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3 results on '"Inserm (UMR 1071)"'

1. When Pathobiont-Carbohydrate Interaction Turns Bittersweet!

Author

Nicolas Barnich, Benoit Chassaing, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Kenneth Rainin Foundation, National Program 'Microbiote' INSERM, Ministere de la Recherche et de la Technologie, INSERM (UMR 1071), INRAe (USC-2018, Universite Clermont Auvergne [I-SITE project (CAP 2025)], Association Francois Aupetit, ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-16-IDEX-0001,CAP 20-25,CAP 20-25(2016), European Project: ERC-2018-StG804135, ROSSI, Sabine, Université de Paris - - Université de Paris2018 - ANR-18-IDEX-0001 - IDEX - VALID, CAP 20-25 - - CAP 20-252016 - ANR-16-IDEX-0001 - IDEX - VALID, and Mucus-Penetrating Microbiota: Characterization, Mechanism and Therapeutic in Metabolic Disease - ERC-2018-StG804135 - INCOMING

Subjects
Phosphotransferase System, NCBI, National Center for Biotechnology Information, PTS, phosphotransferase system, EIIA, enzyme IIA, Carbohydrates, Gene Expression, RC799-869, Computational biology, Biology, cDNA, complementary DNA, PCR, polymerase chain reaction, ComputingMilieux_MISCELLANEOUS, Original Research, Hepatology, IBD, inflammatory bowel disease, Gastroenterology, RNA-seq, RNA sequencing, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Diseases of the digestive system. Gastroenterology, Carbohydrate, Inflammatory Bowel Diseases, WT, wild-type, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, mRNA, messenger RNA, IL, interleukin, rRNA, ribosomal RNA, Ct, cycle threshold, BHI, brain heart infusion
Abstract

Background & Aims The inflammatory bowel diseases (IBDs), Crohn’s disease and ulcerative colitis, are caused in part by aberrant immune responses to resident intestinal bacteria. Certain dietary components, including carbohydrates, are associated with IBDs and alter intestinal bacterial composition. However, the effects of luminal carbohydrates on the composition and colitogenic potential of intestinal bacteria are incompletely understood. We hypothesize that carbohydrate metabolism by resident proinflammatory intestinal bacteria enhances their growth and worsens intestinal inflammation. Methods We colonized germ-free, wild-type, and colitis-susceptible interleukin-10 knockout mice (Il10-/-) with a consortium of resident intestinal bacterial strains and quantified colon inflammation using blinded histologic scoring and spontaneous secretion of IL12/23p40 by colon explants. We measured luminal bacterial composition using real-time 16S polymerase chain reaction, bacterial gene expression using RNA sequencing and real-time polymerase chain reaction, and luminal glucosamine levels using gas chromatography–mass spectrometry. Results We show that a consortium of 8 bacterial strains induces severe colitis in Il10-/- mice and up-regulates genes associated with carbohydrate metabolism during colitis. Specifically, Enterococcus faecalis strain OG1RF is proinflammatory and strongly up-regulates OG1RF_11616-11610, an operon that encodes genes of a previously undescribed phosphotransferase system that we show imports glucosamine. Experimental colitis is associated with increased levels of luminal glucosamine and OG1RF_11616 causes worse colitis, not by increasing E faecalis numbers, but rather by mechanisms that require the presence of complex microbiota. Conclusions Further studies of luminal carbohydrate levels and bacterial carbohydrate metabolism during intestinal inflammation will improve our understanding of the pathogenesis of IBDs and may lead to the development of novel therapies for these diseases.

Published
2021

2. Small-molecule inhibitors prevent the genotoxic and protumoural effects induced by colibactin-producing bacteria

Author

Tiphanie Faïs, Arlette Darfeuille-Michaud, Chiara Romagnoli, Antony Cougnoux, Gabriel Cuevas-Ramos, Richard Bonnet, Lucie Gibold, Guillaume Dalmasso, Julien Delmas, Eric Oswald, Frédéric Robin, Fabio Prati, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA), CHU Clermont-Ferrand, Department of Life Sciences, Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Universitaire de Technologie d'Aubière (IUT d'Aubière), Ministère de la Recherche et de la Technologie, INSERM [UMR 1071], INRA [USC-2018], Centre Hospitalier Régional Universitaire de Clermont-Ferrand, France, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and CHU Toulouse [Toulouse]

Subjects
0301 basic medicine, DNA damage, [SDV]Life Sciences [q-bio], ADJUVANT TREATMENT, BACTERIAL PATHOGENESIS, COLORECTAL CANCER, DRUG DEVELOPMENT, E. COLI, Biology, Ligands, medicine.disease_cause, Mice, 03 medical and health sciences, In vivo, Escherichia coli, medicine, Animals, chemistry.chemical_classification, Mice, Inbred BALB C, Ligand efficiency, Calcium-Binding Proteins, Gastroenterology, Boronic Acids, Small molecule, In vitro, 3. Good health, 030104 developmental biology, Enzyme, chemistry, Biochemistry, Docking (molecular), Polyketides, Colorectal Neoplasms, Peptides, DNA Damage, Mutagens
Abstract

International audience; Objective Colorectal cancers (CRCs) are frequently colonised by colibactin toxin-producing Escherichia coli bacteria that induce DNA damage in host cells and exhibit protumoural activities. Our objective was to identify small molecules inhibiting the toxic effects induced by these colibactin-producing bacteria. Design A structural approach was adopted for the identification of a putative ligand for the ClbP enzyme involved in the synthesis of colibactin. Intestinal epithelial cells and a CRC mouse model were used to assess the activity of the selected compounds in vitro and in vivo. Results Docking experiments identified two boron-based compounds with computed ligand efficiency values (−0.8 and −0.9 kcal/mol/atom) consistent with data expected for medicinal chemistry leads. The crystalline structure of ClbP in complex with the compounds confirmed that the compounds were binding to the active site of ClbP. The two compounds (2 mM) suppressed the genotoxic activity of colibactin-producing E coli both in vitro and in vivo. The mean degree of suppression of DNA damage for the most efficient compound was 98±2% (95% CI). This compound also prevented cell proliferation and colibactin-producing E coli-induced tumourigenesis in mice. In a CRC murine model colonised by colibactin-producing E coli, the number of tumours decreased by 3.5-fold in animals receiving the compound in drinking water (p

Published
2015

3. Glycopolymers as Antiadhesives of E. coli Strains Inducing Inflammatory Bowel Diseases

Author

Christophe Travelet, David Deniaud, Julien Bernard, Adeline Sivignon, Nicolas Barnich, Zhaoli Li, Etienne Fleury, Redouane Borsali, Nao Yamakawa, Arlette Darfeuille-Michaud, Agnes Crepet, Xibo Yan, Julie Bouckaert, Sébastien G. Gouin, Rostyslav Bilyy, Tetiana Dumych, Ingénierie des Matériaux Polymères (IMP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur les Macromolécules Végétales (CERMAV), Université Joseph Fourier - Grenoble 1 (UJF)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université Lille Nord de France (COMUE), Ministère de la Recherche et de la Technologie, Inserm (UMR 1071) and INRA (USC-2018), ANR-12-BSV5-0016,STARLET,Effets thérapeutiques de polymères mannosylés synthétiques capables de contrôler les infections chroniques ntestinales à Escherichia coli en interagissant avec la dynamique de glycosylation des cellules hôtes(2012), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Laboratoire de Chimie des polymères organiques (LCPO), Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Centre National de la Recherche Scientifique (CNRS), Danylo Halytskiy Lviv National Medical University, Université de Nantes - Faculté des Sciences et des Techniques, Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Ingénierie des Matériaux Polymères - Laboratoire des Matériaux Macromoléculaires (IMP-LMM), Laboratoire des Adaptations Métaboliques à l’Exercice en conditions Physiologiques et Pathologiques (AME2P), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA), Laboratoire de Synthèse Organique (Hétérochimie organique, organoéléments et matériaux) (LSOHOOM), Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Adaptations Métaboliques à l'Exercice en Conditions Physiologiques et Pathologiques (AME2P), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-UFR Sciences et Techniques des Activités Physiques et Sportives - Clermont-Auvergne (UFR STAPS - UCA), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Recherche Agronomique (INRA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)

Subjects
Polymers and Plastics, Glycopolymer, Mannose, Bioengineering, Biology, medicine.disease_cause, Virulence factor, Microbiology, Biomaterials, chemistry.chemical_compound, Mice, Intestinal mucosa, Materials Chemistry, medicine, Cell Adhesion, Escherichia coli, [CHIM]Chemical Sciences, Animals, Humans, Intestinal Mucosa, ComputingMilieux_MISCELLANEOUS, Adhesins, Escherichia coli, Polysaccharides, Bacterial, [CHIM.MATE]Chemical Sciences/Material chemistry, Inflammatory Bowel Diseases, In vitro, 3. Good health, Bacterial adhesin, [CHIM.POLY]Chemical Sciences/Polymers, Biochemistry, chemistry, Fimbriae Proteins, Ex vivo, Heptanol, HeLa Cells
Abstract

International audience; n-Heptyl alpha-D-mannose (HM) is a nanomolar antagonist of FimH, a virulence factor of E. coli. Herein we report on the construction of multivalent HM-based glycopolymers as potent antiadhesives of type 1 piliated E. coli. We investigate glycopolymer/FimH and glycopolymer/bacteria interactions and show that HM-based glycopolymers efficiently inhibit bacterial adhesion and disrupt established cell-bacteria interactions in vitro at very low concentration (0.1 mu M on a mannose unit basis). On a valency-corrected basis, HM-based glycopolymers are, respectively, 10(2) and 10(6) times more potent than HM and D-mannose for their capacity to disrupt the binding of adherent-invasive E. coli to T84 intestinal epithelial cells. Finally, we demonstrate that the antiadhesive capacities of HM-based glycopolymers are preserved ex vivo in the colonic loop of a transgenic mouse model of Crohns disease. All together, these results underline the promising scope of HM-based macromolecular ligands for the antiadhesive treatment of E. coli induced inflammatory bowel diseases.

Published
2015

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