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  • 51.
    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.

  • 52.
    Salim, Sa'ad Yislam
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Fru Che, Karlhans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . 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, Department of Surgery Östergötland.
    T-cell expansion capacity of Dendritic cells isolated from patients wiht Chron's diseaseManuscript (preprint) (Other academic)
    Abstract [en]

    Aphtoid lesions at the follicle-associated epithelium (FAE) are one of the earliest observable signs of recurrent ileal Crohn’s disease (CD). In an earlier study, we found an abnormal accumulation of dendritic cells (DCs) situated beneath the FAE, in the sub-epithelial dome (SED) of patients with CD. These DCs were prone to E.coli uptake. The aim here was to isolate and characterise DCs from patients with CD and determine their functional properties in T-cell expansion. Initially, DCs were isolated from eleal mucosa and blood of 5 CD patients and 5 patients with non-IBD disorders, via magnetic bead separation. DCs were also isolated from blood of 5 patients in long-term remission and 5 healthy volunteers, via FACS sorting and separation. Mixed lymphocyte reaction was performed on the isolated DCs and expansion of T-cells was recorded. DCs that were isolated from blood were also characterised via FACS analysis. DCs from patients with active CD had the tendency of having lower T-cell expansion capacity than DCs from non-IBD controls. The capacity to stimulate T-cells proliferation was restored to similar levels as healthy controls in DCs isolated from patients in remission. However, there was more than 10-fold increase in myeloid (CD11c+) DCs present in the peripheral blood mononuclear cells of CD than in healthy controls. The myeloid DCs were primarily immature (CD83-) and expressed the lymph node migratory receptor CCR7. This population of DCs may be responsible for inducing a tolerogenic or regulatory effect. Our results hint to a complex immune-regulatory mechanism where DCs at different stages of chronic inflammation exert different immune-modulatory effects.

  • 53.
    Salim, Sa'ad Yislam
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Myrelid, Pär
    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 Östergötland.
    Darfeuille-Michaud, Arlette
    Pathogénie Bactérienne Intestinale Laboratoire de Bactériologie, CBRV, Université d'Auvergne, Clermont-Ferrand, France.
    Pizzaro, Theresa T.
    Digestive Health Center of Excellence, University of Virginia Health System, Charlottesville, VA, USA.
    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 Östergötland.
    Barrier defect in the follicle-associated epithelium of SAMP1/YitFc mice demonstrates vulnerability to adherent-invasive Escherichia coli LF82Manuscript (preprint) (Other academic)
    Abstract [en]

    SAMP1/YitFc mice are a unique murine model for Crohn’s disease (CD) as they develop spontaneous intestinal inflammation without chemical or genetic manipulations. Inflammation is primarily located in the distal ileum, which is the hallmark location for CD. It is at the distal ileum of CD where small erosions that develop at the follicle-associated epithelium (FAE) and are one of the earliest observable lesions in recurrent ileitis. In the report, we studied the intestinal permeability defect and examined the role of dendritic cells (DCs) in the SAMP1/YitFc mice ileitis. Segments of FAE and VE from 11 and 27 weeks old SAMP1/YitFc mice and AKR control background stains were mounted on Ussing chambers. Electrical conductivity and permeability to 51Cr-EDTA, horseradish peroxidise (HRP) and E.coli HB101 and LF82 were recorded. There was ileal permeability to 51Cr-EDTA and HRP in the 27 weeks old SAMP1/YitFc mice. Both E.coli HB101 and LF82 increased conductance by two-folds in FAE and VE of SAMP1/YitFc mice. Furthermore, both bacterial strains increased tissue conductance and 51Cr-EDTA passage. There was greater passage of E.coli LF82 in the 27 week old DAMP1/YitFc mice than in controls. Confocal microscopy revealed a high number of CD11c+ DCs in the sub-epithelial dome (SED) area, though there was no difference between the SAMP1/YitFc mice than the AKR controls. Immunofluorescence characterisation also did not reveal any phenotypic difference in DCs between the mice strains. These results show that SAMP1/YitFc mice have a barrier defect, which was more pronounced in the FAE of older mice, and demonstrate a mucosal sensitivity bacteria. It also confirms that this model of chronic ileitis is primarily a defect in permeability defect and not DCs.

  • 54. Santos, J
    et al.
    Yang, P-C
    Söderholm, Johan D
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Benjamin, M
    Perdue, MH
    Role of mast cells in chronic stress induced colonic epithelial barrier dysfunction in the rat.2001In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 48, p. 630-636Article in journal (Refereed)
  • 55. Sayer, Brooke
    et al.
    Lu, Jun
    Green, Christina
    Söderholm, Johan D
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Akhtar, Mahmood
    McKay, Derek M
    Dextran sodium sulphate-induced colitis perturbs muscarinic cholinergic control of colonic epithelial ion transport2002In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 135, p. 1794-1800Article in journal (Refereed)
  • 56.
    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.

  • 57.
    Schoultz, Ida
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Kufer, Thomas
    Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Germany.
    Jiang, Tieshan
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Jandu, Narveen
    University of Toronto, Toronto, Canada.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . 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.
    Ubiquitination and degradation of the Crohn’s Disease associated protein Nod2involves the E2 enzyme UBE2G2Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Mutations predisposing to Crohn’s disease (CD) have been mapped to the CARD15/Nod2 locus,which encodes a cytoplasmic receptor hereafter referred to as Nod2, a member of the NACHT-LRR (NLR) familyof pattern recognition receptors. The binding of bacterial muramyl dipeptide (MDP) to Nod2 triggers theactivation of the nuclear factor-κB (NFκB) pathway, thereby inducing a number of pro-inflammatory genes. Themost common variant of Nod2 associated with CD is the frame shift mutation L1007fs, which results in atruncated form of the protein unable to respond to MDP. Despite active research, little is known about howNod2 is regulated. The aim of this study was to investigate if the cellular Nod2 protein level is regulated by theubiquitin-proteasome pathway.

    Material and Methods/Results: Nod2 was shown to be subjected to rapid turnover in the colorectal cancer cellline SW480 as measured by immunoprecipitation following inhibition of protein synthesis with cyklohexamide.Immunoprecipitation of Nod2 also revealed co-precipitation of ubiquitin, suggesting that Nod2 wasubiquitinated. In line with this observation, inhibition of the proteasome using MG-132 or lactacystin, resultedin increased levels of Nod2 in the cells. UBE2G2, an E2 enzyme, thus conferring specificity of ubiquitin binding,was identified to have affinity for the CARD domain of Nod2. Activation of Nod2 with MDP enhanced itsubiquitination, and increasing amounts of UBE2G2 in the cells abrogated NFB-activation, suggesting thatubiquitination of Nod2 may be important for the resolution of the inflammatory signal.

    Conclusion: Taken together, our results show that the cellular level of Nod2 protein is regulated via theubiquitin-proteasome pathway, suggesting that Nod2-driven inflammation may be resolved through rapiddegradation of Nod2. Consequently, not only polymorphisms in Nod2 directly, but also in genes regulatingNod2 protein levels may contribute to the susceptibility to Crohn’s disease.

  • 58.
    Schoultz, Ida
    et al.
    University of Calgary, Canada .
    McKay, Catherine M
    University of Calgary, Canada .
    Graepel, Rabea
    University of Calgary, Canada .
    Phan, Van C
    University of Calgary, Canada .
    Wang, Arthur
    University of Calgary, Canada .
    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.
    McKay, Derek M
    University of Calgary, Canada .
    Indomethacin-induced translocation of bacteria across enteric epithelia is reactive oxygen species-dependent and reduced by vitamin C2012In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 303, no 5, p. G536-G545Article in journal (Refereed)
    Abstract [en]

    Schoultz I, McKay CM, Graepel R, Phan VC, Wang A, Soderholm J, McKay DM. Indomethacin-induced translocation of bacteria across enteric epithelia is reactive oxygen species-dependent and reduced by vitamin C. Am J Physiol Gastrointest Liver Physiol 303: G536-G545, 2012. First published June 14, 2012; doi:10.1152/ajpgi.00125.2012.-The enteric epithelium must absorb nutrients and water and act as a barrier to the entry of luminal material into the body; this barrier function is a key component of innate immunity. Nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy occurs via inhibition of prostaglandin synthesis and perturbed epithelial mitochondrial activity. Here, the direct effect of NSAIDs [indomethacin, piroxicam (cyclooxygenase 1 and 2 inhibitors), and SC-560 (a cyclooxygenase 1 inhibitor)] on the barrier function of human T84 epithelial cell line monolayers was assessed by transepithelial electrical resistance (TER) and internalization and translocation of a commensal Escherichia coli. Exposure to E. coli in the presence and absence of drugs for 16 h reduced TER; however, monolayers cotreated with E. coli and indomethacin, but not piroxicam or SC-560, displayed significant increases in internalization and translocation of the bacteria. This was accompanied by increased reactive oxygen species (ROS) production, which was also increased in epithelia treated with E. coli only. Colocalization revealed upregulation of superoxide synthesis by mitochondria in epithelia treated with E. coli + indomethacin. Addition of antioxidants (vitamin C or a green tea polyphenol, epigallocathechin gallate) quenched the ROS and prevented the increase in E. coli internalization and translocation evoked by indomethacin, but not the drop in TER. Evidence of increased apoptosis was not observed in this model. The data implicate epithelial-derived ROS in indomethacin-induced barrier dysfunction and show that a portion of the bacteria likely cross the epithelium via a transcellular pathway. We speculate that addition of antioxidants as dietary supplements to NSAID treatment regimens would reduce the magnitude of decreased barrier function, specifically the transepithelial passage of bacteria.

  • 59.
    Schoultz, Ida
    et al.
    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 for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    McKay, Derek M
    University of Calgary.
    Is Metabolic Stress a Common Denominator in Inflammatory Bowel Disease?2011In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 17, no 9, p. 2008-2018Article, review/survey (Refereed)
    Abstract [en]

    The enteric epithelium represents the major boundary between the outside world and the body, and in the colon it is the interface between the host and a vast and diverse microbiota. A common feature of inflammatory bowel disease (IBD) is decreased epithelial barrier function, and while a cause-and-effect relationship can be debated, prolonged loss of epithelial barrier function (whether this means the ability to sense bacteria or exclude them) would contribute to inflammation. While there are undoubtedly individual nuances in IBD, we review data in support of metabolic stress-that is, perturbed mitochondrial function-in the enterocyte as a contributing factor to the initiation of inflammation and relapses in IBD. The postulate is presented that metabolic stress, which can arise as a consequence of a variety of stimuli (e.g., infection, bacterial dysbiosis, and inflammation also), will reduce epithelial barrier function and perturb the enterocyte-commensal flora relationship and suggest that means to negate enterocytic metabolic stress should be considered as a prophylactic or adjuvant therapy in IBD.

  • 60.
    Schoultz, Ida
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Halfvarsson, Jonas
    Örebro University Hospital.
    Torkvist, Leif
    Karolinska University Hospital.
    Fredrikson, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine . Linköping University, Faculty of Health Sciences.
    Sjoqvist, Urban
    Karolinska University Hospital.
    Lordal, Mikael
    Karolinska University Hospital.
    Tysk, Curt
    Örebro University Hospital.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. 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.
    Combined Polymorphisms in Genes Encoding the Inflammasome Components NALP3 and CARD8 Confer Susceptibility to Crohns Disease in Swedish Men2009In: American Journal of Gastroenterology, ISSN 0002-9270, E-ISSN 1572-0241, Vol. 104, no 5, p. 1180-1188Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES : Crohns disease (CD) is characterized by overproduction of proinflammatory cytokines like interleukin (IL)-1 beta. Production of mature IL-1 beta is dependent on a caspase-1-activating protein complex called the NALP3 inflammasome, composed of NALP3, ASC, and CARD8. NALP3 shares structural similarities with Nod2, and both of these proteins are required for bacteria-induced IL-1 beta secretion. The combination of the polymorphisms CARD8 (C10X) and NALP3 (Q705K) was recently shown to be associated with rheumatoid arthritis. Our aim was to investigate whether these combined polymorphisms play a role in the susceptibility to CD.

    METHODS: The study included 498 CD patients in two cohorts from different regions and 742 control individuals from a Swedish population. DNA was isolated from whole blood. Polymorphisms of (Q705K) NALP3 and (C10X) CARD8, as well as the Nod2 variants, R702W and G908R, were genotyped using the Taqman single nucleotide polymorphism assay. The Nod2 frameshift mutation, L1007fs, was detected by Megabace SNuPe genotyping.

    RESULTS: Our results show that men who have both the C10X and Q705K alleles in CARD8 and NALP3, and who express wild-type alleles of Nod2 are at an increased risk of developing CD (odds ratio, OR: 3.40 range: 1.32-8.76); P = 0.011). No association with these polymorphisms was found in women (OR: 0.89 (range: 0.44-1.77); P = 0.74).

    CONCLUSIONS: We suggest a role for combined polymorphisms in CARD8 and NALP3 in the development of CD in men, with obvious sex differences in the genetic susceptibility pattern. These findings give further support to the importance of innate immune responses in CD.

  • 61.
    Silva, M.A.
    et al.
    Department of Pathology and Molecular Medicine, McMaster University, Health Science Centre 3N5C, 1200 Main St. West, Hamilton, ON L8N 3Z5, Canada.
    Quera, R.
    Internal Medicine Department, University of Chile Clinical Hospital, Clínica Las Condes, Santiago, Chile.
    Valenzuela, J.
    Internal Medicine Department, University of Chile Clinical Hospital, Clínica Las Condes, Santiago, Chile.
    Salim, Sa´ad
    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.
    Perdue, M.H.
    Department of Pathology and Molecular Medicine, McMaster University, Health Science Centre 3N5C, 1200 Main St. West, Hamilton, ON L8N 3Z5, Canada.
    Dendritic cells and toll-like receptors 2 and 4 in the ileum of Crohn's disease patients2008In: Digestive Diseases and Sciences, ISSN 0163-2116, E-ISSN 1573-2568, Vol. 53, no 7, p. 1917-1928Article in journal (Refereed)
    Abstract [en]

    We investigated myeloid-dendritic cell (DC) marker and Toll-like receptor (TLR)-2 and 4 distributions in ileal samples from Crohn's disease (CD) patients (n = 14) and controls (n = 13). In controls, no TLR-2+ cells were observed, and higher numbers of TLR-4+ and DC-SIGN+ cells (P < 0.01) were detected in ileal samples when compared versus colonic tissues. In non-inflamed CD ileum, TLR-4+ and DC-SGN+ cells were depleted from superficial areas of the villus, and a significant CD1a+ cell infiltration (P < 0.01) was observed when compared to ileal controls and non-inflamed colonic CD samples. In inflamed CD ileum, DC-SIGN+, CD1a+, TLR-4+ and few TLR-4 +DC-SIGN+ cells were detected as well as CD83 depletion. No correlation between TLR-2 and DC markers was detected in CD samples. A unique distribution of myeloid-DC markers characterized the CD ileum. Also, the presence of significant amounts of ileal CD1a+ cells may provide a relevant DC-mediated mechanism for antigen recognition in the pathogenesis of CD. © 2007 Springer Science+Business Media, LLC.

  • 62.
    Sjödahl, Rune
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Myrelid, Pär
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Söderholm, Johan D
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Anal and rectal cancer in Crohn's disease2003In: Colorectal Disease, ISSN 1462-8910, E-ISSN 1463-1318, Vol. 5, no 5, p. 490-495Article in journal (Refereed)
    Abstract [en]

    Several epidemiological studies have been published regarding the risk of Crohn's disease- associated colorectal cancer. The findings are, however, contradictory and it has been particularly difficult to obtain indisputable information on the incidence of cancer limited to the rectum and the anus. During 1987-2000 rectal or anal cancer was diagnosed in 335 patients in Sweden (153 males, 182 females). In other words, approximately 3 Crohn patients per million inhabitants were diagnosed with rectal or anal cancer every year during that time period which is 1% of the total number of cases. At diagnosis of cancer 36% were aged below 50 years and 58% below 60 years. Corresponding figures for all cases of anal and rectal cancer were 5% and 18%, respectively. Present knowledge from the literature implies that there is an increased risk of rectal and anal cancer only in Crohn's disease patients with severe proctitis or severe chronic perianal disease. However, the rectal remnant must also be considered a risk factor. Multimodal treatment is similar to that in sporadic cancer but proctectomy and total or partial colectomy is added depending on the extent of the Crohn's disease. The outcome is the same as in sporadic cancer at a corresponding stage but the prognosis is often poor due to the advanced stage of cancer at diagnosis. We suggest that six high-risk groups should be recommended annual surveillance after a duration of Crohn's disease of 15 years including extensive colitis, chronic severe anorectal disese, rectal remnant, strictures, bypassed segments and sclerosing cholangitis.

  • 63.
    Sjöstedt, Camilla
    et al.
    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.
    Hannestad, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Division of clinical chemistry.
    Franzén, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    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.
    Borch, Kurt
    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.
    Atrophic gastritis is associated with increased sucrose permeability related to chronic inflammation2005In: Digestion, ISSN 0012-2823, E-ISSN 1421-9867, Vol. 72, no 4, p. 201-206Article in journal (Refereed)
    Abstract [en]

    Background: Different theories have been presented to explain how atrophic gastritis may lead to gastric cancer development. One contributing factor could be impaired function of the gastric mucosal barrier. The aim of this study was to investigate if there are changes in gastric mucosal permeability to sucrose in atrophic gastritis. Methods: The study comprised 22 patients with atrophic gastritis and 21 normal controls. Gastritis was classified according to the Sydney system from endoscopic biopsies of the gastric corpus and antrum. All subjects were exposed to oral sucrose load (100 g), and the fraction of sucrose excreted in urine was measured by gas chromatography-mass spectrometry. Results: The fraction of sucrose excreted in urine after oral load was significantly increased in atrophic gastritis compared with controls (median 0.08 vs. 0.04%, p = 0.003). Sucrose excretion was positively related to the degree of chronic inflammation (median fraction excreted: mild inflammation 0.06%, moderate inflammation 0.08%, severe inflammation 0.18%, p = 0.04) rather than to the degree of atrophy in the gastric mucosa. Occurrence of intestinal metaplasia was also associated with significantly higher sucrose excretion. However, in multivariate analysis, including intestinal metaplasia, only the degree of inflammation was positively related to sucrose excretion. Conclusion: Atrophic gastritis is associated with increased sucrose permeability, suggesting paracellular leakage of the gastric mucosa. This leakage seems to be related to the degree of inflammation rather than the degree of atrophy. The findings may have implications for the diseases and complications associated with atrophic gastritis. Copyright © 2005 S. Karger AG.

  • 64.
    Sun, Yi-Qian
    et al.
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Petersson, Fredrik
    Pathology Research Department, Ryhov Hospital, Jönköping.
    Monstein, Hans-Jürg
    Östergötlands Läns Landsting, LMÖ - Laboratoriemedicin i Östergötland.
    Söderholm, Johan D
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Rehfeld, Jens F
    Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen.
    Borch, Kurt
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Long-term morpho-functional development of Helicobacter pylori-induced gastritis in Mongolian gerbils2005In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 40, no 10, p. 1157-1167Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Epidemiological studies have shown that Helicobacter pylori infection with associated chronic gastritis is the main risk factor for development of gastric cancer. The aim of this study was to investigate the long-term development of H. pylori-induced gastritis in Mongolian gerbils in terms of morphology, gastrin secretion, epithelial proliferation and gene expression of pro-inflammatory cytokines.

    MATERIAL AND METHODS:

    A total of 133 gerbils were inoculated with H. pylori and 62 served as controls. The gerbils were killed at different time-points between 6 and 94 weeks after inoculation. Serum concentrations of anti-H. pylori IgG and gastrin were determined by enzyme-linked immunoabsorbent assay (ELISA) and radioimmunoassay (RIA), respectively. Epithelial proliferation was evaluated immunohistochemically after labeling with 5-bromo-2'-deoxy-uridine. Gene expression of beta-actin, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) were measured by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Histological parameters of gastritis were assessed semiquantitatively and expressed as a "gastritis score".

    RESULTS:

    Serum concentrations of anti-H. pylori IgG and gastrin increased over time. Epithelial proliferation in the antrum was increased 6 weeks after inoculation, followed by increased proliferation in the corpus 32 weeks after inoculation. Gene expression of IL-1beta and TNF-alpha were increased in H. pylori-infected gerbils. Beta-actin was not a reliable endogenous control for RT-PCR. With time, gastritis expanded from the antrum to the corpus and the gastritis score increased to reach a peak 32 weeks after inoculation. Pseudopyloric metaplasia (loss of specialized cells) was a characteristic feature in the corpus mucosa. Gastric ulcers, but neither dysplasia nor carcinoma, were observed during 94 weeks of infection.

    CONCLUSIONS:

    Long-term H. pylori infection in Mongolian gerbils led to progressive gastritis, glandular atrophy, hypergastrinemia, increased epithelial proliferation and elevated gene expression of pro-inflammatory cytokines.

  • 65.
    Sun, Yi-Qian
    et al.
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Söderholm, Johan D
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Petersson, Fredrik
    Pathology Research Department, Ryhov Hospital, Jönköping, Sweden.
    Borch, Kurt
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Long-standing gastric mucosal barrier dysfunction in Helicobacter pylori-induced gastritis in Mongolian gerbils2004In: Helicobacter, ISSN 1083-4389, E-ISSN 1523-5378, Vol. 9, no 3, p. 217-227Article in journal (Refereed)
    Abstract [en]

    Background and Aims. Helicobacter pylori infection causes chronic gastritis and leads to peptic ulcer and gastric adenocarcinoma. An impaired gastric mucosal barrier could be involved in these processes. Our aim was to investigate gastric barrier function in H. pylori-induced gastritis.

    Methods.  Stripped gastric mucosal tissues of H. pylori-infected Mongolian gerbils (4 weeks and 70 weeks after inoculation, respectively) and controls were mounted in Ussing chambers. 51Cr-EDTA (paracellular probe) and horseradish peroxidase (HRP, protein antigen) were used to assess mucosal barrier function. The electrophysiological parameters of the mucosa (transepithelial potential, short circuit current, and transepithelial resistance) were monitored as measurements of barrier integrity and viability. Tissue histology was performed to assess inflammation.

    Results.  In the antrum, both short-term gastritis [4.68 (3.88–5.74) × 10−6 vs. control 2.86 (2.34–3.77) × 10−6 cm/s, p < .001] and gastritis of long-standing [5.72 (3.88–10.94) × 10−6 cm/s, p < .001 vs. control] showed increased permeability to 51Cr-EDTA. In long-standing antral gastritis there was also an increased HRP flux [9.01 (2.98–45.02) vs. control 0.52 (0.06–1.20) pmol/h/cm2, p < .001]. In the corpus, permeability to 51Cr-EDTA was increased only in long-standing gastritis [4.63 (3.64–7.45) × 10−6 vs. control 2.86 (2.12–3.98) × 10−6 cm/s, p < .01]. Gastric mucosal permeability to 51Cr-EDTA was correlated to histological inflammation and inflammatory activity. The levels of serum anti-H. pylori immunoglobulin G were positively correlated to HRP flux and 51Cr-EDTA permeation.

    Conclusions. Helicobacter pylori-induced gastritis in Mongolian gerbils was associated with a long-standing gastric mucosal barrier dysfunction. The barrier defect extended from the antrum into the corpus over time. This impaired barrier function may contribute to perpetuation of chronic inflammation and may be involved in H. pylori-associated carcinogenesis.

  • 66.
    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.
    Gut immunology: Nanoparticles ferry gut antigens2015In: Nature Nanotechnology, ISSN 1748-3387, E-ISSN 1748-3395, Vol. 10, no 4, p. 298-299Article in journal (Other academic)
    Abstract [en]

    n/a

  • 67.
    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.
    Intestinal permeability in NEUROGASTROENTEROLOGY AND MOTILITY, vol 24, issue , pp 11-112012In: NEUROGASTROENTEROLOGY AND MOTILITY, Blackwell Publishing , 2012, Vol. 24, p. 11-11Conference paper (Refereed)
    Abstract [en]

    n/a

  • 68.
    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.
    Mast Cells and Mastocytosis2009In: DIGESTIVE DISEASES, ISSN 0257-2753, Vol. 27, p. 129-136Article in journal (Refereed)
    Abstract [en]

    Mast cells (MCs) typically reside at barrier sites of the body, including the intestinal mucosa, and play a vital role in innate host defence. Activated MCs release a wide variety of bioactive mediators. These include preformed mediators stored in the granules (e. g. histamine and tryptase) and newly synthesised mediators (e. g. prostaglandins, leukotrienes and cytokines). MCs are present in all layers throughout the gastrointestinal (GI) tract and there is a close bi-directional connection between MCs and enteric nerves that is of vital importance in the regulation of GI functions. Some gain-of-function mutations in c-kit, encoding the tyrosine kinase-receptor for stem cell factor, are associated with the rare disease entity, systemic mastocytosis. These patients present symptoms arising from MC mediator release or infiltration. GI manifestations are common in this patient group, mainly abdominal pain and diarrhoea. Endoscopy with biopsies reveals MC infiltration in the mucosa. Other diagnostic tools include bone marrow biopsy and serum tryptase. Treatment is symptomatic with antihistamines or cromoglycate in mild cases, whereas severe cases need cytoreductive therapy that should be managed with expert haematologists. From a day-to-day clinical perspective, the important role of MCs in neuroimmune interaction has been implicated in the intestinal response to stress, in alterations of mucosal and neuromuscular function in irritable bowel syndrome or inflammatory bowel disease, and in the pathogenesis of nonerosive oesophageal reflux disease. Thus, MCs have important regulatory and protective roles in innate defence, in addition to being a potential mediator of mucosal pathophysiology in GI diseases. We need to learn how to balance the response of these volatile cells to be able to benefit from their versatility.

  • 69.
    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.
    Stress-related changes in oesophageal permeability: Filling the gaps of GORD?2007In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 56, no 9, p. 1177-1180Article, review/survey (Refereed)
    Abstract [en]

    Albeit remaining a controversial issue, it has become increasingly recognised that psychological stress has a major impact on gut mucosal function and affects the course of gastrointestinal disorders. Research during the last decade has shown that stress causes barrier dysfunction of the gastrointestinal mucosa by mechanisms that mainly involve neuropeptides and mast cells. Moreover, accumulating evidence implicates increased permeability as a pathogenic factor in gastroesophageal reflux disease (GORD). Recent data demonstrating that psychological stress may induce a permeability defect in stratified epithelia, including the oesophagus, shed new light on the pathophysiological events leading to heartburn and GORD.

  • 70.
    Söderholm, Johan D
    et al.
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Holmgren Peterson, Kajsa
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Olaison, Gunnar
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Franzén, Lennart E.
    Department of Pathology, Lund University–MAS, Malmö.
    Weström, Björn
    Department of Animal Physiology, Lund University, Lund, Sweden.
    Magnusson, Karl-Eric
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Sjödahl, Rune
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Epithelial permeability to proteins in the noninflamed ileum of Crohn's disease?1999In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 117, no 1, p. 65-72Article in journal (Refereed)
    Abstract [en]

    Background & Aims: Crohn's disease (CD) is associated with a disturbed intestinal barrier. Permeability studies have focused on inert molecules, but little is known about transepithelial transport of macromolecules with antigenic potential in humans. The aim of this study was to quantify permeation and to characterize passage routes for macromolecules in ileal mucosa in CD.

    Methods: Noninflamed and inflamed ileal mucosa specimens from patients with CD (n = 12) and ileal specimens from patients with colon cancer (n = 7) were studied regarding transmucosal permeation of ovalbumin, dextran (mol wt, 40,000), and 51Cr-EDTA for 90 minutes in vitro in Ussing chambers. Transepithelial passage routes for fluorescent ovalbumin and dextran 40,000 were investigated by confocal microscopy.

    Results: Noninflamed ileum from CD patients showed increased permeation of ovalbumin compared with ileum from colon cancer patients (P < 0.05). Dextran permeation was equal in the three groups, whereas 51Cr-EDTA permeability was increased in inflamed ileum. Ovalbumin passed both transcellularly and paracellularly, but dextran followed a strictly paracellular route. Both markers were subsequently endocytosed by cells of the lamina propria.

    Conclusions: Noninflamed ileal mucosa from patients with CD shows increased epithelial permeability to ovalbumin, probably by augmented transcytosis. This increase in antigen load to the lamina propria could be an initiating pathogenic event in CD.

  • 71.
    Söderholm, Johan D
    et al.
    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.
    Juliusson, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Sjödahl, Rune
    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.
    Long-term endoscopic remission in a case of Crohn's disease after autologous bone marrow transplantation.2000In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 118, no 4, p. 4212-Conference paper (Other academic)
  • 72.
    Söderholm, Johan D
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Malm, Claes
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Hematology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Juliusson, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Hematology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Sjödahl, Rune
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Long-term endoscopic remission of Crohn disease after autologous stem cell transplantation for acute myeloid leukaemia2002In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 37, no 5, p. 613-616Article in journal (Refereed)
    Abstract [en]

    A favourable course of Crohn disease has been observed after allogeneic bone marrow transplantation, and there is now mounting evidence that autologous stem cell may be an effective treatment for severe autoimmune diseases. Here, we present the first long-term endoscopic follow-up of a patient with Crohn disease undergoing autologous stem cell transplantation for haematological disease. A 54-year-old woman developed Crohn disease and was submitted to ileocaecal resection. Four months after surgery, the patient contracted acute myeloid leukaemia. She was initially treated with chemotherapy, and subsequently underwent autologous stem cell transplantation. Following transplantation, the patient has remained in clinical remission regarding both diseases, without anti-inflammatory medication. She has undergone ileo-colonoscopy with normal findings at 1, 2, 3 and 5 years after transplantation. This case suggests that autologous stem cell transplantation can change not only the clinical course, but also the natural history of intestinal inflammation in Crohn disease. This has pathophysiological as well as therapeutic implications.

  • 73.
    Söderholm, Johan D
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Olaison, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Lindberg, E
    Hannestad, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Vindels, A
    Tysk, C
    Janerot, G
    Sjödahl, Rune
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Different intestinal permeability patterns in relative and spouses of patients with Crohn's disease: an inherited defect in mucosal defence?1999In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 44, p. 96-100Article in journal (Refereed)
  • 74.
    Söderholm, Johan D
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Olaison, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Peterson, KH
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Franzén, LE
    Lindmark, T
    Wirén, Mikael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Tagesson, Christer
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Occupational and Environmental Medicine. Östergötlands Läns Landsting, Pain and Occupational Centre, Occupational and Environmental Medicine Centre.
    Sjödahl, Rune
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Augmented increase in tight junction permeability by luminal stimuli in the non-inflamed ileum of crohn's disease2002In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 50, no 3, p. 307-313Article in journal (Refereed)
    Abstract [en]

    Background: Crohn's disease is associated with deranged intestinal permeability in vivo, suggesting dysfunction of tight junctions. The luminal contents are important for development of neoinflammation following resection. Regulation of tight junctions by luminal factors has not previously been studied in Crohn's disease. Aims: The aim of the study was to investigate the effects of a luminal stimulus, known to affect tight junctions, on the distal ileum in patients with Crohn's disease. Patients: Surgical specimens from the distal ileum of patients with Crohn's disease (n=l 2) were studied, and ileal specimens from colon cancer patients (n=l 3) served as controls. Methods: Mucosal permeability to 51Cr-EDTA and electrical resistance were studied in Ussing chambers during luminal exposure to sodium caprate (a constituent of milk fat, affecting tight junctions) or to buffer only. The mechanisms involved were studied by mucosal ATP levels, and by electron and confocal microscopy. Results: Baseline permeability was the same in non-inflamed ileum of Crohn's disease and controls. Sodium caprate induced a rapid increase in paracellular permeability - that is, increased permeation of 51Cr-EDTA and decreased electrical resistance - which was more pronounced in non-inflamed ileum of Crohn's disease, and electron microscopy showed dilatations within the tight junctions. Moreover, sodium caprate induced disassembly of perijunctional filamentous actin was more pronounced in Crohn's disease mucosa. Mucosal permeability changes were accompanied by mitochondrial swelling and a fall in epithelial ATP content, suggesting uncoupling of oxidative phosphorylation. Conclusions: The tight junctions in the non-inflamed distal ileum of Crohn's disease were more reactive to luminal stimuli, possibly mediated via disturbed cytoskeletal contractility. This could contribute to the development of mucosal neoinflammation in Crohn's disease.

  • 75.
    Söderholm, Johan D
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Perdue, Mary H
    Stress and the gastrointestinal tract II. Stress and intestinal barrier function.2001In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 280Article in journal (Refereed)
  • 76.
    Söderholm, Johan D
    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.
    Pettersson, S.
    Institutionen för mikrobiologi, tumör- och cellbiologi (MTC), Karolinska institutet, Stockholm, Sweden.
    Polygenetisk störning i första linjens mukosaförsvar2009In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 106, no 45, p. 2974-2978Article in journal (Refereed)
    Abstract [en]

    [No abstract available]

  • 77.
    Söderholm, Johan D
    et al.
    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.
    Streutker, C
    Yang, P-C
    Paterson, C
    Singh, PK
    McKay, DM
    Sherman, PM
    Croitoru, K
    Perdue, MH
    Increased epithelial uptake of protein antigens in the ileum of Crohn's disease mediated by tumour necrosis factor α2004In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 53, no 12, p. 1817-1824Article in journal (Refereed)
    Abstract [en]

    Background and aims: The exact nature of the epithelial barrier defect in Crohn's disease remains to be elucidated. Previously we showed increased permeability to proteins in ileal Crohn's disease. Our aims were to study if this barrier defect (a) involves endocytotic uptake of antigens and (b) is related to low grade inflammation not detectable by histology. Methods: Macroscopically normal segments of distal ileum of Crohn's disease patients (n = 10) were subgrouped into non-inflamed (histologically unaffected) and slightly inflamed tissues and studied in Ussing chambers, with normal ileal specimens from colon cancer patients (n = 9) as controls. Endocytotic uptake into enterocytes of the protein antigen horseradish peroxidase was assessed by measuring the area of horseradish peroxidase containing endosomes in electron photomicrographs. Mucosal tumour necrosis factor α (TNF-α) mRNA was quantified using real time polymerase chain reaction. For comparison, the effects of low doses of TNF-α on endosomal uptake of horseradish peroxidase were studied in cultured T84 cells grown on filter supports. Results: The area of horseradish peroxidase containing endosomes was increased (p<0.001) in enterocytes of non-inflamed ileum of Crohn's disease (2.8 (0.7) μm2/300 μm2) compared with control ileum (0.6 (0.06)). In non-inflamed mucosa, a significant association between endosomal uptake and mucosal expression of TNF-α mRNA (p = 0.03) was found. Low concentrations of TNF-α (0.25-1.0 ng/ml) enhanced the endosomal uptake of horseradish peroxidase in polarised T84 cells, without affecting transepithelial electrical resistance. Conclusions: Our findings suggest increased endosomal uptake of antigens in ileal Crohn's disease that may be mediated by TNF-α. These data highlight the transcellular route of antigen uptake in barrier dysfunction and implicate the interaction between epithelial cells and the innate immune system in the development of mucosal inflammation.

  • 78.
    Söderholm, Johan D
    et al.
    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.
    Wiren, M
    Linkoping Univ, Linkoping, Sweden McMaster Univ, Hamilton, ON, Canada.
    Franzén, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Perdue, MH
    Linkoping Univ, Linkoping, Sweden McMaster Univ, Hamilton, ON, Canada.
    Olaison, Gunnar
    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.
    "Topical" phase effects of acetysalicylic acid on human small bowel epithelium: Inhibition of oxidative phosphorylation and increased tight junction permeability.2000In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 118, no 4, p. 4298-Conference paper (Other academic)
  • 79.
    Söderholm, Johan D
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Yang, Ping-Chang
    Ceponis, Peter
    Vohra, Angeli
    Riddell, Robert
    Sherman, Philip M
    Perdue, Mary
    Chronic stress induces mast cell-dependent bacterial adherence and initiates mucosal inflammation in rat intestine2002In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 123, p. 1099-1108Article in journal (Refereed)
  • 80.
    Söderholm, Johan D
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Yates, Derrick
    Gareau, Mélanie
    Yang, Ping-Chang
    MacQueen, Glenda
    Perdue, Mary
    Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress2002In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 283, p. 1257-1263Article in journal (Refereed)
  • 81.
    Tiveljung, Annika
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Söderholm, Johan D.
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Olaison, Gunnar
    Linköping University, Department of Biomedicine and Surgery, Surgery. Linköping University, Faculty of Health Sciences.
    Jonasson, Jon
    Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Monstein, Hans-Jürg
    Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Presence of eubacteria in biopsies from Crohn's disease inflammatory lesions as determined by 16S rRNA gene-based PCR1999In: Journal of Medical Microbiology, ISSN 0022-2615, E-ISSN 1473-5644, Vol. 48, no 3, p. 263-268Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to search for putative microbial agents in Crohn's disease (CD) tissues by bacterial broad-range 16S rDNA PCR combined with genus- and species-specific DNA hybridisation analysis. Biopsies taken both surgically and endoscopically from the terminal ileum of 11 CD patients and 11 control patients were investigated. Significant amounts of eubacteria were demonstrated in biopsies taken endoscopically from both affected and unaffected individuals; the biopsies taken at surgery from control patients were negative. Three of five biopsies taken surgically from CD patients harboured Helicobacter spp.-, Mycobacterium paratuberculosis-, Listeria monocytogenes- and Escherichia coli-like 16S rDNA sequences. These findings show the importance of the sampling method chosen when combined with molecular typing of eubacteria in intestinal tissues. The mixed bacterial flora found in the surgical biopsies from CD patients supports the idea that the enteric microflora enters primary lesions where secondary bacterial colonisers may elicit a chronic inflammatory syndrome.

  • 82.
    Van Assche, Gert
    et al.
    University Hospital Gasthuisberg.
    Dignass, Axel
    Frankfurter Diakonie Kliniken.
    Reinisch, Walter
    AKH Wien, Vienna, Austria .
    Janneke van der Woude, C
    Erasmus MC, Rotterdam, Netherlands .
    Sturm, Andreas
    Ghent University Hospital.
    Guslandi, Mario
    IRCCS San Raffaele, Milan, Italy .
    Oldenburg, Bas
    Tel Aviv University.
    Marteau, Philippe
    Lariboisiere Hospital, Paris.
    Ardizzone, Alessandro
    Osped L Sacco, Milan, Italy .
    C Baumgart, Daniel
    Humboldt University.
    DHaens, Geert
    Imelda GI Clin Research Centre, Bonheiden, Belgium .
    Gionchetti, Paolo
    University Bologna.
    Portela, Francisco
    Coimbra University Hospital.
    Vucelic, Boris
    University Hospital Rebro.
    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.
    Escher, Johanna
    Erasmus MC, Sophia Childrens Hospital, Rotterdam, Netherlands .
    Koletzko, Sibylle
    Dr V Haunersches Kinderspital, Munich, Germany .
    Kolho, Kaija-Leena
    Hospital Children and Adolescents, Helsinki, Finland .
    Lukas, Milan
    Clin Centre ISACRE Lighthouse, Prague.
    Mottet, Christian
    University Lausanne Hospital.
    Tilg, Herbert
    Bezirkskrankenhaus Hall Tirol, Hall In Tirol, Austria .
    Vermeire, Severine
    University Hospital Gasthuisberg.
    Carbonnel, Frank
    Besancon University Hospital.
    Cole, Andrew
    Derby Hospital NHS Fdn Trust.
    Novacek, Gottfried
    Med University Vienna.
    Reinshagen, Max
    Klinikum Braunschweig.
    Tsianos, Epameinondas
    University Ioannina.
    Herrlinger, Klaus
    Robert Bosch Krankenhaus.
    Oldenburg, Bas
    University Med Centre Utrecht.
    Bouhnik, Yoram
    Beaujon Hospital.
    Kiesslich, Ralf
    Johannes Gutenberg University Mainz.
    Stange, Eduard
    Robert Bosch Krankenhaus.
    Travis, Simon
    John Radcliffe Hospital.
    Lindsay, James
    Barts and London NHS Trust.
    The second European evidence-based Consensus on the diagnosis and management of Crohns disease: Special situations2010In: JOURNAL OF CROHNS and COLITIS, ISSN 1873-9946, Vol. 4, no 1, p. 63-101Article in journal (Refereed)
    Abstract [en]

    n/a

  • 83.
    Vanheel, H
    et al.
    Katholieke University of Leuven, Belgium .
    Vicario, M
    Institute Recerca, Spain .
    Martinez, C
    Institute Recerca, Spain .
    Vanuytsel, T
    Katholieke University of Leuven, Belgium .
    Pardon, N
    Katholieke University of Leuven, Belgium .
    Santos, J
    Institute Recerca, Spain .
    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.
    Tack, J
    Katholieke University of Leuven, Belgium .
    Farre, R
    Katholieke University of Leuven, Belgium .
    Duodenal low-grade inflammation and impaired mucosal integrity in functional dyspepsia patients in NEUROGASTROENTEROLOGY AND MOTILITY, vol 24, issue , pp 24-252012In: NEUROGASTROENTEROLOGY AND MOTILITY, Blackwell Publishing , 2012, Vol. 24, p. 24-25Conference paper (Refereed)
    Abstract [en]

    n/a

  • 84.
    Vanheel, Hanne
    et al.
    Katholieke University of Leuven, Belgium .
    Vicario, Maria
    University of Autonoma Barcelona, Spain Centre Invest Biomed Red Enfermedades Hepat and Digest, Spain .
    Vanuytsel, Tim
    Katholieke University of Leuven, Belgium .
    Van Oudenhove, Lukas
    Katholieke University of Leuven, Belgium .
    Martinez, Cristina
    University of Autonoma Barcelona, Spain .
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Pardon, Nicolas
    Katholieke University of Leuven, Belgium .
    Santos, Javier
    University of Autonoma Barcelona, Spain Centre Invest Biomed Red Enfermedades Hepat and Digest, Spain .
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Tack, Jan
    Katholieke University of Leuven, Belgium .
    Farre, Ricard
    Katholieke University of Leuven, Belgium Centre Invest Biomed Red Enfermedades Hepat and Digest, Spain .
    Impaired duodenal mucosal integrity and low-grade inflammation in functional dyspepsia2014In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 63, no 2, p. 262-271Article in journal (Refereed)
    Abstract [en]

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

  • 85.
    Velin Keita, Åsa
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Ericson, Ann-Charlott
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Braaf, Ylva
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Wallon, Conny
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Increased antigen and bacterial uptake in follicle-associated epithelium induced by chronic psychological stress in rats2004In: Gut, ISSN 0017-5749, Vol. 53, no 4, p. 494-500Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

  • 86.
    Vicario, Maria
    et al.
    Vall dHebron Institute Recerca, Spain; University of Autonoma Barcelona, Spain; University of Autonoma Barcelona, Spain; Centre Invest Biomed Red Enfermedades Hepat and Digest, Spain.
    Gonzalez-Castro, Ana M.
    Vall dHebron Institute Recerca, Spain; University of Autonoma Barcelona, Spain; University of Autonoma Barcelona, Spain.
    Martinez, Cristina
    Heidelberg University, Germany.
    Lobo, Beatriz
    Vall dHebron Institute Recerca, Spain; University of Autonoma Barcelona, Spain; University of Autonoma Barcelona, Spain.
    Pigrau, Marc
    Vall dHebron Institute Recerca, Spain; University of Autonoma Barcelona, Spain; University of Autonoma Barcelona, Spain.
    Guilarte, Mar
    University of Autonoma Barcelona, Spain; University of Autonoma Barcelona, Spain.
    de Torres, Ines
    University of Autonoma Barcelona, Spain; University of Autonoma Barcelona, Spain.
    Mosquera, Jose L.
    University of Barcelona, Spain.
    Fortea, Marina
    Vall dHebron Institute Recerca, Spain; University of Autonoma Barcelona, Spain; University of Autonoma Barcelona, Spain.
    Sevillano-Aguilera, Cesar
    Vall dHebron Institute Recerca, Spain; University of Autonoma Barcelona, Spain; University of Autonoma Barcelona, Spain.
    Salvo-Romero, Eloisa
    Vall dHebron Institute Recerca, Spain; University of Autonoma Barcelona, Spain; University of Autonoma Barcelona, Spain.
    Alonso, Carmen
    Vall dHebron Institute Recerca, Spain; University of Autonoma Barcelona, Spain; University of Autonoma Barcelona, Spain; Centre Invest Biomed Red Enfermedades Hepat and Digest, Spain.
    Rodino-Janeiro, Bruno K.
    Vall dHebron Institute Recerca, Spain; University of Autonoma Barcelona, Spain; University of Autonoma Barcelona, Spain.
    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.
    Azpiroz, Fernando
    Vall dHebron Institute Recerca, Spain; University of Autonoma Barcelona, Spain; University of Autonoma Barcelona, Spain; Centre Invest Biomed Red Enfermedades Hepat and Digest, Spain.
    Santos, Javier
    Vall dHebron Institute Recerca, Spain; University of Autonoma Barcelona, Spain; University of Autonoma Barcelona, Spain; Centre Invest Biomed Red Enfermedades Hepat and Digest, Spain.
    Increased humoral immunity in the jejunum of diarrhoea-predominant irritable bowel syndrome associated with clinical manifestations2015In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 64, no 9, p. 1379-1388Article in journal (Refereed)
    Abstract [en]

    Background and aims Altered intestinal barrier is associated with immune activation and clinical symptoms in diarrhoea-predominant IBS (IBS-D). Increased mucosal antigen load may induce specific responses; however, local antibody production and its contribution to IBS aetiopathogenesis remain undefined. This study evaluated the role of humoral activity in IBS-D. Methods A single mucosal jejunal biopsy, luminal content and blood were obtained from healthy volunteers (H; n = 30) and IBS-D (n = 49; Rome III criteria) participants. Intraepithelial lymphocytes, mast cells, B lymphocytes and plasma cells were studied by imaging techniques. Differential gene expression and pathway analysis were assessed by microarray and PCR techniques. Blood and luminal immunoglobulins (Igs) were quantified. Gastrointestinal symptoms, respiratory atopy and stress and depression were also recorded. Results Patients with IBS-D showed a higher number and activation of mucosal B lymphocytes and plasma cells (p less than 0.05). Mast cell density was increased in patients with IBS-D (non-atopic) and in close proximity to plasma cells (p less than 0.05). Microarray profiling identified differential humoral activity in IBS-D, involving proliferation and activation of B lymphocytes and Igs production (p less than 0.001). Mucosal humoral activity was higher in IBS-D, with upregulation of germline transcripts and Ig genes (1.3-fold-1.7-fold increase; p less than 0.05), and increased IgG(+) cells and luminal IgG compared with H (p less than 0.05), with no differences in blood. Biological markers of humoral activity correlated positively with bowel movements, stool form and depression. Conclusions Enhanced small bowel humoral immunity is a distinctive feature of IBS-D. Mucosal Ig production contributes to local inflammation and clinical manifestations in IBS-D.

  • 87.
    Wallon, Conny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Braaf, Ylva
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
    Wolving, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.
    Olaison, Gunnar
    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.
    Endoscopic biopsies in Ussing chambers evaluated for studies of macromolecular permeability in the human colon2005In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, Vol. 40, no 5, p. 586-595Article in journal (Refereed)
    Abstract [en]

    Objective Studies of mucosal permeability to protein antigens in humans are limited to in vitro techniques. The use of surgical specimens for such studies has major shortcomings. Endoscopic biopsies in Ussing chambers have been introduced as a means of studying secretion and transepithelial permeability, but have not been evaluated for studies of protein antigen uptake in human intestine.

    Material and methods Standard forceps biopsies from the sigmoid colon of 24 healthy volunteers were mounted in Ussing chambers with an exposed tissue area of 1.76 mm2. 51Cr-EDTA (paracellular probe) and horseradish peroxidase (HRP; 45 kDa protein antigen) were used as permeability markers. Mucosal permeability, electrophysiology, histology and energy contents of the biopsies were studied over time. To evaluate the ability of the technique to detect permeability changes, the mucosa was modulated with capric acid, a medium-chain fatty acid, known to affect tight junctions.

    Results In the Ussing chamber the mucosal biopsies were viable for 160 min with stable levels of ATP and lactate, and only minor changes in morphology. Steady-state permeability with low variability was seen for both markers during the 30-90 min period. Exposure to capric acid induced a rapid decrease in short-circuit current (Isc) and a slower reversible decrease in transepithelial resistance (TER), as well as an increased permeability to 51Cr-EDTA and HRP.

    Conclusions Endoscopic biopsies of human colon are viable in Ussing chambers and are reliable tools for studies of mucosal permeability to protein antigens. The technique offers a broad potential for studies of mucosal function in the pathophysiology of human gastrointestinal diseases.

  • 88.
    Wallon, Conny
    et al.
    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.
    Persborn, Mats
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Jönsson, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Wang, Arthur
    University of Calgary.
    Phan, Van
    University of Calgary.
    Lampinen, Maria
    Uppsala University.
    Vicario, Maria
    CIBERehd.
    Santos, Javier
    CIBERehd.
    Sherman, Philip M
    University of Toronto.
    Carlson, Marie
    Uppsala University.
    Ericson, Ann-Charlott
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    McKay, Derek M
    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 for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Eosinophils Express Muscarinic Receptors and Corticotropin-Releasing Factor to Disrupt the Mucosal Barrier in Ulcerative Colitis2011In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 140, no 5, p. 1597-1607Article in journal (Refereed)
    Abstract [en]

    BACKGROUND andamp; AIMS: Altered intestinal barrier function has been implicated in the pathophysiology of ulcerative colitis (UC) in genetic, functional, and epidemiological studies. Mast cells and corticotropinreleasing factor (CRF) regulate the mucosal barrier in human colon. Because eosinophils are often increased in colon tissues of patients with UC, we assessed interactions among mast cells, CRF, and eosinophils in the mucosal barrier of these patients. METHODS: Transmucosal fluxes of protein antigens (horseradish peroxidase) and paracellular markers (51Cr-EDTA, fluorescein isothiocyanate-dextran 4000) were studied in noninflamed, colonic mucosal biopsy samples collected from 26 patients with UC and 53 healthy volunteers (controls); samples were mounted in Ussing chambers. We also performed fluorescence and electron microscopy of human tissue samples, assessed isolated eosinophils, and performed mechanistic studies using in vitro cocultured eosinophils (15HL-60), mast cells (HMC-1), and a colonic epithelial cell line (T84). RESULTS: Colon tissues from patients with UC had significant increases in permeability to protein antigens compared with controls. Permeability was blocked by atropine (a muscarinic receptor antagonist), alpha-helical CRF(9-41) (a CRF receptor antagonist), and lodoxamide (a mast-cell stabilizer). Eosinophils were increased in number in UC tissues (compared with controls), expressed the most M2 and M3 muscarinic receptors of any mucosal cell type, and had immunoreactivity to CRF. In coculture studies, carbachol activation of eosinophils caused production of CRF and activation of mast cells, which increased permeability of T84 epithelial cells to macromolecules. CONCLUSIONS: We identified a neuroimmune intercellular circuit (from cholinergic nerves, via eosinophils to mast cells) that mediates colonic mucosal barrier dysfunction in patients with UC. This circuit might exacerbate mucosal inflammation.

  • 89.
    Wallon, Conny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Corticotropin-Releasing Hormone and Mast Cells in the Regulation of Mucosal Barrier Function in the Human Colon2009In: MOLECULAR STRUCTURE AND FUNCTION OF THE TIGHT JUNCTION: FROM BASIC MECHANISMS TO CLINICAL MANIFESTATIONS, ISSN 0077-8923, Vol. 1165, p. 206-210Article in journal (Refereed)
    Abstract [en]

    Corticotropin-releasing hormone (CRH) is an important neuro-endocrine mediator of the stress response. Local effects of CRH in the intestinal mucosa have become evident in recent years. We showed that CRH activates CRH receptor subtypes R1 and R2 on subepithelial mast cells, thereby inducing increased transcellular uptake of protein antigens in human colonic biopsies in Ussing chambers. Ongoing studies also implicate local cholinergic signaling in regulation of macromolecular permeability in the human colon. Since increased uptake of antigenic molecules is associated with mucosal inflammation, our findings may have implications for understanding stress-related intestinal disorders.

  • 90.
    Wallon, Conny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Yang, P.
    Intestinal Disease Research Programme, McMaster University, Hamilton, Canada.
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Ericson, Ann-Charlott
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    McKay, D. M.
    Department of Physiology and Biophysics, University of Calgary, Canada.
    Sherman, P. M.
    Departments of Paediatrics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
    Perdue, M. H.
    Intestinal Disease Research Programme, McMaster University, Hamilton, Canada.
    Söderholm, Johan D.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Corticotropin releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro2008In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 57, no 1, p. 50-58Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 91.
    Wang, Arthur
    et al.
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Keita, Åsa V.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Phan, Van
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    McKay, Catherine M.
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Schoultz, Ida
    Nutrition-Gut-Brain Interactions Research Centre, the Faculty of Medicine, Örebro University, Örebro, Sweden.
    Lee, Joshua
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Murphy, Michael P.
    MRC-Mitochondrial Biology Unit, Cambridge, United Kingdom.
    Fernando, Maria
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Ronaghan, Natalie
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Balce, Dale
    Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada.
    Yates, Robin
    Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada.
    Dicay, Michael
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Beck, Paul L.
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
    MacNaughton, Wallace K.
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Söderholm, Johan D.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Mckay, Derek M.
    Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada, Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
    Targeting Mitochondria-Derived Reactive Oxygen Species to Reduce Epithelial Barrier Dysfunction and Colitis2014In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 184, no 9, p. 2516-2527Article in journal (Refereed)
    Abstract [en]

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

  • 92.
    Wang, X.-Y.
    et al.
    Intestinal Disease Research Program, McMaster University, Hamilton, Ont., Canada.
    Zarate, N.
    Intestinal Disease Research Program, McMaster University, Hamilton, Ont., Canada, Centre for Academic Surgery, Alexandra Wing, Royal London Hospital, Whitechapel, London E1 1BB, United Kingdom.
    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.
    Bourgeois, J.M.
    Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ont., Canada.
    Liu, L.W.C.
    Intestinal Disease Research Program, McMaster University, Hamilton, Ont., Canada.
    Huizinga, J.D.
    Intestinal Disease Research Program, McMaster University, Hamilton, Ont., Canada.
    Ultrastructural injury to interstitial cells of Cajal and communication with mast cells in Crohn's disease2007In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 19, no 5, p. 349-364Article in journal (Refereed)
    Abstract [en]

    Crohn's disease associated dysmotility has been attributed to fibrosis and damage to enteric nerves but injury to interstitial cells of Cajal (ICC) could also be involved. We assessed ICC in specimens obtained from patients with Crohn's disease and determined the relation between ICC and the inflammatory infiltrate, particularly mast cells (MC) using quantitative immunohistochemistry and electron microscopy. Ultrastructural injury to ICC was patchy in all ICC subtypes but ICC-Auerbach's plexus (AP) showed damage more frequently, i.e. swelling of mitochondria, decreased electron density, autophagosomes and partial depletion of the cytoplasm. Light microscopy confirmed a significant decrease in c-kit immunoreactivity for ICC-AP and an increased number of MC in the muscularis externa. Electron microscopy showed MC exhibiting piecemeal degranulation and making frequent and selective membrane-to-membrane contact with all types of injured ICC which suggests chronic release of granule content to affect ICC. Extent of ICC injury was not associated with duration of the disease. In conclusion, ultrastructural injury and loss of ICC-AP is evident in Crohn's disease. Epidemiological and morphological data suggest that ICC have the capacity to regenerate in spite of the chronic insult. The muscularis hosts a marked number of MC that exhibit piecemeal degranulation associated with ICC and may facilitate ICC maintenance. © 2007 The Authors.

  • 93.
    Wirén, M
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Söderholm, Johan D
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Lindgren, J
    Olaison, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Permert, J
    Kir klin Huddinge.
    Yang, H
    Effects of starvation and bowel resection on paracellular permeability in rat small-bowel mucosa in vitro.2000In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 2, p. 156-162Article in journal (Refereed)
  • 94.
    Yakymenko, Olena
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
    Schoultz, Ida
    Department of Medical Sciences, Faculty of Health and Medicine, Örebro University, Örebro, Sweden.
    Gullberg, Elisabet
    Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Almer, Sven
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden / GastroCentrum, Karolinska University Hospital, Stockholm, Sweden.
    Wallon, Conny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Wang, Arthur
    Gastrointestinal Research Group, Cumming School of Medicine, University of Calgary, Calgary, Canada..
    Keita, Åsa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Campbell, Barry J.
    Gastroenterology Research Unit, Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, UK.
    McKay, Derek M.
    Gastrointestinal Research Group, Cumming School of Medicine, University of Calgary, Calgary, Canada.
    Söderholm, Johan D
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Infliximab restores colonic barrier to adherent-invasive E. coli in Crohn's disease via effects on epithelial lipid rafts2018In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 53, no 6, p. 677-684Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 95.
    Yang, H
    et al.
    Linkoping Univ, Fac Hlth Sci, Dept Surg, S-58185 Linkoping, Sweden.
    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.
    Larsson, J
    Permert, J
    Linkoping Univ, Fac Hlth Sci, Dept Surg, S-58185 Linkoping, Sweden.
    Lindgren, Johan
    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.
    Wiren, M
    Linkoping Univ, Fac Hlth Sci, Dept Surg, S-58185 Linkoping, Sweden.
    Bidirectional supply of glutamine maintains enterocyte ATP content in the in vitro Ussing chamber model2000In: International Journal of Colorectal Disease, ISSN 0179-1958, E-ISSN 1432-1262, Vol. 15, no 5-6, p. 291-296Article in journal (Refereed)
    Abstract [en]

    Glutamine is the principal energy source for enterocytes, but it is not known whether parenteral or enteral supplementation is most beneficial to gut integrity. The aim of this study was to evaluate the effects of glutamine in uni- or bidirectional supply on the viability of intestinal mucosa of starved rats during incubation in Ussing chambers. Segments of jejunum from rats starved for 48 h were randomly mounted in Ussing chambers with three nutrient solutions: Krebs buffer without glutamine, 6 mM glutamine added to the mucosal side, 6 mM glutamine added to the mucosal side and 0.6 mM glutamine to the serosal side. ATP content of the mucosa, electrophysiology, and Cr-51-ethyl-enediaminetetraacetate (EDTA) permeability were studied during 180 min of incubation. The addition of glutamine to both sides of the stripped mucosa improved ATP levels compared to the Krebs solution (P<0.05), and the addition of glutamine resulted in an increase in short circuit current (P<0.05). No significant differences were seen in Cr-51-EDTA permeability or epithelial electrical resistance. Glutamine supplementation to both the luminal and serosal side in the Ussing chamber was more effective than luminal glutamine only in maintaining ATP levels of intestinal mucosa. Bidirectional supplementation of glutamine might improve intestinal energy metabolism and viability in in vitro studies.

  • 96. Yang, H
    et al.
    Söderholm, Johan D
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Larsson, J
    Kir klin Huddinge.
    Permert, J
    Kir klin Huddinge.
    Olaison, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Lindgren, J
    Glutamine effects on permeability and APT content of jejunal mucosa in starved rat.1999In: Clinical Nutrition, ISSN 0261-5614, E-ISSN 1532-1983, Vol. 18, p. 301-306Article in journal (Refereed)
  • 97.
    Yang, P.
    et al.
    Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ont., Canada.
    Xing, Z.
    Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ont., Canada.
    Berin, C.M.
    Department of Medicine, Division of Clinical Immunology, Mount Sinai School of Medicine, New York, NY, United States.
    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.
    Feng, B.
    Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ont., Canada.
    Wu, L.
    Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ont., Canada.
    Yeh, C.
    Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ont., Canada.
    TIM-4 Expressed by Mucosal Dendritic Cells Plays a Critical Role in Food Antigen-Specific Th2 Differentiation and Intestinal Allergy2007In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 133, no 5, p. 1522-1533Article in journal (Refereed)
    Abstract [en]

    Background & Aims: Food allergy accounts for significant morbidity. The etiology and immune mechanisms of food allergy, however, have remained poorly understood. In this study, we aimed to determine the role of T-cell immunoglobulin-domain and mucin-domain (TIM)-4, a recently identified member of cell surface molecules, in the pathogenesis of intestinal allergy in a murine model. Methods: We report that TIM-4 as well as costimulatory molecules were up-regulated in intestinal mucosal dendritic cells by in vitro or in vivo exposure to Staphylococcus enterotoxin B (SEB). SEB-conditioned intestinal dendritic cells loaded with a food macromolecule ovalbumin (OVA) induced potent OVA-specific T-helper (Th)2 lymphocyte responses in vitro and such Th2 responses were inhibited completely by TIM-4 blockade. Results: In vivo exposure to both SEB and OVA resulted in OVA-specific Th2 differentiation and intestinal allergic responses including increased serum immunoglobulin E and Th2 cytokine levels, activation of OVA-specific Th2 cells detected both ex vivo and in situ, and mast cell degranulation. Of importance, in vivo abrogation of TIM-4 or its cognate ligand TIM-1 by using a polyclonal antibody remarkably dampened Th2 differentiation and intestinal allergy. Conclusions: Our study thus identifies TIM-4 as a novel molecule critically required for the development of intestinal allergy. © 2007 AGA Institute.

  • 98. Yang, Ping-Chang
    et al.
    Jury, Jennifer
    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
    Perdue, Mary H
    Chronic psychological stress in rats induces intestinal sensitization to luminal antigens2006In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 168, no 1, p. 104-114Article in journal (Refereed)
    Abstract [en]

    There is increasing evidence that stress plays a role in the pathophysiology of chronic intestinal disorders, but the mechanisms remain unclear. Previous studies in rats have revealed that stress decreases gut barrier function and allows excessive uptake of luminal material. Here, we investigated whether chronic psychological stress acts to induce sensitization of intestinal tissues to oral antigens. Rats were subjected to 1 hour per day of water avoidance stress or sham stress daily for 10 days, and horseradish peroxidase (HRP) was delivered by gavage on day 5. Studies to determine sensitization were conducted on day 20. All stressed rats developed HRP-specific IgE antibodies, antigen-induced intestinal secretion, and increased numbers of inflammatory cells in gut mucosa. luminal URP was absorbed more readily by enterocytes of stressed animals. In addition, stressed rats had increased expression of interleukin-4 and decreased expression of Interferon-γ in gut mucosa, a cytokine profile that is typical of allergic conditions. Treatment of stressed rats with an antagonist to corticotropin-releasing hormone (previously shown to inhibit stress-enhanced gut permeability) eliminated the manifestations of intestinal hypersensitivity. Our results indicate that the presence of oral antigen during chronic psychological stress alters the immune response (to sensitization rather than oral tolerance) and causes subsequent antigen-induced gut pathophysiology. Copyright © American Society for Investigative Pathology.

  • 99. Yates, Derrick
    et al.
    Santos, Javier
    Söderholm, Johan D
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Surgery. Östergötlands Läns Landsting, MKC-2, GE: Gastrokir.
    Perdue, Mary
    Adaptation of stress-induced mucosal pathophysiology in rat colon involves opioid pathways.2001In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 281, p. 124-128Article in journal (Refereed)
  • 100. Zareie, M
    et al.
    Johnson-Henry, K
    Jury, J
    Yang, P-C
    Ngan, B-Y
    McKay, DM
    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.
    Perdue, MH
    Sherman, PM
    Probiotics prevent bacterial translocation and improve intestinal barrier function in rats following chronic psychological stress2006In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 55, no 11, p. 1553-1560Article in journal (Refereed)
    Abstract [en]

    Background and aim: Chronic psychological stress, including water avoidance stress (WAS), induces intestinal mucosal barrier dysfunction and impairs mucosal defences against luminal bacteria. The aim of this study was to determine the ability of a defined probiotic regimen to prevent WAS induced intestinal pathophysiology. Methods: Male rats were subjected to either WAS or sham stress for one hour per day for 10 consecutive days. Additional animals received seven days of Lactobacillus helveticus and L. rhamnosus in the drinking water prior to stress and remained on these probiotics for the duration of the study. Rats were then sacrificed, intestinal segments assessed in Ussing chambers, and mesenteric lymph nodes cultured to determine bacterial translocation. Results: All animals remained healthy for the duration of the study. Chronic WAS induced excess ion secretion (elevated baseline short circuit current) and barrier dysfunction (increased conductance) in both the ileum and colon, associated with increased bacterial adhesion and penetration into surface epithelial cells. Approximately 70% of rats subjected to WAS had bacterial translocation to mesenteric lymph nodes while there was no bacterial translocation in controls. Probiotic pretreatment alone had no effect on intestinal barrier function. However, WAS induced increased ileal short circuit current was reduced with probiotics whereas there was no impact on altered conductance. Pretreatment of animals with probiotics also completely abrogated WAS induced bacterial adhesion and prevented translocation of bacteria to mesenteric lymph nodes. Conclusion: These findings indicate that probiotics can prevent chronic stress induced intestinal abnormalities and, thereby, exert beneficial effects in the intestinal tract.

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