mediated via macropinocytosis. Y. pseudotuberculosis also induced apical expression of beta 1-integrin on epithelial cells. A slight drop in TER was seen after exposure to inv+ Y. pseudotuberculosis, whereas mannitol flux and tight junction protein expression was unchanged. In summary, Y. pseudotuberculosis induced apical expression of beta 1-integrin and stimulated uptake of nanoparticles via invasin-dependent transcytosis in human intestinal epithelium. Our findings suggest that bacterial factors may initiate transcytosis of luminal exogenous particles across human ileal mucosa, thus presenting a novel mechanism of intestinal barrier dysfunction.

  • 4.
    Schoultz, Ida
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Carlsson, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Gullberg, Elisabet
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Endocrinology and Gastroenterology.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Endocrinology and Gastroenterology.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    McKay, Derek M.
    Department of Physiology and Biophysics, University of Calgary, Calgary, Canada.
    Rhodes, Jonathan M.
    Department of Medicine, Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, University of Liverpool, Liverpool, United Kingdom.
    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.
    Infliximab reduces bacterial uptake in mucosal biopsies of Crohn’s colitis viamicrotubule-dependent pathwayManuscript (preprint) (Other academic)
    Abstract [en]

    Background: A defective intestinal barrier, shown by increased paracellular permeability is an importantpathogenic factor in Crohn’s disease (CD). TNFα is a key mediator in the regulation of the intestinal barrierfunction. Treatment with antibodies directed against TNFα, such as infliximab, has been established as animportant part of the therapeutic arsenal in severe Crohn’s disease, but the mechanisms of action have yet tobe elucidated. Part of infliximab’s effect has been suggested to be reduced apoptosis of epithelial cells andthereby reduced paracellular permeability. Our aim was to study how infliximab affects uptake of adherent E.coli across the colonic mucosa in CD.

    Method: Seven patients with active CD colitis were examined before and after a four week treatment withinfliximab. Control biopsies were taken from healthy volunteers (4) and patients undergoing controlexamination for colonic polyps (4), aged 36 (range 25-81), coloscopy. Biopsies were taken from macroscopicallynon-inflamed descending colon and were mounted in Ussing chambers to study barrier function. Transmucosalpassage of green fluorescent protein (GFP) incorporated E. coli HM427, an adherent bacteria isolated from thecolon of a CD patient, was studied by quantifying the translocated fluorescent bacteria using flow cytometry.

    Results: Bacterial passage across the colonic mucosa was increased in CD (2500 ± 300 arb. units) comparedwith controls (960 ± 280; p<0.05), and was reduced to 500 ± 200 units after the infliximab treatment (p<0.05).In biopsies treated with colchicine (a microtubuline inhibitor) uptake of E. coli HM427 was reduced by 2/3compared to non-treated biopsies.

    Conclusion: Patients with active Crohn’s disease showed a defect in the barrier to adherent E. coli, which waspartly mediated through a microtubule dependent uptake. The four week treatment with infliximab improvedthe intestinal barrier to these bacteria. This may constitute an important part of infliximab’s mechanisms ofaction in active colitis.

  • 5.
    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. Linköping University, Department of Clinical and Experimental Medicine.
    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. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    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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