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  • 1.
    Gerdin, Linda
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US. Surg Clin Jonkoping Cty, Sweden.
    Gonzalez-Castro, Ana M.
    Univ Autonoma Barcelona, Spain; Univ Autonoma Barcelona, Spain.
    Ericson, Ann-Charlott
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Persborn, Mats
    Surg Clin Jonkoping Cty, Sweden.
    Santos, Javier
    Univ Autonoma Barcelona, Spain; Univ Autonoma Barcelona, Spain; Ctr Invest Biomed Red Enfermedades Hepat & Digest, Spain.
    Walter, Susanna
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Vicario, Maria
    Univ Autonoma Barcelona, Spain; Univ Autonoma Barcelona, Spain; Ctr Invest Biomed Red Enfermedades Hepat & Digest, Spain; Nestle Res Soc Prod Nestle SA, Switzerland.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Acute psychological stress increases paracellular permeability and modulates immune activity in rectal mucosa of healthy volunteers2023Ingår i: United European Gastroenterology journal, ISSN 2050-6406, E-ISSN 2050-6414, Vol. 11, nr 1, s. 31-41Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Psychological stress and increased permeability are implicated as contributing factors in the initiation and worsening of gastrointestinal diseases. A link between stress and intestinal permeability has been shown in animal models as well as in human small intestine, but stress effects on the human colorectal mucosal barrier has not been reported. Objective To investigate the potential effects of acute psychological stress on colorectal mucosal barrier function and to explore stress-induced molecular events in the rectal mucosa under healthy conditions. Methods Endoscopic biopsies were taken from the rectosigmoid region of healthy volunteers, who had been subjected to dichotomous listening stress and after a control session, respectively. Paracellular and transcellular permeability were assessed in modified Ussing chambers. RNA expression (microarray technology confirmed by quantitative real-time polymerase chain reaction) and biological pathway analysis were used to investigate the local mucosal response to acute stress. Results Dichotomous listening stress induced a subjective and objective stress response, and significantly increased paracellular but not transcellular permeability. We also identified a stress-induced reduction in RNA expression of genes related to immune cell activation and maturation (CR2, CD20, TCLA1, BANK1, CD22, FDCSP), signaling molecules of homing of immune cells to the gut (chemokines: CCL21, CXCL13, and CCL19, and receptors: CCR7, CXCR5), and innate immunity (DUOX2). Eight of the 10 top down-regulated genes are directly involved in B cell activation, signaling and migration. The systemic stress response correlated positively with paracellular permeability and negatively with DUOX2 expression. Conclusion Dichotomous listening stress increases paracellular permeability and modulates immune cell activity in the rectal mucosa. Further studies are warranted to identify the primary mechanisms of stress-mediated reduction of mucosal defensive activity and barrier dysfunction, and their potential implications for gastrointestinal disorders.

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  • 2.
    Hamed, Samira A.
    et al.
    Univ Calgary, Canada.
    Mohan, Armaan
    Univ Calgary, Canada.
    Navaneetha Krishnan, Saranya
    Univ Calgary, Canada.
    Wang, Arthur
    Univ Calgary, Canada.
    Drikic, Marija
    Univ Calgary, Canada.
    Prince, Nicole L.
    Univ Calgary, Canada.
    Lewis, Ian A.
    Univ Calgary, Canada.
    Shearer, Jane
    Univ Calgary, Canada.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Shutt, Timothy E.
    Univ Calgary, Canada.
    McKay, Derek M.
    Univ Calgary, Canada.
    Butyrate reduces adherent-invasive <i>E. coli</i>-evoked disruption of epithelial mitochondrial morphology and barrier function: involvement of free fatty acid receptor 32023Ingår i: Gut microbes, ISSN 1949-0976, E-ISSN 1949-0984, Vol. 15, nr 2, artikel-id 2281011Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Gut bacteria provide benefits to the host and have been implicated in inflammatory bowel disease (IBD), where adherent-invasive E. coli (AIEC) pathobionts (e.g., strain LF82) are associated with Crohn's disease. E. coli-LF82 causes fragmentation of the epithelial mitochondrial network, leading to increased epithelial permeability. We hypothesized that butyrate would limit the epithelial mitochondrial disruption caused by E. coli-LF82. Human colonic organoids and the T84 epithelial cell line infected with E. coli-LF82 (MOI = 100, 4 h) showed a significant increase in mitochondrial network fission that was reduced by butyrate (10 mM) co-treatment. Butyrate reduced the loss of mitochondrial membrane potential caused by E. coli-LF82 and increased expression of PGC-1$\alpha $alpha mRNA, the master regulator of mitochondrial biogenesis. Metabolomics revealed that butyrate significantly altered E. coli-LF82 central carbon metabolism leading to diminished glucose uptake and increased succinate secretion. Correlating with preservation of mitochondrial network form/function, butyrate reduced E. coli-LF82 transcytosis across T84-cell monolayers. The use of the G-protein inhibitor, pertussis toxin, implicated GPCR signaling as critical to the effect of butyrate, and the free fatty acid receptor three (FFAR3, GPR41) agonist, AR420626, reproduced butyrate's effect in terms of ameliorating the loss of barrier function and reducing the mitochondrial fragmentation observed in E. coli-LF82 infected T84-cells and organoids. These data indicate that butyrate helps maintain epithelial mitochondrial form/function when challenged by E. coli-LF82 and that this occurs, at least in part, via FFAR3. Thus, loss of butyrate-producing bacteria in IBD in the context of pathobionts would contribute to loss of epithelial mitochondrial and barrier functions that could evoke disease and/or exaggerate a low-grade inflammation.

  • 3.
    Zitti, Beatrice
    et al.
    Karolinska Inst, Sweden.
    Hoffer, Elena
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Univ Copenhagen, Denmark.
    Zheng, Wenning
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Univ Copenhagen, Denmark.
    Pandey, Ram Vinay
    Karolinska Inst, Sweden.
    Schlums, Heinrich
    Karolinska Inst, Sweden.
    Casoni, Giovanna Perinetti
    Karolinska Inst, Sweden.
    Fusi, Irene
    Karolinska Inst, Sweden; Univ Siena, Italy.
    Nguyen, Lien
    Karolinska Inst, Sweden.
    Karner, Jaanika
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Kokkinou, Efthymia
    Karolinska Inst, Sweden.
    Carrasco, Anna
    Karolinska Inst, Sweden.
    Gahm, Jessica
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Ehrstrom, Marcus
    Nordiska Kliniken, Sweden.
    Haapaniemi, Staffan
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken ViN.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Hedin, Charlotte R. H.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Mjosberg, Jenny
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Eidsmo, Liv
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Univ Copenhagen, Denmark.
    Bryceson, Yenan T.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Univ Bergen, Norway.
    Human skin-resident CD8+T cells require RUNX2 and RUNX3 for induction of cytotoxicity and expression of the integrin CD49a2023Ingår i: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 56, nr 6, s. 1285-1302.e7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The integrin CD49a marks highly cytotoxic epidermal-tissue-resident memory (TRM) cells, but their differen-tiation from circulating populations remains poorly defined. We demonstrate enrichment of RUNT family tran-scription-factor-binding motifs in human epidermal CD8+CD103+CD49a+ TRM cells, paralleled by high RUNX2 and RUNX3 protein expression. Sequencing of paired skin and blood samples revealed clonal overlap be-tween epidermal CD8+CD103+CD49a+ TRM cells and circulating memory CD8+CD45RA-CD62L+ T cells. In vitro stimulation of circulating CD8+CD45RA-CD62L+ T cells with IL-15 and TGF-b induced CD49a expres-sion and cytotoxic transcriptional profiles in a RUNX2-and RUNX3-dependent manner. We therefore identi-fied a reservoir of circulating cells with cytotoxic TRM potential. In melanoma patients, high RUNX2, but not RUNX3, transcription correlated with a cytotoxic CD8+CD103+CD49a+ TRM cell signature and improved pa-tient survival. Together, our results indicate that combined RUNX2 and RUNX3 activity promotes the differ-entiation of cytotoxic CD8+CD103+CD49a+ TRM cells, providing immunosurveillance of infected and malig-nant cells.

  • 4.
    Bednarska, Olga
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Biskou, Olga
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Israelsen, Hans
    Nord Rebalance AS, Denmark.
    Tinnerfelt Winberg, Martin
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Walter, Susanna
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    A postbiotic fermented oat gruel may have a beneficial effect on the colonic mucosal barrier in patients with irritable bowel syndrome2022Ingår i: Frontiers in Nutrition, E-ISSN 2296-861X, Vol. 9, artikel-id 1004084Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Impaired intestinal permeability and microbial dysbiosis are important pathophysiological mechanisms underlying irritable bowel syndrome (IBS). ReFerm (R)( ), also called Profermin (R), is a postbiotic product of oat gruel fermented with Lactobacillus plantarum 299v. In this study, we investigated whether ReFerm (R) has a beneficial effect on the intestinal epithelial barrier function in patients with IBS.Materials and methods: Thirty patients with moderate to severe IBS-diarrhoea (IBS-D) or IBS-mixed (IBS-M) were treated with enema containing ReFerm (R) or placebo. The patients underwent sigmoidoscopy with biopsies obtained from the distal colon at baseline and after 14 days of treatment with ReFerm (R) or placebo twice daily. The biopsies were mounted in Ussing chambers, and paracellular and transcellular permeabilities were measured for 120 min. In addition, the effects of ReFerm (R) or placebo on the epithelial barrier were investigated in vitro using Caco-2 cells.Results: ReFerm (R) reduced paracellular permeability (p &lt; 0.05) and increased transepithelial resistance (TER) over time (p &lt; 0.01), whereas the placebo had no significant effect in patients. In ReFerm (R)-treated Caco-2 cells, paracellular and transcellular permeabilities were decreased compared to the control (p &lt; 0.05) and placebo (p &lt; 0.01). TER was increased in Caco-2 ReFerm (R)-treated cells, and normalised TER was increased in ReFerm (R)-treated Caco-2 cells compared to control (p &lt; 0.05) and placebo-treated (p &lt; 0.05) cells.Conclusion: ReFerm (R) significantly reduced paracellular permeability and improved TER in colonic biopsies collected from patients with IBS and in a Caco-2 cell model. Our results offer new insights into the potential benefits of ReFerm (R) in IBS management. Further studies are needed to identify the molecular mechanisms underlying the barrier-protective properties of ReFerm (R).

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  • 5.
    Lundquist, Patrik
    et al.
    Uppsala Univ, Sweden.
    Khodus, Georgiy
    Uppsala Univ, Sweden.
    Niu, Zhigao
    Univ Santiago Compostela, Spain.
    Thwala, Lungile Nomcebo
    Univ Santiago Compostela, Spain; Louvain Drug Res Inst, Belgium.
    McCartney, Fiona
    Univ Coll Dublin, Ireland.
    Simoff, Ivailo
    Uppsala Univ, Sweden.
    Andersson, Ellen
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken ViN.
    Beloqui, Ana
    Louvain Drug Res Inst, Belgium.
    Mabondzo, Aloise
    CEA, France.
    Robla, Sandra
    Univ Santiago Compostela, Spain.
    Webb, Dominic-Luc
    Uppsala Univ, Sweden.
    Hellstroem, Per M.
    Uppsala Univ, Sweden.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Sima, Eduardo
    Uppsala Univ, Sweden.
    Csaba, Noemi
    Univ Santiago Compostela, Spain.
    Sundbom, Magnus
    Uppsala Univ, Sweden.
    Preat, Veronique
    Louvain Drug Res Inst, Belgium.
    Brayden, David J.
    Univ Coll Dublin, Ireland.
    Alonso, Maria Jose
    Univ Santiago Compostela, Spain.
    Artursson, Per
    Uppsala Univ, Sweden.
    Barriers to the Intestinal Absorption of Four Insulin-Loaded Arginine-Rich Nanoparticles in Human and Rat2022Ingår i: ACS Nano, ISSN 1936-0851, E-ISSN 1936-086X, Vol. 16, nr 9, s. 14210-14229Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Peptide drugs and biologics provide opportunities for treatments of many diseases. However, due to their poor stability and permeability in the gastrointestinal tract, the oral bioavailability of peptide drugs is negligible. Nanoparticle formulations have been proposed to circumvent these hurdles, but systemic exposure of orally administered peptide drugs has remained elusive. In this study, we investigated the absorption mechanisms of four insulin-loaded arginine-rich nanoparticles displaying differing composition and surface characteristics, developed within the pan-European consortium TRANS-INT. The transport mechanisms and major barriers to nanoparticle permeability were investigated in freshly isolated human jejunal tissue. Cytokine release profiles and standard toxicity markers indicated that the nanoparticles were nontoxic. Three out of four nanoparticles displayed pronounced binding to the mucus layer and did not reach the epithelium. One nanoparticle composed of a mucus inert shell and cell-penetrating octarginine (ENCP), showed significant uptake by the intestinal epithelium corresponding to 28 +/- 9% of the administered nanoparticle dose, as determined by super-resolution microscopy. Only a small fraction of nanoparticles taken up by epithelia went on to be transcytosed via a dynamin-dependent process. In situ studies in intact rat jejunal loops confirmed the results from human tissue regarding mucus binding, epithelial uptake, and negligible insulin bioavailability. In conclusion, while none of the four arginine-rich nanoparticles supported systemic insulin delivery, ENCP displayed a consistently high uptake along the intestinal villi. It is proposed that ENCP should be further investigated for local delivery of therapeutics to the intestinal mucosa.

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  • 6.
    Kokkinou, Efthymia
    et al.
    Karolinska Univ Hosp Huddinge, Sweden.
    Pandey, Ram Vinay
    Karolinska Univ Hosp Huddinge, Sweden.
    Mazzurana, Luca
    Karolinska Univ Hosp Huddinge, Sweden.
    Gutierrez-Perez, Irene
    Karolinska Univ Hosp Huddinge, Sweden.
    Tibbitt, Christopher Andrew
    Karolinska Univ Hosp Huddinge, Sweden.
    Weigel, Whitney
    Karolinska Univ Hosp Huddinge, Sweden.
    Soini, Tea
    Karolinska Univ Hosp Huddinge, Sweden.
    Carrasco, Anna
    Karolinska Univ Hosp Huddinge, Sweden.
    Rao, Anna
    Karolinska Univ Hosp Huddinge, Sweden.
    Nagasawa, Maho
    Univ Amsterdam, Netherlands.
    Bal, Suzanne M.
    Univ Amsterdam, Netherlands.
    Jangard, Mattias
    Sophiahemmet Univ Res Lab & Sophiahemmet Hosp, Sweden.
    Friberg, Danielle
    Uppsala Univ, Sweden.
    Lindforss, Ulrik
    Karolinska Univ Hosp, Sweden; Karolinska Univ Hosp, Sweden.
    Nordenvall, Caroline
    Karolinska Univ Hosp, Sweden; Karolinska Univ Hosp, Sweden.
    Ljunggren, Malin
    Karolinska Univ Hosp, Sweden; Karolinska Univ Hosp, Sweden.
    Haapaniemi, Staffan
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken ViN.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Hedin, Charlotte
    Karolinska Inst, Sweden.
    Spits, Hergen
    Karolinska Univ Hosp, Sweden.
    Bryceson, Yenan T.
    Karolinska Univ Hosp Huddinge, Sweden.
    Mjosberg, Jenny
    Karolinska Univ Hosp Huddinge, Sweden.
    CD45RA(+)CD62L(-) ILCs in human tissues represent a quiescent local reservoir for the generation of differentiated ILCs2022Ingår i: Science immunology, E-ISSN 2470-9468, Vol. 7, nr 70, artikel-id eabj8301Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Innate lymphoid cells (ILCs) are highly plastic and predominantly mucosal tissue-resident cells that contribute to both homeostasis and inflammation depending on the microenvironment. The discovery of naive-like ILCs suggests an ILC differentiation process that is akin to naive T cell differentiation. Delineating the mechanisms that underlie ILC differentiation in tissues is crucial for understanding ILC biology in health and disease. Here, we showed that tonsillar ILCs expressing CD45RA lacked proliferative activity, indicative of cellular quiescence. CD62L distinguished two subsets of CD45RA(+) ILCs. CD45RA(+)CD62L(+) ILCs (CD62L(+) ILCs) resembled circulating naive ILCs because they lacked the transcriptional, metabolic, epigenetic, and cytokine production signatures of differentiated ILCs. CD45RA(+)CD62L(-) ILCs (CD62L(-) ILCs) were epigenetically similar to CD62L(+) ILCs but showed a transcriptional, metabolic, and cytokine production signature that was more akin to differentiated ILCs. CD62L(+) and CD62L(-) ILCs contained uni- and multipotent precursors of ILC1s/NK cells and ILC3s. Differentiation of CD62L(+) and CD62L(-) ILCs led to metabolic reprogramming including up-regulation of genes associated with glycolysis, which was needed for their effector functions after differentiation. CD62L(-) ILCs with preferential differentiation capacity toward IL-22-producing ILC3s accumulated in the inflamed mucosa of patients with inflammatory bowel disease. These data suggested distinct differentiation potential of CD62L(+) and CD62L(-) ILCs between tissue microenvironments and identified that manipulation of these cells is a possible approach to restore tissue-immune homeostasis.

  • 7.
    Nowak, Jan K.
    et al.
    Univ Oxford, England; Poznan Univ Med Sci, Poland.
    Adams, Alex T.
    Univ Oxford, England.
    Kalla, Rahul
    Univ Edinburgh, Scotland.
    Lindstrom, Jonas C.
    Akershus Univ Hosp, Norway; Univ Oslo, Norway.
    Vatn, Simen
    Univ Oslo, Norway; Akershus Univ Hosp, Norway.
    Bergemalm, Daniel
    Orebro Univ, Sweden.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Gomollon, Fernando
    IIS Aragon, Spain.
    Jahnsen, Jorgen
    Univ Oslo, Norway; Akershus Univ Hosp, Norway.
    Vatn, Morten H.
    Univ Oslo, Norway; Univ Oslo, Norway.
    Ricanek, Petr
    Akershus Univ Hosp, Norway.
    Ostrowski, Jerzy
    Maria Sklodowska Curie Natl Res Inst Oncol, Poland; Ctr Postgrad Med Educ, Poland.
    Walkowiak, Jaroslaw
    Poznan Univ Med Sci, Poland.
    Halfvarson, Jonas
    Orebro Univ, Sweden.
    Satsangi, Jack
    Univ Oxford, England; Univ Edinburgh, Scotland.
    Characterisation of the Circulating Transcriptomic Landscape in Inflammatory Bowel Disease Provides Evidence for Dysregulation of Multiple Transcription Factors Including NFE2, SPI1, CEBPB, and IRF22022Ingår i: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 16, nr 8, s. 1255-1268Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim To assess the pathobiological and translational importance of whole-blood transcriptomic analysis in inflammatory bowel disease [IBD]. Methods We analysed whole-blood expression profiles from paired-end sequencing in a discovery cohort of 590 Europeans recruited across six countries in the IBD Character initiative (newly diagnosed patients with Crohns disease [CD; n = 156], ulcerative colitis [UC; n = 167], and controls [n = 267]), exploring differential expression [DESeq2], co-expression networks [WGCNA], and transcription factor involvement [EPEE, ChEA, DoRothEA]. Findings were validated by analysis of an independent replication cohort [99 CD, 100 UC, 95 controls]. In the discovery cohort, we also defined baseline expression correlates of future treatment escalation using cross-validated elastic-net and random forest modelling, along with a pragmatic ratio detection procedure. Results Disease-specific transcriptomes were defined in IBD [8697 transcripts], CD [7152], and UC [8521], with the most highly significant changes in single genes, including CD177 (log(2)-fold change [LFC] = 4.63, p = 4.05 x 10(-118)), MCEMP1 [LFC = 2.45, p = 7.37 x 10(-109)], and S100A12 [LFC = 2.31, p = 2.15 x 10(-93)]. Significantly over-represented pathways included IL-1 [p = 1.58 x 10(-11)], IL-4, and IL-13 [p = 8.96 x 10(-9)]. Highly concordant results were obtained using multiple regulatory activity inference tools applied to the discovery and replication cohorts. These analyses demonstrated central roles in IBD for the transcription factors NFE2, SPI1 [PU.1], CEBPB, and IRF2, all regulators of cytokine signalling, based on a consistent signal across cohorts and transcription factor ranking methods. A number of simple transcriptome-based models were associated with the need for treatment escalation, including the binary CLEC5A/CDH2 expression ratio in UC (hazard ratio = 23.4, 95% confidence interval [CI] 5.3-102.0). Conclusions Transcriptomic analysis has allowed for a detailed characterisation of IBD pathobiology, with important potential translational implications.

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  • 8.
    Holst, Luiza Moraes
    et al.
    Univ Gothenburg, Sweden.
    Halfvarson, Jonas
    Orebro Univ, Sweden.
    Carlson, Marie
    Uppsala Univ, Sweden.
    Hedin, Charlotte
    Karolinska Inst, Sweden.
    Kruse, Robert
    Orebro Univ, Sweden.
    Lindqvist, Carl Mårten
    Orebro Univ, Sweden.
    Bergemalm, Daniel
    Orebro Univ, Sweden.
    Almér, Sven
    Karolinska Inst, Sweden.
    Bresso, Francesca
    Karolinska Univ Hosp, Sweden.
    Lundström, Maria Ling
    Uppsala Univ, Sweden.
    Repsilber, Dirk
    Orebro Univ, Sweden.
    D'Amato, Mauro
    Karolinska Inst, Sweden; Basque Fdn Sci, Spain; CIC bioGUNE BRTA, Spain.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Hjortswang, Henrik
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Sundin, Johanna
    Uppsala Univ, Sweden; Sahlgrens Acad, Sweden.
    Törnblom, Hans
    Univ Gothenburg, Sweden.
    Simrén, Magnus
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Strid, Hans
    Department of Internal Medicine, Södra Älvsborg Hospital, Borås, Sweden.
    Magnusson, Maria K.
    Univ Gothenburg, Sweden.
    Öhman, Lena
    Univ Gothenburg, Sweden; Uppsala Univ, Sweden; Karolinska Inst, Sweden; Orebro Univ, Sweden; Karolinska Univ Hosp, Sweden.
    Downregulated Mucosal Autophagy, Alpha Kinase-1 and IL-17 Signaling Pathways in Active and Quiescent Ulcerative Colitis2022Ingår i: Clinical and Experimental Gastroenterology, E-ISSN 1178-7023, Vol. 15, s. 129-144Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Improved mucosal immune profiling in active and quiescent colonic inflammatory bowel disease (IBD) is needed to develop therapeutic options for treating and preventing flares. This study therefore aimed to provide a comprehensive mucosal characterization with emphasis on immunological host response of patients with active ulcerative colitis (UC active), UC during remission (UC remission) and active colonic Crohns disease (CD active). Methods: Colonic biopsies from 47 study subjects were collected for gene expression and pathway analyses using the NanoString host-response panel, including 776 genes and 56 immune-related pathways. Results: The majority of mucosal gene expression and signaling pathway scores were increased in active IBD (n=27) compared to healthy subjects (n=10). However, both active IBD and UC remission (n=10) demonstrated decreased gene expression and signaling pathway scores related to autophagy, alpha kinase-1 and IL-17 signaling pathways compared to healthy subjects. Further, UC remission was characterized by decreased scores of several signaling pathways linked to homeostasis along with increased mononuclear cell migration pathway score as compared to healthy subjects. No major differences in the colonic mucosal gene expression between CD active (n=7) and UC (n=20) active were observed. Conclusion: This study indicates that autophagy, alpha kinase-1 and IL-17 signaling pathways are persistently downregulated in UC irrespective of disease activity. Further, UC patients in remission present a unique mucosal environment, potentially preventing patients from reaching and sustaining true homeostasis. These findings may enable better comprehension of the remitting and relapsing pattern of colonic IBD and guide future treatment and prevention of flares.

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  • 9.
    Casado Bedmar, Maria Teresa
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Meira de Faria, Felipe
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Biskou, Olga
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Lindqvist, Carl Mårten
    Orebro Univ, Sweden.
    Ranasinghe, Purnika Damindi
    Queens Univ Belfast, North Ireland.
    Bednarska, Olga
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Peterson, Christer
    Uppsala Univ, Sweden; Diagnost Dev, Sweden.
    Walter, Susanna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Carlson, Marie
    Uppsala Univ, Sweden.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Elevated F-EDN correlates with mucosal eosinophil degranulation in patients with IBS - A possible association with microbiota?2022Ingår i: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 111, nr 3, s. 655-665Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Eosinophils have been linked to functional dyspepsia; however, less is known about their role in irritable bowel syndrome (IBS). This study tested the hypothesis of alterations in levels of fecal eosinophil-derived neurotoxin (F-EDN) and eosinophil density and degranulation within the colonic mucosa of IBS patients compared with healthy controls (HC). Colonic biopsies were collected from 37 IBS patients and 20 HC and analyzed for eosinophil numbers and local degranulation of eosinophil cationic protein (ECP) by histologic procedures. Fecal samples were collected for F-EDN and microbiota analysis. Differentiated 15HL-60 cells were used in vitro to investigate the direct effect of live bacteria on eosinophil activation measured by a colorimetric assay with o-phenylenediamine (OPD) substrate. We observed a higher number of eosinophils and increased extracellular ECP in the mucosa of IBS patients compared with HC. Moreover, F-EDN levels in IBS samples were elevated compared with HC and positively correlated to extracellular ECP. Metagenomic analysis showed significant correlations between bacterial composition and eosinophil measurements in both HC and IBS patients. In vitro experiments revealed an increased degranulation of 15HL-60 after stimulation with Salmonella typhimurium, Salmonella enterica, and Yersinia enterocolitica. To conclude, we could demonstrate alterations related to eosinophils in IBS, and, for the first time, a positive correlation between F-EDN levels and degranulated eosinophils in the colonic mucosa of IBS patients. Together our results suggest that eosinophils play a role in the pathophysiology of IBS and the mechanisms might be linked to an altered microbiota.

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  • 10.
    Biskou, Olga
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Meira de Faria, Felipe
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Walter, Susanna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Tinnerfelt Winberg, Martin
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Haapaniemi, Staffan
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken ViN. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi.
    Myrelid, Pär
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Increased Numbers of Enteric Glial Cells in the Peyers Patches and Enhanced Intestinal Permeability by Glial Cell Mediators in Patients with Ileal Crohns Disease2022Ingår i: Cells, E-ISSN 2073-4409, Vol. 11, nr 3, artikel-id 335Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Enteric glial cells (EGC) are known to regulate gastrointestinal functions; however, their role in Crohns disease (CD) is elusive. Microscopic erosions over the ileal Peyers patches are early signs of CD. The aim of this work was to assess the localization of EGC in the follicle and interfollicular region of the Peyers patches and in the lamina propria and study the effects of EGC mediators on barrier function in CD patients and non-inflammatory bowel disease (non-IBD) controls. EGC markers, glial fibrillary acidic protein (GFAP), and S100 calcium-binding protein β (S100β) were quantified by immunofluorescence and Western blotting. Both markers showed significantly more EGC in the Peyers patches and lamina propria of CD patients compared to the non-IBD controls. In CD patients there were significantly more EGC in Peyers patches compared to lamina propria, while the opposite pattern was seen in controls. Barrier function studies using Ussing chambers showed increased paracellular permeability by EGC mediators in CD patients, whereas permeability decreased by the mediators in controls. We show the accumulation of EGC in Peyers patches of CD patients. Moreover, EGC mediators induced barrier dysfunction in CD patients. Thus, EGC might have harmful impacts on ongoing inflammation and contribute to the pathophysiology of the disease.

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  • 11.
    Vatn, Simen Svendsen
    et al.
    Univ Oslo, Norway; Akershus Univ Hosp, Norway.
    Lindstrom, Jonas Christoffer
    Akershus Univ Hosp, Norway; Norwegian Inst Publ Hlth, Norway.
    Moen, Aina E. F.
    Univ Oslo, Norway; Norwegian Inst Publ Hlth, Norway; Akershus Univ Hosp, Norway.
    Brackmann, Stephan
    Univ Oslo, Norway; Akershus Univ Hosp, Norway.
    Tannaes, Tone M.
    Univ Oslo, Norway; Akershus Univ Hosp, Norway.
    Olbjorn, Christine
    Univ Oslo, Norway; Akershus Univ Hosp, Norway.
    Bergemalm, Daniel
    Orebro Univ, Sweden.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Gomollon, Fernando
    IIS Aragon, Spain.
    Detlie, Trond Espen
    Univ Oslo, Norway; Akershus Univ Hosp, Norway.
    Luders, Torben
    Akershus Univ Hosp, Norway.
    Kalla, Rahul
    Univ Edinburgh, Scotland.
    Adams, Alex
    Univ Edinburgh, Scotland; Univ Oxford, England.
    Satsangi, Jack
    Univ Edinburgh, Scotland; Univ Oxford, England.
    Jahnsen, Jorgen
    Univ Oslo, Norway; Akershus Univ Hosp, Norway.
    Vatn, Morten H.
    Univ Oslo, Norway.
    Halfvarson, Jonas
    Orebro Univ, Sweden.
    Ricanek, Petr
    Akershus Univ Hosp, Norway.
    Nilsen, Hilde
    Univ Oslo, Norway; Akershus Univ Hosp, Norway.
    Mucosal Gene Transcript Signatures in Treatment Naive Inflammatory Bowel Disease: A Comparative Analysis of Disease to Symptomatic and Healthy Controls in the European IBD-Character Cohort2022Ingår i: Clinical and Experimental Gastroenterology, E-ISSN 1178-7023, Vol. 15Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Studies of the mucosal transcriptomic landscape have given new insight into the pathogenesis of inflammatory bowel disease (IBD). Recently, the predictive biomarker potential of gene expression signatures has been explored. To further investigate the mucosal gene expression in IBD, we recruited a cohort of treatment naive patients and compared them to both symptomatic and healthy controls. Methods: Altogether, 323 subjects were included: Crohns disease (N = 75), ulcerative colitis (N = 87) and IBD unclassified (N = 3). Additionally, there were two control groups: symptomatic controls (N = 131) and healthy controls (N = 27). Mucosal biopsies were collected during ileocolonoscopy and gene expression in inflamed and non-inflamed mucosa was explored. Gene expression profiling was performed using Agilent G3 Human Gene Expression 860K v3 One-Color microarray. We recorded information about treatment escalation to anti-TNF agents or surgery, and anti-TNF response, to explore predictive opportunities of the mucosal transcriptome. Results: Gene expression profiles in symptomatic controls in whom IBD had been excluded resembled that of IBD patients and diverged from that of healthy controls. In non-inflamed Crohns disease and ulcerative colitis, gene set enrichment analysis revealed dysregulation of pathways involved in basic cellular biological processes. Mitochondria-associated pathways were dysregulated both in non-inflamed and inflamed Crohns disease and ulcerative colitis (&gt;2.6 normalized enrichment scores &lt;-1.8). Gene expression signatures of Crohns disease and ulcerative colitis did not predict time for treatment escalation (p = 0.175). No significant association was found between gene expression signatures and anti-TNF response. Conclusion: Non-inflamed samples are probably superior to inflamed samples when exploring gene expression signatures in IBD and might reveal underlying mechanisms central for disease initiation. The gene expression signatures of the control groups were related to if they were symptomatic or not, which may have important implications for future study designs.

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  • 12.
    Stuart, Charlotte M.
    et al.
    Univ Southampton, England.
    Varatharaj, Aravinthan
    Univ Southampton, England; Univ Hosp Southampton NHS Fdn Trust, England.
    Tinnerfelt Winberg, Martin
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Galea, Pascale
    Biorad, France.
    Larsson, Henrik B. W.
    Rigshospitalet, Denmark.
    Cramer, Stig P.
    Rigshospitalet, Denmark.
    Fasano, Alessio
    Massachusetts Gen Hosp, MA 02114 USA.
    Maherally, Zaynah
    Univ Portsmouth, England.
    Pilkington, Geoffrey J.
    Univ Portsmouth, England.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Galea, Ian
    Univ Hosp Southampton NHS Fdn Trust, England.
    Zonulin and blood-brain barrier permeability are dissociated in humans2022Ingår i: Clinical and Translational Medicine, ISSN 2001-1326, Vol. 12, nr 7, artikel-id e965Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

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  • 13.
    Zimmer, Christine L.
    et al.
    Karolinska Univ Hosp, Sweden.
    von Seth, Erik
    Karolinska Univ Hosp, Sweden; Karolinska Univ Hosp, Sweden.
    Buggert, Marcus
    Karolinska Univ Hosp, Sweden.
    Strauss, Otto
    Karolinska Univ Hosp, Sweden.
    Hertwig, Laura
    Karolinska Univ Hosp, Sweden.
    Nguyen, Son
    Univ Penn, PA 19104 USA; Univ Penn, PA 19104 USA.
    Wong, Alicia Y. W.
    Karolinska Inst, Sweden.
    Zotter, Chiara
    Karolinska Univ Hosp, Sweden.
    Berglin, Lena
    Karolinska Univ Hosp, Sweden.
    Michaelsson, Jakob
    Karolinska Univ Hosp, Sweden.
    Hansson, Marcus Reuterwall
    Karolinska Inst, Sweden.
    Arnelo, Urban
    Karolinska Inst, Sweden; Umea Univ, Sweden.
    Sparrelid, Ernesto
    Karolinska Inst, Sweden.
    Ellis, Ewa C. S.
    Karolinska Inst, Sweden.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Holm, Kristian
    Univ Oslo, Norway; Oslo Univ Hosp, Norway.
    Ozenci, Volkan
    Karolinska Inst, Sweden.
    Hov, Johannes R.
    Univ Oslo, Norway; Oslo Univ Hosp, Norway; Oslo Univ Hosp, Norway; Oslo Univ Hosp, Norway.
    Mold, Jeff E.
    Karolinska Inst, Sweden.
    Cornillet, Martin
    Karolinska Univ Hosp, Sweden.
    Ponzetta, Andrea
    Karolinska Univ Hosp, Sweden.
    Bergquist, Annika
    Karolinska Univ Hosp, Sweden; Karolinska Univ Hosp, Sweden.
    Bjorkstrom, Niklas K.
    Karolinska Univ Hosp, Sweden.
    A biliary immune landscape map of primary sclerosing cholangitis reveals a dominant network of neutrophils and tissue-resident T cells2021Ingår i: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 13, nr 599, artikel-id eabb3107Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The human biliary system, a mucosal barrier tissue connecting the liver and intestine, is an organ often affected by serious inflammatory and malignant diseases. Although these diseases are linked to immunological processes, the biliary system represents an unexplored immunological niche. By combining endoscopy-guided sampling of the biliary tree with a high-dimensional analysis approach, comprehensive mapping of the human biliary immunological landscape in patients with primary sclerosing cholangitis (PSC), a severe biliary inflammatory disease, was conducted. Major differences in immune cell composition in bile ducts compared to blood were revealed. Furthermore, biliary inflammation in patients with PSC was characterized by high presence of neutrophils and T cells as compared to control individuals without PSC. The biliary T cells displayed a CD103(+)CD69(+) effector memory phenotype, a combined gut and liver homing profile, and produced interleukin-17 (IL-17) and IL-22. Biliary neutrophil infiltration in PSC associated with CXCL8, possibly produced by resident T cells, and CXCL16 was linked to the enrichment of T cells. This study uncovers the immunological niche of human bile ducts, defines a local immune network between neutrophils and biliary-resident T cells in PSC, and provides a resource for future studies of the immune responses in biliary disorders.

  • 14.
    Meira de-Faria, Felipe
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Casado-Bedmar, Maite
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Lindqvist, Carl Marten
    Orebro Univ, Sweden.
    Jones, Michael P.
    Macquarie Univ, Australia.
    Walter, Susanna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Altered interaction between enteric glial cells and mast cells in the colon of women with irritable bowel syndrome2021Ingår i: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 33, nr 11, artikel-id e14130Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Enteric glial cells (EGC) and mast cells (MC) are intimately associated with gastrointestinal physiological functions. We aimed to investigate EGC-MC interaction in irritable bowel syndrome (IBS), a gut-brain disorder linked to increased intestinal permeability, and MC. Methods Parallel approaches were used to quantify EGC markers in colonic biopsies from healthy controls (HC) and patients with IBS. Data were correlated with MC, vasoactive intestinal polypeptide (VIP) and VIP receptors (VPAC1/VPAC2) expressions, and bacterial translocation through biopsies mounted in Ussing chambers. In addition, we investigated the effects of EGC mediators on colonic permeability and the pharmacological-induced responses of EGC and MC cell lines. Key Results Immunofluorescence of IBS colonic mucosa, as well as Western blotting and ELISA of IBS biopsy lysates, revealed increased glial fibrillary intermediate filament (GFAP) expression, indicating EGC activation. Mucosal GFAP correlated with increased MC and VPAC1(+)MC numbers and decreased VIP+MC, which seemed to control bacterial translocation in HC. In the contrary, EGC activation in IBS correlated with less MC and VPAC1(+) MC numbers, and more VIP+ MC. In vitro, MC and EGC cell lines showed intracellular calcium responses to each others mediators. Furthermore, EGC mediators prevented VIP-induced MC degranulation, while MC mediators induced a reactive EGC phenotype. In Ussing chambers, EGC mediators decreased paracellular passage through healthy colonic biopsies. Conclusions & Inferences Findings suggest the involvement of EGC and MC in the control of barrier function in the human colon and indicate a potential EGC-MC interaction that seems altered in IBS, with detrimental consequences to colonic permeability. Altogether, results suggest that imbalanced EGC-MC communication contributes to the pathophysiology of IBS.

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  • 15.
    Alkaissi, Lina Y.
    et al.
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi.
    Winberg Tinnerfelt, Martin
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Heil, Stéphanie
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Haapaniemi, Staffan
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken ViN.
    Myrelid, Pär
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Stange, Eduard F
    Department of Gastroenterology, Dept. Internal Medicine I, University of Tübingen, 72076 Tübingen, Germany.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Antagonism of Adherent Invasive E. coli LF82 With Human α-defensin 5 in the Follicle-associated Epithelium of Patients With Ileal Crohn’s Disease2021Ingår i: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 27, nr 7, s. 1116-1127Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The first visible signs of Crohns disease (CD) are microscopic erosions over the follicle-associated epithelium (FAE). The aim of the study was to investigate the effects of human alpha-defensin 5 (HD5) on adherent-invasive Escherichia coli LF82 translocation and HD5 secretion after LF82 exposure in an in vitro model of human FAE and in human FAE ex vivo. Methods: An in vitro FAE-model was set up by the coculture of Raji B cells and Caco-2-cl1 cells. Ileal FAE from patients with CD and controls were mounted in Ussing chambers. The effect of HD5 on LF82 translocation was studied by LF82 exposure to the cells or tissues with or without incubation with HD5. The HD5 secretion was measured in human FAE exposed to LF82 or Salmonella typhimurium. The HD5 levels were evaluated by immunofluorescence, immunoblotting, and ELISA. Results: There was an increased LF82 translocation across the FAE-model compared with Caco-2-cl1 (P < 0.05). Incubation of cell/tissues with HD5 before LF82 exposure reduced bacterial passage in both models. Human FAE showed increased LF82 translocation in CD compared with controls and attenuated passage after incubation with sublethal HD5 in both CD and controls (P < 0.05). LF82 exposure resulted in a lower HD5 secretion in CD FAE compared with controls (P < 0.05), whereas Salmonella exposure caused equal secretion on CD and controls. There were significantly lower HD5 levels in CD tissues compared with controls. Conclusions: Sublethal HD5 reduces the ability of LF82 to translocate through FAE. The HD5 is secreted less in CD in response to LF82, despite a normal response to Salmonella. This further implicates the integrated role of antimicrobial factors and barrier function in CD pathogenesis.

  • 16.
    Meira de Faria, Felipe
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Bednarska, Olga
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Ström, Magnus
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Walter, Susanna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Colonic paracellular permeability and circulating zonulin-related proteins2021Ingår i: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 56, nr 4, s. 424-431Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective Irritable bowel syndrome (IBS) is a gut-brain disorder associated with increased gut permeability. Zonulin has been suggested to regulate the gut barrier and claimed to be pre-haptoglobin 2 (pre-HP2) and circulating zonulin is often used as a proxy for gastrointestinal permeability. This study investigated the correlation between colonic paracellular permeability and levels of circulating zonulin and pre-HP2. Materials and Methods Colonic biopsies from 32 patients with IBS and 15 healthy controls (HC) were used to measure permeability in Ussing chambers and levels of zonulin (Cusabio ELISA). Zonulin was also measured in blood samples from 40 HC, 78 patients with IBS and 20 patients with celiac disease (CeD), before and after a gluten-free diet. In addition, we verified HP genotype and circulating pre-HP2 using a monoclonal pre-HP2 antibody (Bio-Rad) by ELISA. Results Increased colonic paracellular permeability correlated positively with zonulin levels in IBS biopsies, but negatively with plasma zonulin. We found no agreement between circulating zonulin and pre-HP2. Genotyping revealed non-specificity of the zonulin kit, as all pre-HP2 non-producers presented detectable levels. Patients with CeD displayed higher pre-HP2 and zonulin levels compared to HC. A gluten-free diet in patients with CeD led to lower serum zonulin and pre-HP2 concentrations. Conclusions Our study suggests that neither circulating zonulin nor pre-HP2 mirror colonic permeability. Our data corroborate previous reports showing the inability of the Cusabio zonulin kit to target zonulin and highlights that the results of studies using this kit must be re-examined with caution.

  • 17.
    Mancini, Nicole L.
    et al.
    Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada.
    Rajeev, Sruthi
    Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada.
    Jayme, Timothy S.
    Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada.
    Wang, Arthur
    Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Workentine, Matthew L.
    Faculty of Veterinary Medicine, University of Calgary, Alberta, Canada.
    Hamed, Samira
    Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Lopes, Fernando
    Institute of Parasitology, Faculty of Agriculture and Environmental Sciences, Department of Microbiology and Immunology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
    Shutt, Timothy E.
    Department of Medical Genetics, Alberta Childrens Hospital Research Institute, University of Calgary, Alberta, Canada.
    Shearer, Jane
    Department of Biochemistry and Molecular Biology, Faculty of Kinesiology, University of Calgary, Alberta, Canada.
    McKay, Derek M
    Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada. Electronic address dmckay@ucalgary.ca.
    Crohns Disease Pathobiont Adherent-Invasive E coli Disrupts Epithelial Mitochondrial Networks With Implications for Gut Permeability2021Ingår i: Cellular and molecular gastroenterology and hepatology, ISSN 2352-345X, Vol. 11, nr 2, s. 551-571Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background & aims: Adherent-invasive Escherichia coli are implicated in inflammatory bowel disease, and mitochondrial dysfunction has been observed in biopsy specimens from patients with inflammatory bowel disease. As a novel aspect of adherent-invasive E coli-epithelial interaction, we hypothesized that E coli (strain LF82) would elicit substantial disruption of epithelial mitochondrial form and function.

    Methods: Monolayers of human colon-derived epithelial cell lines were exposed to E coli-LF82 or commensal E coli and RNA sequence analysis, mitochondrial function (adenosine triphosphate synthesis) and dynamics (mitochondrial network imaging, immunoblotting for fission and fusion proteins), and epithelial permeability (transepithelial resistance, flux of fluorescein isothiocyanate-dextran and bacteria) were assessed.

    Results: E coli-LF82 significantly affected epithelial expression of ∼8600 genes, many relating to mitochondrial function. E coli-LF82-infected epithelia showed swollen mitochondria, reduced mitochondrial membrane potential and adenosine triphosphate, and fragmentation of the mitochondrial network: events not observed with dead E coli-LF82, medium from bacterial cultures, or control E coli. Treatment with Mitochondrial Division Inhibitor 1 (Mdivi1, inhibits dynamin-related peptide 1, guanosine triphosphatase principally responsible for mitochondrial fission) or P110 (prevents dynamin-related peptide 1 binding to mitochondrial fission 1 protein) partially reduced E coli-LF82-induced mitochondrial fragmentation in the short term. E coli-LF82-infected epithelia showed loss of the long isoform of optic atrophy factor 1, which mediates mitochondrial fusion. Mitochondrial Division Inhibitor 1 reduced the magnitude of E coli-LF82-induced increased transepithelial flux of fluorescein isothiocyanate dextran. By 8 hours after infection, increased cytosolic cytochrome C and DNA fragmentation were apparent without evidence of caspase-3 or apoptosis inducing factor activation.

    Conclusions: Epithelial mitochondrial fragmentation caused by E coli-LF82 could be targeted to maintain cellular homeostasis and mitigate infection-induced loss of epithelial barrier function. Data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO series accession numbers GSE154121 and GSE154122 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154121).

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  • 18.
    Faisal, Mohammed
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Suez Canal Univ, Egypt.
    Schäfer, Christopher Niels
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Norrlands Univ Hosp, Sweden.
    Myrelid, Pär
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Tinnerfelt Winberg, Martin
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Eintrei, Christina
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, ANOPIVA US.
    Effects of analgesic and surgical modality on immune response in colorectal cancer surgery2021Ingår i: Surgial oncology, ISSN 0960-7404, E-ISSN 1879-3320, Vol. 38, artikel-id 101602Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background and objective: Different surgical methods, anesthesia, and analgesia are known to modify the surgical stress response, especially in patients with malignancy. We compared the impact of patient-controlled intravenous (PCA) versus epidural analgesia (EDA) on tumor-related mucosal immune response in patients undergoing open or laparoscopic surgery for colorectal cancer. Methods: In a University Hospital subgroup (n = 43) of a larger cohort (n = 235) of patients undergoing open or laparoscopic surgery for colorectal carcinoma randomized to PCA or EDA, colorectal tissues were stained for interleukin-10 (IL-10), tumor necrosis factor (TNF), and mast cell tryptase and then examined by immunofluorescence microscopy. Results: More IL-10+-cells were found in patients undergoing open compared to laparoscopic surgery in the PCA (P &lt; 0.05) and EDA group (P &lt; 0.0005), respectively, and numbers of TNF+-cells were higher in the open surgery group who received PCA (P &lt; 0.05). No differences in IL-10 or TNF expressions were detected between EDA/PCA within the open or laparoscopic surgery groups, respectively. Fewer mast cells were observed in patients undergoing laparoscopic compared to open surgery combined with PCA (P &lt; 0.05). Within the open surgery group, EDA resulted in fewer mucosal mast cells compared to the PCA group (P &lt; 0.05). Conclusions: The surgical method, rather than type of analgesia, may have higher impact on peri-operative inflammation. Laparoscopic surgery when combined with EDA for colorectal cancer caused a decrease in the TNF and IL-10 expression and mast cells. EDA seems to have an anti-inflammatory effect on cancer-related inflammation during open surgery.

  • 19.
    Norlin, Anna-Karin
    et al.
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för prevention, rehabilitering och nära vård. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Primärvårdscentrum, Vårdcentralen Mantorp.
    Walter, Susanna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Icenhour, Adriane
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
    Keita, Åsa
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi.
    Elsenbruch, Sigrid
    Department of Medical Psychology and Medical Sociology, Ruhr University Bochum, Bochum, Germany.
    Bednarska, Olga
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Jones, Michael P.
    Department of Psychology, Macquarie University, Sydney, Australia.
    Simon, Rozalyn
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Engström, Maria
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Fatigue in irritable bowel syndrome is associated with plasma levels of TNF-α and mesocorticolimbic connectivity2021Ingår i: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 92, s. 211-220Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Irritable bowel syndrome (IBS) is a symptom-based disorder of gut-brain interactions generating abdominal pain. It is also associated with a vulnerability to develop extraintestinal symptoms, with fatigue often reported as one of the most disturbing. Fatigue is related to brain function and inflammation in several disorders, however, the mechanisms of such relations in IBS remain elusive. This study aimed to elucidate fatigue and its association with a resting state network of mesocorticolimbic regions of known importance in fatigue, and to explore the possible role of circulating TNF-α levels in IBS and healthy controls (HC). Resting state functional magnetic resonance imaging (fMRI) was conducted in 88 IBS patients and 47 HC of similar age and gender to investigate functional connectivity between mesocorticolimbic regions. Further, fatigue impact on daily life and plasma levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α), of known relevance to immune activation in IBS, were also measured. The selected mesocorticolimbic regions indeed formed a functionally connected network in all participants. The nucleus accumbens (NAc), in particular, exhibited functional connectivity to all other regions of interest. In IBS, fatigue impact on daily life was negatively correlated with the connectivity between NAc and dorsolateral prefrontal cortex bilaterally (left p = 0.019; right p = 0.038, corrected for multiple comparisons), while in HC, fatigue impact on daily life was positively correlated to the connectivity between the right NAc and anterior middle insula in both hemispheres (left p = 0.009; right p = 0.011). We found significantly higher levels of TNF-α in IBS patients compared to HC (p = 0.001) as well as a positive correlation between TNF-α and fatigue impact on daily life in IBS patients (rho = 0.25, p = 0.02) but not in HC (rho = −0.13, p = 0.37). There was no association between functional connectivity in the mesocorticolimbic network and plasma levels of TNF-α in either group In summary, this novel multimodal study provides the first evidence that the vulnerability to fatigue in IBS is associated with connectivity within a mesocorticolimbic network as well as immune activation. These findings warrant further investigation, both peripherally and potentially with measurements of central immune activation as well.

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  • 20.
    Simon, Rozalyn
    et al.
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Ranasinghe, Purnika
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Queens Univ Belfast, North Ireland.
    Barazanji, Nawroz
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Bergman Jungeström, Malin
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk mikrobiologi.
    Xu, Jie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Bednarska, Olga
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Serrander, Lena
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk mikrobiologi.
    Engström, Maria
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Bazylinski, Dennis A.
    Univ Nevada, NV 89154 USA.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Walter, Susanna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Magnetotactic bacteria from the human gut microbiome associated with orientation and navigation regions of the brain2021Ingår i: Journal of Oceanology and Limnology, ISSN 2096-5508, Vol. 39, nr 6, s. 2044-2052Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Magnetotactic bacteria (MTB), ubiquitous in soil and fresh and saltwater sources have been identified in the microbiome of humans and many animals. MTB endogenously produce magnetic nanocrystals enabling them to orient and navigate along geomagnetic fields. Similar magnetite deposits have been found throughout the tissues of the human brain, including brain regions associated with orientation such as the cerebellum and hippocampus, the origins of which remain unknown. Speculation over the role and source of MTB in humans, as well as any association with the brain, remain unanswered. We performed a metagenomic analysis of the gut microbiome of 34 healthy females as well as grey matter volume analysis in magnetite-rich brain regions associated with orientation and navigation with the goal of identifying specific MTB that could be associated with brain structure in orientation and navigation regions. We identified seven MTB in the human gut microbiome: Magnetococcus marinus, Magnetospira sp. QH-2, Magnetospirillum magneticum, Magnetospirillum sp. ME-1, Magnetospirillum sp. XM-1, Magnetospirillum gryphiswaldense, and Desulfovibrio magneticus. Our preliminary results show significant negative associations between multiple MTB with bilateral flocculonodular lobes of the cerebellum and hippocampus (adjusted for total intracranial volume, uncorrected P&lt;0.05). These findings indicate that MTB in the gut are associated with grey matter volume in magnetite-rich brain regions related to orientation and navigation. These preliminary findings support MTB as a potential biogenic source for brain magnetite in humans. Further studies will be necessary to validate and elucidate the relationship between these bacteria, magnetite concentrations, and brain function.

  • 21.
    Thomson, Amanda
    et al.
    Cardiff Univ, Wales.
    Bento, Diana F. Costa
    Cardiff Univ, Wales.
    Scurr, Martin J.
    Cardiff Univ, Wales.
    Smart, Kathryn
    Cardiff Univ, Wales.
    Somerville, Michelle S.
    Cardiff Univ, Wales.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Gallimore, Awen
    Cardiff Univ, Wales.
    Godkin, Andrew
    Cardiff Univ, Wales; Univ Hosp Wales, Wales.
    Prognostic significance of interleukin-17A-producing colorectal tumour antigen-specific T cells2021Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 124, nr 9, s. 1552-1555Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background The T cell cytokine profile is a key prognostic indicator of post-surgical outcome for colorectal cancer (CRC). Whilst T(H)1 (IFN-gamma(+)) cell-mediated responses generated in CRC are well documented and are associated with improved survival, antigen-specific T(H)17 (IL-17A(+)) responses have not been similarly measured. Methods We sought to determine the cytokine profile of circulating tumour antigen-(5T4/CEA) specific T cells of 34 CRC patients to address whether antigen-specific IL-17A responses were detectable and whether these were distinct to IFN-gamma responses. Results As with IFN-gamma-producing T cells, anti-5T4/CEA T(H)17 responses were detectable predominantly in early stage (TNM I/II) CRC patients. Moreover, whilst IL-17A was always produced in association with IFN-gamma, this release was mainly from two distinct T cell populations rather than by dual producing T cells. Patients mounting both tumour-specific T(H)1(+)/T(H)17(+) responses exhibited prolonged relapse-free survival. Conclusions Tumour antigen-specific T(H)17 responses play a beneficial role in preventing post-operative colorectal tumour recurrence.

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  • 22.
    Bergemalm, Daniel
    et al.
    Orebro Univ, Sweden.
    Andersson, Erik
    Orebro Univ, Sweden.
    Hultdin, Johan
    Umea Univ, Sweden.
    Eriksson, Carl
    Orebro Univ, Sweden.
    Rush, Stephen T.
    Orebro Univ, Sweden.
    Kalla, Rahul
    Univ Edinburgh, Scotland.
    Adams, Alex T.
    Univ Oxford, England.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    DAmato, Mauro
    CIC BioGUNE Basque Res & Technol Alliance & Basqu, Spain; Karolinska Inst, Sweden.
    Gomollon, Fernando
    Hosp Clin Univ Lozano Blesa, Spain.
    Jahnsen, Jorgen
    Akershus Univ Hosp, Norway; Univ Oslo, Norway.
    Ricanek, Petr
    Akershus Univ Hosp, Norway.
    Satsangi, Jack
    Univ Oxford, England; Univ Edinburgh, Scotland.
    Repsilber, Dirk
    Orebro Univ, Sweden; Umea Univ, Sweden.
    Karling, Pontus
    Umea Univ, Sweden.
    Halfvarson, Jonas
    Orebro Univ, Sweden.
    Systemic Inflammation in Preclinical Ulcerative Colitis2021Ingår i: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 161, nr 5, s. 1526-1539Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND & AIMS: Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins. METHODS: We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored. RESULTS: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P &lt; .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1 beta, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-kappa B, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naive patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis. CONCLUSIONS: A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors.

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  • 23.
    Simon, Rozalyn
    et al.
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Barazanji, Nawroz
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Jones, Michael P.
    Macquarie Univ, Australia.
    Bednarska, Olga
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Icenhour, Adriane
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Univ Duisburg Essen, Germany.
    Engström, Maria
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Hamilton, Paul
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Walter, Susanna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Vasoactive intestinal polypeptide plasma levels associated with affective symptoms and brain structure and function in healthy females2021Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 11, nr 1, artikel-id 1406Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Vasoactive intestinal polypeptide (VIP) is a neuroendocrine peptide distributed throughout the human body, including the CNS, where it is particularly abundant in brain regions associated with anxiety and depression. Based on earlier studies indicating that peripheral VIP may cross through the blood-brain barrier, we hypothesized plasma VIP levels to be associated with symptoms of anxiety and depression, as well as brain volume and resting-state functional connectivity in the amygdala, hippocampus, parahippocampus, and orbitofrontal cortex. Plasma VIP concentrations and anxiety/depression symptoms were measured in 37 healthy females. Functional and structural magnetic resonance imaging were used to evaluate functional connectivity and brain volume respectively, and their associations with VIP concentrations within brain regions associated with anxiety and depression. Negative correlations were found between VIP levels and symptoms of anxiety (r=- 0.44, p=0.002) and depression (r=- 0.50, p=0.001). Functional connectivity demonstrated significant VIP-dependent positive associations between the amygdala seed region with both the right parahippocampus (t((33))=3.1, p(FDR)=0.02) and right lateral orbitofrontal cortex (OFC; t((33))=2.9, p(FDR)=0.02). Moreover, VIP concentrations were significantly, positively correlated with brain volume in the left amygdala (r=0.28, p=0.007) and left lateral OFC (r=0.29, p=0.004). The present findings highlight a potential role for VIP in the neurobiology of affective symptoms.

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  • 24.
    Bhattacharya, Pradyot
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Ellegård, Rada
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Khalid, Mohammad
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Svanberg, Cecilia
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Govender, Melissa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Söderholm, Johan D.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Myrelid, Pär
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Shankar, Esaki M.
    Univ Malaya, Malaysia; Cent Univ Tamil Nadu, India.
    Nyström, Sofia
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk immunologi och transfusionsmedicin.
    Larsson, Marie
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Complement opsonization of HIV affects primary infection of human colorectal mucosa and subsequent activation of T cells2020Ingår i: eLIFE, E-ISSN 2050-084X, Vol. 9, artikel-id e57869Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    HIV transmission via genital and colorectal mucosa are the most common routes of dissemination. Here, we explored the effects of free and complement-opsonized HIV on colorectal tissue. Initially, there was higher antiviral responses in the free HIV compared to complementopsonized virus. The mucosal transcriptional response at 24 hr revealed the involvement of activated T cells, which was mirrored in cellular responses observed at 96 hr in isolated mucosal T cells. Further, HIV exposure led to skewing of T cell phenotypes predominantly to inflammatory CD4+ T cells, that is Th17 and Th1Th17 subsets. Of note, HIV exposure created an environment that altered the CD8+ T cell phenotype, for example expression of regulatory factors, especially when the virions were opsonized with complement factors. Our findings suggest that HIV-opsonization alters the activation and signaling pathways in the colorectal mucosa, which promotes viral establishment by creating an environment that stimulates mucosal T cell activation and inflammatory Th cells.

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  • 25.
    Mall, John-Peter Ganda
    et al.
    Orebro Univ, Sweden.
    Fart, Frida
    Orebro Univ, Sweden.
    Sabet, Julia A.
    Orebro Univ, Sweden.
    Lindqvist, Carl Marten
    Orebro Univ, Sweden.
    Nestestog, Ragnhild
    Genet Anal AS, Norway.
    Hegge, Finn Terje
    Genet Anal AS, Norway.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Brummer, Robert J.
    Orebro Univ, Sweden.
    Schoultz, Ida
    Orebro Univ, Sweden.
    Effects of Dietary Fibres on Acute Indomethacin-Induced Intestinal Hyperpermeability in the Elderly: A Randomised Placebo Controlled Parallel Clinical Trial2020Ingår i: Nutrients, E-ISSN 2072-6643, Vol. 12, nr 7, artikel-id 1954Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The effect of dietary fibres on intestinal barrier function has not been well studied, especially in the elderly. We aimed to investigate the potential of the dietary fibres oat beta-glucan and wheat arabinoxylan to strengthen the intestinal barrier function and counteract acute non-steroid anti-inflammatory drug (indomethacin)-induced hyperpermeability in the elderly. A general population of elderly subjects (&gt;= 65 years,n= 49) was randomised to a daily supplementation (12g/day) of oat beta-glucan, arabinoxylan or placebo (maltodextrin) for six weeks. The primary outcome was change in acute indomethacin-induced intestinal permeability from baseline, assessed by an in vivo multi-sugar permeability test. Secondary outcomes were changes from baseline in: gut microbiota composition, systemic inflammatory status and self-reported health. Despite a majority of the study population (85%) showing a habitual fibre intake below the recommendation, no significant effects on acute indomethacin-induced intestinal hyperpermeability in vivo or gut microbiota composition were observed after six weeks intervention with either dietary fibre, compared to placebo.

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  • 26.
    Keita, Åsa
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Yakimenko Alkaissi, Lina
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Boström Holm, Elin
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Heil, Stéphanie
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Chassaing, Benoit
    Georgia State Univ, GA 30303 USA; Georgia State Univ, GA 30303 USA.
    Darfeuille-Michaud, Arlette
    Univ Auvergne, France.
    McKay, Derek M.
    Univ Calgary, Canada.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Enhanced E. coli LF82 Translocation through the Follicle-associated Epithelium in Crohns Disease is Dependent on Long Polar Fimbriae and CEACAM6 expression, and Increases Paracellular Permeability2020Ingår i: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 14, nr 2, s. 216-229Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background and Aims: Patients with Crohns disease [CD] harbour an increased number of adherent-invasive E. coli [AIEC]. The strain LF82, identified in the ileal mucosa of CD patients, has been extensively studied for pathogenic mechanisms. However, understanding of the interaction of LF82 with the intestinal mucosa of CD patients is lacking. Methods: Here, we investigated the importance of long polar fimbriae [LPF] type 1 pili and the carcinoembryonic antigen-related cell-adhesion molecule 6 [CEACAM6] for translocation of LF82 in an in vitro model of follicle-associated epithelium [FAE], and in the FAE and villus epithelium [VE] of patients with CD and controls, using Ussing chambers. Results: Significantly greater LF82 passage occurred in the FAE model compared with in the VE Caco-2cl1 mono-culture. Moreover, bacterial translocation was inhibited by either LPF disruption or pre-incubation with anti-CEACAM6 antibody. Tissue mounted in Ussing chambers showed significantly higher LF82 passage in FAE from patients with CD compared with control FAE, that was diminished in LF82 lacking LPF and by blocking host CEACAM6. Interestingly, addition of LF82 to the CD FAE tissues significantly increased paracellular permeability [of (51)Chromium-EDTA] compared with baseline, and the increase was inhibited by anti-CEACAM6. Immunofluorescence and immunoblots showed higher expression of CEACAM6 in FAE of patients with CD compared with in FAE from controls. Conclusions: These data suggest that the FAE of CD patients is a site of vulnerability for invasion by LF82 via a mechanism that requires both bacterial LPF and host CEACAM6. Further, LF82 has the ability to increase paracellular passage through the FAE of patients with CD. These data can help define novel therapeutic targets in CD for the prevention of clinical recurrence.

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  • 27.
    Wills, John W.
    et al.
    Univ Cambridge, England.
    Robertson, Jack
    Univ Cambridge, England.
    Summers, Huw D.
    Swansea Univ, Wales.
    Miniter, Michelle
    Univ Cambridge, England.
    Barnes, Claire
    Swansea Univ, Wales.
    Hewitt, Rachel E.
    Univ Cambridge, England.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Rees, Paul
    Swansea Univ, Wales; Broad Inst MIT and Harvard, MA 02142 USA.
    Powell, Jonathan J.
    Univ Cambridge, England.
    Image-Based Cell Profiling Enables Quantitative Tissue Microscopy in Gastroenterology2020Ingår i: Cytometry Part A, ISSN 1552-4922, E-ISSN 1552-4930, Vol. 97, nr 12, s. 1222-1237Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Immunofluorescence microscopy is an essential tool for tissue-based research, yet data reporting is almost always qualitative. Quantification of images, at the per-cell level, enables "flow cytometry-type" analyses with intact locational data but achieving this is complex. Gastrointestinal tissue, for example, is highly diverse: from mixed-cell epithelial layers through to discrete lymphoid patches. Moreover, different species (e.g., rat, mouse, and humans) and tissue preparations (paraffin/frozen) are all commonly studied. Here, using field-relevant examples, we develop open, user-friendly methodology that can encompass these variables to provide quantitative tissue microscopy for the field. Antibody-independent cell labeling approaches, compatible across preparation types and species, were optimized. Per-cell data were extracted from routine confocal micrographs, with semantic machine learning employed to tackle densely packed lymphoid tissues. Data analysis was achieved by flow cytometry-type analyses alongside visualization and statistical definition of cell locations, interactions and established microenvironments. First, quantification of Escherichia coli passage into human small bowel tissue, following Ussing chamber incubations exemplified objective quantification of rare events in the context of lumen-tissue crosstalk. Second, in rat jejenum, precise histological context revealed distinct populations of intraepithelial lymphocytes between and directly below enterocytes enabling quantification in context of total epithelial cell numbers. Finally, mouse mononuclear phagocyte-T cell interactions, cell expression and significant spatial cell congregations were mapped to shed light on cell-cell communication in lymphoid Peyers patch. Accessible, quantitative tissue microscopy provides a new window-of-insight to diverse questions in gastroenterology. It can also help combat some of the data reproducibility crisis associated with antibody technologies and over-reliance on qualitative microscopy. (c) 2020 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.

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  • 28.
    Katinios, Georgios
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Casado-Bedmar, Maite
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Walter, Susanna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Vicario, Maria
    Univ Autonoma Barcelona, Spain.
    Gonzalez-Castro, Ana M.
    Univ Autonoma Barcelona, Spain.
    Bednarska, Olga
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Hjortswang, Henrik
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Mag- tarmmedicinska kliniken.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Increased Colonic Epithelial Permeability and Mucosal Eosinophilia in Ulcerative Colitis in Remission Compared With Irritable Bowel Syndrome and Health2020Ingår i: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 26, nr 7, s. 974-984Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Barrier dysfunction is recognized as a pathogenic factor in ulcerative colitis (UC) and irritable bowel syndrome (IBS), but it is unclear to what extent the factors related to barrier dysfunction are disease-specific. The aim of this study was to compare these aspects in UC patients in remission, IBS patients, and healthy controls (HCs).

    Methods

    Colonic biopsies were collected from 13 patients with UC in remission, 15 patients with IBS-mixed, and 15 HCs. Ulcerative colitis patients had recently been treated for relapse, and biopsies were taken from earlier inflamed areas. Biopsies were mounted in Ussing chambers for measurements of intestinal paracellular permeability to 51chromium (Cr)-ethylenediaminetetraacetic acid (EDTA). In addition, biopsies were analyzed for mast cells and eosinophils by histological procedures, and plasma tumor necrosis factor (TNF)-α was assessed by ELISA.

    Results

    Ussing chamber experiments revealed an increased 51Cr-EDTA permeability in UC and IBS (P < 0.05). The 51Cr-EDTA permeability was higher in UC compared with IBS (P < 0.005). There were increased numbers of mucosal mast cells and eosinophils in UC and IBS and more eosinophils in UC compared with IBS (P < 0.05). Also, increased extracellular granule content was found in UC compared with HCs (P < 0.05). The 51Cr-EDTA permeability correlated significantly with eosinophils in all groups. Plasma TNF-α concentration was higher in UC compared with IBS and HCs (P < 0.0005).

    Conclusions

    Results indicate a more permeable intestinal epithelium in inactive UC and IBS compared with HCs. Ulcerative colitis patients, even during remission, demonstrate a leakier barrier compared with IBS. Both eosinophil numbers and activation state might be involved in the increased barrier function seen in UC patients in remission.

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  • 29.
    Hagbom, Marie
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Meira de Faria, Felipe
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Tinnerfelt Winberg, Martin
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Westerberg, Sonja
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Nordgren, Johan
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Sharma, Sumit
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Loitto, Vesa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten.
    Magnusson, Karl-Eric
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för inflammation och infektion. Linköpings universitet, Medicinska fakulteten.
    Svensson, Lennart
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten. Karolinska Inst, Sweden.
    Neurotrophic Factors Protect the Intestinal Barrier from Rotavirus Insult in Mice2020Ingår i: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 11, nr 1, artikel-id e02834-19Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Increased intestinal permeability has been proposed as a mechanism of rotavirus-induced diarrhea. Studies with humans and mice have, however, shown that rotavirus leaves intestinal permeability unaffected or even reduced during diarrhea, in contrast to most bacterial infections. Gastrointestinal permeability is regulated by the vagus nerve and the enteric nervous system, which is composed of neurons and enteric glial cells (EGCs). We investigated whether the vagus nerve, serotonin (5-HT), EGCs, and neurotropic factors contribute to maintaining gut barrier homeostasis during rotavirus infection. Using subdiaphragmatic vagotomized and 5-HT3 receptor knockout mice, we found that the unaffected epithelial barrier during rotavirus infection is independent of the vagus nerve but dependent on 5-HT signaling through enteric intrinsic 5-HT3 receptors. Immunofluorescence analysis showed that rotavirus-infected enterocytes were in close contact with EGCs and enteric neurons and that the glial cell-derived neurotrophic factor (GDNF) was strongly upregulated in enterocytes of infected mice. Moreover, rotavirus and 5-HT activated EGCs (P &lt; 0.001). Using Ussing chambers, we found that GDNF and S-nitrosoglutathione (GSNO) led to denser epithelial barriers in small intestinal resections from noninfected mice (P &lt; 0.01) and humans (P &lt; 0.001) and that permeability was unaffected in rotavirus-infected mice. GSNO made the epithelial barrier denser in Caco-2 cells by increasing the expression of the tight junction protein zona occludens 1 (P &lt; 0.001), resulting in reduced passage of fluorescein isothiocyanate dextran (P &lt; 0.05) in rotavirus-infected monolayers. This is the first report to show that neurotropic factors contribute to maintaining the gut epithelial barrier during viral insult. IMPORTANCE Human and mouse studies have shown that rotavirus infection is associated with low inflammation and unaffected intestinal barrier at the time of diarrhea, properties different from most bacterial and inflammatory diseases of the gut. We showed by in vitro, ex vivo, and in vivo experiments that neurotrophic factors and 5-HT have barrier protective properties during rotavirus insult. These observations advance our understanding of how the gut barrier is protected against rotavirus and suggest that rotavirus affects the gut barrier differently from bacteria. This is the first report to show that neurotrophic factors contribute to maintain the gut epithelial barrier during viral insult.

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  • 30.
    Casado Bedmar, Maite
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Potential neuro-immune therapeutic targets in irritable bowel syndrome2020Ingår i: Therapeutic Advances in Gastroenterology, ISSN 1756-283X, E-ISSN 1756-2848, Vol. 13, artikel-id 1756284820910630Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder characterized by recurring abdominal pain and disturbed bowel habits. The aetiology of IBS is unknown but there is evidence that genetic, environmental and immunological factors together contribute to the development of the disease. Current treatment of IBS includes lifestyle and dietary interventions, laxatives or antimotility drugs, probiotics, antispasmodics and antidepressant medication. The gut-brain axis comprises the central nervous system, the hypothalamic pituitary axis, the autonomic nervous system and the enteric nervous system. Within the intestinal mucosa there are close connections between immune cells and nerve fibres of the enteric nervous system, and signalling between, for example, mast cells and nerves has shown to be of great importance during GI disorders such as IBS. Communication between the gut and the brain is most importantly routed via the vagus nerve, where signals are transmitted by neuropeptides. It is evident that IBS is a disease of a gut-brain axis dysregulation, involving altered signalling between immune cells and neurotransmitters. In this review, we analyse the most novel and distinct neuro-immune interactions within the IBS mucosa in association with already existing and potential therapeutic targets.

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  • 31.
    Beeckmans, Dorien
    et al.
    Katholieke Univ Leuven, Belgium.
    Farre, Ricard
    Katholieke Univ Leuven, Belgium.
    Riethorst, Danny
    Katholieke Univ Leuven, Belgium.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Augustijns, Patrick
    Katholieke Univ Leuven, Belgium.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Vanuytsel, Tim
    Katholieke Univ Leuven, Belgium.
    Vanheel, Hanne
    Katholieke Univ Leuven, Belgium.
    Tack, Jan
    Katholieke Univ Leuven, Belgium.
    Relationship between bile salts, bacterial translocation, and duodenal mucosal integrity in functional dyspepsia2020Ingår i: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 32, nr 5, artikel-id e13788Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Functional dyspepsia (FD) is a complex disorder, in which multiple mechanisms underlie symptom generation, including impaired duodenal barrier function. Moreover, an altered duodenal bile salt pool was recently discovered in patients with FD. We aimed to evaluate the relationship between bile salts, bacterial translocation, and duodenal mucosal permeability in FD. Methods Duodenal biopsies from patients with FD and healthy volunteers (HV) were mounted in Ussing chambers to measure mucosal resistance and bacterial passage in the absence and presence of fluorescein-conjugated Escherichia coli and glyco-ursodeoxycholic acid (GUDCA) exposure. In parallel, duodenal fluid aspirates were collected from patients and bile salts were analyzed. Key results The transepithelial electrical resistance of duodenal biopsies from patients was lower compared with HV (21.4 +/- 1.3 omega.cm(2) vs. 24.4 +/- 1.2 omega.cm(2); P = .02; N = 21). The ratio of glyco-cholic and glyco-chenodeoxycholic acid (GCDCA) to tauro- and GUDCA correlated positively with transepithelial electrical resistance in patients. Glyco-ursodeoxycholic acid slightly altered the mucosal resistance, resulting in similar values between patient and healthy biopsies (22.1 +/- 1.0 omega.cm(2) vs. 23.0 +/- 1.0 omega.cm(2); P = .5). Bacterial passage after 120 minutes was lower for patient than for healthy biopsies (0.0 [0.0-681.8] vs. 1684.0 [0.0-4773.0] E coli units; P = .02). Glyco-ursodeoxycholic acid increased bacterial passage in patient biopsies (102.1 [0.0-733.0] vs. 638.9 [280.6-2124.0] E coli units; P = .009). No correlation was found between mucosal resistance and bacterial passage. Conclusions amp; inferences Patients with FD displayed decreased duodenal mucosal resistance associated with bile salts, however, not associated with bacterial passage in vitro. In addition, the hydrophilic bile salt glyco-ursodeoxycholic acid abolished differences in mucosal resistance and bacterial passage between patient and control group.

  • 32.
    Schoultz, Ida
    et al.
    Orebro Univ, Sweden.
    Keita, Åsa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    The Intestinal Barrier and Current Techniques for the Assessment of Gut Permeability2020Ingår i: Cells, E-ISSN 2073-4409, Vol. 9, nr 8, artikel-id 1909Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The intestinal barrier is essential in human health and constitutes the interface between the outside and the internal milieu of the body. A functional intestinal barrier allows absorption of nutrients and fluids but simultaneously prevents harmful substances like toxins and bacteria from crossing the intestinal epithelium and reaching the body. An altered intestinal permeability, a sign of a perturbed barrier function, has during the last decade been associated with several chronic conditions, including diseases originating in the gastrointestinal tract but also diseases such as Alzheimer and Parkinson disease. This has led to an intensified interest from researchers with diverse backgrounds to perform functional studies of the intestinal barrier in different conditions. Intestinal permeability is defined as the passage of a solute through a simple membrane and can be measured by recording the passage of permeability markers over the epithelium via the paracellular or the transcellular route. The methodological tools to investigate the gut barrier function are rapidly expanding and new methodological approaches are being developed. Here we outline and discuss, in vivo, in vitro and ex vivo techniques and how these methods can be utilized for thorough investigation of the intestinal barrier.

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  • 33.
    Schoultz, Ida
    et al.
    Orebro Univ, Sweden.
    Keita, Åsa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Cellular and Molecular Therapeutic Targets in Inflammatory Bowel Disease-Focusing on Intestinal Barrier Function2019Ingår i: Cells, E-ISSN 2073-4409, Vol. 8, nr 2, artikel-id 193Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The human gut relies on several cellular and molecular mechanisms to allow for an intact and dynamical intestinal barrier. Normally, only small amounts of luminal content pass the mucosa, however, if the control is broken it can lead to enhanced passage, which might damage the mucosa, leading to pathological conditions, such as inflammatory bowel disease (IBD). It is well established that genetic, environmental, and immunological factors all contribute in the pathogenesis of IBD, and a disturbed intestinal barrier function has become a hallmark of the disease. Genetical studies support the involvement of intestinal barrier as several susceptibility genes for IBD encode proteins with key functions in gut barrier and homeostasis. IBD patients are associated with loss in bacterial diversity and shifts in the microbiota, with a possible link to local inflammation. Furthermore, alterations of immune cells and several neuro-immune signaling pathways in the lamina propria have been demonstrated. An inappropriate immune activation might lead to mucosal inflammation, with elevated secretion of pro-inflammatory cytokines that can affect the epithelium and promote a leakier barrier. This review will focus on the main cells and molecular mechanisms in IBD and how these can be targeted in order to improve intestinal barrier function and reduce inflammation.

  • 34.
    Witt, Suzanne Tyson
    et al.
    Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV. Linköpings universitet, Medicinska fakulteten.
    Bednarska, Olga
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Keita, Åsa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Icenhour, Adriane
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Jones, Michael P.
    Department of Psychology, Macquarie University, NSW, Australia.
    Elsenbruch, Sigrid
    Institute of Medical Psychology & Behavioral Immunobiology, Essen University Hospital, Essen, Germany.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Engström, Maria
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Mayer, Emeran A.
    Department of Medicine, UCLA, Los Angeles, CA, United States of America.
    Walter, Susanna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Interactions between gut permeability and brain structure and function in health and irritable bowel syndrome2019Ingår i: NeuroImage: Clinical, E-ISSN 2213-1582, Vol. 21, artikel-id 101602Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Changes in brain-gut interactions have been implicated in the pathophysiology of chronic visceral pain in irritable bowel syndrome (IBS). Different mechanisms of sensitization of visceral afferent pathways may contribute to the chronic visceral pain reports and associated brain changes that characterize IBS. They include increased gut permeability and gut associated immune system activation, and an imbalance in descending pain inhibitory and facilitatory mechanisms. In order to study the involvement of these mechanisms, correlations between gut epithelial permeability and live bacterial passage, and structural and functional brain connectivity were measured in women with moderate-to-severe IBS and healthy women. The relationships between gut permeability and functional and anatomical connectivity were significantly altered in IBS compared with the healthy women. IBS participants with lower epithelial permeability reported increased IBS symptoms, which was associated with increased functional and structural connectivity in endogenous pain facilitation regions. The findings suggest that relationships between gut permeability and the brain are significantly altered in IBS and suggest the existence of IBS subtypes based on these interactions.

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  • 35.
    Christerson, Ulrika
    et al.
    Linnaeus Univ, Sweden.
    Keita, Åsa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Tinnerfelt Winberg, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Gustafson-Svard, Christina
    Linnaeus Univ, Sweden.
    Possible Involvement of Intracellular Calcium-Independent Phospholipase A2 in the Release of Secretory Phospholipases from Mast Cells: Increased Expression in Ileal Mast Cells of Crohns Disease2019Ingår i: Cells, E-ISSN 2073-4409, Vol. 8, nr 7, artikel-id 672Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Increased activity of secretory phospholipases A(2) (sPLA(2)) type-II was previously observed in ileum of Crohns disease (CD). Our aims were to explore the involvement of calcium-independent (i)PLA(2 beta) in the release of sPLA(2)s from the human mast cell (MC) line (HMC-1) and investigate expressions of cytosolic (c)PLA(2) alpha, iPLA(2)beta, sPLA(2)-IIA and sPLA(2)-V in MCs of CD ileum. The release of sPLA(2) was investigated in HMC-1 by immunocytochemistry and ELISA. The expression intensities of PLA(2)s in mucosal MCs, and the proportion of PLA(2)-positive MCs, were investigated in normal ileum and in ileum from patients with CD by immunohistochemistry. The calcium ionophore-stimulated release of sPLA(2)-IIA and sPLA(2)-V from HMC-1 was reduced by the iPLA(2)-inhibitor bromoenol lactone. All four PLA(2)s were detectable in mucosal MCs, both in normal ileum and in CD, but the proportion of iPLA(2)beta-containing mucosal MCs and the expression intensity of sPLA(2)-IIA was increased in CD. Results indicate that iPLA(2)beta is involved in the secretion of sPLA(2)s from HMC-1, and suggest that iPLA(2)beta-mediated release of sPLA(2) from intestinal MCs may contribute to CD pathophysiology. Ex vivo studies on isolated mucosal mast cells are however needed to clarify the precise role of MC PLA(2)s in the inflammatory processes of CD.

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  • 36.
    Thomson, Amanda
    et al.
    Sch Med, Wales; Newcastle Univ, England.
    Smart, Kathryn
    Sch Med, Wales.
    Somerville, Michelle S.
    Sch Med, Wales.
    Lauder, Sarah N.
    Sch Med, Wales.
    Appanna, Gautham
    Sch Med, Wales; Univ Hosp Wales, Wales.
    Horwood, James
    Univ Hosp Wales, Wales.
    Raj, Lawrence Sunder
    Univ Hosp Wales, Wales.
    Srivastava, Brijesh
    Univ Hosp Wales, Wales.
    Durai, Dharmaraj
    Univ Hosp Wales, Wales.
    Scurr, Martin J.
    Sch Med, Wales.
    Keita, Åsa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Gallimore, Awen M.
    Sch Med, Wales.
    Godkin, Andrew
    Sch Med, Wales; Univ Hosp Wales, Wales.
    The Ussing chamber system for measuring intestinal permeability in health and disease2019Ingår i: BMC Gastroenterology, ISSN 1471-230X, E-ISSN 1471-230X, Vol. 19, artikel-id 98Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BackgroundThe relationship between intestinal epithelial integrity and the development of intestinal disease is of increasing interest. A reduction in mucosal integrity has been associated with ulcerative colitis, Crohns disease and potentially could have links with colorectal cancer development. The Ussing chamber system can be utilised as a valuable tool for measuring gut integrity. Here we describe step-by-step methodology required to measure intestinal permeability of both mouse and human colonic tissue samples ex vivo, using the latest equipment and software. This system can be modified to accommodate other tissues.MethodsAn Ussing chamber was constructed and adapted to support both mouse and human tissue to measure intestinal permeability, using paracellular flux and electrical measurements. Two mouse models of intestinal inflammation (dextran sodium sulphate treatment and T regulatory cell depletion using C57BL/6-FoxP3(DTR) mice) were used to validate the system along with human colonic biopsy samples.ResultsDistinct regional differences in permeability were consistently identified within mouse and healthy human colon. In particular, mice showed increased permeability in the mid colonic region. In humans the left colon is more permeable than the right. Furthermore, inflammatory conditions induced chemically or due to autoimmunity reduced intestinal integrity, validating the use of the system.ConclusionsThe Ussing chamber has been used for many years to measure barrier function. However, a clear and informative methods paper describing the setup of modern equipment and step-by-step procedure to measure mouse and human intestinal permeability isnt available. The Ussing chamber system methodology we describe provides such detail to guide investigation of gut integrity.

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  • 37.
    Casado Bedmar, Maria Teresa
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Heil, Stéphanie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Myrelid, Pär
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Keita, Åsa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Upregulation of intestinal mucosal mast cells expressing VPAC1 in close proximity to vasoactive intestinal polypeptide in inflammatory bowel disease and murine colitis2019Ingår i: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 31, nr 3, artikel-id e13503Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    Mast cells (MCs) and vasoactive intestinal polypeptide (VIP) have been proposed as regulators of the intestinal barrier and inflammation. Our aim was to map the distribution in inflammatory bowel disease (IBD) and murine colitis.

    Methods

    MCs, VIP, and VIP‐receptors (VPACs) were quantified by immunofluorescence and enzyme‐immunoassay (EIA) in ileal tissues (villus epithelium (VE) and adjacent VE, ie, VE next to the follicle‐associated epithelium, (FAE)) from Crohn's disease (CD; n = 16) and non‐IBD patients, and in colonic specimens of ulcerative colitis (UC; n = 12) and healthy controls (HCs). In addition, VIP levels were measured in plasma from HCs, non‐IBD, and IBD in remission (CD n = 30; UC n = 30). Colon, ileum, and plasma from mice with dextran sulfate sodium (DSS)‐induced colitis and control mice were analyzed likewise.

    Key Results

    FAE‐adjacent VE in ileum of CD possessed more MCs (P < 0.05) and MCs expressing VPAC1 (P < 0.05), but not VPAC2, compared to controls. Both adjacent and regular VE of CD had more MCs co‐localizing/in close proximity to VIP (P < 0.05). In UC colon, more MCs (P < 0.0005), MCs close to VIP (P < 0.0005), and MCs expressing VPAC1 (P < 0.05) were found compared to controls. VIP levels were elevated in plasma from CD and UC compared to controls (P < 0.0005). Colon of DSS mice showed more MCs and MCs close to VIP (P < 0.05) compared to control mice. In vitro experiments revealed MCs expressing VPACs and internalized VIP after 120 minutes of VIP‐stimulation.

    Conclusions and Inferences

    Communication between MCs and VIP is upregulated during IBD and mice colitis. In CD patients, the epithelium next to FAE seems to be more involved than the surrounding VE, suggesting increased MC‐VIP‐interactions in this intestinal region.

  • 38.
    Da Silva, Stéphanie
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Keita, Åsa V.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Mohlin, Sofie
    Translational Cancer Research, Cancer Center at Medicon Village, Lund University, Lund, Sweden.
    Påhlman, Sven
    Translational Cancer Research, Cancer Center at Medicon Village, Lund University, Lund, Sweden.
    Théodorou, Vassilia
    Toxalim UMR 1331 INRA/INP/UPS Neuro-Gastroenterology and Nutrition Unit, Toulouse, France.
    Påhlman, Ingrid
    Albireo AB, Arvid Wallgrens Backe, Gothenburg, Sweden.
    Mattson, Jan P.
    Albireo AB, Arvid Wallgrens Backe, Gothenburg, Sweden.
    Söderholm, Johan D.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    A novel topical PPARγ agonist induces PPARγ-activity in ulcerative colitis mucosa and prevents and reverses inflammation in induced-colitis models2018Ingår i: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 24, nr 4, s. 792-805Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Peroxisome proliferator-activated receptor-gamma (PPARγ) exerts anti-inflammatory effects and is therefore a potential target in ulcerative colitis (UC). A novel PPARγ agonist (AS002) developed for local action was evaluated ex vivo in biopsies from UC patients and in vivo in mice with low-grade dextran sodium sulfate (DSS)- and trinitrobenzene sulfonic acid (TNBS)-induced colitis.Methods: Colonic biopsies from UC patients (n = 18) and healthy controls (n = 6) were incubated with AS002 or rosiglitazone (positive control) to measure mRNA expression of the PPARγ-responsive gene ADIPOPHILIN and protein levels of UC-related cytokines (enzyme-linked immunosorbent assay). AS002 absorption was determined in the colonic mucosa of UC patients. DSS-colitis mice received PPARγ agonists or vehicle daily by intrarectal administration starting 2 days before induction of colitis (preventive) or from days 3 to 8 (curative). Myeloperoxidase (MPO) and cytokine levels in colonic mucosa were determined. In addition, AS002 effects were studied in TNBS colitis.Results: AS002 displayed an absorption pattern of a lipophilic drug totally metabolized in the mucosa. AS002 and rosiglitazone increased ADIPOPHILIN mRNA expression (3-fold) and decreased TNF-α, IL-1β, and IL-13 levels in human UC biopsies. In DSS, in both preventive and curative treatment and in TNBS colitis, AS002 protected against macroscopic and histological damage and lowered MPO and TNF-α, IL-1β, and IL-13 levels.Conclusions: AS002 triggers anti-inflammatory PPARγ activity in the human colonic mucosa of UC patients and prevents and reverses colitis in mice. Our data suggest that AS002 has potential for topical maintenance treatment of UC, which warrants further studies in vivo in patients.

  • 39.
    Ganda Mall, John-Peter
    et al.
    School of Medical Sciences, Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    Casado-Bedmar, Maite
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Winberg, Martin E.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Brummer, Robert J.
    School of Medical Sciences, Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    Schoultz, Ida
    School of Medical Sciences, Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    Keita, Åsa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. School of Medical Sciences, Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    A ß-Glucan-Based Dietary Fiber Reduces Mast Cell-Induced Hyperpermeability in Ileum From Patients With Crohns Disease and Control Subjects2018Ingår i: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 24, nr 1, s. 166-178Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 40.
    Mall, John-Peter Ganda
    et al.
    Orebro Univ, Sweden; Orebro Univ, Sweden.
    Ostlund-Lagerstrom, Lina
    Orebro Univ, Sweden; Orebro Univ, Sweden.
    Lindqvist, Carl Marten
    Orebro Univ, Sweden.
    Algilani, Samal
    Orebro Univ, Sweden.
    Rasoal, Dara
    Orebro Univ, Sweden.
    Repsilber, Dirk
    Orebro Univ, Sweden.
    Brummer, Robert J.
    Orebro Univ, Sweden.
    Keita, Åsa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Schoultz, Ida
    Orebro Univ, Sweden.
    Are self-reported gastrointestinal symptoms among older adults associated with increased intestinal permeability and psychological distress?2018Ingår i: BMC Geriatrics, ISSN 1471-2318, E-ISSN 1471-2318, Vol. 18, artikel-id 75Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Despite the substantial number of older adults suffering from gastrointestinal (GI) symptoms little is known regarding the character of these complaints and whether they are associated with an altered intestinal barrier function and psychological distress. Our aim was to explore the relationship between self-reported gut health, intestinal permeability and psychological distress among older adults. Methods: Three study populations were included: 1) older adults with GI symptoms (n = 24), 2) a group of older adults representing the general elderly population in Sweden (n = 22) and 3) senior orienteering athletes as a potential model of healthy ageing (n = 27). Questionnaire data on gut-health, psychological distress and level of physical activity were collected. Intestinal permeability was measured by quantifying zonulin in plasma. The level of systemic and local inflammation was monitored by measuring C-reactive protein (CRP), hydrogen peroxide in plasma and calprotectin in stool samples. The relationship between biomarkers and questionnaire data in the different study populations was illustrated using a Principal Component Analysis (PCA). Results: Older adults with GI symptoms displayed significantly higher levels of both zonulin and psychological distress than both general older adults and senior orienteering athletes. The PCA analysis revealed a separation between senior orienteering athletes and older adults with GI symptoms and showed an association between GI symptoms, psychological distress and zonulin. Conclusions: Older adults with GI symptoms express increased plasma levels of zonulin, which might reflect an augmented intestinal permeability. In addition, this group suffer from higher psychological distress compared to general older adults and senior orienteering athletes. This relationship was further confirmed by a PCA plot, which illustrated an association between GI symptoms, psychological distress and intestinal permeability.

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  • 41.
    Mall, J. P. Ganda
    et al.
    Orebro Univ, Sweden; Orebro Univ, Sweden.
    Lofvendahl, L.
    Orebro Univ, Sweden.
    Lindqvist, C. M.
    Orebro Univ, Sweden.
    Brummer, R. J.
    Orebro Univ, Sweden.
    Keita, Åsa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Schoultz, I.
    Orebro Univ, Sweden; Orebro Univ, Sweden.
    Differential effects of dietary fibres on colonic barrier function in elderly individuals with gastrointestinal symptoms2018Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 8, artikel-id 13404Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Gastrointestinal problems are common in elderly and often associated with psychological distress and increased levels of corticotrophin-releasing hormone, a hormone known to cause mast cell (MC) degranulation and perturbed intestinal barrier function. We investigated if dietary fibres (non-digestible polysaccharides [NPS]) could attenuate MC-induced colonic hyperpermeability in elderly with gastrointestinal (GI) symptoms. Colonic biopsies from elderly with diarrhoea and/or constipation (n = 18) and healthy controls (n = 19) were mounted in Ussing chambers and pre-stimulated with a yeast-derived beta (beta)-glucan (0.5 mg/ml) or wheat-derived arabinoxylan (0.1 mg/ml) before the addition of the MC-degranulator Compound (C) 48/80 (10 ng/ml). Permeability markers were compared pre and post exposure to C48/80 in both groups and revealed higher baseline permeability in elderly with GI symptoms. beta-glucan significantly attenuated C48/80-induced hyperpermeability in elderly with GI symptoms but not in healthy controls. Arabinoxylan reduced MC-induced paracellular and transcellular hyperpermeability across the colonic mucosa of healthy controls, but did only attenuate transcellular permeability in elderly with GI symptoms. Our novel findings indicate that NPS affect the intestinal barrier differently depending on the presence of GI symptoms and could be important in the treatment of moderate constipation and/or diarrhoea in elderly.

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  • 42.
    Lopes, Fernando
    et al.
    Univ Calgary, Canada.
    Keita, Åsa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Saxena, Alpana
    Univ Calgary, Canada.
    Reyes, Jose Luis
    Univ Calgary, Canada.
    Mancini, Nicole L.
    Univ Calgary, Canada.
    Al Rajabi, Ala
    Univ Calgary, Canada.
    Wang, Arthur
    Univ Calgary, Canada.
    Baggio, Cristiane H.
    Univ Calgary, Canada.
    Dicay, Michael
    Univ Calgary, Canada.
    van Dalen, Rob
    Univ Toronto, Canada.
    Ahn, Younghee
    Univ Calgary, Canada.
    Carneiro, Matheus B. H.
    Univ Calgary, Canada.
    Peters, Nathan C.
    Univ Calgary, Canada.
    Rho, Jong M.
    Univ Calgary, Canada.
    MacNaughton, Wallace K.
    Univ Calgary, Canada.
    Girardin, Stephen E.
    Univ Toronto, Canada.
    Jijon, Humberto
    Univ Calgary, Canada.
    Philpott, Dana J.
    Univ Toronto, Canada.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    McKay, Derek M.
    Univ Calgary, Canada.
    ER-stress mobilization of death-associated protein kinase-1-dependent xenophagy counteracts mitochondria stress-induced epithelial barrier dysfunction2018Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 293, nr 9, s. 3073-3087Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The gut microbiome contributes to inflammatory bowel disease (IBD), in which bacteria can be present within the epithelium. Epithelial barrier function is decreased in IBD, and dysfunctional epithelial mitochondria and endoplasmic reticulum (ER) stress have been individually associated with IBD. We therefore hypothesized that the combination of ER and mitochondrial stresses significantly disrupt epithelial barrier function. Here, we treated human colonic biopsies, epithelial colonoids, and epithelial cells with an uncoupler of oxidative phosphorylation, dinitrophenol (DNP), with or without the ER stressor tunicamycin and assessed epithelial barrier function by monitoring internalization and translocation of commensal bacteria. We also examined barrier function and colitis in mice exposed to dextran sodium sulfate (DSS) or DNP and co-treated with DAPK6, an inhibitor of death-associated protein kinase 1 (DAPK1). Contrary to our hypothesis, induction of ER stress (i.e. the unfolded protein response) protected against decreased barrier function caused by the disruption of mitochondrial function. ER stress did not prevent DNP-driven uptake of bacteria; rather, specific mobilization of the ATF6 arm of ER stress and recruitment of DAP K1 resulted in enhanced autophagic killing (xenophagy) of bacteria. Of note, epithelia with a Crohns disease susceptibility mutation in the autophagy gene ATG16L.1 exhibited less xenophagy. Systemic delivery of the DAPK1 inhibitor DAPK6 increased bacterial translocation in DSS- or DNP-treated mice. We conclude that promoting ER stress ATF6 DAPK1 signaling in transporting enterocytes counters the transcellular passage of bacteria evoked by dysfunctional mitochondria, thereby reducing the potential for metabolic stress to reactivate or perpetuate inflammation.

  • 43.
    Keita, Åsa
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Lindqvist, Carl Mårten
    Örebro University, Örebro, Sweden .
    Ost, Ake
    Aleris Medilab, Sweden.
    Ley Magana, Carlos Daniel
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Schoultz, Ida
    Örebro University, Örebro, Sweden .
    Halfvarson, Jonas
    Örebro University, Örebro, Sweden .
    Gut Barrier Dysfunction-A Primary Defect in Twins with Crohns Disease Predominantly Caused by Genetic Predisposition2018Ingår i: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 12, nr 10, s. 1200-1209Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background and Aims: The aetiology of Crohns disease is poorly understood. By investigating twin pairs discordant for Crohns disease, we aimed to assess whether the dysregulated barrier represents a cause or a consequence of inflammation and to evaluate the impact of genetic predisposition on barrier function. Methods: Ileal biopsies from 15 twin pairs discordant for Crohns disease [monozygotic n = 9, dizygotic n = 6] and 10 external controls were mounted in Ussing chambers to assess paracellular permeability to (51)Chromium [Cr]-EDTA and trancellular passage to non-pathogenic E. coli K-12. Experiments were performed with and without provocation with acetylsalicylic acid. Immunofluorescence and ELISA were used to quantify the expression level of tight junction proteins. Results: Healthy co-twins and affected twins displayed increased Cr-51-EDTA permeability at 120 min, both with acetylsalicylic acid [p amp;lt; 0.001] and without [p amp;lt; 0.001] when compared with controls. A significant increase in Cr-51-EDTA flux was already seen at 20 min in healthy monozygotic co-twins compared with controls [p amp;lt;= 0.05] when stratified by zygosity, but not in healthy dizygotic co-twins. No difference in E. coli passage was observed between groups. Immunofluorescence of the tight junction proteins claudin-5 and tricellulin showed lower levels in healthy co-twins [p amp;lt; 0.05] and affected twins [p amp;lt; 0.05] compared with external controls, while ELISA only showed lower tricellulin in Crohns disease twins [p amp;lt; 0.05]. Conclusion: Our results suggest that barrier dysfunction is a primary defect in Crohns disease, since changes were predominantly seen in healthy monozygotic co-twins. Passage of E. coli seems to be a consequence of inflammation, rather than representing a primary defect.

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  • 44.
    Yakymenko, Olena
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Schoultz, Ida
    Department of Medical Sciences, Faculty of Health and Medicine, Örebro University, Örebro, Sweden.
    Gullberg, Elisabet
    Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för klinisk och experimentell medicin.
    Ström, Magnus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Almer, Sven
    Department of Medicine, Karolinska Institutet, Stockholm, Sweden / GastroCentrum, Karolinska University Hospital, Stockholm, Sweden.
    Wallon, Conny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Wang, Arthur
    Gastrointestinal Research Group, Cumming School of Medicine, University of Calgary, Calgary, Canada..
    Keita, Åsa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    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
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Infliximab restores colonic barrier to adherent-invasive E. coli in Crohn's disease via effects on epithelial lipid rafts2018Ingår i: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 53, nr 6, s. 677-684Artikel i tidskrift (Refereegranskat)
    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.

  • 45.
    Keita, Åsa
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Söderholm, Johan D
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Mucosal permeability and mast cells as targets for functional gastrointestinal disorders2018Ingår i: Current opinion in pharmacology (Print), ISSN 1471-4892, E-ISSN 1471-4973, Vol. 43, s. 66-71Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The intestinal mucosa is constantly exposed to harmful lumina! content, and uptake is closely controlled and regulated by neuro-immune factors. If control is broken, it might lead to ongoing enhanced mucosal permeability, potentially resulting in functional gastrointestinal disorders. The importance of mast cells in the regulation of the mucosal barrier has become obvious, and increased numbers and more activated mast cells have been observed in irritable bowel syndrome, functional dyspepsia and gastroesophageal reflux disease. To target the disturbed mucosal permeability, directly or via mast cells, is therefore currently of major interest. For example, administration of mast cell stabilizers and probiotics have shown promising effects in patients with functional gastrointestinal disorders.

  • 46.
    Shrestha, Neha
    et al.
    Catholic University of Louvain, Belgium.
    Bouttefeux, Oriane
    Catholic University of Louvain, Belgium.
    Vanvarenberg, Kevin
    Catholic University of Louvain, Belgium.
    Lundquist, Patrik
    Uppsala University, Sweden.
    Cunarro, Juan
    University of Santiago de Compostela, Spain.
    Tovar, Sulay
    University of Santiago de Compostela, Spain.
    Khodus, Georgiy
    Uppsala University, Sweden.
    Andersson, Ellen
    Vrinnevi Hospital, Sweden.
    Keita, Åsa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Gonzalez Dieguez, Carlos
    University of Santiago de Compostela, Spain.
    Artursson, Per
    Uppsala University, Sweden.
    Preat, Veronique
    Catholic University of Louvain, Belgium.
    Beloqui, Ana
    Catholic University of Louvain, Belgium.
    The stimulation of GLP-1 secretion and delivery of GLP-1 agonists &ITvia&IT nanostructured lipid carriers2018Ingår i: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 10, nr 2, s. 603-613Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Nanoparticulate based drug delivery systems have been extensively studied to efficiently encapsulate and deliver peptides orally. However, most of the existing data mainly focus on the nanoparticles as a drug carrier, but the ability of nanoparticles having a biological effect has not been exploited. Herein, we hypothesize that nanostructured lipid carriers (NLCs) could activate the endogenous glucagon-like peptide-1 (GLP-1) secretion and also act as oral delivery systems for GLP-1 analogs (exenatide and liraglutide). NLCs effectively encapsulated the peptides, the majority of which were only released under the intestinal conditions. NLCs, with and without peptide encapsulation, showed effective induction of GLP-1 secretion in vitro from the enteroendocrinal L-cells (GLUTag). NLCs also showed a 2.9-fold increase in the permeability of exenatide across the intestinal cell monolayer. The intestinal administration of the exenatide and liraglutide loaded NLCs did not demonstrate any glucose lowering effect on normal mice. Further, ex vivo studies depicted that the NLCs mainly adhered to the mucus layer. In conclusion, this study demonstrates that NLCs need further optimization to overcome the mucosal barrier in the intestine; nonetheless, this study also presents a promising strategy to use a dual-action drug delivery nanosystem which synergizes its own biological effect and that of the encapsulated drug molecule.

  • 47.
    Bednarska, Olga
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Walter, Susanna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Casado-Bedmar, Maite
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten.
    Ström, Magnus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Salvo-Romero, Eloisa
    University of Autonoma Barcelona, Spain.
    Vicario, Maria
    University of Autonoma Barcelona, Spain.
    Mayer, Emeran A.
    University of Calif Los Angeles, CA 90095 USA.
    Keita, Åsa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Vasoactive Intestinal Polypeptide and Mast Cells Regulate Increased Passage of Colonic Bacteria in Patients With Irritable Bowel Syndrome2017Ingår i: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 153, nr 4, s. 948-+Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND amp; AIMS: Irritable bowel syndrome (IBS) is associated with intestinal dysbiosis and symptoms of IBS develop following gastroenteritis. We aimed to study the passage of live bacteria through the colonic epithelium, and determine the role of mast cells (MCs) and vasoactive intestinal polypeptide (VIP) in barrier regulation in IBS and healthy individuals. METHODS: Colon biopsies from 32 women with IBS and 15 age-matched healthy women (controls) were mounted in Ussing chambers; we measured numbers of fluorescently labeled Escherichia coli HS and Salmonella typhimurium that passed through from the mucosal side to the serosal side of the tissue. Some biopsies were exposed to agents that block the VIP receptors (VPAC1 and VPAC2) or MCs. Levels of VIP and tryptase were measured in plasma and biopsy lysates. Number of MCs and MCs that express VIP or VIP receptors were quantified by immunofluorescence. Biopsies from an additional 5 patients with IBS and 4 controls were mounted in chambers and Salmonella were added; we studied passage routes through the epithelium by transmission electron microscopy and expression of tight junctions by confocal microscopy. RESULTS: In colon biopsies from patients with IBS, larger numbers of E coli HS and S typhimurium passed through the epithelium than in biopsies from controls (P amp;lt;.0005). In transmission electron microscopy analyses, bacteria were found to cross the epithelium via only the transcellular route. Bacterial passage was reduced in biopsies from patients with IBS and controls after addition of antibodies against VPACs or ketotifen, which inhibits MCs. Plasma samples from patients with IBS had higher levels of VIP than plasma samples from controls. Biopsies from patients with IBS had higher levels of tryptase, larger numbers of MCs, and a higher percentage of MCs that express VPAC1 than biopsies from controls. In biopsies from patients with IBS, addition of Salmonella significantly reduced levels of occludin; subsequent addition of ketotifen significantly reversed this effect. CONCLUSIONS: We found that colonic epithelium tissues from patients with IBS have increased translocation of commensal and pathogenic live bacteria compared with controls. The mechanisms of increased translocation include MCs and VIP.

  • 48.
    Parsons, Bryony N.
    et al.
    University of Liverpool, England .