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  • 1.
    Björkqvist, Olle
    et al.
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Seifert, M.
    Microbiol Tumor & Cell Biol, Karolinska Inst, Stockholm, Sweden.
    Engstrand, L.
    Microbiol Tumor & Cell Biol, Karolinska Inst, Stockholm, Sweden.
    Rangel, Ignacio
    Örebro University, School of Medical Sciences.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences.
    Increasing abundance of faecalibacterium prausnitzii is associated with decreased intestinal inflammation in Crohn's disease: A longitudinal study2018In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 12, no Suppl. 1, p. S468-S469Article in journal (Other academic)
  • 2.
    Björkqvist, Olle
    et al.
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Orebro Univ, Sch Med Sci, Orebro, Sweden..
    Seifert, Maike
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Brislawn, Colin
    Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland WA, USA.
    Jansson, Janet
    Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland WA, USA.
    Engstrand, Lars
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Rangel, Ignacio
    Örebro University, School of Medical Sciences.
    Halfvarson, Jonas
    Örebro University, School of Medical Sciences. Department of Gastroenterology.
    Alterations in the relative abundance of Faecalibacterium prausnitzii correlate with changes in fecal calprotectin in patients with ileal Crohn's disease: a longitudinal study2019In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 54, no 4, p. 577-585Article in journal (Refereed)
    Abstract [en]

    Objectives: Crohn's disease is characterized by a gut dysbiosis with decreased abundance of butyrate producers such as Faecalibacterium prausnitzii. Although F. prausnitzii secretes anti-inflammatory molecules, few studies have addressed the importance of F. prausnitzii in a longitudinal setting. We aimed to examine the relationship between temporal profiles of F. prausnitzii, the C. leptum group, overall butyrate production, and inflammatory activity.

    Material and methods: Fecal samples (n = 59) were collected every third month from nine patients with ileal Crohn's disease. The abundance of F. prausnitzii and C. leptum was quantified relative to the total amount of bacteria using quantitative-PCR. To assess butyrate production of gut microbiota, gene copy numbers of the butyryl-CoA:acetate-CoA transferase (BCoAT) gene were quantified by qPCR. The inflammatory activity was defined by fecal (f)-calprotectin.

    Results: No correlation between the relative abundance of F. prausnitzii, the C. leptum group, or copy numbers of the BCoAT gene, and f-calprotectin was observed in the total sample set. By analyzing alterations between consecutive samples, a negative correlation between changes in the relative abundance of F. prausnitzii and f-calprotectin was observed (R = -0.39; p = .009). Changes in C. leptum (R = -0.18, p = .23) and number of copies of the BCoAT gene (R = -0.12; p = .42) did not correlate with f-calprotectin.

    Conclusions: There was an inverse correlation between temporal changes in the relative abundance of F. prausnitzii, but not overall butyrate producing capacity, and changes in inflammatory activity in ileal Crohn's disease. These findings indicate that F. prausnitzii may play a role in gut homeostasis, even though causality is still to be demonstrated.

  • 3.
    Demirel, Isak
    et al.
    Örebro University, School of Medical Sciences. Inflammatory Response and Infection Susceptibility Centre.
    Rangel, Ignacio
    Örebro University, School of Medical Sciences.
    Petersson, Ulrika
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Persson, Katarina
    Örebro University, School of Medical Sciences. Faculty of Medicine and Health, Inflammatory Response and Infection Susceptibility Centre, Örebro University, Örebro, Sweden.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Faculty of Medicine and Health, Inflammatory Response and Infection Susceptibility Centre, Örebro University, Örebro, Sweden; Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Transcriptional Alterations of Virulence-Associated Genes in Extended Spectrum Beta-Lactamase (ESBL)-Producing Uropathogenic Escherichia coli during Morphologic Transitions Induced by Ineffective Antibiotics2017In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 8, article id 1058Article in journal (Refereed)
    Abstract [en]

    It is known that an ineffective antibiotic treatment can induce morphological shifts in uropathogenic Escherichia coli (UPEC) but the virulence properties during these shifts remain to be studied. The present study examines changes in global gene expression patterns and in virulence factor-associated genes in an extended spectrum beta-lactamase (ESBL)-producing UPEC (ESBL019) during the morphologic transitions induced by an ineffective antibiotic and in the presence of human primary bladder epithelial cells. Microarray results showed that the different morphological states of ESBL019 had significant transcriptional alterations of a large number of genes (Transition; 7%, Filamentation; 32%, and Reverted 19% of the entities on the array). All three morphological states of ESBL019 were associated with a decreased energy metabolism, altered iron acquisition systems and altered adhesion expression. In addition, genes associated with LPS synthesis and bacterial motility was also altered in all the morphological states. Furthermore, the transition state induced a significantly higher release of TNF-alpha from bladder epithelial cells compared to all other morphologies, while the reverted state was unable to induce INF-alpha release. Our findings show that the morphological shifts induced by ineffective antibiotics are associated with significant transcriptional virulence alterations in ESBL-producing UPEC, which may affect survival and persistence in the urinary tract.

  • 4.
    Engelsöy, Ulrik
    et al.
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Rangel, Ignacio
    Örebro University, School of Medical Sciences. Nutrition-Gut-Brain Interactions Research Centre.
    Demirel, Isak
    Örebro University, School of Medical Sciences. iRiSC - Inflammatory Response and Infection Susceptibility Centre.
    Impact of Proinflammatory Cytokines on the Virulence of Uropathogenic Escherichia coli2019In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 10, article id 1051Article in journal (Refereed)
    Abstract [en]

    The effect of a urinary tract infection on the host is a well-studied research field. However, how the host immune response affects uropathogenic Escherichia coli (CFT073) virulence is less studied. The aim of the present study was to investigate the impact of proinflammatory cytokine exposure on the virulence of uropathogenic Escherichia coli. We found that all tested proinflammatory cytokines (TNF-alpha, IL-1 beta, IL-6, IL-8 and IFN-gamma) induced an increased CFT073 growth. We also found that biofilm formation and hemolytic activity was reduced in the presence of all proinflammatory cytokines. However, a reduction in siderophore release was only observed in the presence of IL-1 beta, IL-6 and IL-8. Real time-qPCR showed that all proinflammatory cytokines except TNF-alpha significantly increased genes associated with the iron acquisition system in CFT073. We also found that the proinflammatory cytokines induced significant changes in type-1 fimbriae, P-fimbriae and gluconeogenetic genes. Furthermore, we also showed, using a Caenorhabditis elegans (C. elegans) killing assay that all cytokines decreased the survival of C. elegans worms significantly. Taken together, our findings show that proinflammatory cytokines have the ability to alter the virulence traits of UPEC.

  • 5.
    Gorreja, Frida
    et al.
    Örebro University, School of Medical Sciences.
    Rangel, Ignacio
    Örebro University, School of Medical Sciences.
    Rush, Stephen
    Örebro University, School of Medical Sciences.
    Wall, Rebecca
    Örebro University, School of Medical Sciences.
    De Vos, Willem M.
    Wageningen University & Research Centre, Wageningen, Netherlands; Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland.
    Brummer, Robert Jan
    Örebro University, School of Medical Sciences.
    Double-blind cross-over trial reveals human mucosal transcriptome responses to variants of LGG administration in vivo2018In: Targeting microbiota: 6th World congress on targeting microbiota towards clinical revolution / [ed] Peter Konturek, Porto, Portugal: ISM , 2018, Vol. 5, article id 978-2-35609-010-2Conference paper (Other academic)
  • 6.
    Götlind, Y. Y.
    et al.
    Department of Microbiology and Immunology, Institute of Biomedicine and MIVAC, Sahlgrenska Academy, Göteborg, Sweden.
    Fritsch Fredin, M.
    Department of Bioscience, AstraZeneca, Mölndal, Sweden.
    Kumawat, Ashok Kumar
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine.
    Strid, H.
    Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Willén, R.
    Department of Pathology and Cytology, Uppsala University Hospital, Uppsala, Sweden.
    Rangel, Ignacio
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine.
    Bland, P. W.
    Department of Microbiology and Immunology, Institute of Biomedicine and MIVAC, Sahlgrenska Academy, Göteborg, Sweden.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Clinical Medicine.
    Interplay between Th1 and Th17 effector T cell pathways in the pathogenesis of spontaneous colitis and colon cancer in the Gai2-deficient mouse2013In: International Immunology, ISSN 0953-8178, E-ISSN 1460-2377, Vol. 25, no 1, p. 35-44Article in journal (Refereed)
    Abstract [en]

    Gαi2-deficient mice spontaneously develop colitis. Using xMAP technology and RT-PCR, we investigated cytokine/chemokine profiles during histologically defined phases of disease: (i) no/mild, (ii) moderate, (iii) severe colitis without dysplasia/cancer and (iv) severe colitis with dysplasia/cancer, compared with age-matched wild-type (WT) littermates. Colonic dysplasia was observed in 4/11 mice and cancer in 1/11 mice with severe colitis. The histology correlated with progressive increases in colon weight/cm and spleen weight, and decreased thymus weight, all more advanced in mice with dysplasia/cancer. IL-1β, IL-6, IL-12p40, IL-17, TNF-α, CCL2 and CXCL1 protein levels in colons, but not small intestines increased with colitis progression and were significantly increased in mice with moderate and severe colitis compared with WT mice, irrespective of the absence/presence of dysplasia/cancer. CCL5 did not change during colitis progression. Colonic IL-17 transcription increased 40- to 70-fold in all stages of colitis, whereas IFN-γ mRNA was gradually up-regulated 12- to 55-fold with colitis progression, and further to 62-fold in mice with dysplasia/cancer. IL-27 mRNA increased 4- to 15-fold during the course of colitis, and colonic IL-21 transcription increased 3-fold in mice with severe colitis, both irrespective of the absence/presence of dysplasia/cancer. FoxP3 transcription was significantly enhanced (3.5-fold) in mice with moderate and severe colitis, but not in mice with dysplasia/cancer, compared with WT mice. Constrained correspondence analysis demonstrated an association between increased protein levels of TNF-α, CCL2, IL-1β, IL-6 and CXCL1 and dysplasia/cancer. In conclusion, colonic responses are dominated by a mixed T(h)1/T(h)17 phenotype, with increasing T(h)1 cytokine transcription with progression of colitis in Gαi2(-/-) mice.

  • 7.
    König, Julia
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Ganda-Mall, John-Peter
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Rangel, Ignacio
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Edebol-Carlman, Hanna
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Brummer, Robert Jan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    The Role of the Gut Microbiota in Brain Function2015In: Probiotics and Prebiotics: Current Research and Future Trends / [ed] Koen Venema & Ana Paula do Carmo, Poole, UK: Caister Academic Press, 2015Chapter in book (Refereed)
  • 8.
    König, Julia
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Rangel, Ignacio
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Brummer, Robert Jan
    Örebro University, School of Medicine, Örebro University, Sweden.
    The Role of Lactic Acid Bacteria in the Pathophysiology and Treatment of Irritable Bowel Syndrome (IBS)2013In: Food and Nutrition Sciences, ISSN 2157-944X, E-ISSN 2157-9458, Vol. 4, no 11, p. 27-39Article in journal (Refereed)
    Abstract [en]

    Irritable bowel syndrome (IBS) is a multifactorial chronic disorder characterized by various abdominal complaints and a worldwide prevalence of 10% - 20%. Although its etiology and pathophysiology are complex and still not completely understood, aberrations along the microbe-gut-brain axis are known to play a central role. IBS is characterized by inter-related alterations in intestinal barrier function, gut microbe composition, immune activation, afferent sensory signaling and brain activity. Pharmaceutical treatment is generally ineffective and, hence, most therapeutic strategies are based on non-drug approaches. A promising option is the administration of probiotics, in which lactic acid bacteria strains are considered specifically beneficial. This review aims to provide a concise, although comprehensive, overview of the role of lactic acid bacteria in the pathophysiology and treatment of IBS.

  • 9.
    Neumann, Gunter
    et al.
    School of Medical Health (MV), Örebro University, Örebro, Sweden.
    Wall, Rebecca
    Örebro University, School of Medical Sciences.
    Rangel, Ignacio
    Örebro University, School of Medical Sciences.
    Marques, Tatiana M.
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Qualitative modelling of the interplay of inflammatory status and butyrate in the human gut: a hypotheses about robust bi-stability2018In: BMC Systems Biology, ISSN 1752-0509, E-ISSN 1752-0509, Vol. 12, no 1, article id 144Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Gut microbiota interacts with the human gut in multiple ways. Microbiota composition is altered in inflamed gut conditions. Likewise, certain microbial fermentation products as well as the lipopolysaccharides of the outer membrane are examples of microbial products with opposing influences on gut epithelium inflammation status. This system of intricate interactions is known to play a core role in human gut inflammatory diseases. Here, we present and analyse a simplified model of bidirectional interaction between the microbiota and the host: in focus is butyrate as an example for a bacterial fermentation product with anti-inflammatory properties.

    RESULTS: We build a dynamical model based on an existing model of inflammatory regulation in gut epithelial cells. Our model introduces both butyrate as a bacterial product which counteracts inflammation, as well as bacterial LPS as a pro-inflammatory bacterial product. Moreover, we propose an extension of this model that also includes a feedback interaction towards bacterial composition. The analysis of these dynamical models shows robust bi-stability driven by butyrate concentrations in the gut. The extended model hints towards a further possible enforcement of the observed bi-stability via alteration of gut bacterial composition. A theoretical perspective on the stability of the described switch-like character is discussed.

    CONCLUSIONS: Interpreting the results of this qualitative model allows formulating hypotheses about the switch-like character of inflammatory regulation in the gut epithelium, involving bacterial products as constitutive parts of the system. We also speculate about possible explanations for observed bimodal distributions in bacterial compositions in the human gut. The switch-like behaviour of the system proved to be mostly independent of parameter choices. Further implications of the qualitative character of our modeling approach for the robustness of the proposed hypotheses are discussed, as well as the pronounced role of butyrate compared to other inflammatory regulators, especially LPS, NF- κB and cytokines.

  • 10.
    Rangel, Ignacio
    et al.
    Örebro University, School of Medical Sciences.
    Ganda Mall, John Peter
    Örebro University, School of Medical Sciences.
    Roger, Willén
    Department of Pathology and Cytology, Uppsala University Hospital, Uppsala, Sweden.
    Sjöberg, Fei
    Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Göteborg, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences.
    Degree of colitis correlates with microbial composition and cytokine responses in colon and caecum of Gαi2-deficient mice2016In: FEMS Microbiology Ecology, ISSN 0168-6496, E-ISSN 1574-6941, Vol. 92, no 7, article id fiw098Article in journal (Refereed)
    Abstract [en]

    An altered immune response and gut microbiota have been associated with the pathology of Inflammatory Bowel Diseases (IBD). However, there is limited knowledge of how inflammation is associated with changes in the microbiota. We studied the microbiota in the intestine and faeces as well as the cytokine gene expressions in caecum and colon of a mouse model (Gαi2(-/-)) of colitis, and analysed them in relation to the degrees of inflammation in the colon. The degree of colitis was associated with general changes in the complexity of the microbiota and was corroborated by quantitative analyses of the Bacteroides and Lactobacillus High gene expression levels of IL-17 and IFN-γ in colon and caecum were detected in Gαi2(-/-) mice with moderate and severe colitis. High IL-27 gene expression in the colon of mice with moderate and severe colitis and in the caecum of mice with moderate colitis was also detected. Negative correlations between IL-27 and Bacteroides and Lactobacillus and between IFN-γ and Lactobacillus were detected in caecum. This research indicates that the degree of colitis in IBD correlates with the gene expression of cytokines and with disturbances in the gut microbiota. Furthermore, the caecum could have an important role in the pathology of IBD.

  • 11.
    Rangel, Ignacio
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Ganda-Mall, John-Peter
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sjöberg, F.
    University of Gothenburg, Gothenburg, Sweden.
    Willen, R.
    Univ Uppsala Hosp, Uppsala, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    Alterations in gut microbiota composition in tissues and feces of G alpha i2(-/-) mice with colitis in parallel with enhanced cytokine secretion2013In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 140, p. 168-169Article in journal (Other academic)
  • 12.
    Rangel, Ignacio
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sundin, Johanna
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fuentes, S.
    Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands.
    Repsilber, Dirk
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    de Vos, W. M.
    Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands; Departments of Bacteriology & Immunology and Veterinary Biosciences, University of Helsinki, Helsinki, Finland .
    Brummer, Robert Jan
    Örebro University, School of Medicine, Örebro University, Sweden.
    The relationship between faecal-associated and mucosal-associated microbiota in irritable bowel syndrome patients and healthy subjects2015In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 42, no 10, p. 1211-1221Article in journal (Refereed)
    Abstract [en]

    Background: The faecal-associated microbiota is commonly seen as a surrogate of the mucosal-associated microbiota. However, previous studies indicate that they are different. Furthermore, analyses of the mucosal microbiota are commonly done after standard bowel cleansing, affecting the microbial composition.

    Aim: To compare the mucosal-associated microbiota, obtained from unprepared colon, with faecal-associated microbiota in healthy subjects and irritable bowel syndrome (IBS) patients.

    Methods: Faecal and mucosal biopsies were obtained from 33 IBS patients and 16 healthy controls. Of IBS patients, 49% belonged to the diarrhoea-predominant subgroup and 80% suffered from IBS symptoms during at least 5 years. Biopsies were collected from unprepared sigmoid colon and faecal samples a day before colonoscopy. Microbiota analyses were performed with a phylogenetic microarray and redundancy discriminant analysis.

    Results: The composition of the mucosal- and the faecal-associated microbiota in unprepared sigmoid colon differs significantly (P = 0.002). Clinical characteristics of IBS did not correlate with this difference. Bacteroidetes dominate the mucosal-associated microbiota. Firmicutes, Actinobacteria and Proteobacteria dominate the faecal-associated microbiota. Healthy subjects had a significantly higher (P < 0.005) abundance (1.9%) of the bacterial group uncultured Clostridiales I in the mucosal-associated microbiota than IBS patients (0.3%). Bacterial diversity was higher in faecal- compared with mucosal-associated microbiota in IBS patients (P < 0.005). No differences were found in healthy subjects.

    Conclusions: Differences in the mucosal-associated microbiota between healthy individuals and IBS patients are minimal (one bacterial group) compared to differences in the faecal microbiota of both groups (53 bacterial groups). Microbial aberrations characterising IBS are more pronounced in the faeces than in the mucosa.

  • 13.
    Rangel, Ignacio
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sundin, Johanna
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fuentes, Susana
    Wageningen University, Wageningen, The Netherlands.
    Repsilber, Dirk
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    de Vos, Willem M.
    Wageningen University, Wageningen, The Netherlands; University of Helsinki, Finland.
    Brummer, Robert J.
    Örebro University, School of Medicine, Örebro University, Sweden.
    Mucosal-associated microbiota differs less than fecal-associated microbiota between Irritable Bowel Syndrome patients and healthy subjectsManuscript (preprint) (Other academic)
  • 14. Sjöberg, Fei
    et al.
    Nowrouzian, Forough
    Rangel, Ignacio
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Hannoun, Charles
    MooreA, Edward
    Adlerberth, Ingegerd
    Wold, Agnes E.
    Comparison between terminal-restriction fragment length polymorphism (T-RFLP) and quantitative culture for analysis of infants' gut microbiota2013In: Journal of Microbiological Methods, ISSN 0167-7012, E-ISSN 1872-8359, Vol. 94, no 1, p. 37-46Article in journal (Refereed)
    Abstract [en]

    The infantile intestinal microbiota is a major stimulus for immune maturation. Both culture and DNA-based methods can be used for microbiota characterization, but few studies have systematically compared their performance for analysis of the gut microbiota. Here, we examined fecal samples obtained on six occasions between one week and 12 months of age from six vaginally delivered infants. After quantitative aerobic and anaerobic culture of the samples on selective and non-selective media, DNA was extracted from the fecal samples and analyzed regarding 16S rRNA gene polymorphism by terminal-restriction fragment length polymorphism (T-RFLP). A database was constructed for direct identification of T-RFLP peaks by analysis of pure-culture bacteria and analysis of a limited number of samples by 16S rRNA cloning and sequencing. Bacterial genera present at >10(6) CFU/g feces, as determined by quantitative culture, were generally readily detected by T-RFLP, while culture on selective media was more sensitive in detecting facultative anaerobes with lower population counts. In contrast, T-RFLP more readily than culture detected several anaerobic species, also taxa that could not be identified using the database. T-RFLP readily identified bacteria to the genus level and also provided some sub-genus discrimination. Both T-RFLP and culture identified Bifidobacterium, Clostridium and Bacteroides spp. among the most common colonizers of the infantile microbiota throughout the first year of life. T-RFLP analysis showed that microbiota complexity was high in the first weeks of life, declined to a minimum at 1-2 months of age, and thereafter increased again. Principal component analysis revealed that early samples (1 week-6 months) chiefly differed between individual infants, while 12-month samples were similar between children, but different from the early samples. Our results indicate that T-RFLP has high sensitivity and adequate taxonomic discrimination capacity for analysis of gut microbiota composition, but that both culture and molecular based analysis have limitations and both approaches may be needed to obtain a full picture of the complex gut microbiota.

  • 15.
    Sundin, Johanna
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Brummer, Robert
    Örebro University, School of Medicine, Örebro University, Sweden.
    Hultgren Hörnquist, Elisabet
    Örebro University, School of Medicine, Örebro University, Sweden.
    Rangel, Ignacio
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Increased number of double positive CD3+ CD8+ CD4+ lamina propria T lymphocyte in gut mucosa of post infectious IBS patients compared to healthy controls2012In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 24, no Suppl. 2, p. 104-105Article in journal (Other academic)
    Abstract [en]

    Objective: Irritable bowel syndrome (IBS) developed after a gastroenteritis is denoted post infectious IBS (PI-IBS) and is thought to represent a specific patho-physiological entity. Naive CD8+CD45RA+cytotoxic T lymphocytes recognize antigen derived from intracellular bacteria and viruses. Naive CD4+CD45RA+helper T lymphocytes are activated by the antigen from extracellular microorganisms with the help of antigen-presenting cells. Activated CD4+CD45RO+helper T lymphocytes help phagocytes to kill microbes and activate naive B lymphocytes.

    Aim: To characterize subsets of mucosal lymphocytes in PI-IBS with flow cytometry analysis as a lead in identifying new therapeutic methods.

    Methods: 5 PI-IBS patients and 6 healthy individuals were recruited. We performed a distal colonoscopy without bowel cleansing or other preparation. Lamina propria lymphocytes (LPL) and intra-epithelial lymphocytes (IEL) were isolated from sigmodal biopsies and sub classified by CD3, CD4, CD8, CD45RO and CD45RA with flow cytometry.

    Results: We observed a significant deference (P < 0.01, two-tailed Mann–Whitney test) in double positive CD3+CD8+CD4+LPL between PI-IBS patient and healthy controls. We also observed a trend towards increased frequency of CD3+CD4+LPL in PI-IBS patients. Additionally, PI-IBS patients showed an increased frequency of CD3+CD8+LPL and IEL. The proportion of memory / activated CD45RO+CD4+LPL was higher in PI-IBS patients, and its proportion of the CD8+population was lower compared with the healthy controls. On the contrary the proportion of naive CD45RA+CD4+LPL was lower in PI-IBS patients compared with healthy controls. However, we found no differences in the distribution naı¨ve / activated CD4+ and CD8+IEL between PI-IBS patients and healthy controls.

    Conclusion: The difference in double positive (DP) CD3+CD8+CD4+LPL seen between PI-IBS patient and healthy controls is consistent with findings of increased number DP T cells in target organs in immuno-inflammatory conditions. Our analysis revealed that the normal gut has a greater variation in the prevalence of CD3+CD4+and CD4+CD45RO+LPL than that of PI-IBS patients. These findings confirm aberrant mucosal subsets of lymphocytes. However, more subjects need to be included in the study in order to draw firm conclusions.

  • 16.
    Sundin, Johanna
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Rangel, Ignacio
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fuentes, S
    Department of Microbiology, Wageningen University, Wageningen,The Netherlands.
    Jong, Heikamp-de
    Department of Microbiology, Wageningen University, Wageningen,The Netherlands.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    de Vos, W M
    Department of Microbiology, Wageningen University, Wageningen,The Netherlands; Departments of Bacterology & Immunology and Veterinary Biosciences, University of Helsinki, Helsinki, Finland.
    Brummer, Robert-Jan
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Altered faecal and mucosal microbial composition in post-infectious irritable bowel syndrome patients correlates with mucosal lymphocyte phenotypes and psychological distress2015In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 41, no 4, p. 342-351Article in journal (Refereed)
    Abstract [en]

    Background: A subset of irritable bowel syndrome (IBS) patients, denoted post-infectious IBS (PI-IBS), develop symptoms after an enteric infection. Bacterial dysbiosis and mucosal inflammation have been proposed to be involved in the pathophysiology of this entity.

    Aim: To characterise the mucosal and faecal microbiota in PI-IBS, general IBS and healthy controls, and to investigate associations between the microbiota and the mucosal immune system.

    Methods: Mucosal biopsies and faeces were collected from 13 PI-IBS patients, 19 general IBS patients and 16 healthy controls. Global bacterial composition was determined by generating 16S rRNA amplicons that were examined by phylogenetic microarray hybridisation, principal component and redundancy analysis. We correlated previously reported lymphocyte proportions with the microbiota.

    Results: Faecal microbiota composition of PI-IBS patients differed significantly from both general IBS patients and healthy controls (P < 0.02). Both mucosal (P < 0.01) and faecal (P = 0.05) microbial diversity were reduced in PI-IBS compared to healthy controls. In the intraepithelial lymphocytes the previously published proportion of CD8+ CD45RA+ was negatively correlated with mucosal microbial diversity (P < 0.005). The previously published number of lamina propria lymphocytes was negatively correlated with mucosal microbial diversity (P < 0.05). Faecal microbial diversity was significantly negatively correlated with the Hospital Anxiety and Depression scale (P < 0.05).

    Conclusions: We present data that distinguishes the intestinal microbiota of PI-IBS patients from that of both general IBS patients and HC. The microbial composition is significantly associated with the HADs score and alterations in lymphocyte subsets proportions.

  • 17.
    Sundin, Johanna
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Rangel, Ignacio
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University, School of Medicine, Örebro University, Sweden.
    Kumawat, Ashok K
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medicine, Örebro University, Sweden.
    Brummer, Robert J
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital.
    Aberrant mucosal lymphocyte number and subsets in the colon of post-infectious irritable bowel syndrome patients2014In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 49, no 9, p. 1068-1075Article in journal (Refereed)
    Abstract [en]

    Background: Irritable bowel syndrome (IBS) is characterized by chronic abdominal symptoms such as pain, discomfort, and altered bowel habits. A subset of IBS patients, denoted as post-infectious IBS (PI-IBS) patients, develop symptoms after an enteric infection. Distinct abnormalities in the gut mucosa, including mucosal inflammation, have been proposed to contribute to or be the cause of PI-IBS. This study investigated lymphocyte subsets in PI-IBS patients compared to healthy controls.

    Materials and methods: Ten PI-IBS patients and nine healthy controls participated. All PI-IBS patients met the Rome III diagnostic criteria for IBS and reported sustained symptoms at least 1 year after an episode of acute gastroenteritis. Intraepithelial lymphocytes and lamina propria lymphocytes (LPLs), isolated from mucosal tissue samples, were stained and analyzed for a comprehensive set of cell markers using flow cytometry.

    Results: The number of LPLs in PI-IBS was significantly increased compared to those in healthy controls (p < 0.05). PI-IBS patients showed significantly increased proportions of CD45RO(+) CD4(+) activated/memory T cells (p < 0.05) and double-positive CD4(+) CD8(+) cells (p < 0.05), respectively, in the lamina propria. The number of CD19(+) LPLs was decreased in PI-IBS patients compared to healthy controls (p < 0.001).

    Conclusion: This study presents new evidence that PI-IBS is associated with a sustained aberrant mucosal immune response and support future studies of anti-inflammatory or immune-modulating treatments in these patients.

  • 18.
    Sundin, Johanna
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Rangel, Ignacio
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Repsilber, Dirk
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Brummer, Robert J.
    Örebro University, School of Medicine, Örebro University, Sweden.
    Cytokine response after stimulation with key commensal bacteria differ in post-­infectious irritable bowel syndrome (PI-­IBS) patients compared to healthy subjectsManuscript (preprint) (Other academic)
  • 19.
    Sundin, Johanna
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Rangel, Ignacio
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Repsilber, Dirk
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Brummer, Robert-Jan
    Örebro University, School of Medicine, Örebro University, Sweden.
    Cytokine Response after Stimulation with Key Commensal Bacteria Differ in Post-Infectious Irritable Bowel Syndrome (PI-IBS) Patients Compared to Healthy Controls2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, article id e0134836Article in journal (Refereed)
    Abstract [en]

    Background: Microbial dysbiosis and prolonged immune activation resulting in low-grade inflammation and intestinal barrier dysfunction have been suggested to be underlying causes of post-infectious irritable bowel syndrome (PI-IBS). The aim of this study was to evaluate the difference in cytokine response between mucosal specimens of PI-IBS patients and healthy controls (HC) after ex vivo stimulation with key anaerobic bacteria.

    Methods: Colonic biopsies from 11 PI-IBS patients and 10 HC were stimulated ex vivo with the commensal bacteria Bacteroides ovatus, Ruminococcus gnavus, Akkermansia muciniphila, Subdoligranulum variabile and Eubacterium limosum, respectively. The cytokine release (IL-1 beta, IL-2, IL-8, IL-10, IL-13, IL-17, TNF-alpha and IFN-gamma) in stimulation supernatants was analyzed using the LUMINEX assay. Comparison of cytokine release between PI-IBS patients and healthy controls was performed taking both unstimulated and bacterially stimulated mucosal specimens into account.

    Key Results: IL-13 release from mucosal specimens without bacterial stimulation was significantly lower in PI-IBS patients compared to HC (p < 0.05). After stimulation with Subdoligranulum variabile, IL-1 beta release from PI-IBS patients was significantly increased compared to HC (p < 0.05). Stimulation with Eubacterium limosum resulted in a significantly decreased IL-10 release in HC compared to PI-IBS patients (p < 0.05) and a tendency to decreased IL-13 release in HC compared to PI-IBS patients (p = 0.07).

    Conclusions & Inferences: PI-IBS patients differ from HC with regard to cytokine release ex vivo after stimulation with selected commensal bacteria. Hence, our results support that the pathogenesis of PI-IBS comprises an altered immune response against commensal gut microbes.

  • 20.
    Wall, Rebecca
    et al.
    Örebro University, School of Medical Sciences.
    Marques, Tatiana
    Örebro University, School of Medical Sciences.
    Edebol-Carlman, Hanna
    Örebro University, School of Medical Sciences.
    Sundin, J.
    University of Gothenburg, Gothenburg, Sweden.
    Vumma, R.
    Linnaeus University, Kalmar, Sweden.
    Rangel, Ignacio
    Örebro University, School of Medical Sciences.
    Brummer, Robert Jan
    Örebro University, School of Medical Sciences.
    Altered expression of membrane transporters in colonic mucosa of patients with Irritable Bowel Syndrome (IBS) and Post-infectious (PI)-IBS compared to healthy subjects2017In: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 29, no Suppl. 2, p. 107-108Article in journal (Other academic)
    Abstract [en]

    Background: Irritable bowel syndrome (IBS) affects 5%- 15% of adults in the general population, and is characterized by chronic recurrent abdominal pain and discomfort and associated with altered bowel habits. The pathophysiology of IBS is complex and not fully under-stood. Hence, treatment is often based on symptomatology rather than underlying physiological aberrancies.

    Objective: To compare the expression of membrane transporters in mucosal biopsies of healthy subjects, IBS patients and post- infectious (PI)- IBS patients.

    Methods: Mucosal biopsies were obtained from the unprepared sigmoid colon in 18 IBS patients, 9 PI- IBS patients and 10 healthy subjects. Total RNA was isolated and prepared for gene expression analyses using quantitative reverse- transcription polymerase chain reaction (qRT- PCR). We compared the expression of genes encoding membrane- spanning transporters, using GAPDH as a reference gene, and by using the comparative 2- ΔΔCt method.

    Results: Colonic expression of SCL7A5 and SLC3A2 (together com-prising the amino acid transporter LAT1+4F2hc) was significantly lower in IBS patients, but not in PI- IBS patients, compared to healthy controls (P<.001). The expression of SLC7A8 (LAT2) tended to be lower in IBS patients compared to controls (P=.06). Mucosal gene ex-pression of the short chain fatty acid transporter SMCT1 (SLC5A8) was lower in both IBS- patients and PI- IBS patients compared to healthy subjects (P<.01).

    Conclusions: The amino acid transporters LAT1 and LAT2 appeared to be affected in IBS patients, but not in PI- IBS patients, compared to healthy subjects, suggesting a possible alteration in amino acids transport in this patient group. Furthermore, our results suggest a lower uptake of short chain fatty acids in both IBS- and PI- IBS pa-tients. Altered expression of these transporters may be involved in the pathophysiology of IBS as well as being a potential biomarker of this aberration, and therefore deserves further study in IBS.

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