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  • 1.
    Amasheh, Maren
    et al.
    Charite.
    Grotjohann, Ingo
    Charite.
    Amasheh, Salah
    Charite.
    Fromm, Anja
    Charite.
    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.
    Zeitz, Martin
    Charite.
    Fromm, Michael
    Charite.
    Schulzke, Joerg-Dieter
    Charite.
    Regulation of mucosal structure and barrier function in rat colon exposed to tumor necrosis factor alpha and interferon gamma in vitro: A novel model for studying the pathomechanisms of inflammatory bowel disease cytokines2009In: SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, ISSN 0036-5521, Vol. 44, no 10, p. 1226-1235Article in journal (Refereed)
    Abstract [en]

    Objective. In Inflammatory bowel disease (IBD), elevated cytokines are responsible for disturbed intestinal transport and barrier function. The mechanisms of cytokine action have usually been studied in cell culture models only; therefore the aim of this study was to establish an in vitro model based on native intestine to analyze distinct cytokine effects on barrier function, mucosal structure, and inherent regulatory mechanisms. Material and methods. Rat colon was exposed to tumor necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma) in Ussing chambers. Transepithelial resistance (R-t) and H-3-mannitol fluxes were measured for characterization of the paracellular pathway. Transcellular transport was analyzed by horseradish peroxidase (HRP) flux measurements. Expression and distribution of tight junction proteins were characterized in immunoblots and by means of confocal laser-scanning microscopy (LSM). Results. Colonic viability could be preserved for 20 h in a specialized in vitro set-up. This was sufficient to alter mucosal architecture with crypt surface reduction. R-t was decreased (101 +/- 10 versus 189 +/- 10 Omega . cm(2)) with a parallel increase in mannitol permeability after cytokine exposure. Tight junction proteins claudin-1, -5, -7, and occludin decreased (45 +/- 10%, 16 +/- 7%, 42 +/- 8%, and 42 +/- 13% of controls, respectively), while claudin- 2 increased to 208 +/- 32%. Occludin and claudin- 1 translocated from the plasma membrane to the cytoplasm. HRP flux increased from 0.73 +/- 0.09 to 8.55 +/- 2.92 pmol . h(-1) . cm(-2). Conclusions. A new experimental IBD model with native colon in vitro is presented. One-day exposure to TNFa and IFNg alters mucosal morphology and impairs epithelial barrier function by up-regulation of the paracellular pore-former claudin-2 and down-regulation of the barrier-builders claudin-1, -5, and -7. These alterations resemble changes seen in IBD and thus underline their prominent role in IBD pathogenicity.

  • 2.
    Andersson, M.
    et al.
    Kirurgiska kliniken, Universitetssjukhuset, Örebro, Sweden.
    Andersson, P.
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Bohe, M.
    Kirurgiska kliniken, Universitetssjukhuset MAS, Malmö, Sweden.
    Borjesson, L.
    Kirurgiska kliniken, Sahlgrenska Universitetssjukhuset/Östra, Göteborg, Sweden.
    Graf, W.
    Kirurgiska kliniken, Akademiska sjukhuset, Uppsala, Sweden.
    Jeppsson, B.
    Kirurgiska kliniken, Universitetssjukhuset MAS, Malmö, Sweden.
    Torkvist, L.
    Gastrocentrum kirurgi, Karolinska universitetssjukhuset, Huddinge, Sweden.
    Akerlund, J.-E.
    Kirurgiska kliniken, Danderyds sjukhus, Danderyd, Sweden.
    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.
    Kirurgi - Omistligt komplement till medicinsk behandling2009In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 106, no 45, p. 3003-3009Article in journal (Refereed)
    Abstract [en]

    [No abstract available]

  • 3.
    Andersson, Peter
    et al.
    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.
    Norblad, Rickard
    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.
    Myrelid, Pär
    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.
    Ileorectal anastomosis in comparison with ileal pouch anal anastomosis in reconstructive surgery for ulcerative colitis - a single institution experience2014In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 8, no 7, p. 582-589Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION:

    Ileal pouch anal anastomosis (IPAA) is the standard procedure for reconstruction after colectomy for ulcerative colitis (UC). However, ileorectal anastomosis (IRA) as an alternative has, recently experienced a revival. This study from a single center compares the clinical outcomes of these procedures.

    METHODS:

    From 1992 to 2006, 253 patients consecutively underwent either IRA (n=105) or IPAA (n=148). Selection to either procedure was determined on the basis of rectal inflammation, presence of dysplasia/cancer or patient preferences. Patient-records were retrospectively evaluated. Mean follow-up time was 5.4 and 6.3 years respectively.

    RESULTS:

    Major postoperative complications occurred in 12.4% of patients after IRA and in 12.8% after IPAA (ns). Complications of any kind after IRA or IPAA, even including subsequent stoma-closure, occurred in 23.8% and 39.9% respectively (p<0.01). Estimated cumulative failure rates after 5 and 10 years were 10.1% and 24.1% for IRA and 6.1% and 18.6% for IPAA respectively (ns). The most common cause for failure was intractable proctitis (4.8%) and unspecified dysfunction (4.8%) respectively. At follow-up 76.9% of patients with IRA had proctitis and 34.1% with IPAA had pouchitis. Estimated cumulative cancer-risk after 10, 20 and 25 year duration of disease was 0.0%, 2.1% and 8.7% for IRA. Figures for IPAA were 0.7%, 1.8% and 1.8% (ns).

    CONCLUSION:

    Failure-rates did not significantly differ between patients operated with IRA or IPAA. Patients operated with IPAA had a higher cumulative number of postoperative complications. The high long-term cancer-risk after IRA indicates that this procedure should be an interim solution in younger patients.

  • 4.
    Andersson, Peter
    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.
    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.
    Surgery in ulcerative colitis: indication and timing.2009In: Digestive diseases (Basel, Switzerland), ISSN 1421-9875, Vol. 27, no 3, p. 335-340Article in journal (Refereed)
    Abstract [en]

    Surgery continues to play an important role in the therapeutic arsenal in ulcerative colitis. In acute colitis, close collaboration between the gastroenterologist and the surgeon is pertinent. Absolute indications for surgery include toxic megacolon, perforation, and severe colorectal bleeding. In addition, surgery should always be considered upon deterioration during medical therapy. The recommended operation in acute colitis is colectomy and ileostomy, with the rectum left in situ; reconstruction is not an option in the acute setting. In chronic continuous colitis, often with long-term steroid therapy, healing conditions are poor. A staged procedure is preferred also in these cases. In cases with dysplasia, surgery should be done after verifying the dysplasia since these patients often have little symptoms from their colitis. The proctocolectomy should in these cases include total mesorectal excision. Ileal pouch-anal anastomosis is the standard bowel reconstruction in ulcerative colitis. The various options should, however, always be thoroughly discussed, considering the pros and cons in each individual patient, before a choice is made. Ileorectal anastomosis is a temporary alternative in select cases (e.g. young women not having had children). Reconstructive surgery is best done approximately 6 months after primary surgery. Surgery for ulcerative colitis should be seen as complementary to medical treatment and may prevent complications, improve the patients' quality of life and occasionally be life-saving. Correct assessment and optimised medical treatment are prerequisites for surgery on accurate indications and good surgical results. Therefore, close interactions between gastroenterologists and colorectal surgeons are mandatory for optimal patient outcome.

  • 5.
    Biancone, Livia
    et al.
    University of Roma Tor Vergata.
    Michetti, Pierre
    CHU Vaudois.
    Travis, Simon
    John Radcliffe Hospital.
    Escher, Johanna C
    Sophia Childrens University Hospital.
    Moser, Gabriele
    University Hospital Vienna.
    Forbes, Alastair
    University College London Hospital.
    Hoffmann, Joerg C
    St Marien Hospital.
    Dignass, Axel
    University of Frankfurt.
    Gionchetti, Paolo
    University of Bologna.
    Jantschek, Guenter
    University Klinikum Schleswig Holstein.
    Kiesslich, Ralf
    Johannes Gutenberg University.
    Kolacek, Sanja
    Childrens Hospital Zagreb.
    Mitchell, Rod
    European Federat Crohns & Ulcerat Colitis Association.
    Panes, Julian
    Barcelona.
    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.
    Vucelic, Boris
    University Hospital Rebro.
    Stange, Eduard
    Robert Bosch Krankenhaus.
    European evidence-based Consensus on the management of ulcerative colitis: Special situations2008In: JOURNAL OF CROHNS and COLITIS, ISSN 1873-9946, Vol. 2, no 1, p. 63-92Article in journal (Refereed)
  • 6.
    Carlsson, Anders H.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Lutgendorff, Femke
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Gastrointestinal Research Unit, Department of Surgery, University Medical Center, Utrecht, The Netherlands.
    Akkermans, Louis M.A.
    Gastrointestinal Research Unit, Department of Surgery, University Medical Center, Utrecht, The Netherlands..
    McKay, Derek M
    Gastrointestinal Research Group, Department of Physiology & Pharmacology, The Calvin, Phoebe and Joan Snyder Institute of Infection, Inflammation and Immunology, 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.
    Probiotics modulate mast cell degranulation and reduce stress-induced barrier dysfunction in vitro2013Manuscript (preprint) (Other academic)
    Abstract [en]

    BACKGROUND: Stress has well-established deleterious effects on intestinal barrier function and stressful life events are known to contribute to the development and perpetuation of inflammatory bowel diseases. Mast cells play a pivotal role in pathogenesis of stressinduced barrier dysfunction due to the release of barrier-disruptive content. Conversely, they also have recently been suggested to contribute to barrier protective properties of probiotics, through the release of 15d-PGJ2 and enhanced epithelial PPAR-γ activity. However, mechanisms remain to be elucidated.

    AIM: To study if probiotics can modulate mast cell mediator release, resulting in amelioration of stress-induced barrier dysfunction in vitro.

    METHODS: Confluent monolayers of the human colon-derived T84 epithelial cell line were co-cultured with rat basophilic leukemia (RBL)-2H3 mast cells and pretreated with probiotics (125x104 CFU/ml, 1hr) before addition of 100nM CRF to activate mast cells. Release of beta hexosaminidase, TNF-α and 15d-PGJ2 from mast cells was determined. Transepithelial resistance (TER), and permeability to microspheres (0.2μm) were measured over a 24h period. To determine dependence of PPAR-γ, monolayers were incubated with the specific PPAR-γ antagonist T0070907 before treatment with probiotics.

    RESULTS: CRF-induced activation of mast cells resulted in decreased TERs and increased permeability to microspheres. Both pretreatment with probiotics and filter-sterilized probiotic supernatant resulted in lower levels of mast cell-released beta hexosaminidase and TNF-α, and increased 15d-PGJ2. Furthermore, probiotics ameliorated epithelial barrier dysfunction in monolayers exposed to CRF-activated mast cells. However, when T84 monolayers were exposed to conditioned medium of CRF-activated mast cells or were incubated with T0070907, probiotics showed little or no effect.

    CONCLUSIONS: Probiotics modulate mast cell mediator release to a more barrier protective profile, resulting in amelioration of stress-induced epithelial barrier dysfunction, which is putatively mediated by a PPAR-γ dependent pathway.

  • 7.
    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.

  • 8.
    Chassaing, Benoit
    et al.
    University Auvergne.
    Rolhion, Nathalie
    University Auvergne.
    de Vallee, Amelie
    University Auvergne.
    Salim, Sa´ad
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Prorok-Hamon, Maelle
    University of Liverpool.
    Neut, Christel
    University Lille 2.
    Campbell, Barry J
    University of Liverpool.
    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.
    Hugot, Jean-Pierre
    University of Paris Diderot.
    Colombel, Jean-Frederic
    University Lille 2.
    Darfeuille-Michaud, Arlette
    University Auvergne.
    Crohn disease-associated adherent-invasive E. coli bacteria target mouse and human Peyers patches via long polar fimbriae2011In: JOURNAL OF CLINICAL INVESTIGATION, ISSN 0021-9738, Vol. 121, no 3, p. 966-975Article in journal (Refereed)
    Abstract [en]

    Crohn disease (CD) is a multifactorial disease in which an abnormal immune response in the gastrointestinal (GI) tract leads to chronic inflammation. The small intestine, particularly the ileum, of patients with CD is colonized by adherent-invasive E. coil (AIEC) a pathogenic group of E. coil able to adhere to and invade intestinal epithelial cells. As the earliest inflammatory lesions are microscopic erosions of the epithelium lining the Peyers patches (PPs), we investigated the ability of AIEC bacteria to interact with PPs and the virulence factors involved. We found that AIEC bacteria could interact with mouse and human PPs via long polar fimbriae (LPF). An LPF-negative AIEC mutant was highly impaired in its ability to interact with mouse and human PPs and to translocate across monolayers of M cells, specialized epithelial cells at the surface of PPs. The prevalence of AIEC strains harboring the lpf operon was markedly higher in CD patients compared with controls. In addition, increased numbers of AIEC, but not LPF-deficient AIEC, bacteria were found interacting with PPs from Nod2(-/-) mice compared with WT mice. In conclusion, we have identified LPF as a key factor for AIEC to target PPs. This could be the missing link between AIEC colonization and the presence of early lesions in the PPs of CD patients.

  • 9.
    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.

  • 10.
    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.

  • 11.
    Dabrosin-Söderholm, Johan
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Epithelial barrier dysfunction in ileal Crohn's disease1998Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The study aimed at investigating the intestinal barrier in Crohn's disease, with special reference to epithelial responses to luminal stimuli, and to permeation of proteins.

    Ileal mucosa from patients undergoing intestinal resection was studied in vitro in Ussing chambers. Intestinal permeability was also studied in vivo, by oral load of lactulose and mannitol.

    The Ussing chamber was evaluated for intestinal barrier studies. Normal ileal mucosa from patients with colon cancer was subjected to long-term experiments, and investigated in regard to various viability parameters. Mucosal permeability, structural integrity and metabolism were maintained for 90 minutes, and specimens with poor viability were detected by a low transepithelial potential difference. In rat ileal mucosa, luminal sodium caprate, a constituent of milk fat, induced dilatation of the tight junctions as visualised by electron microscopy, and a reversible increase in tight junction permeability. The findings indicate that the Ussing chamber is suitable for studies of the intestinal barrier, including tight junction regulation, provided that experiments are monitored by measurements of transepithelial potential difference and are limited in time.

    In vitro studies of human ileal mucosa showed that luminal sodium caprate caused uncoupling of oxidative phosphorylation, as shown by a fall in epithelial ATP contents, and mitochondrial swelling seen by electron microscopy, paralleled by an increased permeability. Non-inflamed Crohn's disease specimens had an exaggerated permeability increase and an augmented fall in transepithelial electrical resistance. Confocal microscopy revealed rearrangements of perijunctional filamentous actin, causing dilatation of the tight junctions. In Crohn's disease, a more pronounced reorganisation of actin filaments was seen, suggesting the tight junctions to be hyperreactive to luminal stimuli due to a disturbed cytoskeletal regulation.

    In vivo, an increased intestinal permeability was induced by ingestion of acetylsalicylic acid. One third of both Crohn's disease patients and their first-degree relatives showed an augmented permeability increase, whereas spouses were equal to controls, suggesting a genetically determined vulnerability of the intestinal barrier.

    In vitro, non-inflamed ileum from Crohn's disease patients had an increased permeation of ovalbumin. Confocal microscopy suggested this to be caused by an augmented transcytosis, a previously unrecognised defect in the epithelial barrier in Crohn's disease, with a subsequent exposure of antigenic proteins to the subepithelial immunocytes.

    The Crohn's disease patients without residual inflammation after surgery were followed with endoscopy within twelve months, and all revealed recurrent ileal inflammation.

    The study indicates a perturbed intestinal barrier in Crohn's disease, possibly genetically determined. The impaired barrier function is demonstrated both by an augmented epithelial transcytosis and by hyperreactive tight junctions. The epithelial barrier dysfunction precedes the recurrent intestinal inflammation in ileal Crohn's disease. The findings suggest an interplay between an impaired epithelial barrier and luminal factors in the initiation of intestinal inflammation.

  • 12.
    Dignass, A
    et al.
    Markus Krankenhaus.
    Van Assche, G
    University Hospital Gasthuisberg.
    O Lindsay, J
    Barts and London NHS Trust.
    Lemann, M
    Hospital St Louis, Paris, France .
    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.
    F Colombel, J
    Hospital Huriez, Lille, France .
    Danese, S
    Ist Clin Humanitas, Milan, Italy .
    DHoore, A
    University Hospital Gasthuisberg.
    Gassull, M
    Germans Trias and Pujol Fdn, Badalona, Spain .
    Gomollon, F
    Hospital Clin University, Zaragoza, Spain .
    W Hommes, D
    Leiden University.
    Michetti, P
    Gastroenterol La Source Beaulieu, Lausanne, Switzerland .
    OMorain, C
    Adelaide and Meath Hospital, Dublin, Ireland .
    Oresland, T
    Akershus University Hospital.
    Windsor, A
    University Coll London Hospital.
    F Stange, E
    Robert Bosch Krankenhaus.
    P L Travis, S
    John Radcliffe Hospital.
    The second European evidence-based Consensus on the diagnosis and management of Crohns disease: Current management2010In: JOURNAL OF CROHNS and COLITIS, ISSN 1873-9946, Vol. 4, no 1, p. 28-62Article in journal (Refereed)
    Abstract [en]

    n/a

  • 13.
    Geraedts, Maartje C. P.
    et al.
    Maastricht University.
    Troost, Freddy J.
    Maastricht University.
    Tinnemans, Rik
    Maastricht 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.
    Brummer, Robert-Jan
    Maastricht University.
    Saris, Wim H. M.
    Maastricht University.
    Release of Satiety Hormones in Response to Specific Dietary Proteins Is Different between Human and Murine Small Intestinal Mucosa2010In: Annals of Nutrition and Metabolism, ISSN 0250-6807, E-ISSN 1421-9697, Vol. 56, no 4, p. 308-313Article in journal (Refereed)
    Abstract [en]

    Background/Aim: High protein diets are the most effective to stimulate cholecystokinin (CCK) and glucagon-like peptide 1 (GLP-1) release; however, which proteins are the most potent is not known. Here, the effects of specific dietary proteins on intestinal CCK and GLP-1 release were examined. Methods: Duodenal biopsies of 10 healthy male subjects and 10 male rats were taken and placed in an Ussing chamber system. The biopsies were exposed on the luminal side to buffer, egg protein, codfish protein, ovomucoid, pea protein, and wheat protein. After an exposure time of 2 h, samples were taken from the serosal side. Results: Pea protein and wheat protein increased CCK and GLP-1 release in human duodenal tissue, while codfish protein only increased CCK release. No elevated levels of CCK and GLP-1 were found after exposure of rat tissue to different proteins. Conclusion: Pea and wheat protein are the most potent stimulators of CCK and GLP-1 release in human duodenal tissue, and may therefore be good dietary additives in weight management.

  • 14.
    Gerdin, Linda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Department of Surgery, Höglandssjukhuset, Eksjö, Sweden.
    Eriksson, Anders S.
    Sahlgrens University Hospital, Sweden.
    Olaison, Gunnar
    Northern Hospital Zeeland, Denmark.
    Sjödahl, Rune
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology. Linköping University, Faculty of Medicine and Health Sciences.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Myrelid, Pär
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    The Swedish Crohn Trial: A Prematurely Terminated Randomized Controlled Trial of Thiopurines or Open Surgery for Primary Treatment of Ileocaecal Crohns Disease2016In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 10, no 1, p. 50-54Article in journal (Refereed)
    Abstract [en]

    Background and aims: The importance of efficient and safe treatment of Crohns disease is highlighted by its chronicity. Both medical and surgical treatments have shown good results in the symptomatic control of limited ileocaecal Crohns disease. The aim of this study was to compare medical treatment with surgical treatment of ileocaecal Crohns disease. Methods: Thirty-six patients from seven hospitals with primary ileocaecal Crohns disease were randomized to either medical or surgical treatment. The medical treatment was induction of remission with budesonide and thereafter maintenance treatment with azathioprine. The surgical treatment was open ileocaecal resection. Crohns disease activity index over time, expressed as area under the curve at 1, 3 and 5 years, was the primary endpoint. Subjective health measured with the 36-item Short Form Survey Instrument (SF36) and a visual analogue scale (VAS) were secondary endpoints. Results: There were no differences between the treatment groups in Crohns disease activity index over time. General health, measured as SF36 score, was higher in patients receiving surgical treatment than in those receiving medical treatment at 1 year, but there was no corresponding difference in VAS. Due to the slow inclusion rate and changes in clinical practice, the study was t = erminated prematurely. Conclusion: The study ended up being underpowered and should be interpreted with caution, but there was no clinically significant difference between the two treatment arms. Further studies are needed to address this important clinical question.

  • 15. 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.

  • 16.
    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.

  • 17.
    Johansson, K.
    et al.
    n/a.
    Ahn, Henrik Casimir
    Linköping University, Department of Medicine and Health Sciences, Thoracic Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Berg, Sören
    Linköping University, Department of Medicine and Health Sciences, Thoracic Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Brudin, Lars
    Linköping University, Department of Medicine and Health Sciences, Clinical Physiology . Linköping University, Faculty of Health Sciences.
    Olofsson, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland. Linköping University, Faculty of Health Sciences.
    Mellblom, L.
    n/a.
    Soderholm, 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.
    Tholin, M.
    n/a.
    INTESTINAL MICROCIRCULATION, BARRIER FUNCTION AND MORPHOLOGY DURING LOW GRADE IAH/EXPERIMENTAL LAPAROSCOPY IN PIGS2009In: in ACTA CLINICA BELGICA, vol 64, issue 3, 2009, Vol. 64, no 3, p. 261-261Conference paper (Refereed)
    Abstract [en]

    n/a

  • 18.
    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.

  • 19.
    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.

  • 20.
    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.

  • 21.
    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.

  • 22.
    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.

  • 23.
    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.

  • 24.
    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.

  • 25.
    Lewis, K.
    et al.
    Intestinal Disease Research Programme, McMaster University, Hamilton, ON, Canada.
    Caldwell, J.
    Gastrointestinal Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, AB, Canada.
    Phan, V.
    Gastrointestinal Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, AB, Canada.
    Prescott, D.
    Gastrointestinal Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, AB, Canada.
    Nazli, A.
    Intestinal Disease Research Programme, McMaster University, Hamilton, ON, Canada.
    Wang, A.
    Gastrointestinal Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, AB, Canada.
    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.
    Perdue, M.H.
    Intestinal Disease Research Programme, McMaster University, Hamilton, ON, Canada.
    Sherman, P.M.
    Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
    McKay, D.M.
    Gastrointestinal Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, AB, Canada, Gastrointestinal Research Group, Dept. Physiology and Biophysics, Univ. of Calgary, 3330 Hospital Dr. NW, Calgary, AB T2N 4N1, Canada.
    Decreased epithelial barrier function evoked by exposure to metabolic stress and nonpathogenic E. coli is enhanced by TNF-a2008In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 294, no 3Article in journal (Refereed)
    Abstract [en]

    A defect in mitochondrial activity contributes to many diseases. We have shown that monolayers of the human colonic T84 epithelial cell line exposed to dinitrophenol (DNP, uncouples oxidative phosphorylation) and nonpathogenic Escherichia coli (E. coli) (strain HB101) display decreased barrier function. Here the impact of DNP on macrophage activity and the effect of TNF-a, DNP, and E. coli on epithelial permeability were assessed. DNP treatment of the human THP-1 macrophage cell line resulted in reduced ATP synthesis, and, although hyporesponsive to LPS, the metabolically stressed macrophages produced IL-1ß, IL-6, and TNF-a. Given the role of TNF-a in inflammatory bowel disease (IBD) and the association between increased permeability and IBD, recombinant TNF-a (10 ng/ml) was added to the DNP (0.1 mM) + E. coli (106 colony-forming units), and this resulted in a significantly greater loss of T84 epithelial barrier function than that elicited by DNP + E. coli. This increased epithelial permeability was not due to epithelial death, and the enhanced E. coli translocation was reduced by pharmacological inhibitors of NF-?ß signaling (pyrrolidine dithiocarbamate, NF-?ß essential modifier-binding peptide, BAY 11-7082, and the proteosome inhibitor, MG132). In contrast, the drop in transepithelial electrical resistance was unaffected by the inhibitors of NF-?ß. Thus, as an integrative model system, our findings support the induction of a positive feedback loop that can severely impair epithelial barrier function and, as such, could contribute to existing inflammation or trigger relapses in IBD. Thus metabolically stressed epithelia display increased permeability in the presence of viable nonpathogenic E. coli that is exaggerated by TNF-a released by activated immune cells, such as macrophages, that retain this ability even if they themselves are experiencing a degree of metabolic stress. Copyright © 2008 the American Physiological Society.

  • 26.
    Lewis, Kimberley
    et al.
    University of Calgary.
    Lutgendorff, Femke
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Phan, Van
    University of Calgary.
    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.
    Sherman, Philip M.
    University of Toronto.
    McKay, Derek M.
    University of Calgary.
    Enhanced Translocation of Bacteria Across Metabolically Stressed Epithelia is Reduced by Butyrate2010In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 16, no 7, p. 1138-1148Article in journal (Refereed)
    Abstract [en]

    Background: The gut microflora in some patients with Crohns disease can be reduced in numbers of butyrate-producing bacteria and this could result in metabolic stress in the colonocytes. Thus, we hypothesized that the short-chain fatty acid, butyrate, is important in the maintenance and regulation of the barrier function of the colonic epithelium. Methods: Confluent monolayers of the human colon-derived T84 or HT-29 epithelial cell lines were exposed to dinitrophenol (DNP (0.1 mM), uncouples oxidative phosphorylation) + Escherichia coil (strain HB101, 10(6) cfu) +/- butyrate (3-50 mM). Transepithelial resistance (TER), and bacterial internalization and translocation were assessed over a 24-hour period. Epithelial ultrastructure was assessed by transmission electron microscopy. Results: Epithelia under metabolic stress display decreased TER and increased numbers of pseudopodia that is consistent with increased internalization and translocation of the E. coli. Butyrate (but not acetate) significantly reduced the bacterial translocation across DNP-treated epithelia but did not ameliorate the drop in TER in the DNP+E. coli exposed monolayers. Inhibition of bacterial transcytosis across metabolically stressed epithelia was associated with reduced I-kappa B phosphorylation and hence NF-kappa B activation. Conclusions: Reduced butyrate-producing bacteria could result in increased epithelial permeability particularly in the context of concomitant exposure to another stimulus that reduces mitochondria function. We speculate that prebiotics, the substrate for butyrate synthesis, is a valuable prophylaxis in the regulation of epithelial permeability and could be of benefit in preventing relapses in IBD.

  • 27.
    Lutgendorff, Femke
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Akkermans, L. M.
    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.
    The role of microbiota and probiotics in stress-induced gastrointestinal damage2008In: Current molecular medicine, ISSN 1566-5240, E-ISSN 1875-5666, Vol. 8, no 4, p. 282-298Article in journal (Refereed)
    Abstract [en]

    Stress has a major impact on gut physiology and may affect the clinical course of gastro-intestinal diseases. In this review, we focus on the interaction between commensal gut microbiota and intestinal mucosa during stress and discuss the possibilities to counteract the deleterious effects of stress with probiotics. Normally, commensal microbes and their hosts benefit from a symbiotic relationship. Stress does, however, reduce the number of Lactobacilli, while on the contrary, an increased growth, epithelial adherence and mucosal uptake of gram-negative pathogens, e.g. E. coli and Pseudomonas, are seen. Moreover, intestinal bacteria have the ability to sense a stressed host and up-regulate their virulence factors when opportunity knocks. Probiotics are "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host", and mainly represented by Lactic Acid Bacteria. Probiotics can counteract stress-induced changes in intestinal barrier function, visceral sensitivity and gut motility. These effects are strain specific and mediated by direct bacterial-host cell interaction and/or via soluble factors. Mechanisms of action include competition with pathogens for essential nutrients, induction of epithelial heat-shock proteins, restoring of tight junction protein structure, up-regulation of mucin genes, secretion of defensins, and regulation of the NFκB signalling pathway. In addition, the reduction of intestinal pain perception was shown to be mediated via cannabinoid receptors. Based on the studies reviewed here there is clearly a rationale for probiotic treatment in patients with stress-related intestinal disorders. We are however far from being able to choose the precise combination of strains or bacterial components for each clinical setting. © 2008 Bentham Science Publishers Ltd.

  • 28.
    Lutgendorff, Femke
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Gastrointestinal Research Unit, Department of Surgery, University Medical Center, Utrecht, The Netherlands.
    Carlsson, Anders H.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Timmerman, Harro M.
    Gastrointestinal Research Unit, Department of Surgery, University Medical Center, Utrecht, The Netherlands.
    Akkermans, Louis M.A.
    Gastrointestinal Research Unit, Department of Surgery, University Medical Center, Utrecht, The Netherlands..
    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.
    Protective Effects of Probiotics on Chronic Stress-Induced Intestinal Permeability in Rats are mediated via Mast Cells and PPARγ2013Manuscript (preprint) (Other academic)
    Abstract [en]

    BACKGROUND: Chronic stress, which may affect in the clinical course of inflammatory and functional bowel diseases, disrupts intestinal barrier function by routes involving mast cells. Probiotics have been shown to ameliorate the deleterious effects of stress on intestinal function, but mechanisms remain to be elucidated. Peroxisome proliferator-activated receptor (PPAR)-γ signaling is activated as an endogenous defense mechanism during chronic stress and evidence suggests that probiotics reduce the degradation of PPAR-γ. As a source of the endogenous agonist for PPAR-γ, 15d-PGJ2, and as an important mediator of the stress response, mast cells may have both a beneficial and a deleterious role in the effects on intestinal function by probiotics.

    AIM: Our aim was to study if mast cells contribute to the positive effects of probiotic therapy on intestinal function in a rat model of chronic stress.

    METHODS: 32 Mast cell deficient (Ws/Ws) and 32 wild-type (+/+) rats were subjected to water avoidance stress (WAS) or sham stress (SS) 1hr/day for 10 days. Seven days prior to the onset of stress, probiotics (PB, multispecies combination of 10 different lactic acid bacteria) were added to the standard diet (St) in half of the animals. To determine dependence of PPAR-γ, 8 probiotic-fed wild-type rats subjected to WAS were injected daily with the specific PPAR-γ antagonist T0070907. The colonic mucosa was exposed to E. coli HB101 incorporated with green fluorescent protein and permeability was assessed in Ussing chambers. Mesenteric lymph nodes (MLN) were cultured to determine bacterial translocation.

    RESULTS: Chronic stress induced a marked increase in ileal permeability to E.coli HB101 in +/+ rats (0.17±0.1 x106CFU/hr in SS/St/++ vs. 2.13±0.4 in WAS/St/++; P<0.001). This breach in barrier integrity was less pronounced in Ws/Ws rats (2.13±0.4 in WAS/St/++ vs. 1.19±0.3 in WAS/St/WsWs; P<0.01). Probiotics prevented stress-induced effects in E.coli HB101 passage only in wild-type rats (82% decrease in +/+ vs. 0% in Ws/Ws rats). Furthermore, only in the presence of mast cells did probiotics reduce the enhanced bacterial translocation to MLNs during chronic stress. In wild-type rats treated with a PPAR-γ antagonist, the barrier protective effects of probiotics were diminished.

    CONCLUSIONS: Mast cells acting via a PPAR-γ dependent pathway contribute to the beneficial effects of probiotics on chronic stress-induced mucosal dysfunction in rats.

  • 29.
    Lutgendorff, Femke
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Nijmeijer, Rian M
    Utrecht University Medical Center.
    Sandström, Per A
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Trulsson, Lena M
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Timmerman, Harro M
    Utrecht University Medical Center.
    van Minnen, L Paul
    Utrecht University Medical Center.
    Rijkers, Ger T
    Utrecht University Medical Center.
    Gooszen, Hein G
    Utrecht University Medical Center.
    Akkermans, Louis M A
    Utrecht University Medical Center.
    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.
    Probiotics prevent intestinal barrier dysfunction in acute pancreatitis in rats via induction of ileal mucosal glutathione biosynthesis.2009In: PLoS ONE, ISSN 1932-6203, Vol. 4, no 2, p. e4512-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: During acute pancreatitis (AP), oxidative stress contributes to intestinal barrier failure. We studied actions of multispecies probiotics on barrier dysfunction and oxidative stress in experimental AP. METHODOLOGY/PRINCIPAL FINDINGS: Fifty-three male Spraque-Dawley rats were randomly allocated into five groups: 1) controls, non-operated, 2) sham-operated, 3) AP, 4) AP and probiotics and 5) AP and placebo. AP was induced by intraductal glycodeoxycholate infusion and intravenous cerulein (6 h). Daily probiotics or placebo were administered intragastrically, starting five days prior to AP. After cerulein infusion, ileal mucosa was collected for measurements of E. coli K12 and (51)Cr-EDTA passage in Ussing chambers. Tight junction proteins were investigated by confocal immunofluorescence imaging. Ileal mucosal apoptosis, lipid peroxidation, and glutathione levels were determined and glutamate-cysteine-ligase activity and expression were quantified. AP-induced barrier dysfunction was characterized by epithelial cell apoptosis and alterations of tight junction proteins (i.e. disruption of occludin and claudin-1 and up-regulation of claudin-2) and correlated with lipid peroxidation (r>0.8). Probiotic pre-treatment diminished the AP-induced increase in E. coli passage (probiotics 57.4+/-33.5 vs. placebo 223.7+/-93.7 a.u.; P<0.001), (51)Cr-EDTA flux (16.7+/-10.1 vs. 32.1+/-10.0 cm/s10(-6); P<0.005), apoptosis, lipid peroxidation (0.42+/-0.13 vs. 1.62+/-0.53 pmol MDA/mg protein; P<0.001), and prevented tight junction protein disruption. AP-induced decline in glutathione was not only prevented (14.33+/-1.47 vs. 8.82+/-1.30 nmol/mg protein, P<0.001), but probiotics even increased mucosal glutathione compared with sham rats (14.33+/-1.47 vs. 10.70+/-1.74 nmol/mg protein, P<0.001). Glutamate-cysteine-ligase activity, which is rate-limiting in glutathione biosynthesis, was enhanced in probiotic pre-treated animals (probiotics 2.88+/-1.21 vs. placebo 1.94+/-0.55 nmol/min/mg protein; P<0.05) coinciding with an increase in mRNA expression of glutamate-cysteine-ligase catalytic (GCLc) and modifier (GCLm) subunits. CONCLUSIONS: Probiotic pre-treatment diminished AP-induced intestinal barrier dysfunction and prevented oxidative stress via mechanisms mainly involving mucosal glutathione biosynthesis.

  • 30.
    Lutgendorff, Femke
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Trulsson, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
    van Minnen, L. Paul
    Department of Surgery University Medical Center, Utrecht, The Netherlands.
    Rijkers, Ger T.
    Department of Surgery University Medical Center, Utrecht, The Netherlands.
    Timmerman, Harro M.
    Department of Surgery University Medical Center, Utrecht, The Netherlands.
    Franzén, Lennart E.
    3Department of Pathology and Cytology Aleris Medilab, Täby.
    Gooszen, Hein G.
    Department of Surgery University Medical Center, Utrecht, The Netherlands.
    Akkermans, Louis M. A.
    Department of Surgery University Medical Center, Utrecht, The Netherlands.
    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.
    Sandström, Per
    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.
    Probiotics enhance pancreatic glutathione biosynthesis and reduce oxidative stress in experimental acute pancreatitis2008In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 295, no 5Article in journal (Refereed)
    Abstract [en]

    Factors determining severity of acute pancreatitis (AP) are poorly understood. Oxidative stress causes acinar cell injury and contributes to the severity, whereas prophylactic probiotics ameliorate experimental pancreatitis. Our objective was to study how probiotics affect oxidative stress, inflammation, and acinar cell injury during the early phase of AP. Fifty-three male Sprague-Dawley rats were randomly allocated into groups: 1) control, 2) sham procedure, 3) AP with no treatment, 4) AP with probiotics, and 5) AP with placebo. AP was induced under general anesthesia by intraductal glycodeoxycholate infusion (15 mM) and intravenous cerulein (5 μg·kg-1·h-1, for 6 h). Daily probiotics or placebo were administered intragastrically, starting 5 days prior to AP. After cerulein infusion, pancreas samples were collected for analysis including lipid peroxidation, glutathione, glutamate-cysteine-ligase activity, histological grading of pancreatic injury, and NF-κB activation. The severity of pancreatic injury correlated to oxidative damage (r = 0.9) and was ameliorated by probiotics (1.5 vs. placebo 5.5, P = 0.014). AP-induced NF-κB activation was reduced by probiotics (0.20 vs. placebo 0.53 OD 450nm/mg nuclear protein, P < 0.001). Probiotics attenuated AP-induced lipid peroxidation (0.25 vs. placebo 0.51 pmol malondialdehyde/mg protein, P < 0.001). Not only was AP-induced glutathione depletion prevented (8.81 vs. placebo 4.1 μmol/mg protein, P < 0.001), probiotic pretreatment even increased glutathione compared with sham rats (8.81 vs. sham 6.18 μmol/mg protein, P < 0.001). Biosynthesis of glutathione (glutamate-cysteine-ligase activity) was enhanced in probiotic-pretreated animals. Probiotics enhanced the biosynthesis of glutathione, which may have reduced activation of inflammation and acinar cell injury and ameliorated experimental AP, via a reduction in oxidative stress. Copyright © 2008 the American Physiological Society.

  • 31.
    Munch, Andreas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    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.
    Ost, A
    Medilab, Taby, Sweden .
    Carlsson, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Low levels of bile acids increase bacterial uptake in colonic biopsies from patients with collagenous colitis in remission2011In: ALIMENTARY PHARMACOLOGY and THERAPEUTICS, ISSN 0269-2813, Vol. 33, no 8, p. 954-960Article in journal (Refereed)
    Abstract [en]

    Pandgt;Background Patients with collagenous colitis have an impaired mucosal barrier. Moreover, collagenous colitis is associated with bile acid malabsorption. Bile acids can increase bacterial mucosal uptake in humans. Mucosal barrier function was investigated by exposing colonic biopsies to chenodeoxycholic acid (CDCA) or deoxycholic acid (DCA) in Ussing chamber experiments. Aim To find if low levels of bile acids increase bacterial uptake in colonic biopsies from collagenous colitis patients. Methods The study comprised 33 individuals; 25 with collagenous colitis (14 in clinical remission without treatment, 11 with active disease and 10 examined in clinical remission resulting from treatment with 6 mg budesonide); eight healthy individuals undergoing screening colonoscopy served as controls. Endoscopic biopsies from the sigmoid colon were mounted in modified Ussing chambers and assessed for short-circuit current (Isc), potential difference, trans-epithelial resistance and transmucosal passage of Escherichia coli K12 after adding 100 mu mol/L CDCA or DCA. Results When adding 100 mu mol/L CDCA or DCA, bacterial uptake increased fourfold in biopsies of patients in remission; CDCA 6.5 units [2.5-9.8] and DCA 6.2 units [2.1-22] (median [IQR]), compared with uptake in biopsies without added bile acids 1.6 units [1.1-3] (P = 0.004 and P = 0.01 respectively). In active disease and in patients in remission due to budesonide treatment, bile acids did not affect bacterial uptake. Confocal microscopy revealed trans-epithelial passage of E. coli K12 within 30 min. Conclusions Low concentrations of dihydroxy-bile acids exacerbate mucosal barrier dysfunction in colonic biopsies of patients with collagenous colitis in remission. This allows a substantially increased bacterial uptake, which may contribute to recurrence of inflammation.

  • 32.
    Munch, Andreas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    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.
    Ost, Åke
    Medilab, Taby, Sweden.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Increased Transmucosal Uptake of E-coli K12 in Collagenous Colitis Persists After Budesonide Treatment2009In: American Journal of Gastroenterology, ISSN 0002-9270, E-ISSN 1572-0241, Vol. 104, no 3, p. 679-685Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Collagenous colitis is increasingly recognized as a common diarrheal disorder of inflammatory origin. Intestinal inflammation is generally associated with increased mucosal permeability, but little is known about barrier function in microscopic colitis. Our aim was to investigate the mucosal barrier to nonpathogenic bacteria in collagenous colitis.

    METHODS: The study included 33 individuals, 25 with collagenous colitis (14 in clinical remission, 11 with active disease, and 8 of these again after 6 weeks budesonide treatment) and 8 control patients. Bowel movements were registered for 1 week. Endoscopic biopsies from the sigmoid colon were mounted in modified Ussing chambers and assessed for short-circuit current (I-sc), transepithelial resistance (TER), and transmucosal passage of chemically killed Escherichia coli K12.

    RESULTS: Bacterial uptake was increased in patients in remission, 1.6 U (1.1-3.0) and in those with active disease, 4.6 U (2.5-5.8; median (IQR)), compared to controls, 0.7 U (0.1-1.1; P=0.004 and P=0.001, respectively). Active disease also had significant decrease in transepithelial resistance (TER) after 120 min, -9.7 Omega cm(2) ((-13)-(-4.3)), compared to controls, -5.2 Omega cm(2) ((-7.2)-(-3.1)), P=0.03; or patients in remission, -4.8 Omega cm(2) ((-8.0)-(-1.2)), P=0.04. Budesonide decreased median stool frequency to 1.9 (1.3-2.2) compared to 3.8 (3.7-4.2) before treatment (P=0.01), but bacterial uptake was still increased after budesonide 2.9 U (1.5-3.8), (P=0.006 compared to controls), and there were no significant changes in histology.

    CONCLUSIONS: Collagenous colitis presents with significantly increased uptake and altered mucosal reactivity to nonpathogenic bacteria. Budesonide induces clinical remission and restores mucosal reactivity but does not abolish the increased bacterial uptake. An underlying barrier dysfunction may explain the frequent and rapid relapses in CC.

  • 33.
    Myrelid, Pär
    et al.
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Salim, Sa´ad
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Darby, Trevor
    National University of Ireland University of Coll Cork, Ireland.
    Almer, Sven
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Melgar, Silvia
    National University of Ireland University of Coll Cork, Ireland.
    Andersson, Peter
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Söderholm, Johan D.
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Effects of anti-inflammatory therapy on bursting pressure of colonic anastomosis in murine dextran sulfate sodium induced colitis2015In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 50, no 8, p. 991-1001Article in journal (Refereed)
    Abstract [en]

    Background. The aim of this study was to examine the effect of colitis and anti-inflammatory therapies on the healing of colonic anastomoses in mice. Methods. Female C57BL/6 mice were randomized into eight groups; four groups receiving plain tap-water and four groups receiving dextran sulfate sodium. Intra-peritoneal treatment was given therapeutically for 14 days with placebo, prednisolone, azathioprine, or infliximab (IFX). Colonic anastomoses were performed and bursting pressure (BP) measurements were recorded and the inflammation evaluated with histology and zymography. Results. The mice with colitis had a more active inflammation based on histology and bowel weight compared with the tap water group, 8.3 (7.6-9.5) mg/mm and 5.5 (4.8-6.2) mg/mm respectively (p less than 0.0001). Similarly mice with colitis receiving placebo had a more active inflammation, 12.8 (10.6-15.0) mg/mm, which differed significantly from all the other therapy arms among the colitic mice; prednisolone 8.1 (7.5-9.1) mg/mm (p = 0.014), azathioprine 8.2 (7.0-8.5) mg/mm (p = 0.0046), IFX 6.7 (6.4-7.9) mg/mm (p = 0.0055). BP for the placebo group was 90.0 (71.5-102.8) mmHg and did not differ from azathioprine or IFX groups, 84.4 (70.5-112.5) and 92.3 (75.8-122.3) mmHg respectively. In contrast BP for the prednisolone group was significantly decreased compared to placebo, 55.5 (42.8-73.0) mmHg (p = 0.0004). Conclusions. All therapies had a beneficial effect on the colitis. An impaired BP of colonic anastomoses was noted after preoperative steroids but not after azathioprine or IFX in this model.

  • 34.
    Myrelid, Pär
    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, Oncology Centre.
    Salim, Sa’ad
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Melgar, Silvia
    Biosciences Institute, University College Cork, Cork City, Ireland.
    Pruteanu, Mihaela
    Biosciences Institute, University College Cork, Cork City, Ireland.
    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, Oncology Centre.
    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, Oncology Centre.
    Effects of Anti-Inflammatory Therapy on Bursting Pressure of colonic Anastomosis in Dextran Sulfate Sodium Induced Colitis in MiceManuscript (preprint) (Other academic)
    Abstract [en]

    Background: The aim of this experimental study was to evaluate the effect of colitis and anti inflammatory therapies, respectively, on the healing of colonic anastomoses in mice.

    Methods: Eighty four female C57BL/6 mice where randomized into eight groups; four groups continued receiving plain tap water and four groups receiving dextran sulfate sodium. Intraperitoneal treatment was given for 14 days with placebo, prednisolone (2 mg/kg bodyweight), azathioprine (5 mg/kg bodyweight) or infliximab (5 mg/kg bodyweight) until surgery with transsection of the colon and an end to end colonic anastomosis was performed. All mice were sacrificed on day 2 and bursting pressure measurements were recorded.

    Results: In the DSS group the mice receiving placebo (n=4) had a more active inflammation with a bowel weight of 12.8 (10.6-15.0) mg/mm, which differed significantly from all the other therapy arms; prednisolone 8.1 (7.5-9.1) mg/mm (p=0.014), azathioprine 8.2 (7.0-8.5) mg/mm (p=0.0046), infliximab 6.7 (6.4-7.9) mg/mm (p=0.0055). Bursting pressure for the placebo group was 90.0 (71.5-102.8) mmHg and did not differ from the azathioprine or infliximab groups, 84.4 (70.5-112.5) and 92.3 (75.8-122.3) mmHg respectively. In contrast bursting pressure for the prednisolone-treated group was decreased compared to placebo, 55.5 (42.8-73.0) mmHg (p=0.0004), as well as compared with azathioprine (p=0.0004) and infliximab (p=0.0015).

    Conclusions: All given therapies had effect on the DSS-induced colitis. A severe decrease in bursting pressure of a colonic anastomosis was seen after preoperative steroids but we found no effect of azathioprine or infliximab. Thus, AZA and IFX may not increase the risk for anastomotic complications per se; the need for these therapies may rather be seen as markers of severe IBD with increased risk of surgical complications.

  • 35.
    Myrelid, Pär
    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, Oncology Centre.
    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, Oncology Centre.
    Sjödahl, Rune
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Oncology Centre.
    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, Oncology Centre.
    Split Stoma in Resectional Surgery of High Risk Patients with Ileocolonic Crohn’s Disease2012In: Colorectal Disease, ISSN 1462-8910, E-ISSN 1463-1318, Vol. 14, no 2, p. 188-193Article in journal (Refereed)
    Abstract [en]

    Objectives: Surgery for Crohn’s disease (CD) is at high risk of anastomotic complications, with severe postoperative morbidity and even mortality. This retrospective study of high risk CD patients compared the outcome of primary anastomosis (PA) with that of split stoma (SS) and delayed anastomosis (DA).

    Methods: We performed 146 operations for ileocolonic CD from 1995-2006. Patient data were obtained from a prospectively registered data base. Patients with ≥2 preoperative risk factors (n=76) constituted high risk patients. Outcomes following PA or SS with DA were assessed.

    Results: The number of risk factors (mean) was 2.4 in the PA group and 3.5 in the SS group at time of resection and 0.2 (p<0.0001) at time of DA after 5.0 (2.3-12.6) months. Anastomotic complications occurred in 19 % (11/57) after PA compared with 0 % (0/19) after DA (p=0.038). The total number of operations and in-hospital time was 1.9 (±1.5) and 20.9 (±35.6) days after PA compared with 2.0 (±0.2) and 17.8 (±10.4) days after DA (p=0.70 and p=0.74).

    Conclusions: SS in high risk ileocolonic resections for CD, reduces the number of risk factors at the time of DA and the risk for anastomotic complications, compared to PA, without adding inhospital time or number of operations.

  • 36.
    Münch, Andreas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology.
    Ström, Magnus
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    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.
    Dihydroxy bile acids increase mucosal permeability and bacterial uptake in human colon biopsies2007In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 42, no 10, p. 1167-1174Article in journal (Refereed)
    Abstract [en]

    Objective. Bile acids in mM concentrations are known to increase chloride secretion and alter mucosal permeability in animal colon. Increased mucosal permeability is believed to play an important role in the development of intestinal inflammation. The aim of this study was to investigate the influence of μM concentrations of dihydroxy bile acids on permeability and bacterial uptake in the normal human colon. Material and methods. Endoscopic biopsies from the sigmoid colon of 18 subjects with normal colonic histology were mounted in modified Ussing chambers. Chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) were added to the mucosal compartment. Short-circuit current (Isc) and transepithelial resistance (TER) were studied for 120 min. Cr-EDTA and horseradish peroxidase (HRP) were used to assess paracellular and transcellular permeability, respectively. The transmucosal passage of chemically killed Escherichia coli was quantified and investigated using confocal microscopy. Results. A significant decrease in TER was seen after 60 min of exposure to 1000 μmol/l CDCA and DCA. The combination of E. coli and 100 μmol/l CDCA gave a decrease in TER compared to controls (p=0.06). DCA showed a dose-related increase in Cr-EDTA permeability, which was most pronounced at 1000 μmol/l (p=0.02). Increased E. coli uptake was induced by 500 μmol/l (p=0.01) and 1000 μmol/l CDCA (p=0.04). Bacterial uptake was increased at 100 μmol/l by exposure to DCA (p=0.03). Confocal microscopy revealed the presence of E. coli bacteria in the lamina propria after 15 min of exposure to 1000 μmol/l CDCA and DCA. Conclusions. Our study suggests that dihydroxy bile acids in μM concentrations alter barrier function in normal human colon biopsies, causing increased antigen and bacterial uptake, thereby bile acids may contribute to the development of intestinal inflammation. © 2007 Taylor & Francis.

  • 37.
    Münch, Andreas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences.
    Söderholm, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology.
    Carlsson, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Öst, Åke
    Medilab, Täby, Sweden.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland.
    Physiological levels of bile acids increase bacterial uptake in colonic biopsies of collagenous colitis patients in remissionManuscript (preprint) (Other academic)
    Abstract [en]

    Objective: Patients with collagenous colitis (CC) have an impaired mucosal barrier. Moreover CC is associated with bile acid malabsorption. Bile acids may increase bacterial mucosal uptake in humans. To elucidate the possible role of bile acids in CC pathophysiology, the mucosal barrier function was investigated by exposing colonic biopsies to physiological concentrations of chenodeoxycholic acid (CDCA) or deoxycholic acid (DCA) in Ussing chamber experiments.

    Patients/Interventions: The study included 33 individuals; 25 with collagenous colitis (14 in clinical remission without treatment, 11 with active disease, and 8 of these again after 6 weeks budesonide treatment); 8 healthy individuals undergoing screening colonoscopy served as controls. Endoscopic biopsies from the sigmoid colon were mounted in modified Ussing chambers and assessed for short circuit current (Isc), transepithelial resistance (TER), and transmucosal passage of chemically killed E. coli K12 after addition of 100 μmol/l CDCA or DCA. The biopsies were further investigated with confocal microscopy to asses bacterial transepithelial passage routes.

    Results: By adding 100μmol/l CDCA or DCA the bacterial uptake was increased by 4-fold in biopsies of patients in remission; CDCA 6.5 units [2.5-9.8] and DCA 6.2 units [2.1-22] (median [IQR]), compared with uptake in biopsies without added bile acids 1.6 units [1.1-3]; (p=0.004 and p=0.01, respectively). In active disease and in patients in remission on budesonide, bile acids had no effect on bacterial uptake. Isc and TER were unaffected by the bile acids at 100μmol/l in all groups. Confocal microscopy demonstrated transepithelial passage of E.coli K12 via the paracellular route.

    Conclusions: Physiological concentrations of dihydroxy-bile acids augment mucosal barrier dysfunction in colonic biopsies of patients with CC in remission. This leads to a substantially increased bacterial uptake that may contribute to relapse of inflammation. Budesonide seems to counteract the bile acid-induced mucosal impairment.

  • 38.
    Münch, Andreas
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology.
    Söderholm, Johan D
    Linköping University, Department of Biomedicine and Surgery, Division of surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Wallon, Conny
    Linköping University, Department of Biomedicine and Surgery, Division of surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Öst, Åke
    Medilab, Täby, Sweden.
    Olaison, Gunnar
    Linköping University, Department of Biomedicine and Surgery, Division of surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Ström, Magnus
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Dynamics of mucosal permeability and inflammation in collagenous colitis before, during, and after loop ileostomy2005In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 54, no 8, p. 1126-1128Article in journal (Refereed)
    Abstract [en]

    Collagenous colitis has become a more frequent diagnosis but the aetiology of this disease is still unknown. We describe a female patient with intractable collagenous colitis who was treated with a temporary loop ileostomy. She was followed clinically, histopathologically, and functionally by measuring mucosal permeability before surgery, after ileostomy, and after bowel reconstruction. In our case report, active collagenous colitis was combined with increased transcellular and paracellular mucosal permeability. Diversion of the faecal stream decreased inflammation of the mucosa and normalised epithelial degeneration and mucosal permeability. After restoration of bowel continuity, mucosal permeability was altered prior to the appearance of a collagenous layer.

  • 39. Nazli, Aisha
    et al.
    Wang, Arthur
    Steen, Oren
    Prescott, David
    Lu, Jun
    Perdue, Mary H
    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.
    Sherman, Philip M
    McKay, Derek M
    Enterocyte cytoskeleton changes are crucial for enhanced translocation of nonpathogenic Escherichia coli across metabolically stressed gut epithelia2006In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 74, no 1, p. 192-201Article in journal (Refereed)
    Abstract [en]

    Substantial data implicate the commensal flora as triggers for the initiation of enteric inflammation or inflammatory disease relapse. We have shown that enteric epithelia under metabolic stress respond to non-pathogenic bacteria by increases in epithelial paracellular permeability and bacterial translocation. Here we assessed the structural basis of these findings. Confluent filter-grown monolayers of the human colonic T84 epithelial cell line were treated with 0.1 mM dinitrophenol (which uncouples oxidative phosphorylation) and noninvasive, nonpathogenic Escherichia coli (strain HB101, 106 CFU) with or without pretreatment with various pharmacological agents. At 24 h later, apoptosis, tight-junction protein expression, transepithelial resistance (TER, a marker of paracellular permeability), and bacterial internalization and translocation were assessed. Treatment with stabilizers of microtubules (i.e., colchicine), microfilaments (i.e., jasplakinolide) and clathrin-coated pit endocytosis (i.e., phenylarsine oxide) all failed to block DNP+E. coli HB101-induced reductions in TER but effectively prevented bacterial internalization and translocation. Neither the TER defect nor the enhanced bacterial translocations were a consequence of increased apoptosis. These data show that epithelial paracellular and transcellular (i.e., bacterial internalization) permeation pathways are controlled by different mechanisms. Thus, epithelia under metabolic stress increase their endocytotic activity that can result in a microtubule-, microfilament-dependent internalization and transcytosis of bacteria. We speculate that similar events in vivo would allow excess unprocessed antigen and bacteria into the mucosa and could evoke an inflammatory response by, for example, the activation of resident or recruited immune cells. Copyright © 2006, American Society for Microbiology. All Rights Reserved.

  • 40. Nazli, Aisha
    et al.
    Yang, Ping-Chang
    Jury, Jennifer
    Howe, Kathryn
    Watson, James L
    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.
    Sherman, Philip M
    Perdue, Mary H
    McKay, Derek M
    Epithelia under metabolic stress perceive commensal bacteria as a threat2004In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 164, p. 947-957Article in journal (Refereed)
  • 41.
    Olaison, Gunnar
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Andersson, Peter
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Myrelid, Pär
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Smedh, Kenneth
    Söderholm, Johan D
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Sjödahl, Rune
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    On-table endoscopy to define strictures and resection margins: Experience from 178 operations for Crohn's disease using intraoperative endoscopy2001In: Colorectal Disease, ISSN 1462-8910, E-ISSN 1463-1318, Vol. 3, no SUPPL. 2, p. 58-62Article in journal (Refereed)
    Abstract [en]

    [No abstract available]

  • 42.
    Olofsson, Pia H.
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Mellblom, Lennart
    Department of Pathology, County Hospital, Kalmar, Sweden.
    Berg, Sören
    Linköping University, Department of Medicine and Health Sciences, Thoracic Surgery. Linköping University, Faculty of Health Sciences.
    Ahn, Henrik Casimir
    Linköping University, Department of Medicine and Health Sciences, Thoracic Surgery. Linköping University, Faculty of Health Sciences.
    Wikström, Thore
    Linköping University, Department of Clinical and Experimental Medicine, Disaster Medicine and Traumatology. Linköping University, Faculty of Health Sciences.
    Johansson, Kenth J. M.
    Department of Surgery, Västervik Hospital, Sweden.
    Söderholm, Johan D.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Increased transmucosal uptake of E. coli K12 in porcine small bowel following experimental short term abdominal compartment syndrome2009Article in journal (Other academic)
    Abstract [en]

    Background: Abdominal compartment syndrome (ACS) may lead to bacterial translocation and possibly be of importance for development of multiorgan failure. However, the underlying mechanisms have not been fully elucidated. In a porcine model we recently demonstrated preserved intestinal mucosal blood flow during experimental short duration ACS. In the present study we used the same model to determine mucosal barrier function and morphology in the small bowel and colon of pigs before and after short term ACS.

    Methods: The study comprised 12 anaesthetized pigs exposed to experimental ACS and 6 control animals. Via laparotomy, samples of small bowel and colon were taken out for studies before short term ACS, where the abdomen was inflated with CO2 and IAP was increased stepwise by 10 mm Hg at 10-minute intervals up to 50 mm Hg, and again 10 minutes after exsufflation. Mucosal microcirculation was measured by laser Doppler flowmetry, and mucosal tissues were mounted in modified Ussing chambers for assessment of barrier function (E. coli K12 uptake and 51Cr-EDTA permeability). Specimens were also fixed in formaldehyde, stained with eosin-hematoxylin and evaluated blindly using an 8-grade scale for assessment of mucosal damage.

    Results: Transmucosal passage of E. coli was three-fold increased in the small bowel after ACS (22.6 [18.2 – 54.4] units) vs. baseline (8.1 [2.0 – 13.9]; P< 0.050) with a significant correlation to alterations of mucosal microcirculation. In the colon bacterial passage was unchanged, whereas 51Cr-EDTA permeability after ACS increased to 181% of baseline (P<0.05) and was correlated to significant mucosal histopathological changes (P<0.03).

    Conclusion: Short term ACS with reperfusion induced significant dysfunction of the intestinal mucosal barrier. The response patterns concerning barrier dysfunction differed between small bowel and colonic mucosa, with increased bacterial passage and paracellular permeability, respectively.

  • 43.
    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.

  • 44.
    Persborn, Mats
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Gerritsen, J
    Wageningen University, Netherlands .
    Wallon, Conny
    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.
    Carlsson, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Akkermans, L M A .
    University of Medical Centre, Netherlands .
    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.
    The effects of probiotics on barrier function and mucosal pouch microbiota during maintenance treatment for severe pouchitis in patients with ulcerative colitis2013In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 38, no 7, p. 772-783Article in journal (Refereed)
    Abstract [en]

    Background less thanbrgreater than less thanbrgreater thanA total of 10-15% of patients with an ileoanal pouch develop severe pouchitis necessitating long-term use of antibiotics or pouch excision. Probiotics reduce the risk of recurrence of pouchitis, but mechanisms behind these effects are not fully understood. less thanbrgreater than less thanbrgreater thanAim less thanbrgreater than less thanbrgreater thanTo examine mucosal barrier function in pouchitis, before and after probiotic supplementation and to assess composition of mucosal pouch microbiota. less thanbrgreater than less thanbrgreater thanMethods less thanbrgreater than less thanbrgreater thanSixteen patients with severe pouchitis underwent endoscopy with biopsies of the pouch on three occasions: during active pouchitis; clinical remission by 4 weeks of antibiotics; after 8 weeks of subsequent probiotic supplementation (Ecologic 825, Winclove, Amsterdam, the Netherlands). Thirteen individuals with a healthy ileoanal pouch were sampled once as controls. Ussing chambers were used to assess transmucosal passage of Escherichia coli K12, permeability to horseradish peroxidase (HRP) and Cr-51-EDTA. Composition and diversity of the microbiota was analysed using Human Intestinal Tract Chip. less thanbrgreater than less thanbrgreater thanResults less thanbrgreater than less thanbrgreater thanPouchitis Disease Activity Index (PDAI) was significantly improved after antibiotic and probiotic supplementation. Escherichia coli K12 passage during active pouchitis [3.7 (3.4-8.5); median (IQR)] was significantly higher than in controls [1.7 (1.0-2.4); P andlt; 0.01], did not change after antibiotic treatment [5.0 (3.3-7.1); P = ns], but was significantly reduced after subsequent probiotic supplementation [2.2 (1.7-3.3); P andlt; 0.05]. No significant effects of antibiotics or probiotics were observed on composition of mucosal pouch microbiota; however, E. coli passage correlated with bacterial diversity (r = -0.40; P = 0.018). Microbial groups belonging to Bacteroidetes and Clostridium clusters IX, XI and XIVa were associated with healthy pouches. less thanbrgreater than less thanbrgreater thanConclusions less thanbrgreater than less thanbrgreater thanProbiotics restored the mucosal barrier to E. coli and HRP in patients with pouchitis, a feasible factor in prevention of recurrence during maintenance treatment. Restored barrier function did not translate into significant changes in mucosal microbiota composition, but bacterial diversity correlated with barrier function.

  • 45.
    Persborn, Mats
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. 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.
    Editorial Material: Commentary: the effects of probiotics on barrier function and mucosal pouch microbiota during maintenance treatment for severe pouchitis in patients with ulcerative colitis - authors reply2013In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 38, no 11-12, p. 1406-1407Article in journal (Other academic)
    Abstract [en]

    n/a

  • 46.
    Persborn, Mats
    et al.
    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 for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Carlsson, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Timmerman, Harro
    Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, 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 for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Effects of probiotics (Ecologic 825) on barrier function during maintenance treatment for severe pouchitisManuscript (preprint) (Other academic)
    Abstract [en]

    Background : About 10-15% of patients with an ileoanal pouch develop a severe, form of pouchitis that necessitates long and/or frequent use of antibiotics and in rare cases even pouch excision. Probiotics have been shown to reduce the risk of recurrence after induction treatment with antibiotics. The mechanisms behind the positive effects of probiotics are not fully understood. The aim of our study was to examine the mucosal barrier function in relation to pouchitis, before and after treatment with probiotics.

    Methods: 16 patients with a history of severe pouchitis underwent endoscopy with biopsies of the pouch on three occasions: Once during active pouchitis, second after 4 weeks of treatment with antibiotics until clinical remission and third after eight weeks of probiotic treatment. 13 controls with an ileoanal pouch with no recent history of pouchitis were used. The biopsies were mounted in Ussing chambers and mucosal barrier function was assessed by electrophysiology, transmucosal uptake of E coli K12, permeability to Cr-EDTA and Horseradish peroxidase (HRP). Pouchitis Disease Activity Index (PDAI) was used in all subjects.

    Results: PDAI was significantly improved after treatment with antibiotics and probiotics. There was a significant difference in E. coli K12 passage before treatment compared to controls (3.7 units (3.4-8.5) vs 1.7 units (1.0-2.4) p< 0.01). E. coli K12 passage did not change after antibiotic treatment (5.0 units (3.3-7.1) p = ns vs controls). In contrast a significant reduction in bacterial uptake was seen after probiotics (2.2 units (1.8-3.3) p< 0.05). Likewise, a significant normalization of HRP flux was seen after probiotic treatment. Pouchitis did not affect paracellular permability or electrophysiology.

    Conclusion: Probiotic treatment restored the increased permeation to E. coli and HRP in patients with chronic pouchitis. This could be an important factor behind the positive effects of probiotics in patients with chronic pouchitis.

  • 47.
    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.

  • 48. 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

  • 49.
    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.

  • 50.
    Salim, Sa´ad
    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.
    Importance of Disrupted Intestinal Barrier in Inflammatory Bowel Diseases2011In: INFLAMMATORY BOWEL DISEASES, ISSN 1078-0998, Vol. 17, no 1, p. 362-381Article, review/survey (Refereed)
    Abstract [en]

    The current paradigm of inflammatory bowel diseases (IBD), both Crohns disease (CD) and ulcerative colitis (UC), involves the interaction between environmental factors in the intestinal lumen and inappropriate host immune responses in genetically predisposed individuals. The intestinal mucosal barrier has evolved to maintain a delicate balance between absorbing essential nutrients while preventing the entry and responding to harmful contents. In IBD, disruptions of essential elements of the intestinal barrier lead to permeability defects. These barrier defects exacerbate the underlying immune system, subsequently resulting in tissue damage. The epithelial phenotype in active IBD is very similar in CD and UC. It is characterized by increased secretion of chloride and water, leading to diarrhea, increased permeability via both the transcellular and paracellular routes, and increased apoptosis of epithelial cells. The main cytokine that seems to drive these changes is tumor necrosis factor alpha in CD, whereas interleukin (IL)-13 may be more important in UC. Therapeutic restoration of the mucosal barrier would provide protection and prevent antigenic overload due to intestinal "leakiness. Here we give an overview of the key players of the intestinal mucosal barrier and review the current literature from studies in humans and human systems on mechanisms underlying mucosal barrier dysfunction in IBD.

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