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  • 1.
    Carlsson, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Role of mast cells and probiotics in the regulation of intestinal barrier function2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The intestinal mucosa is the largest contact area and one of the most important barriers to the outside environment. It is highly specialized in aiding us digest and absorb nutrients. It is daily exposed to several potentially dangerous substances and microorganisms, which if they were allowed to pass into the body, could give rise to diseases. Throughout the small intestine certain sites specialized in antigen sampling are found. These sites are named Peyer’s patches and are lymphoid follicles. The epithelium covering the Peyer’s patches is called follicle-associated epithelium and is specialized in antigen sampling and uptake. The special epithelium enables presentation of luminal antigen to immune cells in the underlying follicle.

    Persistent life stress and stressful life events affect the course of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) through largely unknown mechanisms. Regulation of epithelial permeability to antigens is crucial for the balance between inflammation and immune-surveillance, and increased intestinal permeability has been shown in patients with ulcerative colitis and Crohns disease. Vasoactive intestinal polypeptide (VIP) and corticotropin-releasing factor have been implicated as important mediators of stress-induced abnormalities in intestinal mucosal functions in animal models. Both of these mediators have been reported to regulate bowel ion secretion in humans during stress and uptake of horseradish peroxidase in rodents. Probiotics have been shown to ameliorate the deleterious effects of stress on intestinal function, but mechanisms remain to be elucidated.

    The aim of this thesis was to elucidate whether mast cells play an important role in intestinal barrier function during stress and inflammation. Moreover, we wanted to determine whether probiotics can ameliorate the mucosal barrier integrity during stress and inflammation.

    To study the function of mast cells we conducted in vitro experiments on cell lines and ex vivo experiments in Ussing chambers on mouse, rat and human intestinal tissue. The Ussing chamber technique measures electrophysiological properties of the tissue and also gives the possibility to study transcellular and paracellular passage of markers and bacteria. Immunohistology and confocal microscopy have been used to identify mast cells and receptors of interest.

    Our results show that stress affects the follicle-associated epithelium barrier by mechanisms involving VIP and mast cells. These findings were corroborated by the localization of VIP receptors on mucosal mast cells. Furthermore, pretreatment with probiotics was effective in protecting the gut against stress-induced intestinal barrier dysfunction and mucosal inflammation. This protection appeared to involve a mast cell and peroxisome proliferatoractivated receptor-γ dependent mechanism.

    List of papers
    1. Vasoactive intestinal polypeptide regulates barrier function via mast cells in human intestinal follicle-associated epithelium and during stress in rats
    Open this publication in new window or tab >>Vasoactive intestinal polypeptide regulates barrier function via mast cells in human intestinal follicle-associated epithelium and during stress in rats
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    2013 (English)In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 25, no 6, p. e406-e417Article in journal (Refereed) Published
    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.

    Place, publisher, year, edition, pages
    Wiley-Blackwell, 2013
    Keywords
    Inflammatory bowel disease, permeability, Peyers patch, Ussing chamber
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-94315 (URN)10.1111/nmo.12127 (DOI)000318945400005 ()
    Note

    Funding Agencies|Swedish Research Council|K2012-55X-12618-16-3|

    Available from: 2013-06-24 Created: 2013-06-24 Last updated: 2017-12-06
    2. Protective Effects of Probiotics on Chronic Stress-Induced Intestinal Permeability in Rats are mediated via Mast Cells and PPARγ
    Open this publication in new window or tab >>Protective Effects of Probiotics on Chronic Stress-Induced Intestinal Permeability in Rats are mediated via Mast Cells and PPARγ
    Show others...
    2013 (English)Manuscript (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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-100767 (URN)
    Available from: 2013-11-12 Created: 2013-11-12 Last updated: 2014-03-25
    3. Probiotics modulate mast cell degranulation and reduce stress-induced barrier dysfunction in vitro
    Open this publication in new window or tab >>Probiotics modulate mast cell degranulation and reduce stress-induced barrier dysfunction in vitro
    Show others...
    2013 (English)Manuscript (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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-100768 (URN)
    Available from: 2013-11-12 Created: 2013-11-12 Last updated: 2014-03-25Bibliographically approved
    4. Faecalibacterium prausnitzii supernatant improves intestinal barrier function in mice DSS colitis
    Open this publication in new window or tab >>Faecalibacterium prausnitzii supernatant improves intestinal barrier function in mice DSS colitis
    Show others...
    2013 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 48, no 10, p. 1136-1144Article in journal (Refereed) Published
    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.

    Place, publisher, year, edition, pages
    Informa Healthcare, 2013
    Keywords
    dextran sodium sulfate, inflammatory bowel disease, permeability, probiotics, tight junctions
    National Category
    Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-99406 (URN)10.3109/00365521.2013.828773 (DOI)000324761000005 ()
    Note

    Funding Agencies|Swedish Research Council|VR-M: K2012-55X-12618-16-3|

    Available from: 2013-10-17 Created: 2013-10-17 Last updated: 2018-04-27
  • 2.
    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.

  • 3.
    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.

  • 4.
    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.

  • 5.
    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.

  • 6.
    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.

  • 7.
    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.

  • 8.
    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.

  • 9.
    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.

  • 10.
    Schoultz, Ida
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Carlsson, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Gullberg, Elisabet
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Almer, Sven
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Endocrinology and Gastroenterology.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Endocrinology and Gastroenterology.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    McKay, Derek M.
    Department of Physiology and Biophysics, University of Calgary, Calgary, Canada.
    Rhodes, Jonathan M.
    Department of Medicine, Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, University of Liverpool, Liverpool, United Kingdom.
    Söderholm, Johan D.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Infliximab reduces bacterial uptake in mucosal biopsies of Crohn’s colitis viamicrotubule-dependent pathwayManuscript (preprint) (Other academic)
    Abstract [en]

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

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

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

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

  • 11.
    Sjöwall, Johanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Carlsson, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics.
    Bergstrom, S.
    Bergström, S., Department of Microbiology, University of Umeå, Umeå, Sweden.
    Ernerudh, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Forsberg, Pia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases. Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Ekerfelt, Christina
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Innate immune responses in Lyme borreliosis: Enhanced tumour necrosis factor-a and interleukin-12 in asymptomatic individuals in response to live spirochetes2005In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 141, no 1, p. 89-98Article in journal (Refereed)
    Abstract [en]

    Innate immunity is important for early defence against borrelia spirochetes and should play a role in the clinical outcome of the infection. In order to study early cytokine responses, in vitro differentiated dendritic cells (DCs) and whole blood cells from 21 patients with different clinical outcomes of Lyme neuroborreliosis were stimulated with live borrelia spirochetes. The borrelia-induced secretion of interleukin (IL)-4, IL-10, IL-12p70, Interferon (INF)-? and tumour necrosis factor (TNF)-a in DCs and IL-1ß, IL-6, IL-8, IL-10, IL-12p70, TNF-a, regulated upon activation normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1a, MIP-1ß and eotaxin in whole blood cells was measured by enzyme-linked immunospot (ELISPOT) and multiplex arrays, respectively. We found increased numbers of TNF-a-secreting DCs (P = 0.018) in asymptomatic seropositive individuals compared to patients with subacute neuroborreliosis and seronegative controls. Asymptomatic individuals were also found to have elevated levels of IL-12p70 (P = 0.031) in whole blood cell supernatants compared to seronegative controls. These results are in line with previous experiments using cells of the adaptive immune response, indicating that strong T helper type 1 (Th1) proinflammatory responses might be associated with a successful resolution of Lyme disease. © 2005 British Society for Immunology.

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