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  1. Article ; Online: Differential intestinal M-cell gene expression response to gut commensals.

    Lapthorne, Susan / Macsharry, John / Scully, Paul / Nally, Kenneth / Shanahan, Fergus

    Immunology

    2012  Volume 136, Issue 3, Page(s) 312–324

    Abstract: Different rates of bacterial translocation across the gut mucosa have been reported but few studies have examined translocation of commensals at the level of the gut epithelial microfold (M) cell. We used an in vitro M-cell model to quantify ... ...

    Abstract Different rates of bacterial translocation across the gut mucosa have been reported but few studies have examined translocation of commensals at the level of the gut epithelial microfold (M) cell. We used an in vitro M-cell model to quantify translocation and determine the transcriptional response of M cells to various commensal bacteria. The transport kinetics and gene expression profile of M cells in response to different bacterial strains, namely Lactobacillus salivarius, Escherichia coli and Bacteroides fragilis, was assessed. Bacterial strains translocated across M cells with different efficiencies; E. coli and B. fragilis translocated with equal efficiency whereas L. salivarius translocated with less efficiency. Microarray analysis of the M cell response showed both common and differential gene expression changes between the bacterial strains. In the presence of bacteria, but not control beads, up-regulated genes were mainly involved in transcription regulation whereas pro-inflammatory and stress response genes were primarily up-regulated by E. coli and B. fragilis, but not L. salivarius nor beads. Translocation of bacteria and M-cell gene expression responses were confirmed in murine M cells following bacterial challenge in vivo. These results demonstrate that M cells have the ability to discriminate between different commensal bacteria and modify subsequent immune responses.
    MeSH term(s) Animals ; Bacteroides fragilis/immunology ; Biological Transport, Active/immunology ; Caco-2 Cells ; Chemokines/biosynthesis ; Cytokines/biosynthesis ; Escherichia coli/immunology ; Female ; Gene Expression Profiling ; Humans ; Intestinal Mucosa/cytology ; Intestinal Mucosa/immunology ; Intestinal Mucosa/microbiology ; Lactobacillus/immunology ; Metagenome/immunology ; Mice ; Mice, Inbred BALB C ; Models, Immunological ; Monocytes/immunology ; Monocytes/microbiology ; Peyer's Patches/cytology ; Peyer's Patches/immunology ; Peyer's Patches/microbiology ; Species Specificity
    Chemical Substances Chemokines ; Cytokines
    Language English
    Publishing date 2012-03-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80124-0
    ISSN 1365-2567 ; 0019-2805 ; 0953-4954
    ISSN (online) 1365-2567
    ISSN 0019-2805 ; 0953-4954
    DOI 10.1111/j.1365-2567.2012.03581.x
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  2. Article ; Online: Identification of TLR10 as a key mediator of the inflammatory response to Listeria monocytogenes in intestinal epithelial cells and macrophages.

    Regan, Tim / Nally, Ken / Carmody, Ruaidhri / Houston, Aileen / Shanahan, Fergus / Macsharry, John / Brint, Elizabeth

    Journal of immunology (Baltimore, Md. : 1950)

    2013  Volume 191, Issue 12, Page(s) 6084–6092

    Abstract: Listeria monocytogenes is a Gram-positive bacterium that can cause septicemia and meningitis. TLRs are central receptors of the innate immune system that drive inflammatory responses to invading microbes such as L. monocytogenes. Although intestinal ... ...

    Abstract Listeria monocytogenes is a Gram-positive bacterium that can cause septicemia and meningitis. TLRs are central receptors of the innate immune system that drive inflammatory responses to invading microbes such as L. monocytogenes. Although intestinal epithelial cells (IECs) represent the initial point of entry used by L. monocytogenes for infection, the innate immune response to L. monocytogenes in these cells has been poorly characterized to date. The aim of this study was to determine which TLRs are involved in mediating the immune response to L. monocytogenes in IECs. We performed an RNA interference screen of TLRs 1-10 in the HT-29 IEC cell line and observed the most significant reduction in chemokine output following silencing of TLR10. This effect was also observed in the macrophage cell line THP-1. The chemokines CCL20, CCL1, and IL-8 were reduced following knockdown of TLR10. Silencing of TLR10 resulted in increased viability of L. monocytogenes in both HT-29 and THP-1 cells. TLR10 was found to be predominantly expressed intracellularly in epithelia, and activation required viable L. monocytogenes. NF-κB activation was seen to require TLR2 in addition to TLR10. Taken together, these data indicate novel roles for TLR10 in sensing pathogenic infection in both the epithelium and macrophages and have identified L. monocytogenes as a source of ligand for the orphan receptor TLR10.
    MeSH term(s) Chemokines/biosynthesis ; Chemokines/genetics ; Epithelial Cells/immunology ; Epithelial Cells/microbiology ; Gene Expression Regulation/immunology ; HCT116 Cells ; HEK293 Cells ; HT29 Cells ; Humans ; Immunity, Innate ; Immunity, Mucosal ; In Vitro Techniques ; Interleukins/biosynthesis ; Interleukins/genetics ; Intestinal Mucosa/cytology ; Intestinal Mucosa/immunology ; Ligands ; Listeria monocytogenes/immunology ; Macrophages/immunology ; Macrophages/microbiology ; NF-kappa B/metabolism ; Organ Specificity ; RNA Interference ; RNA, Small Interfering/pharmacology ; Toll-Like Receptor 10/antagonists & inhibitors ; Toll-Like Receptor 10/genetics ; Toll-Like Receptor 10/immunology ; Toll-Like Receptor 10/physiology ; Toll-Like Receptor 2/physiology ; Toll-Like Receptors/biosynthesis ; Toll-Like Receptors/genetics
    Chemical Substances Chemokines ; Interleukins ; Ligands ; NF-kappa B ; RNA, Small Interfering ; TLR10 protein, human ; TLR2 protein, human ; Toll-Like Receptor 10 ; Toll-Like Receptor 2 ; Toll-Like Receptors
    Language English
    Publishing date 2013-12-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1203245
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Cellodextrin utilization by bifidobacterium breve UCC2003.

    Pokusaeva, Karina / O'Connell-Motherway, Mary / Zomer, Aldert / Macsharry, John / Fitzgerald, Gerald F / van Sinderen, Douwe

    Applied and environmental microbiology

    2011  Volume 77, Issue 5, Page(s) 1681–1690

    Abstract: Cellodextrins, the incomplete hydrolysis products from insoluble cellulose, are accessible as a carbon source to certain members of the human gut microbiota, such as Bifidobacterium breve UCC2003. Transcription of the cldEFGC gene cluster of B. breve ... ...

    Abstract Cellodextrins, the incomplete hydrolysis products from insoluble cellulose, are accessible as a carbon source to certain members of the human gut microbiota, such as Bifidobacterium breve UCC2003. Transcription of the cldEFGC gene cluster of B. breve UCC2003 was shown to be induced upon growth on cellodextrins, implicating this cluster in the metabolism of these sugars. Phenotypic analysis of a B. breve UCC2003::cldE insertion mutant confirmed that the cld gene cluster is exclusively required for cellodextrin utilization by this commensal. Moreover, our results suggest that transcription of the cld cluster is controlled by a LacI-type regulator encoded by cldR, located immediately upstream of cldE. Gel mobility shift assays using purified CldR(His) (produced by the incorporation of a His(12)-encoding sequence into the 3' end of the cldC gene) indicate that the cldEFGC promoter is subject to negative control by CldR(His), which binds to two inverted repeats. Analysis by high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) of medium samples obtained during growth of B. breve UCC2003 on a mixture of cellodextrins revealed its ability to utilize cellobiose, cellotriose, cellotetraose, and cellopentaose, with cellotriose apparently representing the preferred substrate. The cldC gene of the cld operon of B. breve UCC2003 is, to the best of our knowledge, the first described bifidobacterial β-glucosidase exhibiting hydrolytic activity toward various cellodextrins.
    MeSH term(s) Bifidobacterium/growth & development ; Bifidobacterium/metabolism ; Cellulose/analogs & derivatives ; Cellulose/metabolism ; DNA, Bacterial/chemistry ; DNA, Bacterial/genetics ; Dextrins/metabolism ; Humans ; Molecular Sequence Data ; Multigene Family ; Mutagenesis, Insertional ; Operon ; Sequence Analysis, DNA
    Chemical Substances DNA, Bacterial ; Dextrins ; Cellulose (9004-34-6) ; cellodextrin (9061-30-7)
    Language English
    Publishing date 2011-01-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 223011-2
    ISSN 1098-5336 ; 0099-2240
    ISSN (online) 1098-5336
    ISSN 0099-2240
    DOI 10.1128/AEM.01786-10
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.B 201: Show issues Location:
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  4. Article ; Online: Technical Advance: Function and efficacy of an {alpha}4-integrin antagonist using bioluminescence imaging to detect leukocyte trafficking in murine experimental colitis.

    Murphy, Carola T / Moloney, Gerard / Macsharry, John / Haynes, Andrea / Faivre, Emilie / Quinlan, Aoife / McLean, Peter G / Lee, Kevin / O'Mahony, Liam / Shanahan, Fergus / Melgar, Silvia / Nally, Kenneth

    Journal of leukocyte biology

    2010  Volume 88, Issue 6, Page(s) 1271–1278

    Abstract: Leukocyte trafficking is a therapeutic target in IBD. The integrins α₄β and α₄β₁ regulate leukocyte migration into tissues and lymphoid organs. Current strategies rely on biologics, such as mAb, to inhibit leukocyte recruitment. Here we show the in vivo ... ...

    Abstract Leukocyte trafficking is a therapeutic target in IBD. The integrins α₄β and α₄β₁ regulate leukocyte migration into tissues and lymphoid organs. Current strategies rely on biologics, such as mAb, to inhibit leukocyte recruitment. Here we show the in vivo therapeutic effects of a small molecule α4-integrin antagonist (GSK223618A) in a leukocyte-trafficking model and a murine model of colitis. Leukocytes isolated from MLNs of transgenic β-actin-luc+ mice were injected i.v. into recipients with DSS-induced colitis. Recipient mice were orally gavaged with vehicle or an α₄-integrin antagonist 1 h pre-adoptive transfer, followed by bioluminescence whole body and ex vivo organ imaging 4 h post-transfer. To confirm its therapeutic effect, the α₄-integrin antagonist was given orally twice daily for 6 days to mice with DSS-induced colitis, starting on Day 3. Clinical, macroscopic, and histological signs of inflammation were assessed and gene-expression profiles analyzed. Using bioluminescence imaging, we tracked and quantified leukocyte migration to the inflamed gut and demonstrated its inhibition by a small molecule α₄-integrin antagonist. Additionally, the therapeutic effect of the antagonist was confirmed in DSS-induced colitis in terms of clinical, macroscopic, and histological signs of inflammation. Gene expression analysis suggested enhancement of tissue healing in compound-treated animals. Inhibition of leukocyte trafficking using small molecule integrin antagonists is a promising alternative to large molecule biologics. Furthermore, in vivo bioluminescence imaging is a valuable strategy for preclinical evaluation of potential therapeutics that target leukocyte trafficking in inflammatory diseases.
    MeSH term(s) Animals ; Cell Movement ; Colitis/drug therapy ; Colitis/immunology ; Colon/metabolism ; Cytokines/genetics ; Dextran Sulfate ; Integrin alpha4/physiology ; Leukocytes/physiology ; Luminescent Measurements ; Male ; Mice ; Mice, Inbred C57BL ; Neovascularization, Physiologic ; RNA, Messenger/analysis
    Chemical Substances Cytokines ; RNA, Messenger ; Integrin alpha4 (143198-26-9) ; Dextran Sulfate (9042-14-2)
    Language English
    Publishing date 2010-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 605722-6
    ISSN 1938-3673 ; 0741-5400
    ISSN (online) 1938-3673
    ISSN 0741-5400
    DOI 10.1189/jlb.0909627
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    Zs.A 603: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (1.OG)
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  5. Article ; Online: Mucosal cytokine imbalance in irritable bowel syndrome.

    Macsharry, John / O'Mahony, Liam / Fanning, Aine / Bairead, Emer / Sherlock, Graham / Tiesman, Jay / Fulmer, Andy / Kiely, Barry / Dinan, Timothy G / Shanahan, Fergus / Quigley, Eamonn M M

    Scandinavian journal of gastroenterology

    2008  Volume 43, Issue 12, Page(s) 1467–1476

    Abstract: Objective: To systematically examine mucosal biopsies for differences in cytokine gene expression and protein secretion.: Material and methods: The study included 59 females with irritable bowel syndrome (IBS) and 39, otherwise healthy, female ... ...

    Abstract Objective: To systematically examine mucosal biopsies for differences in cytokine gene expression and protein secretion.
    Material and methods: The study included 59 females with irritable bowel syndrome (IBS) and 39, otherwise healthy, female volunteers presenting for colonoscopy. Colonic biopsies from subsets were studied by microarray analysis (IBS, n=9; controls, n=8), quantitative reverse transcription-polymerase chain reaction (qRT-PCR) (IBS, n=22; controls, n=21), and ex vivo biopsy culture (IBS, n=28, controls, n=10). Biopsies from patients with active colitis were used as inflammatory disease controls.
    Results: While gene array analysis revealed extensive overlapping between controls and IBS patients, reduced expression of genes linked to chemokine function was evident among the IBS patients alone. Differential expression was confirmed by qRT-PCR or ex vivo biopsy culture for 5 out of 6 selected genes. Reduced secretion of chemokines (IL-8, CXCL-9 and MCP-1) but not pro-inflammatory cytokines (TNF-alpha, IL-6 and IL-1beta) was established on the basis of the ex vivo biopsy cultures. These findings were in marked contrast to the IBD patients who demonstrated increased production of both chemokines and pro-inflammatory cytokines.
    Conclusions: Despite the expected heterogeneity of the disorder, differences in mucosal chemokine signalling were evident in this cross-sectional study of IBS patients at the level of both gene expression and protein secretion, with IBS patients demonstrating a consistent deficit in the expression and secretion of chemokines known to play a critical role in mucosal defence.
    MeSH term(s) Adolescent ; Adult ; Aged ; Chemokine CCL2 ; Chemokine CXCL9 ; Colonoscopy ; Cytokines/genetics ; Female ; Gene Expression ; Humans ; Interleukin-1beta ; Interleukin-6 ; Interleukin-8 ; Intestinal Mucosa/metabolism ; Irritable Bowel Syndrome/genetics ; Irritable Bowel Syndrome/metabolism ; Irritable Bowel Syndrome/pathology ; Middle Aged ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Necrosis Factor-alpha
    Chemical Substances CCL2 protein, human ; CXCL9 protein, human ; Chemokine CCL2 ; Chemokine CXCL9 ; Cytokines ; Interleukin-1beta ; Interleukin-6 ; Interleukin-8 ; TNF protein, human ; Tumor Necrosis Factor-alpha
    Language English
    Publishing date 2008
    Publishing country England
    Document type Comparative Study ; Journal Article
    ZDB-ID 82042-8
    ISSN 1502-7708 ; 0036-5521
    ISSN (online) 1502-7708
    ISSN 0036-5521
    DOI 10.1080/00365520802276127
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    Zs.A 567: Show issues Location:
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  6. Article: Functional modulation of human intestinal epithelial cell responses by Bifidobacterium infantis and Lactobacillus salivarius.

    O'Hara, Ann M / O'Regan, Padraig / Fanning, Aine / O'Mahony, Caitlin / Macsharry, John / Lyons, Anne / Bienenstock, John / O'Mahony, Liam / Shanahan, Fergus

    Immunology

    2006  Volume 118, Issue 2, Page(s) 202–215

    Abstract: Intestinal epithelial cells (IECs) and dendritic cells (DCs) play a pivotal role in antigen sampling and the maintenance of gut homeostasis. However, the interaction of commensal bacteria with the intestinal surface remains incompletely understood. Here ... ...

    Abstract Intestinal epithelial cells (IECs) and dendritic cells (DCs) play a pivotal role in antigen sampling and the maintenance of gut homeostasis. However, the interaction of commensal bacteria with the intestinal surface remains incompletely understood. Here we investigated immune cell responses to commensal and pathogenic bacteria. HT-29 human IECs were incubated with Bifidobacterium infantis 35624, Lactobacillus salivarius UCC118 or Salmonella typhimurium UK1 for varying times, or were pretreated with a probiotic for 2 hr prior to stimulation with S. typhimurium or flagellin. Gene arrays were used to examine inflammatory gene expression. Nuclear factor (NF)-kappaB activation, interleukin (IL)-8 secretion, pathogen adherence to IECs, and mucin-3 (MUC3) and E-cadherin gene expression were assayed by TransAM assay, enzyme-linked immunosorbent assay (ELISA), fluorescence, and real-time reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. IL-10 and tumour necrosis factor (TNF)-alpha secretion by bacteria-treated peripheral blood-derived DCs were measured using ELISA. S. typhimurium increased expression of 36 of the 847 immune-related genes assayed, including NF-kappaB and IL-8. The commensal bacteria did not alter expression levels of any of the 847 genes. However, B. infantis and L. salivarius attenuated both IL-8 secretion at baseline and S. typhimurium-induced pro-inflammatory responses. B. infantis also limited flagellin-induced IL-8 protein secretion. The commensal bacteria did not increase MUC3or E-cadherin expression, or interfere with pathogen binding to HT-29 cells, but they did stimulate IL-10 and TNF-alpha secretion by DCs. The data demonstrate that, although the intestinal epithelium is immunologically quiescent when it encounters B. infantis or L. salivarius, these commensal bacteria exert immunomodulatory effects on intestinal immune cells that mediate host responses to flagellin and enteric pathogens.
    MeSH term(s) Antigens, Bacterial/immunology ; Bifidobacterium/immunology ; Cadherins/biosynthesis ; Cadherins/genetics ; Cell Survival/immunology ; Colon/immunology ; Cytokines/biosynthesis ; Dendritic Cells/immunology ; Epithelial Cells/immunology ; Flagellin/immunology ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/immunology ; HT29 Cells ; Humans ; Immunity, Mucosal ; Inflammation Mediators/immunology ; Interleukin-8/biosynthesis ; Interleukin-8/genetics ; Intestinal Mucosa/immunology ; Lactobacillus/immunology ; Mucin-3 ; Mucins/biosynthesis ; Mucins/genetics ; NF-kappa B/metabolism ; Probiotics/pharmacology ; RNA, Messenger/genetics ; Reverse Transcriptase Polymerase Chain Reaction/methods ; Salmonella typhimurium/immunology
    Chemical Substances Antigens, Bacterial ; Cadherins ; Cytokines ; Inflammation Mediators ; Interleukin-8 ; Mucin-3 ; Mucins ; NF-kappa B ; RNA, Messenger ; Flagellin (12777-81-0)
    Language English
    Publishing date 2006-06
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80124-0
    ISSN 1365-2567 ; 0019-2805 ; 0953-4954
    ISSN (online) 1365-2567
    ISSN 0019-2805 ; 0953-4954
    DOI 10.1111/j.1365-2567.2006.02358.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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