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54 results on '"Patricia Lepage"'

1. Mucosal Healing and Bacterial Composition in Response to Enteral Nutrition Vs Steroid-based Induction Therapy—A Randomised Prospective Clinical Trial in Children With Crohn’s Disease

Author

Patricia Lepage, Stanislas Mondot, Joël Doré, Jacques Schmitz, Frank M. Ruemmele, Olivier Goulet, Bénédicte Pigneur, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Sorbonne Paris Cité (COMUE) (USPC), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris Saclay (COmUE), MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), ProdInra, Migration, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Randomization, Adolescent, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Gut flora, Gastroenterology, 03 medical and health sciences, Enteral Nutrition, 0302 clinical medicine, Crohn Disease, Adrenal Cortex Hormones, Internal medicine, medicine, Humans, Child, Adverse effect, Neoadjuvant therapy, Crohn's disease, Mucous Membrane, biology, business.industry, Remission Induction, Mucous membrane, General Medicine, medicine.disease, biology.organism_classification, DNA Fingerprinting, Gastrointestinal Microbiome, 3. Good health, [SDV] Life Sciences [q-bio], Clinical trial, 030104 developmental biology, medicine.anatomical_structure, Parenteral nutrition, Female, 030211 gastroenterology & hepatology, business
Abstract

AimsExclusive enteral nutrition [EEN] is as efficacious as corticosteroids [CS] to induce remission in Crohn’s disease [CD], without their adverse effects. EEN seems to be more efficient than steroids to induce mucosal healing, but the underlying molecular mechanisms are only sparsely understood. We aimed in the present work to study the anti-inflammatory effects of EEN with Modulen IBD® vs CS in active paediatric CD, and to assess its modulatory effects on the intestinal microbiota as compared with steroids.Materials and MethodsNineteen patients with new-onset active CD (Harvey-Bradshaw index [HBI] >5), aged from 6 to 17 years, were included in this prospective randomised induction trial with CS [n = 6] or EEN [n = 13]. Patients were assessed at Weeks 0 and 8 using clinical parameters HBI, endoscopic findings (Crohn’s Disease Endoscopic Index of Severity [CDEIS] score) and analysis of faecal microbiota composition.ResultsAt 8 weeks, clinical remission [HBI ConclusionsBoth steroid and EEN induced clinical remission. However, patients with EEN-induced remission showed a higher rate of mucosal healing and this was associated with a different gut microbiota compositional shift in these children.

Published
2018

2. Perturbed Microbiota/Immune Homeostasis in Multiple Sclerosis

Author

Catherine Juste, Catherine Lubetzki, Marina Vignes, Gaëlle Autaa, Romain Deschamps, Jennifer Aboab, Caroline Papeix, Christophe Parizot, Patricia Lepage, Karim Dorgham, Jehane Fadlallah, Savine Vicart, Guy Gorochov, Delphine Sterlin, Martin Larsen, Olivier Gout, Elisabeth Maillart, HAL-SU, Gestionnaire, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Fondation Ophtalmologique Adolphe de Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Adult, Male, Multiple Sclerosis, Adolescent, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Context (language use), Gut flora, digestive system, Article, Flow cytometry, Young Adult, 03 medical and health sciences, Multiple Sclerosis, Relapsing-Remitting, 0302 clinical medicine, Immune system, Immunity, RNA, Ribosomal, 16S, medicine, Homeostasis, Humans, 030304 developmental biology, 0303 health sciences, biology, medicine.diagnostic_test, business.industry, Microbiota, Multiple sclerosis, Patient Acuity, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Middle Aged, medicine.disease, biology.organism_classification, Commensalism, Gastrointestinal Microbiome, Immunoglobulin A, 3. Good health, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Neurology, Immunoglobulin G, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Immunology, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Bacteria
Abstract

ObjectiveBased on animal models and human studies, there is now strong suspicion that host/microbiota mutualism in the context of gut microbial dysbiosis could influence immunity and multiple sclerosis (MS) evolution. Our goal was to seek evidence of deregulated microbiota-induced systemic immune responses in patients with MS.MethodsWe investigated gut and systemic commensal-specific antibody responses in healthy controls (n = 32), patients with relapsing-remitting MS (n = 30), and individuals with clinically isolated syndromes (CISs) (n = 15). Gut microbiota composition and diversity were compared between controls and patients by analysis of 16S ribosomal ribonucleic acid (rRNA) sequencing. Autologous microbiota and cultivable bacterial strains were used in bacterial flow cytometry assays to quantify autologous serum IgG and secretory IgA responses to microbiota. IgG-bound bacteria were sorted by flow cytometry and identified using 16S rRNA sequencing.ResultsWe show that commensal-specific gut IgA responses are drastically reduced in patients with severe MS, disease severity being correlated with the IgA-coated fecal microbiota fraction (r = −0.647, p < 0.0001). At the same time, IgA-unbound bacteria elicit qualitatively broad and quantitatively increased serum IgG responses in patients with MS and CIS compared with controls (4.1% and 2.5% vs 1.9%, respectively, p < 0.001).ConclusionsGut and systemic microbiota/immune homeostasis are perturbed in MS. Our results argue that defective IgA responses in MS are linked to a breakdown of systemic tolerance to gut microbiota leading to an enhanced triggering of systemic IgG immunity against gut commensals occurring early in MS.

Published
2021

3. Nutritional strategies and gut microbiota composition as risk factors for necrotizing enterocolitis in very-preterm infants

Author

Jean-Christophe Rozé, Pierre-Yves Ancel, Patricia Lepage, Laetitia Martin-Marchand, Ziad Al Nabhani, Johanne Delannoy, Jean-Charles Picaud, Alexandre Lapillonne, Julio Aires, Mélanie Durox, Dominique Darmaun, Josef Neu, Marie-José Butel, Farid Boudred, Delphine Mitanchez, Charlotte Casper, Valerie Biran, Laurent Storme, Olivier Claris, Gilles Cambonie, Jacques Sizun, Anne Sauret, Odile Dicky, Emmanuel Lopez, Jean-Michel Hascoet, Geraldine Gascoin, Rachel Vieux, Blandine de Lauzon, Luc Desfrere, Clement Chollat, Marie-Jose Butel, Clotilde Rousseau, Joel Doré, Karine Le Roux, Céline Monot, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), AP-HP Hôpitaux Universitaires Paris Centre, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Ecosystème intestinal, probiotiques, antibiotiques (EA 4065), Department of Neonatal Medicine, University Hospital, Paris Descartes Univ, Risks Pregnancy Dept, Paris, France, Partenaires INRAE, Paris Descartes Univ, EA Intestinal Ecosyst Probiot Antibiot 4065, Fac Pharm, Paris, France, University of Florida [Gainesville] (UF), French Institute of Public Health Research/Institute of Public Health, French Health Ministry, NIH and Medical Research, National Institute of Cancer, National Solidarity Fund for Autonomy, National Research Agency [ANR-11-EQPX-0038, ANR-12-SV, ANR-12-BSV3-0025001/EPIFLORE], PremUp Foundation, and Nestec Research Center (Vers-chez-les-Blanc, Switzerland)

Subjects
Time Factors, Neonatal intensive care unit, breastfeeding, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), Enteral administration, Gastroenterology, 0302 clinical medicine, Risk Factors, RNA, Ribosomal, 16S, Odds Ratio, Prospective Studies, 030212 general & internal medicine, speed of increasing enteral nutrition, 2. Zero hunger, Enterocolitis, education.field_of_study, Nutrition and Dietetics, Infant Formula, 3. Good health, Breast Feeding, Necrotizing enterocolitis, France, medicine.symptom, clostridia, Infant, Premature, Staphylococcus aureus, medicine.medical_specialty, Population, preterm infant, 03 medical and health sciences, Enteral Nutrition, Enterocolitis, Necrotizing, Intensive Care Units, Neonatal, 030225 pediatrics, Intensive care, Internal medicine, medicine, Humans, education, Clostridium, necrotizing enterocolitis, Bacteria, Milk, Human, business.industry, Infant, Newborn, Editorials, medicine.disease, digestive system diseases, Gastrointestinal Microbiome, Parenteral nutrition, Case-Control Studies, Intensive Care, Neonatal, business, Breast feeding
Abstract

International audience; Background: The pathophysiology of necrotizing enterocolitis (NEC) remains poorly understood. Objective: We assessed the relation between feeding strategies, intestinal microbiota composition, and the development of NEC. Design: We performed a prospective nationwide population-based study, EPIPAGE 2 (Etude Epidemiologique sur les Petits Ages Ges-tationnels), including preterm infants born at,32 wk of gestation in France in 2011. From individual characteristics observed during the first week of life, we calculated a propensity score for the risk of NEC (Bell's stage 2 or 3) after day 7 of life. We analyzed the relation between neonatal intensive care unit (NICU) strategies concerning the rate of progression of enteral feeding, the direct-breastfeeding policy, and the onset of NEC using general linear mixed models to account for clustering by the NICU. An ancillary propensitymatched case-control study, EPIFLORE (Etude Epidemiologique de la flore), in 20 of the 64 NICUs, analyzed the intestinal microbiota by culture and 16S ribosomal RNA gene sequencing. Results: Among the 3161 enrolled preterm infants, 106 (3.4%; 95% CI: 2.8%, 4.0%) developed NEC. Individual characteristics were significantly associated with NEC. Slower and intermediate rates of progression of enteral feeding strategies were associated with a higher risk of NEC, with an adjusted OR of 2.3 (95% CI: 1.2, 4.5; P = 0.01) and 2.0 (95% CI: 1.1, 3.5; P = 0.02), respectively. Less favorable and intermediate direct-breastfeeding policies were associated with higher NEC risk as well, with an adjusted OR of 2.5 (95% CI: 1.1, 5.8; P = 0.03) and 2.3 (95% CI: 1.1, 4.8; P = 0.02), respectively. Microbiota analysis performed in 16 cases and 78 controls showed an association between Clostridium neonatale and Staphylococcus aureus with NEC (P = 0.001 and P = 0.002). Conclusions: A slow rate of progression of enteral feeding and a less favorable direct-breastfeeding policy are associated with an increased risk of developing NEC. For a given level of risk assessed by propensity score, colonization by C. neonatale and/or S. aureus is significantly associated with NEC. This trial (EPIFLORE study) was registered at clinicaltrials.gov as NCT01127698.

Published
2017

4. Inflammatory bowel disease and cancer response due to anti-CTLA-4: is it in the flora?

Author

Franck Carbonnel, Emilie Soularue, Christine Mateus, Caroline Robert, Patricia Lepage, Clélia Coutzac, Nathalie Chaput, Department of Gastroenterology, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université Paris Sud (Paris 11), Laboratoire d’Immunomonitoring en Oncologie (LIO), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), US23 Institut de recherche intégrée en cancérologie, Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de pharmacie, Université catholique du Graben, Service de dermatologie, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, and Université Paris-Saclay

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Immunology, chemical and pharmacologic phenomena, Ipilimumab, Pembrolizumab, Gut flora, Inflammatory bowel disease, Immunomodulation, 03 medical and health sciences, 0302 clinical medicine, Cancer immunotherapy, Neoplasms, medicine, Humans, Immunology and Allergy, CTLA-4 Antigen, Molecular Targeted Therapy, Intestinal Mucosa, Enterocolitis, biology, business.industry, Antibodies, Monoclonal, Cancer, Colitis, Inflammatory Bowel Diseases, medicine.disease, biology.organism_classification, 3. Good health, Intestines, 030104 developmental biology, 030220 oncology & carcinogenesis, Immunotherapy, medicine.symptom, Nivolumab, business, medicine.drug
Abstract

Checkpoint inhibitors blocking CTLA-4 (ipilimumab) and PD-1 (nivolumab, pembrolizumab) have transfigured our cancer treatment paradigm. However, these drugs can induce immune-related adverse events that share clinical and pathological characteristics with immune-mediated diseases. One of the most severe immune-related adverse event observed with anti-CTLA-4 is an enterocolitis that mirrors naturally occurring inflammatory bowel disease. This paper reviews the clinical, immunological, and microbiota data associated with the immune-related enterocolitis induced by the cancer immunotherapy blocking CTLA-4, ipilimumab. A parallel analysis of the mechanisms underlying inflammatory bowel diseases on the one hand, and anti-CTLA-4-induced colitis on the other hand, stresses the crucial role of the gut microbiota and of resident T-reg in the genesis of both iatrogenic and spontaneous inflammatory bowel diseases.

Published
2017

5. Mucosal healing progression after acute colitis in mice

Author

Anne Blais, Sandra Vidal-Lletjós, François Blachier, Anne-Marie Davila, Mireille Andriamihaja, Claire Gaudichon, Patricia Lepage, Marta Grauso, Marion Leclerc, Annaïg Lan, Physiologie de la Nutrition et du Comportement Alimentaire (PNCA), AgroParisTech-Institut National de la Recherche Agronomique (INRA), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, SocieteFrancaise de Nutrition, Association Francois Aupetit, and INRA-Universite Paris-Saclay (ALIAS program)

Subjects
Male, Pathology, medicine.medical_specialty, Colon, Context (language use), Inflammation, Permeability, Acute colitis, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, RNA, Ribosomal, 16S, medicine, Animals, Humans, Regeneration, Intestinal Mucosa, Colitis, Barrier function, Cell Proliferation, Dextran sodium sulfate-induced colitis, Goblet cell, business.industry, Dextran Sulfate, Gastroenterology, Interleukin, General Medicine, Basic Study, medicine.disease, Gastrointestinal Microbiome, Colon luminal environment, 3. Good health, Mice, Inbred C57BL, Disease Models, Animal, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Dysbiosis, Colitis, Ulcerative, 030211 gastroenterology & hepatology, Epithelial repair, Inflammation Mediators, medicine.symptom, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

International audience; BACKGROUNDMucosal healing has become a therapeutic goal to achieve stable remission in patients with inflammatory bowel diseases. To achieve this objective, overlapping actions of complex cellular processes, such as migration, proliferation, and differentiation, are required. These events are longitudinally and tightly controlled by numerous factors including a wide range of distinct regulatory proteins. However, the sequence of events associated with colon mucosal repair after colitis and the evolution of the luminal content characteristics during this process have been little studied.AIMTo document the evolution of colon mucosal characteristics during mucosal healing using a mouse model with chemically-induced colitis.METHODSC57BL/6 male mice were given 3.5% dextran sodium sulfate (DSS) in drinking water for 5 d. They were euthanized 2 (day 7), 5 (day 10), 8 (day 13), and 23 (day 28) d after DSS removal. The colonic luminal environment and epithelial repair processes during the inflammatory flare and colitis resolution were analyzed with reference to a non-DSS treated control group, euthanized at day 0. Epithelial repair events were assessed histo-morphologically in combination with functional permeability tests, expression of key inflammatory and repairing factors, and evaluation of colon mucosa-adherent microbiota composition by 16S rRNA sequencing.RESULTSThe maximal intensity of colitis was concomitant with maximal alterations of intestinal barrier function and histological damage associated with goblet cell depletion in colon mucosa. It was recorded 2 d after termination of the DSS-treatment, followed by a progressive return to values similar to those of control mice. Although signs of colitis were severe (inflammatory cell infiltrate, crypt disarray, increased permeability) and associated with colonic luminal alterations (hyperosmolarity, dysbiosis, decrease in short-chain fatty acid content), epithelial healing processes were launched early during the inflammatory flare with increased gene expression of certain key epithelial repair modulators, including transforming growth factor-β, interleukin (Il)-15, Il-22, Il-33, and serum amyloid A. Whereas signs of inflammation progressively diminished, luminal colonic environment alterations and microscopic abnormalities of colon mucosa persisted long after colitis induction.CONCLUSIONThis study shows that colon repair can be initiated in the context of inflamed mucosa associated with alterations of the luminal environment and highlights the longitudinal involvement of key modulators.

Published
2019

6. Gut bacteria are critical for optimal muscle function: a potential link with glucose homeostasis

Author

Kevin Nay, Maxence Jollet, Frédéric Derbré, Vincent Ollendorff, Christelle Koechlin-Ramonatxo, Luz Lefeuvre-Orfila, Anne Bonnieu, Bénédicte Goustard, Barbara Vernus, Mahendra Mariadassou, Claude Bendavid, Olivier Rué, Patricia Lepage, Maria Pontones, Narjes Baati, Dynamique Musculaire et Métabolisme (DMEM), Institut National de la Recherche Agronomique (INRA)-Université de Montpellier (UM), Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de la Recherche Agronomique (INRA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Institut National de la Recherche Agronomique (INRA), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Laboratoire Mouvement Sport Santé (M2S), Université de Rennes (UR)-École normale supérieure - Rennes (ENS Rennes)-Université de Brest (UBO)-Université de Rennes 2 (UR2)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Conseil Régional de Bretagne, Centre National d’Etudes Spatiales, INRA-Département AlimH, Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA), École normale supérieure - Cachan (ENS Cachan)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Brest (UBO)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Jonchère, Laurent

Subjects
0301 basic medicine, Male, mitochondrial biogenesis, Physiology, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Gut flora, chemistry.chemical_compound, Mice, 0302 clinical medicine, Glucose homeostasis, Homeostasis, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, biology, Glycogen, dysbiosis, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Anti-Bacterial Agents, medicine.anatomical_structure, muscle fatigue, medicine.symptom, maximal aerobic velocity, Muscle Contraction, medicine.medical_specialty, 030209 endocrinology & metabolism, Inflammation, digestive system, Extensor digitorum longus muscle, 03 medical and health sciences, Physiology (medical), Internal medicine, medicine, Animals, Muscle, Skeletal, Muscle fatigue, Skeletal muscle, biology.organism_classification, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Gastrointestinal Microbiome, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Glucose, chemistry, contractile properties, Energy Metabolism, Dysbiosis, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

International audience; Gut microbiota is involved in the development of several chronic diseases, including diabetes, obesity, and cancer, through its interactions with the host organs. It has been suggested that the cross talk between gut microbiota and skeletal muscle plays a role in different pathological conditions, such as intestinal chronic inflammation and cachexia. However, it remains unclear whether gut microbiota directly influences skeletal muscle function. In this work, we studied the impact of gut microbiota modulation on mice skeletal muscle function and investigated the underlying mechanisms. We determined the consequences of gut microbiota depletion after treatment with a mixture of a broad spectrum of antibiotics for 21 days and after 10 days of natural reseeding. We found that, in gut microbiota-depleted mice, running endurance was decreased, as well as the extensor digitorum longus muscle fatigue index in an ex vivo contractile test. Importantly, the muscle endurance capacity was efficiently normalized by natural reseeding. These endurance changes were not related to variation in muscle mass, fiber typology, or mitochondrial function. However, several pertinent glucose metabolism markers, such as ileum gene expression of short fatty acid chain and glucose transporters G protein-coupled receptor 41 and sodium-glucose cotransporter 1 and muscle glycogen level, paralleled the muscle endurance changes observed after treatment with antibiotics for 21 days and reseeding. Because glycogen is a key energetic substrate for prolonged exercise, modulating its muscle availability via gut microbiota represents one potent mechanism that can contribute to the gut microbiota-skeletal muscle axis. Taken together, our results strongly support the hypothesis that gut bacteria are required for host optimal skeletal muscle function.

Published
2019

7. Synergistic convergence of microbiota-specific systemic IgG and secretory IgA

Author

Pascale Ghillani-Dalbin, Lionel Galicier, Claire Fieschi, Hela El Kafsi, Martin Larsen, Karim Dorgham, Patricia Lepage, Jehane Fadlallah, David Boutboul, Makoto Miyara, Christophe Parizot, Guy Gorochov, Christophe Tresallet, Gaëlle Autaa, Marion Malphettes, Hans Yssel, Alexis Mathian, Sébastien André, Karine Clément, Catherine Juste, Zahir Amoura, Delphine Sterlin, Eric Oksenhendler, Florian Marquet, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'immunologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Service d'immunologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris Diderot - Paris 7 (UPD7), CHU Saint Louis [APHP], MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Institut National de la Recherche Agronomique (INRA), Service de nutrition [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [APHP], Service d'Immunologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Gestionnaire, Hal Sorbonne Université, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]

Subjects
0301 basic medicine, Immunology, Inflammation, Gut microbiota, Gut flora, Selective IgA deficiency, Systemic inflammation, anticommensal IgG, 03 medical and health sciences, Feces, 0302 clinical medicine, Western blot, intravenous immunoglobulin, medicine, Immunology and Allergy, Humans, biology, medicine.diagnostic_test, Common variable immunodeficiency, common variable immunodeficiency, biology.organism_classification, medicine.disease, Antibodies, Bacterial, 3. Good health, Gastrointestinal Microbiome, 030104 developmental biology, secretory IgA, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, Immunoglobulin G, Immunoglobulin A, Secretory, biology.protein, IgA deficiency, medicine.symptom, Antibody
Abstract

International audience; BACKGROUND: Commensals induce local IgA responses essential to the induction of tolerance to gut microbiota, but it remains unclear whether antimicrobiota responses remain confined to the gut.OBJECTIVE: The aim of this study was to investigate systemic and intestinal responses against the whole microbiota under homeostatic conditions and in the absence of IgA.METHODS: We analyzed blood and feces from healthy donors, patients with selective IgA deficiency (SIgAd), and patients with common variable immunodeficiency (CVID). Immunoglobulin-coated bacterial repertoires were analyzed by using combined bacterial fluorescence-activated cell sorting and 16S rRNA sequencing. Bacterial lysates were probed by using Western blot analysis with healthy donor sera.RESULTS: Although absent from the healthy gut, serum antimicrobiota IgG are present in healthy subjects and increased in patients with SIgAd. IgG converges with nonoverlapping secretory IgA specificities to target the same bacteria. Each individual subject targets a diverse microbiota repertoire with a proportion that correlates inversely with systemic inflammation. Finally, intravenous immunoglobulin preparations target CVID gut microbiota much less efficiently than healthy microbiota.CONCLUSION: Secretory IgA and systemic IgG converge to target gut microbiota at the cellular level. SIgAd-associated inflammation is inversely correlated with systemic anticommensal IgG responses, which might serve as a second line of defense. We speculate that patients with SIgAd could benefit from oral IgA supplementation. Our data also suggest that intravenous immunoglobulin preparations can be supplemented with IgG from IgA-deficient patient pools to offer better protection against gut bacterial translocations in patients with CVID.

Published
2019

8. Dietary Protein Intake Level Modulates Mucosal Healing and Mucosa-Adherent Microbiota in Mouse Model of Colitis

Author

Marta Grauso, Patricia Lepage, Roselyne Viel, Marion Leclerc, François Blachier, Mireille Andriamihaja, Claire Gaudichon, Sandra Vidal-Lletjós, Annaïg Lan, Anne Blais, Anne-Marie Davila, Physiologie de la Nutrition et du Comportement Alimentaire (PNCA), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de Recherche Agronomique - AgroParisTech, Societe Francaise de Nutrition, Association Francois Aupetit, INRA-Universite Paris-Saclay (ALIAS program), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and AgroParisTech-Institut National de la Recherche Agronomique (INRA)

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, colitis, [SDV]Life Sciences [q-bio], epithelial repair, Inflammation, lcsh:TX341-641, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Inflammation resolution, dietary protein level, mucosa-adherent microbiota, Internal medicine, Animals, Medicine, Intestinal Mucosa, Colitis, Beneficial effects, 2. Zero hunger, 030109 nutrition & dietetics, Nutrition and Dietetics, business.industry, medicine.disease, Animal Feed, Diet, Gastrointestinal Microbiome, 3. Good health, Mice, Inbred C57BL, Disease Models, Animal, Dietary protein, Endocrinology, Mucosal healing, 030211 gastroenterology & hepatology, Dietary Proteins, medicine.symptom, business, lcsh:Nutrition. Foods and food supply, Dietary protein intake, Microbiota composition, Food Science
Abstract

International audience; Mucosal healing after an inflammatory flare is associated with lasting clinical remission. The aim of the present work was to evaluate the impact of the amount of dietary protein on epithelial repair after an acute inflammatory episode. C57BL/6 DSS-treated mice received isocaloric diets with different levels of dietary protein 14% (P14), 30% (P30) and 53% (P53) for 3 (day 10), 6 (day 13) and 21 (day 28) days after the time of colitis maximal intensity. While the P53 diet worsened the DSS- induced inflammation both in intensity and duration, the P30 diet, when compared to the P14 diet, showed a beneficial effect during the epithelial repair process by accelerating inflammation resolution, reducing colonic permeability and increasing epithelial repair together with epithelial hyperproliferation. Dietary protein intake also impacted mucosa-adherent microbiota composition after inflammation since P30 fed mice showed increased colonization of butyrate-producing genera throughout the resolution phase. This study revealed that in our colitis model, the amount of protein in the diet modulated mucosal healing, with beneficial effects of a moderately high-protein diet, while very high-protein diet displayed deleterious effects on this process.

Published
2019

9. Nod2Deficiency Leads to a Specific and Transmissible Mucosa-associated Microbial Dysbiosis Which Is Independent of the Mucosal Barrier Defect

Author

Patricia Lepage, Jean-Pierre Hugot, Nicolas Montcuquet, Karine Le Roux, Frédérick Barreau, Ziad Al Nabhani, Dominique Berrebi, Maryline Roy, Monique Dussaillant, and Pascal Mauny

Subjects
0301 basic medicine, Nod2 Signaling Adaptor Protein, Biology, Real-Time Polymerase Chain Reaction, Microbiology, Mice, Peyer's Patches, 03 medical and health sciences, Immune system, Intestinal mucosa, RNA, Ribosomal, 16S, NOD2, medicine, Animals, Intestinal Mucosa, Barrier function, Mice, Knockout, Intestinal permeability, Mucin, Mucins, Gastroenterology, Peyer's patch, General Medicine, medicine.disease, digestive system diseases, Gastrointestinal Microbiome, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Dysbiosis, Female, Antimicrobial Cationic Peptides
Abstract

Background and Aims: Crohn’s disease [CD] is a complex disorder characterised by an inappropriate immune response, impaired barrier function and microbial dysbiosis. Mutations in nucleotide oligomeriation domain 2 [ NOD2 ] are CD risk factors. Increase of intestinal permeability, CD4+ T cell infiltration, and bacterial dysbiosis are also seen in Nod2 -knockout [ Nod2 KO] mice. However, the specificity and relationship between these Nod2 -associated abnormalities remain largely unexplored. Methods: Wild-type [WT], Nod1 -knockout [ Nod1 KO] and Nod2 KO mice were analysed in parallel. Microbial composition was defined by 454-pyrosequencing of bacterial 16S rRNA genes. Mucin and antimicrobial peptide expression was assessed by RT-PCR. Cell populations from Peyer’s patches were determined by flow cytometry. Ussing chambers were used to measure intestinal permeability and bacterial translocation. Finally, to explore the impact of colonisation with mother’s microbiota at birth, analyses were also performed in Nod2 KO and WT mice born from WT surrogate mothers after embryo transfer. Results: Nod2 KO mice exhibited colonic bacterial dysbiosis different from WT and Nod1 KO mice. Altered expression of antimicrobial peptides and mucins in ileum and colon was associated with the microbial composition. Bacterial composition of Nod2 KO and WT mice obtained by embryo transfer was similar to that observed in Nod2 KO mice, arguing for a dominant effect of Nod2 KO-associated dysbiosis. In contrast, increased levels of CD4+ T cells and gut barrier defects across Peyer’s patches were specific to Nod2 deficiency and independent of Microbial dysbiosis. Conclusions: Nod2 deficiency is associated with a specific dominant dysbiosis which does not drive mucosal tissue and immune alterations.

Published
2016

10. The human gut microbiome and its dysfunctions through the meta-omics prism

Author

Patricia Lepage and Stanislas Mondot

Subjects
0301 basic medicine, biology, General Neuroscience, digestive, oral, and skin physiology, 030106 microbiology, Gastrointestinal Microbiome, Disease, Computational biology, Gut flora, biology.organism_classification, medicine.disease, digestive system, General Biochemistry, Genetics and Molecular Biology, 3. Good health, Microbiology, 03 medical and health sciences, 030104 developmental biology, Metabolomics, History and Philosophy of Science, Metagenomics, Metaproteomics, medicine, Microbiome, Irritable bowel syndrome
Abstract

The microorganisms inhabiting the human gut are abundant (10(14) cells) and diverse (approximately 500 species per individual). It is now acknowledged that the microbiota has coevolved with its host to achieve a symbiotic relationship, leading to physiological homeostasis. The gut microbiota ensures vital functions, such as food digestibility, maturation of the host immune system, and protection against pathogens. Over the last few decades, the gut microbiota has also been associated with numerous diseases, such as inflammatory bowel disease, irritable bowel syndrome, obesity, and metabolic diseases. In most of these pathologies, a microbial dysbiosis has been found, indicating shifts in the taxonomic composition of the gut microbiota and changes in its functionality. Our understanding of the influence of the gut microbiota on human health is still growing. Working with microorganisms residing in the gut is challenging since most of them are anaerobic and a vast majority (approximately 75%) are uncultivable to date. Recently, a wide range of new approaches (meta-omics) has been developed to bypass the uncultivability and reveal the intricate mechanisms that sustain gut microbial homeostasis. After a brief description of these approaches (metagenomics, metatranscriptomics, metaproteomics, and metabolomics), this review will discuss the importance of considering the gut microbiome as a structured ecosystem and the use of meta-omics to decipher dysfunctions of the gut microbiome in diseases.

Published
2016

11. Multi-hit early life adversity affects gut microbiota, brain and behavior in a sex-dependent manner

Author

Julien Chevalier, Jean Christophe Helbling, Patricia Lepage, Élodie Lévy, Pierre-Antoine Grohard, Marion Leboyer, Lilian Basso, Marion Rincel, Gérard Eberl, Muriel Darnaudéry, Hélène Boudin, Camille Monchaux de Oliveira, Sophie Layé, Nathalie Vergnolle, Michel Neunlist, Philippe Aubert, Lucile Capuron, Grégoire Chevalier, Nutrition et Neurobiologie intégrée (NutriNeuro), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Microenvironnement et Immunité - Microenvironment and Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Est Créteil, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, University of Bordeaux, INRA, AVIESAN Immunology, Hematology and Pneumology, French Ministry of Research, Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1 (UB)-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique, The Enteric Nervous System in gut and brain disorders [U1235] (TENS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Lipopolysaccharides, Male, MESH: Maternal Deprivation, Physiology, Gut flora, Anxiety, MESH: Animals, Newborn, Marble burying, Behavioral Neuroscience, Mice, 0302 clinical medicine, MESH: Behavior, Animal, MESH: Animals, Mice, Inbred C3H, biology, Behavior, Animal, Maternal Deprivation, Microbiota, Brain, MESH: Stress, Psychological, Compulsive behavior, Female, medicine.symptom, Gut-brain axis, Emotional behavior, MESH: Social Behavior, Elevated plus maze, Offspring, Immunology, Gut–brain axis, Prefrontal Cortex, Intestinal permeability, MESH: Gastrointestinal Microbiome, 03 medical and health sciences, MESH: Brain, Sex Factors, MESH: Sex Factors, medicine, MESH: Microbiota, Animals, Early-life stress, MESH: Mice, Inbred C3H, Social Behavior, MESH: Mice, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, MESH: Anxiety, Endocrine and Autonomic Systems, HPA axis, [SCCO.NEUR]Cognitive science/Neuroscience, Lachnospiraceae, Ultrasonic vocalizations, biology.organism_classification, medicine.disease, Medial prefrontal cortex, MESH: Male, Gastrointestinal Microbiome, 030104 developmental biology, MESH: Dysbiosis, Animals, Newborn, Dysbiosis, MESH: Prefrontal Cortex, MESH: Female, 030217 neurology & neurosurgery, Stress, Psychological
Abstract

International audience; The accumulation of adverse events in utero and during childhood differentially increases the vulnerability to psychiatric diseases in men and women. Gut microbiota is highly sensitive to the early environment and has been recently hypothesized to affect brain development. However, the impact of early-life adversity on gut microbiota, notably with regards to sex differences, remains to be explored. We examined the effects of multifactorial early-life adversity on behavior and microbiota composition in C3H/HeN mice of both sexes exposed to a combination of maternal immune activation (lipopolysaccharide injection on embryonic day 17, 120 μg/kg, i.p.), maternal separation (3hr per day from postnatal day (PND)2 to PND14) and maternal unpredictable chronic mild stress. At adulthood, offspring exposed to multi-hit early adversity showed sex-specific behavioral phenotypes with males exhibiting deficits in social behavior and females showing increased anxiety in the elevated plus maze and increased compulsive behavior in the marble burying test. Early adversity also differentially regulated gene expression in the medial prefrontal cortex (mPFC) according to sex. Interestingly, several genes such as Arc, Btg2, Fosb, Egr4 or Klf2 were oppositely regulated by early adversity in males versus females. Finally, 16S-based microbiota profiling revealed sex-dependent gut dysbiosis. In males, abundance of taxa belonging to Lachnospiraceae and Porphyromonadaceae families or other unclassified Firmicutes, but also Bacteroides, Lactobacillus and Alloprevotella genera was regulated by early adversity. In females, the effects of early adversity were limited and mainly restricted to Lactobacillus and Mucispirillum genera. Our work reveals marked sex differences in a multifactorial model of early-life adversity, both on emotional behaviors and gut microbiota, suggesting that sex should systematically be considered in preclinical studies both in neurogastroenterology and psychiatric research.

Published
2018

12. The gut microbiota drives the impact of bile acids and fat source in diet on mouse metabolism

Author

Patricia Lepage, Valentin Bieth, Katrin Wegner, Eva Rath, Dirk Haller, Geneviève Héry-Arnaud, Josef Ecker, Sarah Just, Thomas Hofmann, Sinah Schmidt, Theresa Streidl, Andreas Dunkel, Till Robin Lesker, Laura Gau, Till Strowig, Stanislas Mondot, Philippe Gérard, Thomas Clavel, Sascha Rohn, Gerhard Liebisch, ZIEL–Institute for Food and Health, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris-Saclay, Nutritional Physiology, Institute of Food Chemistry, Hamburg School of Food Science, University of Hamburg, Nutrition and Immunology, Institute of Medical Microbiology, Functional Microbiome Research Group, University Hospital RWTH Aachen, Food Chemistry and Molecular and Sensory Science, Research Group Microbial Immune Regulation, Helmholtz Centre for Infection Research (HZI), Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Jena, ANR CoriFunc, German Research Foundation (joint DFG/ANR initiative) [CL481/1-1, RO3477/9-1], French National Research Agency [ANR-13-ISV3-0008-04], Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany., Technical University of Munich (TUM), Lepage, Patricia, and Clavel, Thomas

Subjects
Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Enteroendocrine cell, Palm Oil, Gut flora, Mice, Cecum, RNA, Ribosomal, 16S, Amino Acids, 16S rRNA gene amplicon sequencing, Phylogeny, Metatranscriptomics, 2. Zero hunger, Diet-induced obesity, Fatty liver, ddc, 3. Good health, medicine.anatomical_structure, lcsh:QR100-130, DNA, Bacterial, Microbiology (medical), medicine.medical_specialty, Metabolic diseases, Gut microbiota, Germ-free mice, Bile acids, Dietary fat, Lard, Lipidomics, 030106 microbiology, Biology, Diet, High-Fat, DNA, Ribosomal, digestive system, Microbiology, lcsh:Microbial ecology, Bile Acids and Salts, 03 medical and health sciences, Internal medicine, medicine, Animals, Obesity, Bacteria, Gene Expression Profiling, Research, Lachnospiraceae, Metabolism, Lipid Metabolism, medicine.disease, biology.organism_classification, Dietary Fats, Gastrointestinal Microbiome, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology
Abstract

Background As the gut microbiota contributes to metabolic health, it is important to determine specific diet-microbiota interactions that influence host metabolism. Bile acids and dietary fat source can alter phenotypes of diet-induced obesity, but the interplay with intestinal microorganisms is unclear. Here, we investigated metabolic consequences of diets enriched in primary bile acids with or without addition of lard or palm oil, and studied gut microbiota structure and functions in mice. Results In combination with bile acids, dietary lard fed to male C57BL/6N mice for a period of 8 weeks enhanced fat mass accumulation in colonized, but not in germ-free mice when compared to palm oil. This was associated with impaired glucose tolerance, lower fasting insulin levels, lower counts of enteroendocrine cells, fatty liver, and elevated amounts of hepatic triglycerides, cholesteryl esters, and monounsaturated fatty acids. Lard- and bile acid-fed mice were characterized by shifts in dominant gut bacterial communities, including decreased relative abundances of Lachnospiraceae and increased occurrence of Desulfovibrionaceae and the species Clostridium lactatifermentans and Flintibacter butyricus. Metatranscriptomic analysis revealed shifts in microbial functions, including lipid and amino acid metabolism. Conclusions Caution is required when interpreting data from diet-induced obesity models due to varying effects of dietary fat source. Detrimental metabolic consequences of a diet enriched with lard and primary bile acids were dependent on microbial colonization of the host and were linked to hepatic lipid rearrangements and to alterations of dominant bacterial communities in the cecum. Electronic supplementary material The online version of this article (10.1186/s40168-018-0510-8) contains supplementary material, which is available to authorized users.

Published
2018

13. Modulation of the microbiota by oral antibiotics treats immunoglobulin A nephropathy in humanized mice

Author

Jonathan M. Chemouny, Erwan Boedec, Karine Le Roux, Gabriella Lauriero, Céline Monot, Marion Leclerc, Julie Bex-Coudrat, Laureline Berthelot, Loreto Gesualdo, Patricia Lepage, Maxime Bredel, Patrick J. Gleeson, Sanae Ben Mkaddem, François Vrtovsnik, Aurélie Sannier, Renato C. Monteiro, Eric Daugas, Lilia Abbad, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), UMR 1599, Centre National de la Recherche Scientifique (CNRS), Service de Néphrologie [Bichat - Claude Bernard], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), CeRTA, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), LABEX Inflamex [ANR-11-IDEX-000502], Agence Nationale pour la Recherche Jeune Chercheur TRAIN, Departement hospitalo-universitaire FIRE projet Emergence et Association pour l'Information et la Recherche sur les maladies Renales Genetiques-FranceFrench National Research Agency (ANR), HUPNVS of Assistance Publique Hopitaux de Paris, Equipe Fondation pour la Recherche Medicale, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Immunoglobulin A, Male, medicine.drug_class, Gut-associated lymphoid tissue, Antibiotics, 030232 urology & nephrology, gut microbiome, Administration, Oral, 030204 cardiovascular system & hematology, Gut flora, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Immunoglobulin G, antibiotics, 03 medical and health sciences, Mice, 0302 clinical medicine, medicine, GALT, Animals, ComputingMilieux_MISCELLANEOUS, Transplantation, Proteinuria, biology, business.industry, Glomerulonephritis, Glomerulonephritis, IGA, IgA nephropathy, medicine.disease, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Anti-Bacterial Agents, Gastrointestinal Microbiome, Disease Models, Animal, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Nephrology, Humanized mouse, Immunology, biology.protein, Female, medicine.symptom, business, IgA
Abstract

Background Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgA is mainly produced by the gut-associated lymphoid tissue (GALT). Both experimental and clinical data suggest a role of the gut microbiota in this disease. We aimed to determine if an intervention targeting the gut microbiota could impact the development of disease in a humanized mouse model of IgAN, the α1KI-CD89Tg mice. Methods Four- and 12-week old mice were divided into two groups to receive either antibiotics or vehicle control. Faecal bacterial load and proteinuria were quantified both at the beginning and at the end of the experiment, when blood, kidneys and intestinal tissue were collected. Serum mouse immunoglobulin G (mIgG) and human immunoglobulin A1 (hIgA1)-containing complexes were quantified. Renal and intestinal tissue were analysed by optical microscopy after haematoxylin and eosin colouration and immunohistochemistry with anti-hIgA and anti-mouse CD11b antibodies. Results Antibiotic treatment efficiently depleted the faecal microbiota, impaired GALT architecture and impacted mouse IgA production. However, while hIgA1 and mIgG serum levels were unchanged, the antibiotic treatment markedly prevented hIgA1 mesangial deposition, glomerular inflammation and the development of proteinuria. This was associated with a significant decrease in circulating hIgA1–mIgG complexes. Notably, final faecal bacterial load strongly correlated with critical clinical and pathophysiological features of IgAN such as proteinuria and hIgA1–mIgG complexes. In addition, treatment with broad-spectrum antibiotics reverted established disease. Conclusions These data support an essential role of the gut microbiota in the generation of mucosa-derived nephrotoxic IgA1 and in IgAN development, opening new avenues for therapeutic approaches in this disease.

Published
2018

14. Enterocolitis due to immune checkpoint inhibitors: a systematic review

Author

Patricia Lepage, Clélia Coutzac, David Faleck, Franck Carbonnel, Lysiane Marthey, Michael Collins, Nathalie Chaput, Emilie Soularue, Jean-Frederic Colombel, Caroline Robert, Department of Gastroenterology, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Faculté de Médecine, Université de Ngozi, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris Saclay (COmUE), Icahn School of Medicine at Mount Sinai, Partenaires INRAE, Centre National de la Recherche Scientifique (CNRS), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Pharmacie, Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), AbbVie, Takeda, and Janssen

Subjects
0301 basic medicine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], chemical and pharmacologic phenomena, Gut flora, Inflammatory bowel disease, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Agents, Immunological, Risk Factors, medicine, Cytotoxic T cell, Humans, Adverse effect, Enterocolitis, biology, business.industry, Gastroenterology, Cancer, Endoscopy, Immunotherapy, Cell Cycle Checkpoints, biology.organism_classification, medicine.disease, 3. Good health, Blockade, Gastrointestinal Microbiome, 030104 developmental biology, 030220 oncology & carcinogenesis, Immunology, medicine.symptom, business
Abstract

International audience; Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed death-1 (PD-1)/ ligand are increasingly used to treat several types of cancer. These drugs enhance antitumour T-cell activity and therefore induce immunerelated adverse effects (irAE), of which gastrointestinal (GI) irAE are among the most frequent and severe. This systematic literature review summarises the clinical manifestations, management and pathophysiology of GI irAE due to immune checkpoint inhibitors. GI irAE induced by anti-CTLA-4 are frequent, potentially severe and resemble IBD, whereas those induced by PD-1 blockade seem to be less frequent and clinically more diverse. Baseline symbiotic gut microbiota is associated with an enhanced antitumour response to immune checkpoint inhibitors and an increased susceptibility to developing enterocolitis, in patients treated with anti-CTLA-4. These findings open new perspectives for possible manipulation of the gut microbiota in order to better identify responders to immune checkpoint inhibitors and to increase their efficacy and safety.

Published
2018

15. TREM-1 Inhibition Restores Impaired Autophagy Activity and Reduces Colitis in Mice

Author

Silvia D'Alessio, Hélène Busby-Venner, Julie Hablot, Laurent Peyrin-Biroulet, David Moulin, Céline Monot, Silvio Danese, Franck Hansmannel, Tunay Kökten, Benjamin Garnier, Jean-Yves Jouzeau, Sébastien Gibot, Ndeye-Coumba Ndiaye, Sylviane Muller, Patricia Lepage, Jean-Louis Guéant, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Faculté de Médecine [Nancy], Université de Lorraine (UL), Service de Réanimation Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Humanitas Clinical and Research Institute, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Département d’Anatomie et Cytologie Pathologiques [CHRU Nancy], Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), Service d'Hépato-gastro-entérologie [CHRU Nancy], Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), and MOULIN, David

Subjects
0301 basic medicine, DNA, Bacterial, Male, autophagy, TREM-1, Atg1, ATG5, 03 medical and health sciences, Feces, Mice, inflammatory bowel disease, Medicine, Animals, Colitis, Animal models of IBD, endoscopy, ATG16L1, innovative therapy, Mice, Knockout, business.industry, Autophagy, Dextran Sulfate, Gastroenterology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, General Medicine, dysbiosis, Autophagy-related protein 13, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Triggering Receptor Expressed on Myeloid Cells-1, 3. Good health, Gastrointestinal Microbiome, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, inflammation, peptide-based therapy, Cancer research, Unfolded protein response, Unfolded Protein Response, LR12 peptide, endoplasmic reticulum stress, business, Peptides, Dysbiosis
Abstract

International audience; Background and Aims: Triggering receptor expressed on myeloid cells-1 [TREM-1] is known to amplify inflammation in several diseases. Autophagy and endoplasmic reticulum [ER] stress, which activate the unfolded protein response [UPR], are closely linked and defects in these pathways contribute to the pathogenesis of inflammatory bowel disease [IBD]. Both autophagy and UPR are deeply involved in host-microbiota interactions for the clearance of intracellular pathogens, thus contributing to dysbiosis. We investigated whether inhibition of TREM-1 would prevent aberrant inflammation by modulating autophagy and ER stress and preventing dysbiosis.Methods: An experimental mouse model of colitis was established by dextran sulphate sodium treatment. TREM-1 was inhibited, either pharmacologically by LR12 peptide or genetically with Trem-1 knock-out [KO] mice. Colon tissues and faecal pellets of control and colitic mice were used. Levels of macroautophagy, chaperone-mediated autophagy [CMA], and UPR proteins were evaluated by western blotting. The composition of the intestinal microbiota was assessed by MiSeq sequencing in both LR12-treated and KO animals.Results: We confirmed that inhibition of TREM-1 attenuates the severity of colitis clinically, endoscopically and histologically. We observed an increase in macroautophagy [ATG1/ULK-1, ATG13, ATG5, ATG16L1, and MAP1LC3-I/II] and in CMA [HSPA8 and HSP90AA1], whereas there was a decrease in the UPR [PERK, IRE-1α, and ATF-6α] protein expression levels in TREM-1 inhibited colitic mice. TREM-1 inhibition prevented dysbiosis.Conclusions: TREM-1 may represent a novel drug target for the treatment of IBD, by modulating autophagy activity and ER stress.

Published
2018

16. Baseline gut microbiota in metastatic melanoma patients treated with ipilimumab: Relation with clinical response and colitis

Author

Christine Mateus, Franck Carbonnel, V. Asvatourian, Clélia Coutzac, Nathalie Chaput, Emilie Soularue, Patricia Lepage, Emilie Lanoy, C. Robert, Institut Gustave Roussy (IGR), Département d'hématologie [Gustave Roussy], MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Equipe Mobile d’Accompagnement et de Soins Palliatifs (EMASP), Gustave Roussy Cancer Campus, Fondation Gustave Roussy, Direction Generale de l'Offre de Soins (DGOS) [GOLD TRANSLA 12-174], Institut National du Cancer (INCa) [2012-1-RT-14-IGR-01], SIRIC SOCRATE [INCa DGOS INSERM 6043], MMO program [ANR-10IBHU-0001], and European Society Medical Oncology. CHE.

Subjects
Oncology, medicine.medical_specialty, biology, Metastatic melanoma, business.industry, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Ipilimumab, Hematology, Gut flora, biology.organism_classification, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, Colitis, business, ComputingMilieux_MISCELLANEOUS, medicine.drug
Abstract

International audience

Published
2017

17. Microbiota Is Involved in Post-resection Adaptation in Humans with Short Bowel Syndrome

Author

Isabelle Pingenot, Véronique Robert, Muriel Thomas, Francisca Joly, Camille Mayeur, Patricia Lepage, André Bado, Laura Gillard, Johanne Le Beyec, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Service de Gastroentérologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Recherche Agronomique (INRA), Biocodex through Societe Nationale Francaise de Gastro-enterologie, French Ministry of Education and Research, Service de Biochimie Endocrinienne et Oncologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Thomas, Muriel, Joly, Francisca, HAL UPMC, Gestionnaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Hôpital Beaujon, Service de Biochimie Endocrinienne et Oncologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)

Subjects
0301 basic medicine, Physiology, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Glucagon-like peptide, Encephalopathy, microbiome, Microbiology, entero-endocrine hormones, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Lactobacillus, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], resection, dysbiosis, lactate, short chain fatty acids, Feces, Original Research, biology, Clostridium leptum, biology.organism_classification, Short bowel syndrome, medicine.disease, Small intestine, 030104 developmental biology, medicine.anatomical_structure, 030211 gastroenterology & hepatology, Anaerobic exercise, Dysbiosis
Abstract

International audience; Short bowel syndrome (SBS) is characterized by severe intestinal malabsorption following restrictive surgery. The objective of this study was to determine the functional contribution of SBS-microbiota after resection. It is well-known that SBS-microbiota displayed specific features with a prevalence of Lactobacillus, a low amount of some anaerobic microbes (Clostridium leptum) and an accumulation of fecal lactate in some patients. Patients with jejuno-colonic anastomosis were stratified according to the presence of lactate in their feces and, we observe that the lactate-producing bacteria were predominant in the sub-group of patients accumulating fecal lactate. One case of D-encephalopathy crisis occurred when the D-lactate isoform accumulated in the feces and plasma bicarbonate levels decreased. The fecal sample at the time of the encephalopathy was transferred to germ free rats (SBS-H rats). The SBS-H microbiota conserved some characteristics of the SBS donnor, predominated by lactate-producing bacteria (mainly Lactobacillus), a low level of lactate-consuming bacteria and undetectable C. leptum. However, lactate did not accumulate in feces of recipient rats and the D-encephalopathy was not reproduced in SBS-H rats. This suggests that the intact small bowel of the recipient rats protected them from lactate accumulation and that D-lactate encephalopathy can occur only in the absence of small intestine. After fecal transfer, we also show that gnotobiotic rats exhibited high levels of circulating GLP-1 and ghrelin, two hormones that are known to be induced in SBS patients. Therefore, the microbiota of SBS is a reservoir of biological signals involved in post-resection adaptation.

Published
2017

18. Effects of enteral polymeric diet on gut microbiota in children with Crohn's disease

Author

Patricia Lepage, Chloé Guinet-Charpentier, Alain Morali, Laurent Peyrin-Biroulet, Mathias Chamaillard, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Disease, macromolecular substances, Gut flora, Enteral administration, Inflammatory bowel disease, digestive system, 03 medical and health sciences, 0302 clinical medicine, weight reduction diet, medicine, maladie inflammatoire, Crohn's disease, 030109 nutrition & dietetics, biology, business.industry, Gastrointestinal Microbiome, régime alimentaire thérapeutique, Gastroenterology, technology, industry, and agriculture, maladie de crohn, crohn disease, pédiatrie, biology.organism_classification, medicine.disease, digestive system diseases, 3. Good health, inflammatory disease, stomatognathic diseases, Parenteral nutrition, Immunology, 030211 gastroenterology & hepatology, business, Cohort study
Abstract

We read with great interest the article by Wu et al 1 showing that the impact of diet on the composition of the gut microbiota was milder than its impact on metabolites produced by the gut microbiota, in healthy humans. Enteral nutrition is an effective treatment to manage active Crohn's disease (CD) in children.2 CD is known to be associated with gut microbial dysbiosis that is characterised by decreased diversity and imbalances in the intestinal microbiome. Recent evidence indicates that exclusive enteral nutrition (EEN) may affect gut microbiota in children with CD,3 but it remains elusive whether the aforementioned changes may occur independently of disease flares. We thus studied the impact of either EEN with Modulen (EXCL-MOD) or partial enteral nutrition (PEN) with Modulen (MOD) IBD on the bacterial composition of the gut microbiota from children with CD during either remission or active phase. In this single-centre, prospective, observational cohort study, 34 children followed at Nancy University Children Hospital …

Published
2017

19. Colon Immune-Related Adverse Events: Anti-CTLA-4 and Anti-PD-1 Blockade Induce Distinct Immunopathological Entities

Author

Emilie Soularue, Melinda Charrier, Antoine Racine, Christine Mateus, Clélia Coutzac, Lydie Cassard, Nyam Kamsu-Kom, Karim Fizazi, Patricia Lepage, Nathalie Chaput, L. Boselli, Charlotte Mussini, Michael Collins, Yohann Loriot, Caroline Robert, Jean-Yves Scoazec, Julien Adam, Franck Carbonnel, Vincent Ribrag, David Planchard, Institut Gustave Roussy (IGR), Department of Gastroenterology, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Faculté de médecine, Université Paris-Sud - Paris 11 (UP11), Service de dermatologie, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Univ Paris Sud, Fac Med, F-94276 Le Kremlin Bicetre, France, Partenaires INRAE, Dept Canc Med, Gustave Roussy Canc Campus, F-94805 Villejuif, France, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Gustave Roussy Cancer Campus, Fondation Gustave Roussy, Institut national de la sante et de la recherche medicale [INSERM], Direction Generale de l'Offre de Soins [GOLD TRANSLA 12-174], Institut National du Cancer [GOLD 2012-062, Canceropole: 2012-1-RT-14-IGR-01], SIRIC SOCRATE [INCa DGOS INSERM 6043], MMO programme [ANR-10IBHU-0001], and Fondation pour la Recherche Medicale [FRM]

Subjects
Adult, CD4-Positive T-Lymphocytes, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Colon, colitis, Biopsy, T cell, [SDV]Life Sciences [q-bio], Programmed Cell Death 1 Receptor, chemical and pharmacologic phenomena, CD8-Positive T-Lymphocytes, Anti-CTLA-4, Inflammatory bowel disease, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Humans, CTLA-4 Antigen, Intestinal Mucosa, Colitis, Aged, Aged, 80 and over, Lamina propria, business.industry, Gastroenterology, hemic and immune systems, General Medicine, Middle Aged, immune checkpoint blockade, Flow Cytometry, medicine.disease, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, Intraepithelial lymphocyte, anti-PD-1, immune-related adverse events, Tumor necrosis factor alpha, business, CD8
Abstract

International audience; Background and Aim: Immune checkpoint inhibitors targeting CTLA-4 and PD-1 improve survival in cancer patients but may induce immune-related adverse events, including colitis. The immunological characteristics of anti-CTLA-4 [alpha CTLA-4]- and anti-PD-1 [alpha PD-1]-related colitis have been poorly described. The aim of the present study was to compare the immunological and histological characteristics of alpha CTLA-4-induced colitis and alpha PD-1-induced colitis. Methods: Colonic biopsies from patients with alpha CTLA-4-induced colitis, alpha PD-1-induced colitis, and inflammatory bowel disease [IBD] were analysed by immunohistochemistry and flow cytometry. Tumour necrosis factor alpha [TNF alpha] concentration was assessed in biopsy supernatants. Results: CD8(+) T cells were found in the lamina propria and epithelium in alpha PD-1-induced colitis, whereas CD4(+) T cells were found in the lamina propria in alpha CTLA-4-induced colitis. No or low intraepithelial lymphocytes were observed in alpha CTLA-4-induced colitis. No difference in numbers of mucosal regulatory T cells was observed between alpha CTLA-4- or alpha PD-1-induced colitis and IBD patients. Higher numbers of activated ICOS+ conventional CD4(+) T cells were observed in alpha CTLA-4- induced colitis compared with patients with IBD. Among ICOS+ CD4(+) T cells, conventional CD4(+) T cells were the main T cell population in patents with alpha CTLA-4-induced colitis, whereas Treg cells were predominant in IBD or alpha PD-1-induced colitis. High mucosal TNF alpha concentrations were observed in alpha CTLA-4-induced colitis. Low mucosal TNF alpha concentrations were associated with steroid sensitivity. Conclusions: These observations show that alpha CTLA-4- and alpha PD-1-induced colitis have distinct immunological characteristics. Mucosal TNF alpha concentration might detect patients at risk of developing corticosteroid resistance after CTLA-4 blockade.

Published
2017

20. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab

Author

K. Le Roux, L. Marthey, Franck Carbonnel, Emilie Lanoy, Michael Collins, Emilie Routier, Lydie Cassard, Christine Mateus, T. Vaysse, Patricia Lepage, C. Monot, Nathalie Chaput, Caroline Robert, V. Asvatourian, Alexander M.M. Eggermont, L. Boselli, Emilie Soularue, Clélia Coutzac, Laboratoire d’Immunomonitoring en Oncologie (LIO), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Pharmacie [Châtenay-Malabry], Université Paris-Sud 11 - Faculté de médecine (UP11 UFR Médecine)-Université Paris-Saclay, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris-Saclay, Faculté de Médecine, Université de Ngozi, Faculté de Pharmacie, Université Paris-Sud - Paris 11 (UP11)-Université Paris-Saclay, Département de Gastroentérologie, Hôpital Européen [Fondation Ambroise Paré - Marseille], Service de dermatologie, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôpital Bicêtre, Assistance Publique - Hôpitaux de Paris (AP-HP), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre de recherche en épidémiologie et santé des populations (CESP), Hôpital Paul Brousse-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Paris-Sud - Paris 11 (UP11), Université Paris-Saclay-Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11)-Université Paris-Sud - Paris 11 (UP11), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11)-Université Paris-Sud - Paris 11 (UP11)-Université Paris-Saclay, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11)

Subjects
0301 basic medicine, Male, colitis, [SDV]Life Sciences [q-bio], Faecalibacterium prausnitzii, Ipilimumab, Gut flora, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Agents, Immunological, RNA, Ribosomal, 16S, medicine, microbiota, melanoma, Humans, IL-2 receptor, Microbiome, Prospective Studies, Colitis, Neoplasm Metastasis, ipilimumab, 030304 developmental biology, Aged, Enterocolitis, 0303 health sciences, biology, business.industry, Melanoma, Hematology, biology.organism_classification, medicine.disease, 3. Good health, Intestines, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Immunology, Female, medicine.symptom, business, medicine.drug
Abstract

Background Ipilimumab, an immune checkpoint inhibitor targeting CTLA-4, prolongs survival in a subset of patients with metastatic melanoma (MM) but can induce immune-related adverse events, including enterocolitis. We hypothesized that baseline gut microbiota could predict ipilimumab anti-tumor response and/or intestinal toxicity. Patients and methods Twenty-six patients with MM treated with ipilimumab were prospectively enrolled. Fecal microbiota composition was assessed using 16S rRNA gene sequencing at baseline and before each ipilimumab infusion. Patients were further clustered based on microbiota patterns. Peripheral blood lymphocytes immunophenotypes were studied in parallel. Results A distinct baseline gut microbiota composition was associated with both clinical response and colitis. Compared with patients whose baseline microbiota was driven by Bacteroides (cluster B,n = 10), patients whose baseline microbiota was enriched with Faecalibacterium genus and other Firmicutes (cluster A,n = 12) had longer progression-free survival (P = 0.0039) and overall survival (P = 0.051). Most of the baseline colitis-associated phylotypes were related to Firmicutes (e.g. relatives of Faecalibacterium prausnitzii and Gemmiger formicilis), whereas no colitis-related phylotypes were assigned to Bacteroidetes. A low proportion of peripheral blood regulatory T cells was associated with cluster A, long-term clinical benefit and colitis. Ipilimumab led to a higher inducible T-cell COStimulator induction on CD4+ T cells and to a higher increase in serum CD25 in patients who belonged to Faecalibacterium-driven cluster A. Conclusion Baseline gut microbiota enriched with Faecalibacterium and other Firmicutes is associated with beneficial clinical response to ipilimumab and more frequent occurrence of ipilimumab-induced colitis.

Published
2017

21. Statement of Retraction. Replication of Obesity and Associated Signaling Pathways Through Transfer of Microbiota From Obese-Prone Rats. Diabetes 2014;63:1624-1636. DOI: 10.2337/db13-1526

Author

Yassine Sakar, Fabienne Devime, Mihai Covasa, Frank A. Duca, Patricia Lepage, Bénédicte Langelier, and Joël Doré

Subjects
0301 basic medicine, medicine.medical_specialty, business.industry, Endocrinology, Diabetes and Metabolism, 030106 microbiology, medicine.disease, Obesity, 03 medical and health sciences, Endocrinology, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Signal transduction, business
Published
2016

22. Respective roles of hematopoietic and nonhematopoietic nod2 on the gut microbiota and mucosal homeostasis

Author

Ziad Alnabhani, Nicolas Montcuquet, Marion Leclerc, Frédérick Barreau, Maryline Roy, Monique Dussaillant, Nadine Cerf-Bensussan, Patricia Lepage, Jean-Pierre Hugot, Karine Le Roux, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Coordination des Cellules et Morphogenèse / Heart Morphogenesis (Imagine - Institut Pasteur U1163), Institut Pasteur [Paris]-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR, Investissements d'Avenir programme [ANR-11-IDEX-0005 to 02], Sorbonne-Paris-Cite Laboratoire d'excellence INFLAMEX, CNRS, INSERM, Universite Paris Diderot-Sorbonne Paris-Cite, ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), Institut Pasteur [Paris] (IP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Antimicrobial peptides, Nod2 Signaling Adaptor Protein, Peyer's patches, Biology, Gut flora, Nod2, 03 medical and health sciences, Mice, antimicrobial peptides, Immune system, NOD2, medicine, microbiota, Immunology and Allergy, Animals, Homeostasis, Intestinal Mucosa, Mice, Knockout, Intestinal permeability, Mucin, Gastroenterology, Peptide secretion, medicine.disease, biology.organism_classification, Hematopoietic Stem Cells, digestive system diseases, Gastrointestinal Microbiome, Crohn's disease, 030104 developmental biology, medicine.anatomical_structure, Immunology, Dysbiosis, gut permeability, Bone marrow
Abstract

International audience; Background: NOD2 mutations are associated with Crohn's disease (CD). Both CD (in human) and Nod2 deficiency (in mice) are characterized by increased mucosal CD4(+) T-cells, an altered permeability and a microbial dysbiosis. However, the respective roles of the gut epithelial and immune compartments on the phenotype are not known. Methods: Microbial composition, epithelial peptide secretion, intestinal permeability, and immune cell composition of Peyer patches were studied in Nod2 knock-out mice transplanted with wild-type bone marrow cells and vice versa. Results: The nonhematopoietic cells control the microbiota composition and epithelial secretion of mucins and antimicrobial peptides. These parameters are correlated with recurrent associations between bacterial species and luminal products. In contrast, Nod2 in the hematopoietic compartment regulates the epithelial permeability and the gut-associated lymphoid tissue independently of the bacterial composition. Conclusions: The immune system and the gut permeability in one hand and the microbial and epithelial peptide compositions in the other hand are separate couples of interdependent parameters, both controlled by Nod2 in either the hematopoietic or nonhematopoietic lineages.

Published
2016

23. Structural robustness of the gut mucosal microbiota is associated with Crohn's disease remission after surgery

Author

Marion Leclerc, Yoram Bouhnik, Joël Doré, Matthieu Allez, P Pochart, Philippe Marteau, J-F Colombel, P. Seksik, Patricia Lepage, Stanislas Mondot, Xavier Treton, MICrobiologie de l'ALImentation au Service de la Santé humaine ( MICALIS ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Institut Curie, Université Pierre et Marie Curie - Paris 6 ( UPMC ), Alloimmunité-Autoimmunité-Transplantation ( A2T ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Gastroentérologie [Hôpital Beaujon], Hôpital Beaujon, Icahn School of Medicine at Mount Sinai [New York], Laboratoire de Biologie, Conservatoire National des Arts et Métiers [CNAM] ( CNAM ), Université Paris Descartes - Paris 5 ( UPD5 ), Service de Gastroentérologie [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Pierre et Marie Curie - Paris 6 (UPMC), Alloimmunité-Autoimmunité-Transplantation (A2T), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Université Paris Descartes - Paris 5 (UPD5), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière, Institut Curie [Paris], Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), and HAL-UPMC, Gestionnaire

Subjects
0301 basic medicine, medicine.medical_specialty, Colon, Biopsy, IBD, Faecalibacterium prausnitzii, Biology, Inflammatory bowel disease, 03 medical and health sciences, Intestinal mucosa, Crohn Disease, Double-Blind Method, Ruminococcus gnavus, INFLAMMATORY BOWEL DISEASES, Ileum, Recurrence, medicine, Humans, COHORT, Intestinal Mucosa, Lactobacillus johnsonii, Crohn's disease, Lachnospiraceae, Remission Induction, Gastroenterology, RIBOSOMAL-RNA, COLITIS, RECURRENCE, BACTERIA, PATHWAYS, HEALTH, TRACT, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, biology.organism_classification, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Surgery, Gastrointestinal Microbiome, 030104 developmental biology, Immunology, Dysbiosis, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Follow-Up Studies
Abstract

the GETAID : Groupe d'Etude des Traitements des Affections Inflammatoires Digestives, Paris, France; International audience; Objectives: Preventing postoperative recurrence after ileocolonic resection (ICR) for Crohn's disease (CD) is challenging. Defining the disturbances of the microbial composition and community structure after ICR and their link with early disease recurrence is crucial.Design: Microbiota composition (fingerprinting and 16S rDNA sequencing) and community structure (correlation networks of bacterial species) were assessed from ileal mucosa sampled in 20 patients undergoing ICR and 6 months later during endoscopy from above (neoterminal ileum) and below (subanastomotic colon) the surgical anastomosis.Results: ICR had a dramatic effect on gut microbial ecosystem. At surgery, CD mucosa harboured a dysbiotic microbiota with high proportions of α/β Proteobacteria and Bacilli. Six months later, half of the patients had recurrent lesions at ileocolonoscopy and presented higher numbers of Lachnospiraceae. Recurrence of endoscopic lesions was associated with enrichment in Enterococcus durans while patients in remission had increased proportions of Dorea longicatena and Bacteroides plebeius. Structural differences were striking between recurrence and remission microbiota; while the microbiota of patients with CD recurrence exhibited a loose community structure, the microbiota of patients in remission displayed communities that were robustly correlated to each other. Microbiota colonising the neoterminal ileum and subanastomotic colon 6 months after ICR only differed in patients with recurrence.Conclusions: ICR modifies the gut microbiome. Remission after 6 months was associated with homogenous bacterial distribution around the anastomosis. Community structure and bacterial networks highlight target species, including Faecalibacterium prausnitzii and Ruminococcus gnavus, which may allow precise modulations of the overall microbial ecosystem towards remission pattern.

Published
2016

24. Does Our Food (Environment) Change Our Gut Microbiome (‘In-Vironment’): A Potential Role for Inflammatory Bowel Disease?

Author

Tomas de Wouters, Patricia Lepage, Joël Doré, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), and Institut National de la Recherche Agronomique (INRA)-AgroParisTech

Subjects
[SDV.SA]Life Sciences [q-bio]/Agricultural sciences, HOST, DIETARY FIBER, Population, Environment, Biology, Gut flora, BIFIDOBACTERIA, Microbiology, 03 medical and health sciences, 0302 clinical medicine, COLON, medicine, Animals, Humans, Genetic Predisposition to Disease, education, Irritable bowel syndrome, Nutrition, 030304 developmental biology, INDIGENOUS GASTROINTESTINAL MICROFLORA, 2. Zero hunger, Genetics, 0303 health sciences, Crohn's disease, education.field_of_study, Microbiota, Ruminococcus, Human gastrointestinal tract, Gastroenterology, General Medicine, HUMAN INTESTINAL MICROBIOTA, Inflammatory Bowel Diseases, medicine.disease, biology.organism_classification, CROHNS-DISEASE, Gastrointestinal Tract, medicine.anatomical_structure, Ulcerative colitis, ULCERATIVE-COLITIS, Enterotypes, Food, Metagenomics, BACTERIA, Metagenome, 030211 gastroenterology & hepatology, Enterotype, HEALTH
Abstract

Human biology can only be fully assessed by combining an analysis of both the host and its surrounding environment. As a part of the environment, the human gastrointestinal tract hosts more than 100 trillion bacteria making up the gut microbiota. The human host provides a nutrient-rich environment while the microbiota provides indispensable functions that humans cannot exert themselves. Shifts in the bacterial makeup of the human gut microbiota have been associated with disorders such as inflammatory bowel disease (IBD), irritable bowel syndrome and obesity. However, since most bacteria inhabiting our gut are not cultivable to date, until recently little was known about their individual functions. Metagenomics, i.e. the analysis of the collective genomes present in a defined ecosystem, gives insight into these specific functions. The first extensive catalogue of the intestinal metagenome outnumbers the size of the human genome by a factor of 150. Recently, 3 distinct ‘types’ of gut composition within the human population have been highlighted. These so-called ‘enterotypes’ are characterized by the dominant genera (Bacteroides, Prevotella and Ruminococcus) and their co-occurring phylogenetic groups. In accordance with the previously described impact of nutritional behavior (diet, probiotics and prebiotics) on specific bacterial populations, an association has been observed between long-term dietary habits and enterotypes. This recent discovery, i.e. that belonging to one or the other enterotype might be modulated by the diet opens up new perspectives in the fields of IBD, nutrition and therapeutic strategies.

Published
2012

25. Hemidesmosome integrity protects the colon against colitis and colorectal cancer

Author

Adèle De Arcangelis, Michel Labouesse, Sylvain Normand, Patricia Simon-Assmann, Fabien Alpy, Doulaye Dembélé, Emilie Bruyère, Elisabeth Georges-Labouesse, Stéphanie Siebert, Sophie Rodius, Patrice Laquerriere, Agnès Méchine-Neuville, Patricia Lepage, Mathias Chamaillard, Sylvie Robine, Isabelle Van Seuningen, Véronique Pfister, Hussein Hamade, Michèle Kedinger, Olivier Lefebvre, Anne Delanoye-Crespin, Forces mécaniques et morphogénèse des tissus = Mechanical forces behind tissue morphogenesis (LBD-E08), Laboratoire de Biologie du Développement (LBD), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), CNRS, Inserm, Universite de Strasbourg, Association pour la Recherche sur le Cancer and Ligue Regionale contre le Cancer (EG-L), Fondation pour la Recherche Medicale ('Equipe FRM'), Institut National du Cancer (Appel a projets 'Formes precoces du cancer colorectal'), Agence Nationale pour la Recherche, LabEx INRT (IGBMC, UdS), Ligue contre le Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), De Arcangelis, Adèle, and Labouesse, Michel

Subjects
0301 basic medicine, Basement Membrane/physiopathology, Integrins, Pathology, INTESTINAL BARRIER FUNCTION, T-Lymphocytes, Aucun, Intestinal Mucosa/*metabolism/pathology/physiopathology, Mucus/metabolism, Adaptive Immunity, Integrin alpha6, Intestinal barrier function, Lymphocyte Activation, Severity of Illness Index, Basement Membrane, Caspase 1/metabolism, Mice, Intestinal mucosa, Colorectal Neoplasms/genetics/metabolism/*physiopathology, intestinal inflammation, Homeostasis, genetics, physiology, Myeloid Differentiation Factor 88/genetics, Intestinal Mucosa, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS, COLORECTAL CANCER, B-Lymphocytes, Hemidesmosome, Caspase 1, alpha-6-beta-4 integrin, CELL MATRIX INTERACTION, Gastroenterology, tumor-growth, Hyperplasia, Colitis, Epithelial Cells/metabolism, Cell matrix interaction, 3. Good health, barrier, Adenocarcinoma, Cytokines, medicine.symptom, Colorectal Neoplasms, Signal Transduction, Integrin alpha6/*genetics, medicine.medical_specialty, Ibd, IBD, metabolism, physiopathology, Inflammation, inflammatory-bowel-disease, epidermolysis-bullosa, mice, cells, expression, absence, Biology, Physique [physics]/Physique [physics], digestive system, pathology, Permeability, 03 medical and health sciences, Hemidesmosomes/genetics/*physiology, medicine, Animals, Neoplastic transformation, Adenocarcinoma/genetics/metabolism/*physiopathology, Integrin alpha6beta4, Keratin-18, Keratin-8, Inflammatory Bowel Disease, Epithelial Cells, Hemidesmosomes, Homeostasis/genetics, Keratin-18/metabolism, Keratin-8/metabolism, medicine.disease, Colorectal cancer, INTEGRINS, Mucus, 030104 developmental biology, Colitis/genetics/metabolism/pathology/*physiopathology, Dysplasia, Myeloid Differentiation Factor 88, Integrin alpha6beta4/*metabolism, Cytokines/genetics/*metabolism
Abstract

Objective Epidemiological and clinical data indicate that patients suffering from IBD with long-standing colitis display a higher risk to develop colorectal high-grade dysplasia. Whereas carcinoma invasion and metastasis rely on basement membrane (BM) disruption, experimental evidence is lacking regarding the potential contribution of epithelial cell/BM anchorage on inflammation onset and subsequent neoplastic transformation of inflammatory lesions. Herein, we analyse the role of the alpha 6 beta 4 integrin receptor found in hemidesmosomes that attach intestinal epithelial cells (IECs) to the laminin-containing BM. Design We developed new mouse models inducing IEC-specific ablation of alpha 6 integrin either during development (alpha 6(Delta IEC)) or in adults (alpha 6(Delta IEC-TAM)). Results Strikingly, all alpha 6(Delta IEC) mutant mice spontaneously developed long-standing colitis, which degenerated overtime into infiltrating adenocarcinoma. The sequence of events leading to disease onset entails hemidesmosome disruption, BM detachment, IL-18 overproduction by IECs, hyperplasia and enhanced intestinal permeability. Likewise, IEC-specific ablation of alpha 6 integrin induced in adult mice (alpha 6(Delta IEC-TAM)) resulted in fully penetrant colitis and tumour progression. Whereas broad-spectrum antibiotic treatment lowered tissue pathology and IL-1 beta secretion from infiltrating myeloid cells, it failed to reduce Th1 and Th17 response. Interestingly, while the initial intestinal inflammation occurred independently of the adaptive immune system, tumourigenesis required B and T lymphocyte activation. Conclusions We provide for the first time evidence that loss of IECs/BM interactions triggered by hemidesmosome disruption initiates the development of inflammatory lesions that progress into high-grade dysplasia and carcinoma. Colorectal neoplasia in our mouse models resemble that seen in patients with IBD, making them highly attractive for discovering more efficient therapies.

Published
2015

26. Transcriptional activity of the dominant gut mucosal microbiota in chronic inflammatory bowel disease patients

Author

Stefan Schreiber, Andreas Nolte, Stephan Hellmig, Ateequr Rehman, Patricia Lepage, and Stephan J. Ott

Subjects
Adult, Microbiology (medical), Transcription, Genetic, Firmicutes, Microbiology, Inflammatory bowel disease, Pathogenesis, Intestinal mucosa, RNA, Ribosomal, 16S, medicine, Humans, Aged, Gene Library, Crohn's disease, Bacteria, biology, Gene Expression Regulation, Bacterial, General Medicine, Middle Aged, Ribosomal RNA, Inflammatory Bowel Diseases, medicine.disease, biology.organism_classification, Ulcerative colitis, Chronic Disease, Immunology, Dysbiosis
Abstract

Dysbiosis of the gut mucosa-associated microbiota (MAM) plays a pivotal role in the pathogenesis of chronic inflammatory bowel diseases (IBD). To date, dysbiosis only describes the altered composition of the different bacterial populations, but little is known about transcriptional activity, metabolism and the ‘live’ status of the MAM. In this study we investigated the transcriptional activity of the dominant intestinal bacterial populations in patients with IBD. Colonic mucosal biopsies from patients with active Crohn's disease (CD; n=10), active ulcerative colitis (UC; n=10) and healthy individuals (HI; n=10) were compared by 16S rRNA gene and rRNA profiles using clone libraries with more than 1700 sequenced clones. Bacterial richness was significantly lower in clone libraries based on rRNA compared to those based on the rRNA genes in the CD group (3.01 vs 3.91) and the UC group (3.61 vs 4.15), but showed no difference in HI (3.81 vs 3.85). The qualitative composition of rRNA and rRNA gene clone libraries was significantly different, with the phylum Bacteroidetes being the most active (PActinobacteria and Firmicutes were inactive in the CD group, while Escherichia sp. were both abundant and active in the CD and UC groups. Most of the phylotypes showing the highest activity index ratios represented less than 1 % of the microbiota. Our findings indicate that specific bacterial populations are activated in IBD patients, while other groups are in an inactive or ‘dormant’ state. The transcriptional activity points to a more functional role of the intestinal mucosal microbiota and may lead to the identification of therapeutic targets in the active modulation of microbial factors.

Published
2010

27. Intestinal TM7 bacterial phylogenies in active inflammatory bowel disease

Author

Patricia Lepage, Stephan J. Ott, Ateequr Rehman, Stefan Schreiber, Stephan Hellmig, Ulrich R. Fölsch, and Tanja Kuehbacher

Subjects
Adult, Male, Microbiology (medical), Adolescent, Colon, Clone (cell biology), Gram-Positive Bacteria, Microbiology, Inflammatory bowel disease, Pathogenesis, Young Adult, Antibiotic resistance, Crohn Disease, RNA, Ribosomal, 16S, Drug Resistance, Bacterial, medicine, Humans, Intestinal Mucosa, Gene, Phylogeny, Aged, biology, Sequence Analysis, DNA, General Medicine, Middle Aged, Inflammatory Bowel Diseases, medicine.disease, 16S ribosomal RNA, biology.organism_classification, Ulcerative colitis, Immunology, Colitis, Ulcerative, Female, Bacteria
Abstract

TM7 is a recently described subgroup of Gram-positive uncultivable bacteria originally found in natural environmental habitats. An association of the TM7 bacterial division with the inflammatory pathogenesis of periodontitis has been previously shown. This study investigated TM7 phylogenies in patients with inflammatory bowel diseases (IBDs). The mucosal microbiota of patients with active Crohn's disease (CD; n=42) and ulcerative colitis (UC; n=31) was compared with that of controls (n=33). TM7 consortia were examined using molecular techniques based on 16S rRNA genes, including clone libraries, sequencing and in situ hybridization. TM7 molecular signatures could be cloned from mucosal samples of both IBD patients and controls, but the composition of the clone libraries differed significantly. Taxonomic analysis of the sequences revealed a higher diversity of TM7 phylotypes in CD (23 different phylotypes) than in UC (10) and non-IBD controls (12). All clone libraries showed a high number of novel sequences (21 for controls, 34 for CD and 29 for UC). A highly atypical base substitution for bacterial 16S rRNA genes associated with antibiotic resistance was detected in almost all sequences from CD (97.3 %) and UC (100 %) patients compared to only 65.1 % in the controls. TM7 bacteria might play an important role in IBD similar to that previously described in oral inflammation. The alterations of TM7 bacteria and the genetically determined antibiotic resistance of TM7 species in IBD could be a relevant part of a more general alteration of bacterial microbiota in IBD as recently found, e.g. as a promoter of inflammation at early stages of disease.

Published
2008

28. Enterococcus hirae and Barnesiella intestinihominis Facilitate Cyclophosphamide-Induced Therapeutic Immunomodulatory Effects

Author

Vichnou Poirier-Colame, Silvia C. Formenti, Alexander M. M. Eggermont, Christophe Isnard, Elisabeth Chachaty, Didier Raoult, Maria Paula Roberti, Harry Sokol, Patricia Lepage, Encouse B. Golden, David Enot, Ivo G. Boneca, Guido Kroemer, Laurence Zitvogel, Nicolas Jacquelot, Mutsa Tatenda Madondo, Mathias Chamaillard, Jean-Charles Soria, Caroline Flament, Philip Rosenstiel, Marie Vétizou, Takahiro Yamazaki, Romain Daillère, Antoine Roux, Sylvie Rusakiewicz, Sonia Becharef, Vincent Cattoir, Nadine Waldschmitt, Bertrand Routy, Paul Louis Woerther, Magdalena Plebanski, Eric Tartour, Lionel Apetoh, Philippe Langella, Connie P.M. Duong, Ludger Johannes, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche Risques Microbiens (U2RM), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Apoptose, cancer et immunité (U848), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut Gustave Roussy (IGR), Université Paris Descartes - Paris 5 (UPD5), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Microbiologie, Département de biologie et pathologie médicales [Gustave Roussy], Université Paris-Saclay, Department Radiation Oncology (Weill Cornell Medicine), Weill Medical College of Cornell University [New York], Monash University [Clayton], Unabhängiges Landeszentrum für Datenschutz Schleswig-Holstein [Kiel, Germany] (ULD), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, Institut des sciences biologiques (INSB-CNRS)-Institut des sciences biologiques (INSB-CNRS)-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes], Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Institut Pasteur [Paris] (IP), La Ligue contre le cancer, Ligue Nationale contre le Cancer (Equipes labellisees), European Research Council Advanced Investigator Grant, Fondation pour la Recherche Medicale (FRM), Institut National du Cancer (INCa), Fondation de France, LabEx Immuno-Oncology, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), SIRIC, Paris Alliance of Cancer Research Institutes (PACRI), ISREC, Swiss Bridge Foundation, NIH [R01 CA161879], FRM [DEQ20130326475], INCa [Plbio-2012-106], Agence Nationale de la Recherche [ANR- 13-BSV3-0014-01], Association pour la Recherche contre le cancer [PGA120140200851], Ministere de l'enseignement superieur et de la recherche, Institut de veille sanitaire (InVS), Interreg IVA France (Manche) - Angleterre (Risk Manche), Anti-Cancer Fund, Monash PhD Scholarship, NHMRC SRF Award, DFG CE Inflammation at Interfaces, European Union's FP7 [305564, SFB1182 TP C2], Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), INSB-INSB-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie-Université Paris Descartes - Paris 5 (UPD5), Institut Hospitalier Universitaire Méditerranée Infection (IHU AMU), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 ( CIIL ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR142-Université de Lille-Centre National de la Recherche Scientifique ( CNRS ), Unité de Recherche Risques Microbiens ( U2RM ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), MICrobiologie de l'ALImentation au Service de la Santé humaine ( MICALIS ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Apoptose, cancer et immunité ( U848 ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Institut Gustave Roussy ( IGR ), Université Paris Descartes - Paris 5 ( UPD5 ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Chimie biologique des membranes et ciblage thérapeutique ( CBMCT - UMR 3666 / U1143 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Unabhängiges Landeszentrum für Datenschutz Schleswig-Holstein [Kiel, Germany] ( ULD ), Institut Hospitalier Universitaire Méditerranée Infection ( IHU AMU ), Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes ( URMITE ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR48, INSB-INSB-Centre National de la Recherche Scientifique ( CNRS ), and Biologie et Génétique de la Paroi bactérienne

Subjects
0301 basic medicine, Richness, Nod2 Signaling Adaptor Protein, medicine.disease_cause, Mice, 0302 clinical medicine, Enterococcus hirae, NOD2, Neoplasms, Intestine, Small, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Gut Microbiota, Cancer, biology, 3. Good health, Immunosurveillance, Infectious Diseases, 030220 oncology & carcinogenesis, Barnesiella intestinihominis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunotherapy, medicine.symptom, Infection, medicine.drug, Cyclophosphamide, Colon, Immunology, Translocation, Inflammation, 03 medical and health sciences, Interferon-gamma, Immune system, Monitoring, Immunologic, medicine, Animals, Immunologic Factors, Antitumor Immunity, Bacteria, Dendritic Cells, Th1 Cells, medicine.disease, biology.organism_classification, Mice, Inbred C57BL, 030104 developmental biology, Intestinal Microbiota, Ovarian cancer, Immunologic Memory
Abstract

International audience; The efficacy of the anti-cancer immunomodulatory agent cyclophosphamide (CTX) relies on intestinal bacteria. How and which relevant bacterial species are involved in tumor immunosurveillance, and their mechanism of action are unclear. Here, we identified two bacterial species, Enterococcus hirae and Barnesiella intestinihominis that are involved during CTX therapy. Whereas E. hirae translocated from the small intestine to secondary lymphoid organs and increased the intratumoral CD8/ Treg ratio, B. intestinihominis accumulated in the colon and promoted the infiltration of IFN-gamma-producing gamma delta Tau cells in cancer lesions. The immune sensor, NOD2, limited CTX-induced cancer immunosurveillance and the bioactivity of these microbes. Finally, E. hirae and B. intestinihominis specific-memory Th1 cell immune responses selectively predicted longer progression-free survival in advanced lung and ovarian cancer patients treated with chemo-immunotherapy. Altogether, E. hirae and B. intestinihominis represent valuable ''oncomicrobiotics'' ameliorating the efficacy of the most common alkylating immunomodulatory compound.

Published
2015

29. Intestinal inhibition of Atg7 prevents tumour initiation through a microbiome-influenced immune response and suppresses tumour growth

Author

Franck Letourneur, Carmen Marchiol, Florent Dumont, Myriam Delacre, Benoit Terris, Anne-Marie Crain, Alain Schmitt, Medhi Ait Bara, Jean-Pierre Couty, Coralie Trentesaux, Christine Perret, Béatrice Romagnolo, Wulfran Cacheux, Julie Lemarchand, Gilles Renault, Marie Fraudeau, Jonathan I. Levy, Patricia Lepage, Aurélie Durand, Antoine L’Hermitte, Mathias Chamaillard, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UMR_S567 / UMR 8104), Département d'Oncologie Médicale, Institut Curie [Paris], MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris Diderot - Paris 7 - UFR Sciences du Vivant (UPD7 UFR Sciences du Vivant), Université Paris Diderot - Paris 7 (UPD7), Université Paris Descartes - Paris 5 (UPD5), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National du Cancer, Comite de Paris de la Ligue Contre le Cancer, Cancer Research Personalized Medicine (CARPEM), Poste d'acceuil INSERM, Ministere de la Recherche et de la Technologie, la Fondation Arc, Inserm, Fondation pour la Recherche Medicale ('Equipe FRM'), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)

Subjects
Adenoma, Male, Genes, APC, Time Factors, Colon, [SDV]Life Sciences [q-bio], Ubiquitin-Activating Enzymes, Mouse model of colorectal and intestinal cancer, Biology, AMP-Activated Protein Kinases, Adenocarcinoma, CD8-Positive T-Lymphocytes, Autophagy-Related Protein 7, Immune system, medicine, Autophagy, Animals, Humans, Immunity, Mucosal, Cell Proliferation, Mice, Knockout, Microbiota, AMPK, Cell Biology, Cell Cycle Checkpoints, medicine.disease, Intestinal epithelium, Epithelium, 3. Good health, Cell biology, Tumor Burden, Enzyme Activation, Mice, Inbred C57BL, Disease Models, Animal, medicine.anatomical_structure, Cell Transformation, Neoplastic, Host-Pathogen Interactions, Cancer research, Dysbiosis, Female, Tumor Suppressor Protein p53, Colorectal Neoplasms, Microtubule-Associated Proteins
Abstract

International audience; Here, we show that autophagy is activated in the intestinal epithelium in murine and human colorectal cancer and that the conditional inactivation of Atg7 in intestinal epithelial cells inhibits the formation of pre-cancerous lesions in Apc(+/-) mice by enhancing anti-tumour responses. The antibody-mediated depletion of CD8(+) T cells showed that these cells are essential for the anti-tumoral responses mediated by the inhibition of autophagy. We show that Atg7 deficiency leads to intestinal dysbiosis and that the microbiota is required for anticancer responses. In addition, Atg7 deficiency resulted in a stress response accompanied by metabolic defects, AMPK activation and p53-mediated cell-cycle arrest in tumour cells but not in normal tissue. This study reveals that the inhibition of autophagy within the epithelium may prevent the development and progression of colorectal cancer in genetically predisposed patients.

Published
2015

30. Host–microbe interactions in distal airways: relevance to chronic airway diseases

Author

Jacques Brouard, Gaëtan Deslée, Philippe Gosset, Clémence Martin, Daniel Dusser, Pascal Chanez, Lhousseine Touqui, Jean-Charles Dalphin, Antoine Deschildre, Jacques de Blic, Patricia Lepage, Pierre-Régis Burgel, Arnaud Bourdin, Claire Andrejak, Département des maladies respiratoires [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Cochin [AP-HP], MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, CHU Amiens-Picardie, CHU Necker - Enfants Malades [AP-HP], Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Aix Marseille Université (AMU), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Défense innée et inflammation, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Service de pneumologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Publication of this peer-reviewed article was supported by Chiesi SA, Courbevoie, France (article sponsor, European Respiratory Review issue 135)., Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], CHU Cochin [AP-HP], Hôpital Jean Minjoz, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)

Subjects
Pulmonary and Respiratory Medicine, Cystic Fibrosis, [SDV]Life Sciences [q-bio], Respiratory Tract Diseases, Bronchiolitis obliterans, Disease, Cystic fibrosis, Mycobacterium, Pulmonary Disease, Chronic Obstructive, Immune system, Flora (microbiology), medicine, Humans, Lung, Asthma, lcsh:RC705-779, Bronchiectasis, business.industry, Microbiota, lcsh:Diseases of the respiratory system, medicine.disease, Gastrointestinal Microbiome, 3. Good health, Host-Pathogen Interactions, Immunology, Airway, business
Abstract

This article is the summary of a workshop, which took place in November 2013, on the roles of microorganisms in chronic respiratory diseases. Until recently, it was assumed that lower airways were sterile in healthy individuals. However, it has long been acknowledged that microorganisms could be identified in distal airway secretions from patients with various respiratory diseases, including cystic fibrosis (CF) and non-CF bronchiectasis, chronic obstructive pulmonary disease, asthma and other chronic airway diseases (e.g.post-transplantation bronchiolitis obliterans). These microorganisms were sometimes considered as infectious agents that triggered host immune responses and contributed to disease onset and/or progression; alternatively, microorganisms were often considered as colonisers, which were considered unlikely to play roles in disease pathophysiology. These concepts were developed at a time when the identification of microorganisms relied on culture-based methods. Importantly, the majority of microorganisms cannot be cultured using conventional methods, and the use of novel culture-independent methods that rely on the identification of microorganism genomes has revealed that healthy distal airways display a complex flora called the airway microbiota. The present article reviews some aspects of current literature on host–microbe (mostly bacteria and viruses) interactions in healthy and diseased airways, with a special focus on distal airways.

Published
2015

31. Gut microbiome and anticancer immune response: really hot Sh(star)t!

Author

Romain Daillère, Mikael J. Pittet, François Ghiringhelli, Laurence Zitvogel, Sophie Viaud, Ivo G Boneca, Giorgio Trinchieri, Patricia Lepage, Philippe Langella, Romina S. Goldszmid, Mathias Chamaillard, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Institut Pasteur [Paris], Groupe Avenir, Institut National de la Santé et de la Recherche Médicale (INSERM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre for System Biology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Cancer and Inflammation Program [NCI], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Centre d'Investigation Clinique Biothérapie (CICBT), Institut National du Cancer (INCa) Ligue contre le cancer (LIGUE labellisee) SIRIC Socrate LABEX PACRI Onco-Immunology European Research Council 202283 ISREC Foundation, ANR-11-PHUC-0002/11-PHUC-0002,PACRI,PACRI(2011), European Project: 202283,EC:FP7:ERC,ERC-2007-StG,PGNFROMSHAPETOVIR(2008), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), ANR-11-PHUC-0002,PACRI,Alliance Parisienne des Instituts de Recherche en Cancérologie(2011), Institut Pasteur [Paris] (IP), and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cyclophosphamide, medicine.drug_class, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Antibiotics, Antineoplastic Agents, Review, Biology, Gut flora, Inflammatory bowel disease, GERM-FREE MICE, COLORECTAL-CANCER, Mice, Immune system, LUNG-CANCER, Neoplasms, medicine, Animals, Humans, Intestinal Mucosa, Molecular Biology, TOLL-LIKE RECEPTORS, Chemotherapy, Tumor microenvironment, INDUCED COLITIS, Innate immune system, Microbiota, Cell Biology, medicine.disease, biology.organism_classification, 3. Good health, Anti-Bacterial Agents, Intestines, COLON TUMORIGENESIS, Immunology, INNATE IMMUNITY, Th17 Cells, INTESTINAL EPITHELIAL-CELLS, BETA-GLUCURONIDASE, medicine.drug, INFLAMMATORY-BOWEL-DISEASE
Abstract

The impact of gut microbiota in eliciting innate and adaptive immune responses beneficial for the host in the context of effective therapies against cancer has been highlighted recently. Chemotherapeutic agents, by compromising, to some extent, the intestinal integrity, increase the gut permeability and selective translocation of Gram-positive bacteria in secondary lymphoid organs. There, anticommensal pathogenic Th17 T-cell responses are primed, facilitating the accumulation of Th1 helper T cells in tumor beds after chemotherapy as well as tumor regression. Importantly, the redox equilibrium of myeloid cells contained in the tumor microenvironment is also influenced by the intestinal microbiota. Hence, the anticancer efficacy of alkylating agents (such as cyclophosphamide) and platinum salts (oxaliplatin, cis-platin) is compromised in germ-free mice or animals treated with antibiotics. These findings represent a paradigm shift in our understanding of the mode of action of many compounds having an impact on the host-microbe mutualism.

Published
2015

32. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota

Author

Elisabeth Chachaty, Alexander M.M. Eggermont, Vichnou Poirier-Colame, Jérôme Nigou, Antoine Roux, Gérard Eberl, Caroline Robert, Nicolas Jacquelot, Caroline Flament, Laurence Zitvogel, Franck Carbonnel, Silvia C. Formenti, Guido Kroemer, Didier Raoult, Paul Louis Woerther, Nadine Waldschmitt, David Enot, Marie Vétizou, Jonathan M. Pitt, Sonia Becharef, Romain Daillère, Christina Mateus, Sascha Cording, Paule Opolon, Sridhar Mani, Connie P.M. Duong, Nathalie Chaput, Bertrand Routy, Takahiro Yamazaki, Patricia Lepage, Ivo G. Boneca, Marion Bérard, Mathias Chamaillard, Florent Ginhoux, Sylvie Rusakiewicz, Maria Paula Roberti, Andreas Schlitzer, Encouse B. Golden, Université Paris-Sud - Paris 11 (UP11), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité (USPC), New York University [New York] (NYU), NYU System (NYU), Microenvironnement et Immunité - Microenvironment and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Albert Einstein College of Medicine [New York], Animalerie centrale (Plate-forme), Institut Pasteur [Paris] (IP), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Pôle de biologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Université de la Méditerranée - Aix-Marseille 2, Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Hôpital Bicêtre, La Ligue contre le cancer, ARC, Ligue Nationale contre le Cancer (Equipes labelisees), Agence Nationale pour la Recherche (ANR AUTOPH), Agence Nationale pour la Recherche (ANR, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), ProdInra, Migration, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Adoptive cell transfer, Skin Neoplasms, medicine.medical_treatment, T-Lymphocytes, [SDV]Life Sciences [q-bio], B7-H1 Antigen, Mice, Cancer immunotherapy, Bacteroides, Innate, CTLA-4 Antigen, Melanoma, Cancer, Aged, 80 and over, Multidisciplinary, Host, Antibodies, Monoclonal, hemic and immune systems, Fecal Microbiota Transplantation, Middle Aged, 3. Good health, Anti-Bacterial Agents, [SDV] Life Sciences [q-bio], Intestines, medicine.anatomical_structure, Female, Immunotherapy, Adult, T cell, T-Cells, chemical and pharmacologic phenomena, Biology, Article, Polysaccharides, medicine, Germ-Free Life, Animals, Humans, Antibody, Aged, Molecule, medicine.disease, Ipilimumab, Blockade, Gastrointestinal Microbiome, Transplantation, Mice, Inbred C57BL, CTLA-4, Immunology, Dysbiosis, Bifidobacterium, Immunologic Memory, Model
Abstract

International audience; Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, Tcell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis-specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.

Published
2015

33. Review article: the role of bacteria in onset and perpetuation of inflammatory bowel disease

Author

Nadia Vasquez, P Marteau, Harry Sokol, Philippe Pochart, Joël Doré, Irène Mangin, P. Seksik, Patricia Lepage, Chaysavanh Manichanh, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de recherche d'Écologie et Physiologie du Système Digestif (UEPSD), Institut National de la Recherche Agronomique (INRA), Laboratoire de Biologie, and Conservatoire National des Arts et Métiers [CNAM] (CNAM)

Subjects
medicine.drug_class, [SDV]Life Sciences [q-bio], Antibiotics, Inflammatory bowel disease, 03 medical and health sciences, 0302 clinical medicine, INTESTINAL MICROBIOTA, Humans, Medicine, Pharmacology (medical), Colitis, 030304 developmental biology, 0303 health sciences, Hepatology, biology, business.industry, Probiotics, PROBIOTIC, INFLAMMATORY BOWEL DISEASE, Gastroenterology, Bacterial Infections, Inflammatory Bowel Diseases, biology.organism_classification, medicine.disease, Ulcerative colitis, 3. Good health, Review article, Immunology, 030211 gastroenterology & hepatology, Age of onset, business, Dysbiosis, Bacteria
Abstract

International audience; We review the evidence that strongly suggests a role of the intestinal microbiota in the onset and perpetuation of inflammatory bowel disease (IBD). Experimental studies consisted of suppressing micro-organisms from the microbiota (using germ-free or gnotoxenic animals or antibiotics), introducing new micro-organisms or microbial components (e.g. probiotics, CpG-DNA) or selectively increasing some endogenous bacteria (e.g. using prebiotics). Intervention studies were performed in patients or animal models of spontaneous or chemically-induced colitis. Information was also obtained from observational studies that described the composition of the faecal and mucosal microbiota at various stages of the disease process and in controls. Many have used culture-independent techniques that identify bacteria based on the nucleic acid sequence of ribosomal RNA molecules. Microbiota in patients with IBD seem to be characterized by high concentrations of bacteria in contact with the mucosa, instability, the presence of high numbers of unusual bacteria and sometimes a reduction in the biodiversity. Studies searching for a generalized or localized dysbiosis in IBD are discussed, as well as those trying to identify bacterial molecules and receptors, which may be implicated in triggering the inflammatory process.

Published
2006

34. Search for Localized Dysbiosis in Crohn's Disease Ulcerations by Temporal Temperature Gradient Gel Electrophoresis of 16S rRNA

Author

Malène Sutren, Arnaud Bourreille, Jean-Paul Galmiche, Philippe Marteau, Marie-France de la Cochetière, Philippe Seksik, Joël Doré, and Patricia Lepage

Subjects
DNA, Bacterial, Electrophoresis, Microbiology (medical), Pathology, medicine.medical_specialty, Colon, CROHN'S DISEASE, INTESTINAL MUCOSA, INTESTINAL MICROBIOTA, TTGE, 16S rRNA, Rectum, Colonoscopy, Ileum, Biology, DNA, Ribosomal, Gastroenterology, Crohn Disease, Intestinal mucosa, RNA, Ribosomal, 16S, Internal medicine, Biopsy, medicine, Humans, Intestinal Mucosa, Ulcer, Crohn's disease, medicine.diagnostic_test, Microbiology and Parasitology, Bacteriology, medicine.disease, Microbiologie et Parasitologie, digestive system diseases, medicine.anatomical_structure, Dysbiosis, Temperature gradient gel electrophoresis
Abstract

The mucosa-associated microbiota lining the gut epithelium might play a central role in the activation and/or perpetuation of mucosal inflammation in Crohn's disease (CD). We sought for localized dysbiosis by comparing the biodiversity and composition of the microbiotas in ulcerated and nonulcerated mucosal samples from patients with CD. Biopsy samples ( n = 75) of ulcerated and adjacent nonulcerated mucosa were collected during colonoscopy from 15 patients, from the ileum, right colon, left colon, and rectum. Temporal temperature gradient gel electrophoresis (TTGE) of bacterial 16S rRNAs was used to evaluate the dominant bacterial species. TTGE profiles were compared using software that calculates similarity percentages. For a given patient, average similarity indexes between ulcerated and nonulcerated mucosal TTGE profiles ranged from 95.2% ± 4.2% to 97.9% ± 1.7% (means ± standard deviations) for the different segments. The mean values did not differ significantly. Average interindividual similarity indexes for a given segment among the different patients ranged from 33.6% ± 15.5% to 42.0% ± 25.6%. In CD, the dominant microbiotas do not differ qualitatively between ulcerated and nonulcerated mucosae. Biodiversity remains high in ulcerated mucosa. This argues against a pathogenic role of localized qualitative dysbiosis in CD-associated ulceration.

Published
2005

35. Biodiversity of the Mucosa-Associated Microbiota Is Stable Along the Distal Digestive Tract in Healthy Individuals and Patients With Ibd

Author

Patricia Lepage, Marie-France de la Cochetière, Malène Sutren, Philippe Marteau, Joël Doré, Raymond Jian, Philippe Seksik, Unité de recherche d'Écologie et Physiologie du Système Digestif (UEPSD), Institut National de la Recherche Agronomique (INRA), Biologie et physiopathologie intestinales. Pharmacologie nutritionnelle, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, [SDV]Life Sciences [q-bio], Gastroenterology, Inflammatory bowel disease, Feces, 0302 clinical medicine, Crohn Disease, Immunology and Allergy, Aged, 80 and over, 0303 health sciences, education.field_of_study, Middle Aged, Ulcerative colitis, 3. Good health, medicine.anatomical_structure, Female, 030211 gastroenterology & hepatology, Adult, DNA, Bacterial, medicine.medical_specialty, Adolescent, Population, Rectum, Ileum, Biology, DNA, Ribosomal, digestive system, 03 medical and health sciences, Enterobacteriaceae, INTESTINAL MUCOSA, Internal medicine, medicine, Humans, Intestine, Large, Microbiome, Colitis, education, TTGE, Aged, 030304 developmental biology, INFLAMMATORY BOWEL DISEASE, medicine.disease, Case-Control Studies, FECAL MICROBIOTA, Colitis, Ulcerative, BIODIVERSITY, ASSOCIATED-MUCOSA MICROBIOTA
Abstract

International audience; BACKGROUND: The mucosa-associated microbiota, being very close to the inflammatory process associated with inflammatory bowel disease (IBD), may have a pathogenic role. We used a culture-independent method to analyze the mucosa-associated microbiota in IBD patients at various points of the distal digestive tract. METHODS: Thirty-five patients (20 with Crohn's disease, 11 with ulcerative colitis, and 4 controls) underwent colonoscopy. Biopsies (n = 126) were taken from 4 sites: the ileum, right colon, left colon, and rectum. Fecal samples were also obtained from 7 individuals. Temporal temperature gradient gel electrophoresis (TTGE) of 16S rDNA was used to evaluate dominant species diversity. TTGE profiles were compared using software that measures the degree of similarity. RESULTS: In a given individual, the overall similarity percentage between the 4 segments of the distal digestive tract was 94.7 +/- 4.0%, regardless of clinical status. The average similarity of all profiles for a given segment was 59.3 +/- 18.3% in the overall population. Dendrogram analysis showed that TTGE profiles did not cluster with clinical status. Differences were observed between the dominant fecal microbiota and the mucosa-associated microbiota of all 4 sites, with similarity percentages less than 92%. CONCLUSIONS: These results confirm that the dominant species differ between the mucosa-associated and fecal microbiota. They also show that, in a given individual, the microbiota is relatively stable along the distal digestive tract, showing a slight evolution in dominant species diversity from the ileum to the rectum, in both healthy subjects and patients with IBD.

Published
2005

36. Gut flora and inflammatory bowel disease

Author

P. Seksik, P Marteau, Philippe Pochart, Joël Doré, Patricia Lepage, Antonia Suau, and Irène Mangin

Subjects
2. Zero hunger, 0303 health sciences, Gastrointestinal tract, Hepatology, biology, business.industry, Exogenous bacteria, Gastroenterology, Gut flora, biology.organism_classification, medicine.disease, Inflammatory bowel disease, Mucus, 3. Good health, Review article, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Immunology, Medicine, 030211 gastroenterology & hepatology, Pharmacology (medical), business, Bacteria, 030304 developmental biology
Abstract

The pathogenesis of inflammatory bowel disease involves interactions between the host susceptibility, mucosal immunity and intestinal microflora. There is therefore great interest in the changes in the endogenous flora in inflammatory bowel disease patients and in the establishment of potential genetic variations in host responses to endogenous bacteria. In this review, we summarize the modifications in the various regional ecosystems in the gastrointestinal tract during inflammatory bowel disease (luminal bacteria in faeces or inside the gastrointestinal tract, bacteria in mucus and bacteria directly attached to the mucosa). Results were obtained following a 'candidate microorganism strategy' and, as is occurring increasingly frequently, following a 'full description strategy', which has progressed largely due to the development of culture-independent techniques. The possibility of modifying the ecosystem using prebiotics or probiotics offers hope for new treatment developments, particularly in the prevention of relapse.

Published
2004

37. Why should we need the gut microbiota to respond to cancer therapies?

Author

Giorgio Trinchieri, Sophie Viaud, Patricia Lepage, Laurence Zitvogel, Romain Daillère, Romina S. Goldszmid, Takahiro Yamazaki, Ivo G Boneca, ProdInra, Archive Ouverte, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Groupe Avenir, Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Institut Pasteur [Paris] (IP), Cancer and Inflammation Program, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut Pasteur [Paris], and Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
pTh17, Cyclophosphamide, medicine.drug_class, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, Antibiotics, Gut flora, chemotherapy, antibiotics, antibiotique, immunomodulateur, microbiote, medicine, chimiothérapie, microbiota, Immunology and Allergy, cancer, Author's View, immunomodulatory regimen, Chemotherapy, biology, Effector, business.industry, Cancer, Gram-positive bacteria, medicine.disease, biology.organism_classification, 3. Good health, [SDV] Life Sciences [q-bio], Oncology, Intestinal bacteria, business, bactérie gram positif, medicine.drug
Abstract

Cyclophosphamide, one of the most efficient tumoricidal, antiangiogenic, and immunostimulatory drugs employed to date mediates part of its effects through intestinal bacteria, against which the host becomes immunized during treatment. Our recent work suggests that anti-commensal effector pT(H)17 and memory T(H)1 CD4(+) T-cell responses are indispensable for optimal anticancer effects as mediated by cyclophosphamide.

Published
2014

38. Metabolic interplay between gut bacteria and their host

Author

Patricia Lepage, Mihai Covasa, Frank Duca, Philippe Gérard, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Healh Network, University of Toronto, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Department of Human and Health Development, University Stefan cel Mare of Suceava (USU), Delhanty, PJD, and VanDerLely, AJ

Subjects
biology, Human studies, Host (biology), [SDV]Life Sciences [q-bio], Inflammatory Bowel Diseases, Gut flora, medicine.disease, biology.organism_classification, digestive system, Microbiology, Human gut, Gut bacteria, Immunology, medicine, Intestinal bacteria, Dysbiosis
Abstract

Shifts in the bacterial composition of the human gut microbiota (i.e. dysbiosis) have been associated with digestive tract dysfunctions such as inflammatory bowel diseases. More strikingly, strong evidence, from both human studies and germ-free animal models, links intestinal microbiota dysbiosis with metabolic disorders, such as obesity and liver diseases.[br/]This chapter focuses on the changes and impact of the gut microbiota during these diseased states, and describes the possible direct and indirect mechanisms that an aberrant gut microbiota can promote metabolic dysregulations. The possible involvement of the 'microbiota-gut-brain' axis in the development of obesity is further discussed, as is the perspective of meta-omic technologies that give insight into the functions and potential effect of the non-cultured intestinal bacteria on the host health.[br/]Understanding how modifications in this finely tuned ecosystem lead to these pathological processes is crucial for the development of new therapeutic approaches to treat and hopefully ameliorate these metabolic diseases. (C) 2014 S. Karger AG, Basel

Published
2014

39. Serotonergic dysfunction in women with pure premenstrual dysphoric disorder: is the fenfluramine challenge test still relevant?

Author

A. Wilkins, M. Coote, Patricia Lepage, Lakshmi N. Yatham, and Meir Steiner

Subjects
endocrine system, medicine.medical_specialty, business.industry, Fenfluramine, media_common.quotation_subject, Luteal phase, medicine.disease, Serotonergic, Prolactin, Psychiatry and Mental health, Endocrinology, Internal medicine, Follicular phase, medicine, business, Premenstrual dysphoric disorder, hormones, hormone substitutes, and hormone antagonists, Biological Psychiatry, Menstrual cycle, media_common, Hydrocortisone, medicine.drug
Abstract

The fenfluramine (FEN) neuroendocrine challenge paradigm, which involves measuring the response of prolactin (PRL) release to an oral challenge dose of FEN, provides a means of assessing serotonin (5-HT) function. The purpose of this study was to ascertain the role of 5-HT in premenstrual dysphoric disorder (PMDD) by measuring: (1) PRL and cortisol (CORT) responses to FEN; and (2) platelet 3 H-imipramine binding levels, in females with pure PMDD (without a past or present comorbid mood disorder) in comparison to healthy controls. FEN challenge tests were administered to nine female patients with pure PMDD and nine healthy female controls during the follicular and late luteal phases of a menstrual cycle. There were no differences in the PRL response to FEN for women with PMDD compared to healthy controls. However, the trend toward a delayed response to FEN and a significant negative correlation between Δmax PRL and basal CORT in patients but not in controls during both phases of the menstrual cycle suggest an underlying 5-HT dysfunction in patients as compared to controls. This is further supported by the finding of significantly lower B max 3 H-imipramine binding levels in the patients during the late luteal phase.

Published
1999

40. Serotonin and gender-specific psychiatric disorders

Author

E. Dunn, Patricia Lepage, and Meir Steiner

Subjects
medicine.medical_specialty, Human studies, Serotonergic, medicine.disease, Psychiatry and Mental health, Eating disorders, medicine, Etiology, Anxiety, Serotonin, medicine.symptom, Psychology, Psychiatry, Depression (differential diagnoses), Clinical psychology
Abstract

The serotonergic system has been linked to the etiology of several, albeit disparate, psychiatric disorders. The accumulation of many lines of evidence support the view that there are gender differences in the serotonergic system in humans. It is further proposed that a gender differentiated serotonergic system acts as the nidus for the development of gender-specific psychiatric disorders. Depression, anxiety and eating disorders are largely seen in females, whereas alcoholism, aggressivity and suicide predominate in males. Evidence from both animal and human studies suggesting that the serotonergic system mediates between social-environmental experience and biological states is presented and reviewed. A reconceptualization of the serotonergic system as a gender-specific psychobiological interface is proposed. (Int J Psych Clin Prac 1997; 1: 3-13).

Published
1997

41. Intestinal microbiota determines development of non-alcoholic fatty liver disease in mice

Author

Patrice Martin, Catherine Philippe, Gabriel Perlemuter, Francine Walker, Tiphaine Le Roy, Anne-Marie Cassard-Doulcier, Sylvie Rabot, Marta Llopis, Philippe Gérard, Aurélia Bruneau, Claudia Bevilacqua, Patricia Lepage, André Bado, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Génétique Animale et Biologie Intégrative (GABI), UFR de médecine, U773, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (Inserm), Cytokines, chimiokines et immunopathologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Faculté de médecine, Université Paris-Sud - Paris 11 (UP11), Hôpital Antoine Béclère, Service d'hépato-gastroentérologie, Assistance Publique - Hôpitaux de Paris, Science Committee Syndifrais/CNIEL, CNIEL (Centre National Interprofessionnel de l'Economie Laitiere) [S2234], Gerard, Philippe, ProdInra, Archive Ouverte, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), and AgroParisTech-Institut National de la Recherche Agronomique (INRA)

Subjects
Blood Glucose, Male, [SDV]Life Sciences [q-bio], Gut flora, Systemic inflammation, Polymerase Chain Reaction, Mice, Colonic Microflora, Cytokines, Fatty Liver, Real Time PCR, Lipid Metabolism, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, RNA, Ribosomal, 16S, cytokine, 0303 health sciences, biology, Microbiota, Fatty liver, Gastroenterology, Intestines, [SDV] Life Sciences [q-bio], RNA, Bacterial, Liver, Lipogenesis, 030211 gastroenterology & hepatology, medicine.symptom, medicine.medical_specialty, digestive system, 03 medical and health sciences, stéatose hépatique, Internal medicine, medicine, Animals, Triglycerides, 030304 developmental biology, pcr en temps réel, métabolisme lipidique, nutritional and metabolic diseases, Lipid metabolism, Fatty Acids, Volatile, medicine.disease, biology.organism_classification, Dietary Fats, Obesity, Mice, Inbred C57BL, Transplantation, Endocrinology, microflore digestive, Metabolic syndrome
Abstract

Objective: Non-alcoholic fatty liver disease (NAFLD) is prevalent among obese people and is considered the hepatic manifestation of metabolic syndrome. However, not all obese individuals develop NAFLD. Our objective was to demonstrate the role of the gut microbiota in NAFLD development using transplantation experiments in mice. [br/] Design: Two donor C57BL/6J mice were selected on the basis of their responses to a high-fat diet (HFD). Although both mice displayed similar body weight gain, one mouse, called the responder', developed hyperglycaemia and had a high plasma concentration of pro-inflammatory cytokines. The other, called a non-responder', was normoglycaemic and had a lower level of systemic inflammation. Germ-free mice were colonised with intestinal microbiota from either the responder or the non-responder and then fed the same HFD. [br/] Results: Mice that received microbiota from different donors developed comparable obesity on the HFD. The responder-receiver (RR) group developed fasting hyperglycaemia and insulinaemia, whereas the non-responder-receiver (NRR) group remained normoglycaemic. In contrast to NRR mice, RR mice developed hepatic macrovesicular steatosis, which was confirmed by a higher liver concentration of triglycerides and increased expression of genes involved in de-novo lipogenesis. Pyrosequencing of the 16S ribosomal RNA genes revealed that RR and NRR mice had distinct gut microbiota including differences at the phylum, genera and species levels. [br/] Conclusions: Differences in microbiota composition can determine response to a HFD in mice. These results further demonstrate that the gut microbiota contributes to the development of NAFLD independently of obesity.

Published
2013

42. Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept

Author

Pascale Klopp, Jason S. Iacovoni, Joël Doré, Céline Lange, Olivier Bouchez, Rémy Burcelin, Jérôme Mariette, Jacques Amar, Olivier Lantieri, Marie-Aline Charles, Matteo Serino, L. Perez, Christophe Klopp, Michael Courtney, B. Balkau, Michel Marre, Chantal Chabo, Patricia Lepage, Stanislas Mondot, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Service de Médecine Interne et Hypertension Artérielle [Toulouse], CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Unité de Biométrie et Intelligence Artificielle de Toulouse [Castanet-Tolosan] (UBIA), Institut National de la Recherche Agronomique (INRA)-Plateforme bioinformatique du GIS GENOTOUL - Génopole Toulouse Midi-Pyrénées, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Vaiomer, Déterminants génétiques du diabète de type 2 et de ses complications vasculaires ((U 695)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Service d'endocrinologie, diabétologie et nutrition [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut inter-Régional pour la SAnté (IRSA), This work was funded by the Agence Nationale de la Recherche (French national research agency) (to R. Burcelin) and by the Societe Francophone de Diabete (to B. Balkau). The D.E.S.I.R. study has been supported by Inserm contracts with CNAMTS, Lilly, Novartis Pharma and sanofi-aventis, by Inserm (Reseaux en Sante Publique, Interactions entre les determinants de la sante, Cohortes Sante TGIR 2008), the Association Diabete Risque Vasculaire, the Federation Francaise de Cardiologie, La Fondation de France, ALFEDIAM, ONIVINS, Societe Francophone du Diabete, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics., Service d'hypertension artérielle et thérapeutique [CHU Toulouse] (HTA et thérapeutique), Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Biométrie et Intelligence Artificielle (ancêtre de MIAT) (UBIA), Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), VAIOMER SAS, VAIOMMER, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), and Plateforme bioinformatique du GIS GENOTOUL - Génopole Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)

Subjects
Male, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], [MATH] Mathematics [math], 0302 clinical medicine, MESH: Metabolic Syndrome X, RNA, Ribosomal, 16S, MESH: Obesity, Longitudinal Studies, [MATH]Mathematics [math], MESH: Longitudinal Studies, Genetics, MESH: Aged, Metabolic Syndrome, 0303 health sciences, education.field_of_study, MESH: Middle Aged, biology, Middle Aged, MESH: Case-Control Studies, 3. Good health, [SDV] Life Sciences [q-bio], MESH: RNA, Ribosomal, 16S, Obesity, Abdominal, Female, France, MESH: Diabetes Mellitus, Type 2, Adult, Population, abdominal adiposity, 030209 endocrinology & metabolism, [INFO] Computer Science [cs], MESH: Obesity, Abdominal, 03 medical and health sciences, endocrinology, Diabetes mellitus, Internal Medicine, medicine, microbiota, Humans, [INFO]Computer Science [cs], Obesity, education, 16s rdna gene, 030304 developmental biology, Aged, MESH: Humans, Bacteria, Case-control study, MESH: Biological Markers, MESH: Adult, Human physiology, MESH: Metagenome, biology.organism_classification, medicine.disease, MESH: Male, MESH: France, MESH: Bacteria, Diabetes Mellitus, Type 2, Case-Control Studies, Immunology, Metagenome, metabolism, MESH: Female, Biomarkers
Abstract

Chantier qualité GA; International audience; AIMS/HYPOTHESIS: Evidence suggests that bacterial components in blood could play an early role in events leading to diabetes. To test this hypothesis, we studied the capacity of a broadly specific bacterial marker (16S rDNA) to predict the onset of diabetes and obesity in a general population. METHODS: Data from an Epidemiological Study on the Insulin Resistance Syndrome (D.E.S.I.R.) is a longitudinal study with the primary aim of describing the history of the metabolic syndrome. The 16S rDNA concentration was measured in blood at baseline and its relationship with incident diabetes and obesity over 9 years of follow-up was assessed. In addition, in a nested case-control study in which participants later developed diabetes, bacterial phylotypes present in blood were identified by pyrosequencing of the overall 16S rDNA gene content. RESULTS: We analysed 3,280 participants without diabetes or obesity at baseline. The 16S rDNA concentration was higher in those destined to have diabetes. No difference was observed regarding obesity. However, the 16S rDNA concentration was higher in those who had abdominal adiposity at the end of follow-up. The adjusted OR (95% CIs) for incident diabetes and for abdominal adiposity were 1.35 (1.11, 1.60), p = 0.002 and 1.18 (1.03, 1.34), p = 0.01, respectively. Moreover, pyrosequencing analyses showed that participants destined to have diabetes and the controls shared a core blood microbiota, mostly composed of the Proteobacteria phylum (85-90%). CONCLUSIONS/INTERPRETATION: 16S rDNA was shown to be an independent marker of the risk of diabetes. These findings are evidence for the concept that tissue bacteria are involved in the onset of diabetes in humans.

Published
2011

43. Twin Study Indicates Loss of Interaction Between Microbiota and Mucosa of Patients With Ulcerative Colitis

Author

Stefan Schreiber, Aida Zvirbliene, Stephan J. Ott, Ateequr Rehman, Martina E. Spehlmann, Joël Doré, Limas Kupčinskas, Alexander Begun, Robert Häsler, Andreas Raedler, Patricia Lepage, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Inst Clin Mol Biol, University of Kiel, Inst Digest Res, Lithuanian Univ Hlth Sci, Inst Clin Mol Biol, Dept Internal Med 1, Dept Gastroenterol, Dept Internal Med, Asklepios Westklinikum Hamburg, National German Genome Network, SFB 415 Project, Excellence Cluster Inflammation at Interfaces, and MFG Educative Science, Hamburg, Germany

Subjects
Male, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Heredity, Aerobic bacteria, Biopsy, COLONIC-MUCOSA, VARIANTS, Ribotyping, Inflammatory bowel disease, 0302 clinical medicine, Intestinal mucosa, Crohn Disease, Germany, RNA, Ribosomal, 16S, Twins, Dizygotic, Cluster Analysis, STENOTROPHOMONAS-MALTOPHILIA, Intestinal Mucosa, GENE-EXPRESSION, Principal Component Analysis, 0303 health sciences, Gastroenterology, INTESTINAL-MUCOSA, Middle Aged, Transcript, Ulcerative colitis, CROHNS-DISEASE, 3. Good health, Host-Pathogen Interactions, Female, 030211 gastroenterology & hepatology, RIBOSOMAL-RNA, Adult, DNA, Bacterial, Adolescent, Molecular Sequence Data, Biology, Young Adult, 03 medical and health sciences, Colon, Sigmoid, medicine, Humans, Microbiome, GENOME-WIDE ASSOCIATION, 030304 developmental biology, Inflammation, Discordant Twin, Bacteria, Hepatology, Gene Expression Profiling, Lachnospiraceae, Lithuania, Twins, Monozygotic, medicine.disease, Gene Expression Regulation, Case-Control Studies, Immunology, FECAL MICROBIOTA, Dysbiosis, Colitis, Ulcerative, INFLAMMATORY-BOWEL-DISEASE
Abstract

BACKGROUND & AIMS: Interactions between genetic and environmental factors are believed to be involved in onset and initiation of inflammatory bowel disease. We analyzed the interaction between gastrointestinal mucosal microbiota and host genes in twin pairs discordant for ulcerative colitis (UC) to study the functional interaction between microbiota and mucosal epithelium. METHODS: Biopsy were collected from sigmoid colon of UC patients and their healthy twins (discordant twin pairs) and from twins without UC. Microbiota profiles were determined from analysis of 16S ribosomal DNA libraries; messenger RNA profiles were determined by microarray analysis. RESULTS: Patients with UC had dysbiotic microbiota, characterized by less bacterial diversity and more Actinobacteria and Proteobacteria than that of their healthy siblings; healthy siblings from discordant twins had more bacteria from the Lachnospiraceae and Ruminococcaceae families than twins who were both healthy. In twins who were both healthy, 34 mucosal transcripts correlated with bacterial genera, whereas only 25 and 11 correlated with bacteria genera in healthy individuals and their twins with UC, respectively. Transcripts related to oxidative and immune responses were differentially expressed between patients with UC and their healthy twins. CONCLUSIONS: The transcriptional profile of the mucosa appears to interact with the colonic microbiota; this interaction appears to be lost in colon of patients with UC. Bacterial functions, such as butyrate production, might affect mucosal gene expression. Patients with UC had different gene expression profiles and lower levels of biodiversity than their healthy twins, as well as unusual aerobic bacteria. Patients with UC had lower percentages of potentially protective bacterial species than their healthy twins.

Published
2011

44. P057 Influence of colitis on ileal epithelial barrier and its environment in a new mouse model of ulcerative colitis

Author

Eric Pedruzzi, Dominique Cazals-Hatem, Z. Alnabhani, Frédérick Barreau, Shirin Sedghi, Patricia Lepage, Eric Ogier-Denis, Fanny Daniel, and Xavier Treton

Subjects
Epithelial barrier, Pathology, medicine.medical_specialty, business.industry, Gastroenterology, Ileum, General Medicine, medicine.disease, Ulcerative colitis, Epithelium, medicine.anatomical_structure, Medicine, Colitis, business
Published
2014

45. Cytotoxicity and regenerative proliferation as the mode of action for diuron-induced urothelial carcinogenesis in the rat

Author

Patricia Lepage Alves de Lima, Maria Luiza Cotrim Sartor de Oliveira, João Lauro Viana de Camargo, Merielen Garcia Nascimento, Edneia Aparecida Zelandi, Ana Paula Ferragut Cardoso, and Mitscheli Sanches da Rocha

Subjects
Male, Necrosis, Time Factors, Stereochemistry, Struvite, Urinary Bladder, Magnesium Compounds, Urine, CHO Cells, Toxicology, Ammonium Chloride, Phosphates, Urothelial Hyperplasia, Cricetulus, Cricetinae, medicine, Animals, Regeneration, Rats, Wistar, Mode of action, Cytotoxicity, Carcinogen, Cell Proliferation, Hyperplasia, Chemistry, Herbicides, Body Weight, Hydrogen-Ion Concentration, medicine.disease, Molecular biology, Rats, Comet assay, Urinary Bladder Neoplasms, Diuron, Carcinogens, Urinary Calculi, Comet Assay, medicine.symptom, Urothelium, DNA Damage
Abstract

Diuron, a substituted urea herbicide, is carcinogenic to the urinary bladder of rats at high dietary levels. Its proposed carcinogenic mode of action (MOA) includes urothelial cytotoxicity and necrosis followed by regenerative cell proliferation and sustained urothelial hyperplasia. Cytotoxicity could be induced either by urinary solids or by chemical toxicity by diuron and/or metabolites excreted in the urine. Diuron was not genotoxic in a previous single-cell gel (comet) assay, but possible cross-linking activity remained to be evaluated. The present study explored the MOA of diuron and the effect of urinary acidification on the development of urothelial lesions. Male Wistar rats were fed diuron (2500 ppm, about 130 mg/kg of body weight) either with or without NH 4 Cl 10,000 ppm to acidify the urine. Reversibility of urothelial changes was also examined. The animals were euthanized after 15, 25, or 30 weeks. Diuron-fed rats had urinary amorphous precipitate and magnesium ammonium phosphate crystals similar to control animals. Groups treated with diuron + NH 4 Cl showed decreased urinary pH and reduced amounts of urinary crystals and precipitate. Urothelial necrosis and simple hyperplasia were observed by light microscopy and scanning electron microscopy both in diuron- and in diuron + NH 4 Cl-treated groups. Cytotoxicity and proliferative changes were mostly reversible. A modified comet assay developed in vitro with Chinese hamster ovary cells showed that diuron did not induce DNA cross-links. These data suggest that cytotoxicity with consequent regenerative cell proliferation is the predominant MOA for diuron rat urothelial carcinogenesis, the cytotoxicity being chemically induced and not due to urinary solids.

Published
2009

46. Dysbiosis in inflammatory bowel disease: a role for bacteriophages?

Author

Jonathan Colombet, Télesphore Sime-Ngando, P Marteau, Marion Leclerc, Joël Doré, Patricia Lepage, Unité d'écologie et physiologie du système digestif (LEPSD), Institut National de la Recherche Agronomique (INRA), Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Centre National de la Recherche Scientifique (CNRS), AP-HP, Hôpital Lariboisière, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Université d'Auvergne - Clermont-Ferrand I (UdA), and Hôpital Lariboisière

Subjects
0303 health sciences, biology, 030306 microbiology, Population structure, Gastroenterology, Gene transfer, medicine.disease, biology.organism_classification, Inflammatory bowel disease, Microbiology, 03 medical and health sciences, Intestinal inflammation, Immunology, medicine, Natural ecosystem, Intestinal bacteria, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, Dysbiosis, Bacteria, 030304 developmental biology
Abstract

Intestinal bacteria have been implicated in the initiation and amplification of inflammatory bowel disease (IBD). The dysbiosis theory, reviewed by Tamboli et al ( Gut 2004; 53 :1), is that an imbalance between putative “harmful” versus “protective” bacterial species may promote chronic intestinal inflammation. Although several studies published so far support this hypothesis, the most vexing question posed by Tamboli et al remains “what is the origin of dysbiosis?”. Bacteriophages outnumber bacteria by a factor of 10 in many natural ecosystems, exert a strong influence on bacterial diversity and population structure, and are probably involved in dysbiosis by destabilising bacterial communities.1 They could be involved indirectly through gene transfer and genome reorganisation within the bacterial population or directly as …

Published
2008

47. Epidemiology of inflammatory bowel disease in a German twin cohort: results of a nationwide study

Author

Jens Burghardt, Alexander Begun, Patricia Lepage, Stefan Schreiber, Andreas Raedler, and Martina E. Spehlmann

Subjects
Adult, Male, medicine.medical_specialty, Concordance, Inflammatory bowel disease, Cohort Studies, Crohn Disease, Internal medicine, Germany, Surveys and Questionnaires, medicine, Genetic predisposition, Diseases in Twins, Twins, Dizygotic, Immunology and Allergy, Humans, Discordant Twin, Crohn's disease, business.industry, Gastroenterology, Twins, Monozygotic, Middle Aged, medicine.disease, Twin study, digestive system diseases, Zygosity, Immunology, Colitis, Ulcerative, Female, business, Cohort study
Abstract

Background: Genetic predisposition as a cause of inflammatory bowel disease (IBD) has been proven by both family and twin studies and genetic variants associated with the disease have been identified. The aim of our study was to determine the concordance rates for IBD in German twin pairs and to evaluate clinical characteristics of concordant and discordant twin pairs. Methods: Patients with IBD were asked to participate and complete a questionnaire that contained questions about zygosity, demographic data, and medical history. Results: A total of 189 twin pairs in which at least 1 member had IBD were recruited (68 monozygotic and 121 dizygotic pairs). Within monozygotic pairs, 11 out of 31 (35%) were concordant for Crohn's disease (CD) and 6 out of 37 (16%) for ulcerative colitis (UC). Two of the 58 (3%) dizygotic pairs with CD and 1 out of 63 (2%) dizygotic pairs with UC were concordant for the disease. In 14 out of 20 (70%) discordant monozygotic CD pairs and 25 out of 31 (81%) discordant monozygotic pairs with UC, the first-born was affected by IBD. For discordant dizygotic twins, the first in birth order had IBD in 33 out of 56 (59%) pairs with CD and 40 out of 62 (64.5%) pairs with UC. Conclusions: This study confirms a stronger genetic influence in CD than in UC. The high preponderance in being affected of the first-born twin and the fact that concordance was only 35% for CD and 16% for UC monozygotic twins highlight the important role of environmental trigger factors. (Inflamm Bowel Dis 2008)

Published
2008

48. Patchy distribution of mucosal lesions in ileal Crohn's disease is not linked to differences in the dominant mucosa-associated bacteria: a study using fluorescence in situ hybridization and temporal temperature gradient gel electrophoresis

Author

Philippe Pochart, Patricia Lepage, Gwenola Vernier, Xavier Treton, Nadia Vasquez, Philippe Marteau, Jean-Paul Duong, Joël Doré, Stephanie Blum, Antonia Suau, Eduardo Schiffrin, Irène Mangin, Matthieu Allez, and Philippe Seksik

Subjects
Adult, DNA, Bacterial, Electrophoresis, Male, Pathology, medicine.medical_specialty, Firmicutes, Biopsy, Colony Count, Microbial, Ileum, In situ hybridization, Polymerase Chain Reaction, Pathogenesis, Crohn Disease, Double-Blind Method, medicine, Immunology and Allergy, Humans, Intestinal Mucosa, In Situ Hybridization, Fluorescence, Crohn's disease, medicine.diagnostic_test, biology, Bacteria, Probiotics, Gastroenterology, Temperature, Bacteroidetes, Middle Aged, biology.organism_classification, medicine.disease, Lactobacillus, medicine.anatomical_structure, Female, Fluorescence in situ hybridization
Abstract

Background: The mucosa-associated bacteria (MAB) are suspected of being involved in the pathogenesis of Crohn's disease. We analyzed and compared the MAB in noninflamed and inflamed ileal mucosa of Crohn's disease patients (n = 22). Methods: Tissue samples from the inflamed ileal mucosa and from the adjacent noninflamed ileal mucosa were taken from surgical resection specimens. The MAB were investigated using fluorescence in situ hybridization with 7 group-specific probes and temporal temperature gradient gel electrophoresis (TTGE). Results: Samples from both noninflamed and inflamed mucosa were obtained from 15 patients. The distribution of the bacterial populations was not different between noninflamed and inflamed mucosa. The Bacteroidetes phylum was dominant and accounted for 29% of MAB (0%–74%) in noninflamed tissues and 32% (0%–70%) in inflamed areas. The γ Proteobacteria represented 12% (0%–70%) of MAB both in noninflamed and inflamed areas. The Clostridium coccoides group (Firmicutes phylum) represented 15% of MAB in noninflamed tissues versus 7% in inflamed areas. For most of the patients the similarity index between TTGE paired profiles was very high. Conclusion: The dominant MAB do not differ between noninflamed and inflamed ileal mucosa in Crohn's disease. This argues against a localized dysbiosis to explain the patchy distribution of mucosal lesions. (Inflamm Bowel Dis 2007)

Published
2007

49. 392 Short Bowel Syndrome: A Case Study to Illustrate How Gut Remodeling Can Impact Fecal Microbiota That in Turn Becomes Central to Understanding Clinical Outcome

Author

Johanne Le Beyec Le Bihan, Véronique Robert, Patricia Lepage, Muriel Thomas, Laura Gillard, Camille Mayeur, Sylvie Miquel, André Bado, and Francisca Joly

Subjects
medicine.medical_specialty, Hepatology, Internal medicine, Gastroenterology, medicine, Fecal microbiota, Biology, Short bowel syndrome, medicine.disease, Intensive care medicine, Outcome (game theory)
Published
2015

50. Molecular comparison of dominant microbiota associated with injured versus healthy mucosa in ulcerative colitis

Author

Patricia Lepage, Joël Doré, P. Seksik, P Marteau, and Harry Sokol

Subjects
medicine.medical_specialty, Colon, Rectum, Inflammation, Gut flora, digestive system, Gastroenterology, Inflammatory bowel disease, Intestinal mucosa, Internal medicine, medicine, Humans, Letters, Colitis, Intestinal Mucosa, biology, business.industry, medicine.disease, biology.organism_classification, Ulcerative colitis, digestive system diseases, medicine.anatomical_structure, Immunology, Colitis, Ulcerative, Electrophoresis, Polyacrylamide Gel, medicine.symptom, business, Dysbiosis
Abstract

Ulcerative colitis is an inflammatory bowel disease (IBD) characterised by a chronic inflammation of the colorectal mucosa. The role of the gut microbiota in triggering or maintenance of the mucosal inflammation is strongly suspected.1 We may postulate that a localised dysbiosis could explain the localisation of the lesions. Many of the recent studies have been made possible by the development of culture-independent techniques, which identify bacteria on the basis of comparisons of the nucleic acid sequence of rRNA molecules. Temporal temperature-gradient gel electrophoresis (TTGE) showed that in healthy people dominant microbiota associated with colonic mucosa is similar from the caecum to the rectum.2 This has also been observed in Crohn’s disease,2 and the dominant microbiota associated with ulcerated mucosa did not differ markedly from the microbiota associated with non-ulcerated mucosa.3 The aim of this study was to compare the dominant microbiota associated with injured colonic mucosa versus healthy colonic mucosa, using TTGE in patients with active ulcerative colitis. Ten patients with active ulcerative colitis were studied, after informed consent was obtained. …

Published
2006

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