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1. Changes in Gut Microbiota of Patients with Atopic Dermatitis During Balneotherapy

Author

Thirion F, Guilly S, Fromentin S, Plaza Oñate F, Alvarez AS, Le Chatelier E, Pons N, Levenez F, Quinquis B, Ehrlich S, Doré J, Martin R, and Seité S

Subjects
atopic dermatitis, balneotherapy, gut microbiota, shotgun metagenomics, thermal spring water, Dermatology, RL1-803
Abstract

Florence Thirion,1,* Susie Guilly,1,* Sébastien Fromentin,1 Florian Plaza Oñate,1 Anne-Sophie Alvarez,1 Emmanuelle Le Chatelier,1 Nicolas Pons,1 Florence Levenez,1 Benoît Quinquis,1 Stanislav Ehrlich,1 Joel Doré,1,2 Richard Martin,3 Sophie Seité4 1University Paris-Saclay, INRAE, MGP, Jouy-en-Josas, 78350, France; 2University Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France; 3Mercurialis Biotech, Rochecorbon, France; 4La Roche-Posay Dermatological Laboratories, Levallois-Perret, France*These authors contributed equally to this workCorrespondence: Sophie Seit&#x00E9La Roche-Posay Dermatological Laboratories, 62 quai Charles Pasqua, Levallois-Perret, 92300, France, Tel +33 1 49 64 33 40, Email sophie.seite@loreal.comIntroduction: Balneotherapy (BT) is the treatment of disease through the use of thermal spring water (TSW). It has been used for centuries and remains a popular form of treatment for dermatologic diseases such as atopic dermatitis (AD). Recent findings highlighted the role of the gut microbiota in AD and the possible crosstalk between gut and skin microbiomes in this pathology. Nevertheless, changes in the composition of the gut microbiota after balneotherapy remain to be elucidated.Methods: A total of 96 patients, with moderate to severe AD according to the SCORAD, were enrolled. Stool samples were collected prior and post a 3-week balneotherapy at the thermal care center of La Roche-Posay (France). Composition of the gut microbiota was assessed by shotgun metagenomic sequencing.Results: Species associated with high gut microbiota richness tended to correlate negatively with disease severity (SCORAD) and positively with SCORAD reduction, while species associated with low richness displayed the opposite pattern. Relative abundance of 23 species was significantly altered during BT, these changes being significantly associated with SCORAD reduction during BT, suggesting that gut microbiota composition and AD progression were associated through the treatment. Microbial functions related to gut-brain axis such as GABA and tryptophan metabolism were also altered by the treatment. Long-standing AD patients exhibited a better gut microbial profile than recently diagnosed patients, with higher MSP richness and species associated with SCORAD reduction.Conclusion: In patients with AD, clinical disease parameters such as SCORAD or disease duration are intricately linked to the gut microbiota composition. SCORAD reduction occurring during BT was also associated with gut microbiota. The gut-brain-skin axis via neurotransmitter such as GABA should be further studied in diseases such as AD.Keywords: atopic dermatitis, balneotherapy, gut microbiota, shotgun metagenomics, thermal spring water

Published
2022

2. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients

Author

Gopalakrishnan, V., Spencer, C. N., Nezi, L., Reuben, A., Andrews, M. C., Karpinets, T. V., Prieto, P. A., Vicente, D., Hoffman, K., Wei, S. C., Cogdill, A. P., Zhao, L., Hudgens, C. W., Hutchinson, D. S., Manzo, T., de Macedo, M. Petaccia, Cotechini, T., Kumar, T., Chen, W. S., Reddy, S. M., Sloane, R. Szczepaniak, Galloway-Pena, J., Jiang, H., Chen, P. L., Shpall, E. J., Rezvani, K., Alousi, A. M., Chemaly, R. F., Shelburne, S., Vence, L. M., Okhuysen, P. C., Jensen, V. B., Swennes, A. G., McAllister, F., Sanchez, E. Marcelo Riquelme, Zhang, Y., Le Chatelier, E., Zitvogel, L., Pons, N., Austin-Breneman, J. L., Haydu, L. E., Burton, E. M., Gardner, J. M., Sirmans, E., Hu, J., Lazar, A. J., Tsujikawa, T., Diab, A., Tawbi, H., Glitza, I. C., Hwu, W. J., Patel, S. P., Woodman, S. E., Amaria, R. N., Davies, M. A., Gershenwald, J. E., Hwu, P., Lee, J. E., Zhang, J., Coussens, L. M., Cooper, Z. A., Futreal, P. A., Daniel, C. R., Ajami, N. J., Petrosino, J. F., Tetzlaff, M. T., Sharma, P., Allison, J. P., Jenq, R. R., and Wargo, J. A.

Published
2018

3. Towards Control of Steady State Plasma on Tore Supra

Author

Moreau, Philippe-Jacques, Barana, Oliviero, Brémond, Sylvain, Bucalossi, Jérome, Joffrin, Emmanuel, Chatelier, E., Mazon, Didier, Witrant, Emmanuel, Schuster, Eugenio, and Ariola, Marco

Subjects
Physics - Plasma Physics
Abstract

The Tore Supra tokamak is the largest superconducting magnetic fusion facility, has been devoted to long-duration high-performance discharge research. With a steady-state magnetic field and water cooled plasma facing components, discharges up to 6 minutes 24 seconds duration with injected / extracted energy up to 1 GJ have been performed. The Tore Supra real time measurements and control (RTMC) system has been upgraded to address schemes dedicated to long pulse operation with simultaneous control of an increasing number of plasma parameters. This includes plasma equilibrium control with possible self calibration during the discharge, plasma density control with possible pellet injection, current profile control to avoid magneto-hydrodynamic (MHD) instabilities and infrared monitoring of plasma facing components preventing overheating. Most of these improvements are relevant to the tokamaks operation in a fully steady state regime.

Published
2007
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4. Combinatorial, additive and dose-dependent drug-microbiome associations

Author

Forslund, SK, Chakaroun, R, Zimmermann-Kogadeeva, M, Markó, L, Aron-Wisnewsky, J, Nielsen, T, Moitinho-Silva, L, Schmidt, TSB, Falony, G, Vieira-Silva, S, Adriouch, S, Alves, RJ, Assmann, K, Bastard, J-P, Birkner, T, Caesar, R, Chilloux, J, Coelho, LP, Fezeu, L, Galleron, N, Helft, G, Isnard, R, Ji, B, Kuhn, M, Le Chatelier, E, Myridakis, A, Olsson, L, Pons, N, Prifti, E, Quinquis, B, Roume, H, Salem, J-E, Sokolovska, N, Tremaroli, V, Valles-Colomer, M, Lewinter, C, Søndertoft, NB, Pedersen, HK, Hansen, TH, Amouyal, C, Andersson Galijatovic, EA, Andreelli, F, Barthelemy, O, Batisse, J-P, Belda, E, Berland, M, Bittar, R, Blottière, H, Bosquet, F, Boubrit, R, Bourron, O, Camus, M, Cassuto, D, Ciangura, C, Collet, J-P, Dao, M-C, Djebbar, M, Doré, A, Engelbrechtsen, L, Fellahi, S, Fromentin, S, Galan, P, Gauguier, D, Giral, P, Hartemann, A, Hartmann, B, Holst, JJ, Hornbak, M, Hoyles, L, Hulot, J-S, Jaqueminet, S, Jørgensen, NR, Julienne, H, Justesen, J, Kammer, J, Krarup, N, Kerneis, M, Khemis, J, Kozlowski, R, Lejard, V, Levenez, F, Lucas-Martini, L, Massey, R, Martinez-Gili, L, Maziers, N, Medina-Stamminger, J, Montalescot, G, Moute, S, Neves, AL, Olanipekun, M, Le Pavin, LP, Poitou, C, Pousset, F, Pouzoulet, L, Rodriguez-Martinez, A, Rouault, C, Silvain, J, Svendstrup, M, Swartz, T, Vanduyvenboden, T, Vatier, C, Walther, S, Gøtze, JP, Køber, L, Vestergaard, H, Hansen, T, Zucker, J-D, Hercberg, S, Oppert, J-M, Letunic, I, Nielsen, J, Bäckhed, F, Ehrlich, SD, Dumas, M-E, Raes, J, Pedersen, O, Clément, K, Stumvoll, M, Bork, P, The MetaCardis Consortium (Hoyles, L.), European Molecular Biology Laboratory [Heidelberg] (EMBL), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Berlin Institute of Health (BIH), German Center for Cardiovascular Research (DZHK), Universität Leipzig, Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Copenhagen = Københavns Universitet (UCPH), University of New South Wales [Sydney] (UNSW), Paul Scherrer Institute (PSI), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Heidelberg University, Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Henri Mondor [Créteil], 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], University of Gothenburg (GU), Imperial College London, MetaGenoPolis (MGP (US 1367)), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Paris-Saclay, Institut de cardiologie [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), Chalmers University of Technology [Gothenburg, Sweden], Unité de modélisation mathématique et informatique des systèmes complexes [Bondy] (UMMISCO), Université de Yaoundé I-Institut de la francophonie pour l'informatique-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cadi Ayyad [Marrakech] (UCA)-Sorbonne Université (SU)-Institut de Recherche pour le Développement (IRD [France-Nord]), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), 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), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Biobyte Solutions [Heidelberg, Germany] (BS), IT University of Copenhagen (ITU), Sahlgrenska University Hospital [Gothenburg], Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), 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), National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, McGill University and Genome Quebec Innovation Centre, Helmholtz Institute Ulm (HIU), Helmholtz Zentrum München = German Research Center for Environmental Health, University of Würzburg = Universität Würzburg, Yonsei University, MetaCardis Consortium*: Chloe Amouyal, Ehm Astrid Andersson Galijatovic, Fabrizio Andreelli, Olivier Barthelemy, Jean-Paul Batisse, Eugeni Belda, Magalie Berland, Randa Bittar, Hervé Blottière, Frederic Bosquet, Rachid Boubrit, Olivier Bourron, Mickael Camus, Dominique Cassuto, Cecile Ciangura, Jean-Philippe Collet, Maria-Carlota Dao, Morad Djebbar, Angélique Doré, Line Engelbrechtsen, Soraya Fellahi, Sebastien Fromentin, Pilar Galan, Dominique Gauguier, Philippe Giral, Agnes Hartemann, Bolette Hartmann, Jens Juul Holst, Malene Hornbak, Lesley Hoyles, Jean-Sebastien Hulot, Sophie Jaqueminet, Niklas Rye Jørgensen, Hanna Julienne, Johanne Justesen, Judith Kammer, Nikolaj Krarup, Mathieu Kerneis, Jean Khemis, Ruby Kozlowski, Véronique Lejard, Florence Levenez, Lea Lucas-Martini, Robin Massey, Laura Martinez-Gili, Nicolas Maziers, Jonathan Medina-Stamminger, Gilles Montalescot, Sandrine Moute, Ana Luisa Neves, Michael Olanipekun, Laetitia Pasero Le Pavin, Christine Poitou, Francoise Pousset, Laurence Pouzoulet, Andrea Rodriguez-Martinez, Christine Rouault, Johanne Silvain, Mathilde Svendstrup, Timothy Swartz, Thierry Vanduyvenboden, Camille Vatier, Stefanie Walther., ANR-16-IDEX-0004,ULNE,ULNE(2016), ANR-18-IBHU-0001,PreciDIAB,PreciDIAB Institute, the holistic approach of personal diabets care(2018), Dumas, Marc-Emmanuel, Universität Leipzig [Leipzig], Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], CHU Henri Mondor, Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-1901(ex CIC-1421)), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Imperial College London - National Heart and Lung Institute, and Division of Computational and Systems Medicine, Imperial College London, London, SW7 2AZ, UK

Subjects
Clostridiales, Science & Technology, Multidisciplinary, ANTIBIOTIC USE, IMPACT, Microbiota, [SDV]Life Sciences [q-bio], HUMAN GUT MICROBIOME, Atherosclerosis, Gastrointestinal Microbiome, [SDV] Life Sciences [q-bio], Multidisciplinary Sciences, PROTON PUMP INHIBITORS, Cardiovascular and Metabolic Diseases, GUIDELINE, Metabolome, MANAGEMENT, Humans, Science & Technology - Other Topics, ALTERS
Abstract

During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1-5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug-host-microbiome interactions in cardiometabolic disease. ispartof: NATURE vol:600 issue:7889 pages:500-+ ispartof: location:England status: published

Published
2021

5. Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology (vol 11, 5881, 2020)

Author

Molinaro, A, Lassen, PB, Henricsson, M, Wu, H, Adriouch, S, Belda, E, Chakaroun, R, Nielsen, T, Bergh, P-O, Rouault, C, Andre, S, Marquet, F, Andreelli, F, Salem, J-E, Assmann, K, Bastard, J-P, Forslund, S, Le Chatelier, E, Falony, G, Pons, N, Prifti, E, Quinquis, B, Roume, H, Vieira-Silva, S, Hansen, TH, Pedersen, HK, Lewinter, C, Sonderskov, NB, Kober, L, Vestergaard, H, Hansen, T, Zucker, J-D, Galan, P, Dumas, M-E, Raes, J, Oppert, J-M, Letunic, I, Nielsen, J, Bork, P, Ehrlich, SD, Stumvoll, M, Pedersen, O, Aron-Wisnewsky, J, Clement, K, Backhed, F, and Commission of the European Communities

Subjects
Multidisciplinary Sciences, MetaCardis Consortium, Science & Technology, Science & Technology - Other Topics
Published
2020

6. Statin therapy is associated with lower prevalence of gut microbiota dysbiosis [plus Methods, Extended data figures, Supplementary information, and Nature Research reporting summary]

Author

Vieira-Silva, S., Falony, G., Belda, E., Nielsen, T., Aron-Wisnewsky, J., Chakaroun, R., Forslund, S.F., Assmann, K., Valles-Colomer, M., Nguyen, T.T.D., Proost, S., Prifti, E., Tremaroli, V., Pons, N., Le Chatelier, E., Andreelli, F., Bastard, J.P., Coelho, L.P., Galleron, N., Hulot, J.S., Lewinter, C., Pedersen, H.K., Quinquis, B., Rouault, C., Roume, H., Salem, J.E., Søndertoft, N.B., Touch, S., Dumas, M.E., Ehrlich, S.D., Galan, P., Gøtze, J.P., Hansen, T.H., Holst, J.S., Køber, L., Letunic, I., Nielsen, J., Oppert, J.M., Stumvoll, M., Vestergaard, H., Zucker, Jean-Daniel, Bork, P., Pedersen, O., Bäckhed, F., Clément, K., Raes, J., Nutrition et obésités: approches systémiques (nutriomics) (UMR-S 1269 INSERM - Sorbonne Université), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université (SU), Service de nutrition [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Unité de modélisation mathématique et informatique des systèmes complexes [Bondy] (UMMISCO), Sorbonne Université (SU)-Universtié Yaoundé 1 [Cameroun]-Université Cadi Ayyad [Marrakech] (UCA)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de la francophonie pour l'informatique-Institut de Recherche pour le Développement (IRD [France-Nord]), Service de diabétologie [CHU Pitié-Salpétrière], Service de biochimie et hormonologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Centre de Recherche Saint-Antoine (CR Saint-Antoine), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), CIC - HEGP (CIC 1418), 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 National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service de pharmacologie biologique [CHU Pitié-Salpêtrière], CIC Paris Est, Sorbonne Université - Faculté de Médecine (SU FM), and Sorbonne Université (SU)

Subjects
[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Microbiome community typing analyses have recently identified the Bacteroides2 (Bact2) enterotype, an intestinal microbiota configuration that is associated with systemic inflammation and has a high prevalence in loose stools in humans. Bact2 is characterized by a high proportion of Bacteroides, a low proportion of Faecalibacterium and low microbial cell densities and its prevalence varies from 13% in a general population cohort to as high as 78% in patients with inflammatory bowel disease. Reported changes in stool consistency and inflammation status during the progression towards obesity and metabolic comorbidities led us to propose that these developments might similarly correlate with an increased prevalence of the potentially dysbiotic Bact2 enterotype. Here, by exploring obesity-associated microbiota alterations in the quantitative faecal metagenomes of the cross-sectional MetaCardis Body Mass Index Spectrum cohort (n = 888), we identify statin therapy as a key covariate of microbiome diversification. By focusing on a subcohort of participants that are not medicated with statins, we find that the prevalence of Bact2 correlates with body mass index, increasing from 3.90% in lean or overweight participants to 17.73% in obese participants. Systemic inflammation levels in Bact2-enterotyped individuals are higher than predicted on the basis of their obesity status, indicative of Bact2 as a dysbiotic microbiome constellation. We also observe that obesity-associated microbiota dysbiosis is negatively associated with statin treatment, resulting in a lower Bact2 prevalence of 5.88% in statin-medicated obese participants. This finding is validated in both the accompanying MetaCardis cardiovascular disease dataset (n = 282) and the independent Flemish Gut Flora Project population cohort (n = 2,345). The potential benefits of statins in this context will require further evaluation in a prospective clinical trial to ascertain whether the effect is reproducible in a randomized population and before considering their application as microbiota-modulating therapeutics.

Published
2020

7. La consommation pendant deux mois d’un pain enrichi en mix de fibres modifie la composition du microbiote intestinal et améliore le profil lipidique et d’insulino-sensibilité chez les sujets à risque cardiométabolique

Author

Ranaivo, H., primary, Guilly, S., additional, Sothier, M., additional, Van Den Berghe, L., additional, Lambert-Porcheron, S., additional, Feugier-Favier, N., additional, Blond, E., additional, Dussous, I., additional, Roger, L., additional, Béra-Maillet, C., additional, Roume, H., additional, Galleron, N., additional, Pons, N., additional, Le Chatelier, E., additional, Ehrlich, D., additional, Laville, M., additional, Doré, J., additional, and Nazare, J.-A., additional

Published
2020
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8. Elevated serum ceramides are linked with obesity-associated gut dysbiosis and impaired glucose metabolism

Author

Kayser, B. D., Prifti, E., Lhomme, M., Belda, E., Dao, M. C., Aron-Wisnewsky, J., Kontush, A., Zucker, Jean-Daniel, Rizkalla, S. W., Dugail, I., Clement, K., Kennedy, S. P., Pons, N., Le Chatelier, E., Almeida, M., Quinquis, B., Galleron, N., Batto, J. M., Renault, P., Ehrlich, S. D., Blottiere, H., Leclerc, M., de Wouters, T., Lepage, P., Dore, J., and MICRO-Obes Consortium

Subjects
Sphingolipids, Glucose metabolism, Endotoxin, Microbiome, Ceramides
Abstract

Introduction Low gut microbiome richness is associated with dyslipidemia and insulin resistance, and ceramides and other sphingolipids are implicated in the development of diabetes. Objectives Determine whether circulating sphingolipids, particularly ceramides, are associated with alterations in the gut microbiome among obese patients with increased diabetes risk. Methods This was a cross-sectional and longitudinal retrospective analysis of a dietary/weight loss intervention. Fasted serum was collected from 49 participants (41 women) and analyzed by HPLC-MS/MS to quantify 45 sphingolipids. Shotgun metagenomic sequencing of stool was performed to profile the gut microbiome. Results Confirming the link to deteriorated glucose homeostasis, serum ceramides were positively correlated with fasting glucose, but inversely correlated with fasting and OGTT-derived measures of insulin sensitivity and beta-cell function. Significant associations with gut dysbiosis were demonstrated, with SM and ceramides being inversely correlated with gene richness. Ceramides with fatty acid chain lengths of 20-24 carbons were the most associated with low richness. Diet-induced weight loss, which improved gene richness, decreased most sphingolipids. Thirty-one MGS, mostly corresponding to unidentified bacteria species, were inversely correlated with ceramides, including a number of Bifidobacterium and Methanobrevibacter smithii. Higher ceramide levels were also associated with increased metagenomic modules for lipopolysaccharide synthesis and flagellan synthesis, two pathogen-associated molecular patterns, and decreased enrichment of genes involved in methanogenesis and bile acid metabolism. Conclusion This study identifies an association between gut microbiota richness, ceramides, and diabetes risk in overweight/obese humans, and suggests that the gut microbiota may contribute to dysregulation of lipid metabolism in metabolic disorders.

Published
2019

13. Identification and assembly of genomes and genetic elements in complex metagenomic samples without using reference genomes

Author

Nielsen, H.B., Almeida, M., Sierakowska Juncker, A., Rasmussen, S., Li, J., Sunagawa, S., Plichta, D.R., Gautier, L., Pedersen, A.G., Le Chatelier, E., Pelletier, E., Bonde, I., Nielsen, T., Manichanh, C., Arumugam, M., Batto, J.M., Quintanilha dos Santos, M.B., Blom, N., Borruel, N., Burgdorf, K.S., Boumezbeur, F., Casellas, F., Doré, J., Dworzynski, P., Guarner, F., Hansen, T., Hildebrand, F., Kaas, R.S., Kennedy, S., Kristiansen, K., Kultima, J.R., Leonard, P., Levenez, F., Lund, O., Moumen, B., Le Paslier, D., Pons, N., Pedersen, O., Prifti, E., Qin, J., Raes, J., Sørensen, S., Tap, J., Tims, S., Ussery, D.W., Yamada, T., Jamet, A., Mérieux, A., Cultrone, A., Torrejon, A., Quinquis, B., Brechot, C., Delorme, C., M'Rini, C., de Vos, W.M., Maguin, E., Varela, E., Guedon, E., Gwen, F., Haimet, F., Artiguenave, F., Vandemeulebrouck, G., Denariaz, G., Khaci, G., Blottière, H., Knol, J., Weissenbach, J., van Hylckama Vlieg, J.E., Torben, J., Parkhil, J., Turner, K., van de Guchte, M., Antolin, M., Rescigno, M., Kleerebezem, M., Derrien, M., Galleron, N., Sanchez, N., Grarup, N., Veiga, P., Oozeer, R., Dervyn, R., Layec, S., Bruls, T., Winogradski, Y., Zoetendal, E.G., Renault, D., Sicheritz-Ponten, Bork, P., Wang, J., Brunak, S., Ehrlich, S.D., Center for Biological Sequence Analysis, Technical University of Denmark [Lyngby] (DTU), Novo Nordisk Foundation Center for Biosustainability, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Department of Computer Science [Baltimore], Johns Hopkins University (JHU), BGI Hong Kong Researche Institute, BGI Shenzhen, School of Bioscience and Biotechnology, Southern University of Science and Technology [Shenzhen] (SUSTech), European Molecular Biology Laboratory, US 1367 MetaGénoPolis, Institut National de la Recherche Agronomique (INRA)-Département Microbiologie et Chaîne Alimentaire (MICA), Institut National de la Recherche Agronomique (INRA)-MetaGénoPolis (MGP), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Université d'Évry-Val-d'Essonne (UEVE), Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Digestive System Research Unit, Vall d'Hebron University Hospital [Barcelona], Faculty of Health Sciences, University of Southern Denmark (SDU), Department of Structural Biology, Flanders Institute for Biotechnology, Department of Bioscience Engineering, Vrije Universiteit [Brussels] (VUB), 8National Food Institute - Division for Epidemiology and Microbial Genomics, Department of Biology [Copenhagen], Faculty of Science [Copenhagen], Hagedorn Research Institute, Faculty of Health, Aarhus University [Aarhus], BGI Hong Kong research Institute, Rega Institute - Department of Microbiology and Immunology, Université Catholique de Louvain (UCL), VIB Center for the Biology of Disease, Section of Microbiology [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU)-Faculty of Science [Copenhagen], Laboratory of Microbiology, Wageningen University and Research Centre [Wageningen] (WUR), Department of Biological Information, Tokyo Institute of Technology [Tokyo] (TITECH), Max-Delbrück Center for Molecular Medicine, Princess Al Jawhara Center of Excellence in the Research of Hereditary Disorders, King Abdulaziz University, Centre for Host-Microbiome Interactions, Dental Institute Central Office, Guy’s Hospital, King‘s College London, Département Microbiologie et Chaîne Alimentaire (MICA), Institut National de la Recherche Agronomique (INRA), European Community's Seventh Framework Programme [FP7-HEALTH-F4-2007-201052, FP7-HEALTH-2010-261376], OpenGPU FUI collaborative research projects, DGCIS, Instituto de Salud Carlos III (Spain), Ministere de la Recherche et de l'Education Nationale (France), [ANR-11-DPBS-0001], Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Beijing Genomics Institute [Shenzhen] (BGI), Southern University of Science and Technology (SUSTech), MetaGenoPolis, Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Vrije Universiteit Brussel (VUB), Université Catholique de Louvain = Catholic University of Louvain (UCL), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH)-Faculty of Science [Copenhagen], Wageningen University and Research [Wageningen] (WUR), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, European Project: 201052,EC:FP7:HEALTH,FP7-HEALTH-2007-A,METAHIT(2008), Department of Systems Biology, Center for Biological Sequence Analysis, Ctr Biol Sequence Anal, National University of Singapore (NUS), European Molecular Biology Laboratory [Heidelberg] (EMBL), Department of Mathematics and Computer Science [Odense] (IMADA), Génomique métabolique (UMR 8030), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Vall d’Hebron Research Institute (VHIR), Faculty of Health and Medical Sciences, The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen = Københavns Universitet (KU), INRA US1367 MetaGenoPolis, European Molecular Biology Laboratory [Grenoble] (EMBL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], Center for Biological Sequence Analysis [Lyngby], Chinese Academy of Agricultural Mechanization Sciences (CCCME), 1Génétique Microbienne, INRA, Domaine de Vilvert, 78352 Jouy en Josas Cedex, and Department of Bio-engineering Sciences

Subjects
Cellular immunity, polypeptide, [SDV]Life Sciences [q-bio], SHORT READ ALIGNMENT SEQUENCES SYSTEMS ALGORITHMS MICROBIOTA PROTEIN LIFE SETS TREE TOOL, complex metagenomic sample, Applied Microbiology and Biotechnology, Genome, Microbiologie, Databases, Genetic, genetic element, Cluster Analysis, sets, short read alignment, ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, tool, metagenomic, tree, Lactococcus lactis, IL-12, Molecular Medicine, Biotechnology, life, Microbial Genomes, antigen specific immune response, Biomedical Engineering, Bioengineering, Computational biology, [SDV.BID]Life Sciences [q-bio]/Biodiversity, cellular immunity, Biology, algorithms, Microbiology, 03 medical and health sciences, Genetic variation, microbiota, Microbiome, Gene, genome, 030304 developmental biology, adjuvant activity, VLAG, 030306 microbiology, Metagenomics, WIAS, Microbial genetics, sequences, systems, protein
Abstract

Most current approaches for analyzing metagenomic data rely on comparisons to reference genomes, but the microbial diversity of many environments extends far beyond what is covered by reference databases. De novo segregation of complex metagenomic data into specific biological entities, such as particular bacterial strains or viruses, remains a largely unsolved problem. Here we present a method, based on binning co-abundant genes across a series of metagenomic samples, that enables comprehensive discovery of new microbial organisms, viruses and co-inherited genetic entities and aids assembly of microbial genomes without the need for reference sequences. We demonstrate the method on data from 396 human gut microbiome samples and identify 7,381 co-abundance gene groups (CAGs), including 741 metagenomic species (MGS). We use these to assemble 238 high-quality microbial genomes and identify affiliations between MGS and hundreds of viruses or genetic entities. Our method provides the means for comprehensive profiling of the diversity within complex metagenomic samples.

Published
2014

14. Gut microbiome is profoundly altered in acute-on-chronic liver failure as evaluated by quantitative metagenomics. Relationship with liver cirrhosis severity

Author

Sole, C., primary, Llopis, M., additional, Solà, E., additional, Da Silva, K., additional, Guilly, S., additional, Le-Chatelier, E., additional, Huelin, P., additional, Moreira, R., additional, Carol, M., additional, De Prada, G., additional, Ehrlich, S., additional, Graupera, I., additional, Napoleone, L., additional, Pose, E., additional, Juanola, A., additional, Fabrellas, N., additional, Doré, J., additional, Ehrlich, D., additional, and Ginès, P., additional

Published
2018
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15. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity : relationship with gut microbiome richness and ecology [plus Supplementary data]

Author

Dao, M.C., Everard, A., Aron-Wisnewsky, J., Sokolovska, N., Prifti, E., Verger, E.O., Kayser, B.D., Levenez, F., Chilloux, J., Hoyles, L., Dumas, M.E., Rizkalla, S.W., Dore, J., Cani, P.D., Clement, K., MICRO-Obes Consortium, Le Mouhaër, S. (collab.), Cotillard, A. (collab.), Kennedy, S.P. (collab.), Pons, N. (collab.), Le Chatelier, E. (collab.), Almeida, M. (collab.), Quinquis, B. (collab.), Galleron, N. (collab.), Batto, J.M. (collab.), Renault, P. (collab.), Zucker, Jean-Daniel (collab.), Dusko Ehrlich, S. (collab.), Blottière, H. (collab.), Leclerc, M. (collab.), Juste, C. (collab.), De Wouters, T. (collab.), and Lepage, P. (collab.)

Abstract

Objective. Individuals with obesity and type 2 diabetes differ from lean and healthy individuals in their abundance of certain gut microbial species and microbial gene richness. Abundance of Akkermansia muciniphila, a mucin-degrading bacterium, has been inversely associated with body fat mass and glucose intolerance in mice, but more evidence is needed in humans. The impact of diet and weight loss on this bacterial species is unknown. Our objective was to evaluate the association between faecal A. muciniphila abundance, faecal microbiome gene richness, diet, host characteristics, and their changes after calorie restriction (CR). Design. The intervention consisted of a 6-week CR period followed by a 6-week weight stabilisation diet in overweight and obese adults (N=49, including 41 women). Faecal A. muciniphila abundance, faecal microbial gene richness, diet and bioclinical parameters were measured at baseline and after CR and weight stabilisation. Results. At baseline A. muciniphila was inversely related to fasting glucose, waist-to-hip ratio and subcutaneous adipocyte diameter. Subjects with higher gene richness and A. muciniphila abundance exhibited the healthiest metabolic status, particularly in fasting plasma glucose, plasma triglycerides and body fat distribution. Individuals with higher baseline A. muciniphila displayed greater improvement in insulin sensitivity markers and other clinical parameters after CR. These participants also experienced a reduction in A. muciniphila abundance, but it remained significantly higher than in individuals with lower baseline abundance. A. muciniphila was associated with microbial species known to be related to health. Conclusions. A. muciniphila is associated with a healthier metabolic status and better clinical outcomes after CR in overweight/obese adults. The interaction between gut microbiota ecology and A. muciniphila warrants further investigation.

Published
2016

16. Specific gut microbiota features and metabolic markers in postmenopausal women with obesity

Author

Brahe, Lena Kirchner, Le Chatelier, E, Prifti, E, Pons, N, Kennedy, S, Hansen, Torben, Pedersen, Oluf Borbye, Astrup, Arne, Ehrlich, S D, Larsen, Lesli Hingstrup, University of Copenhagen = Københavns Universitet (KU), MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR), Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), The Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care and The Danish Dairy Board and Arla Foods amba provided financial support. Metagenopolis is funded by the Investissement d’Avenir grant ANR-11-DPBS-0001., We wish to thank the study participants and the staff from INRA/MetaGenoPolis: Florence Levenez and Joël Doré for sample preparation, Nathalie Galleron and Benoit Quinquis for microbiome sequencing, Jean-Michel Batto and Pierre Leonard for informatics. The study is part of The Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care (www.LuCAMP.org)., ANR-11-DPBS-0001,MGP,MetaGenoPolis(2011), Brahe, L. K., and Le Chatelier, Emmanuelle

Subjects
Endocrinology, Diabetes and Metabolism, MEDLINE, Gut flora, Bioinformatics, digestive system, fluids and secretions, microbiote, Internal Medicine, Medicine, Obesity, 2. Zero hunger, Postmenopausal women, biology, Bacteria, business.industry, digestive, oral, and skin physiology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, biology.organism_classification, stomatognathic diseases, obésité, activité métabolique, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Risk factors, Metabolic markers, femme menopausée, Original Article, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background: Gut microbial gene richness and specific bacterial species are associated with metabolic risk markers in humans, but the impact of host physiology and dietary habits on the link between the gut microbiota and metabolic markers remain unclear. The objective of this study was to identify gut metagenomic markers associated with estimates of insulin resistance, lipid metabolism and inflammation in obesity, and to explore whether the associations between metagenomic and metabolic markers persisted after adjustment for body fat, age and habitual dietary intake. Methods: Faecal DNA from 53 women with obesity was analysed through quantitative metagenomic sequencing and analysis, and a systematic search was performed for bacterial genes associated with estimates of insulin resistance, inflammation and lipid metabolism. Subsequently, the correlations between metagenomic species and metabolic markers were tested by linear regression models, with and without covariate adjustment. Results: One hundred and fourteen metagenomic species correlated with metabolic markers (PAkkermansia muciniphila, Bilophila wadsworthia, Bifidobacterium longum and Faecalibacterium prausnitzii, but also species not previously associated with metabolic markers including Bacteroides faecis and Dorea longicatena. The majority of the identified correlations between bacterial species and metabolic markers persisted after adjustment for differences in body fat, age and dietary macronutrient composition; however, the negative correlation with insulin resistance observed for B. longum and F. prausnitzii appeared to be modified by the intake of dietary fibre and fat, respectively. Conclusions: This study shows that several gut bacterial species are linked to metabolic risk markers in obesity, also after adjustment for potential confounders, such as long-term diet composition. The study supports the use of gut metagenomic markers for metabolic disease prediction and warrants further investigation of causality.

Published
2015

18. P1016 The pig’s other genome: A reference gene catalog of the gut microbiome as a new resource for deep studies of the interplay between the host and its microbiome

Author

Xiao, L., primary, Estellé, J., additional, Kiilerich, P., additional, Ramayo-Caldas, Y., additional, Xia, Z., additional, Feng, Q., additional, Pedersen, A. Ø., additional, Kjeldsen, N. J., additional, Maguin, E., additional, Doré, J., additional, Pons, N., additional, le Chatelier, E., additional, Madsen, L., additional, Wang, J., additional, Ehrlich, S. D., additional, Kristiansen, K., additional, and Rogel-Gaillard, C., additional

Published
2016
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20. TORE SUPRA Team Mmembers 1988-2008

Author

Abgrall, R., Achard, M.H., Adam, J., Agarici, G., Agostini, E., Airaj, M., Albajar-Vinas, F., Allegretti, L., Allibert, J.P., Alliez, J.C., Allouche, A., Andreoletti, J., Ane, J.M., Angelino, P., Aniel, T., Antar, G., Arcis, N., Argouarch, A., Arnas, C., Arnoux, G., Arslanbekov, R., Artaud, J.F., Asp, E., Assas, S., Atttuel, G., Aymar, R., Azeroual, A., Balme, S., Barana, O., Bareyt, B., Basiuk, V., Basko, M., Bayetti, P., Baylor, L., Beaumont, B., Becherer, R., Becoulet, A., Becoulet, M., Begrambekov, L., Benkadda, S., Benoit, F., Bergeaud, V., Berger-By, G., Berio, S., Bernascolle, P., Bernier, N., Berroukeche, M., Bertrand, B., Bessette, D., Beyer, P., Bibet, P., Bizzaro, J., Blanchard, P., Blum, J., Boddeker, S., Boilson, D., Mardion, G.B., Bonnel, P., Bonnin, X., Boscary, J., Bosia, G., Bottereau, J.M., Bottiglioni, F., Bottollier-Curtet, H., Bouchand, C., Bouligand, G., Bouquey, F., Bourdelle, C., Bregeon, R., Bremond, F., Bremond, S., Breton, C., Breton, M., Brosset, C., Brugnetti, R., Bruneau, J.L., Bucalossi, J., Budny, R.V., Buravand, Y., Bush, C., Bussac, M.N., Cambe, A., Capes, H., Capitain, J.J., Cara, P., Carbonnier, J.L., Carpentier, S., Carrasco, J., Casati, A., Chaibi, O., Chamouard, C., Chantant, M., Chappuis, P., Chatain, D., Chatelier, E., Chatelier, M., Chatenet, J.H., Chen, X.P., Cherigier, L., Chevet, G., Chiarazzo, L., Ciazynski, D., Ciraolo, G., Cismondi, F., Clairet, F., Clary, J., Clement, C., Colas, L., Commaux, N., Corbel, E., Cordier, J.J., Corre, Y., Costanzo, L., Cote, A., Coulon, J.P., Courtois, L., Courtois, X., Couturier, B., Crenn, J.P., Cristofani, P., Crouseilles, N., Czarny, O., Rosa, P.D., Darbos, C., Darmet, G., Davi, M., Daviot, R., De Esch, H., De Gentile, B., De Haas, J.C., De La Cal, E., De Michelis, C., Deck, C., Decker, J., Decool, P., Degond, P., Dejarnac, R., Delchambre, E., Delmas, E., Delpech, L., Demarthe, H., Dentan, M., Depret, G., Deschamps, P., Desgranges, C., Devynck, P., Doceul, L., Dolgetta, N., Doloc, C., Dong, Y., Dore, P., Douai, D., Dougnac, H., Drawin, H.W., Druaux, J., Druetta, M., Dubois, F., Dubois, M., Dubuit, N., Duchateau, J.L., de Wit, T.D., Dufour, E., Dumont, R., Dunand, G., Dupas, L., Duran, Y., Durocher, A., Edery, D., Ekedahl, A., Elbeze, D., Eriksson, L.G., Escande, D., Escarguel, A., Escourbiac, F., Evans, T., Faisse, F., Falchetto, G., Fall, T., Farge, M., Farjon, J.L., Faudot, E., Fazilleau, P., Fedorczak, N., Fenzi-Bonizec, C., Ferron, J.R., Fidone, I., Figarella, C., Fleurence, E., Fleury, I., Fois, M., Forrest, C., Foster, C.A., Fouquet, S., Fourment, C., Fraboulet, D., Francois, P., Franel, B., Frigione, D., Froissard, P., Fubiani, G., Fuchs, V., Fumelli, M., Gagey, B., Galindo, V., Gambier, D., Garampon, L., Garbet, X., Garbil, R., Garcia, J., Gardarein, J.L., Gargiulo, L., Garibaldi, P., Garin, P., Gauthier, E., Geraud, A., Gerbaud, T., Gervais, F., Geynet, M., Ghendrih, P., Gianakon, T., Giannella, R., Gil, C., Girard, J.P., Giruzzi, G., Godbert-Mouret, L., Gomez, P., Goniche, M., Gordeev, A., Granata, G., Grandgirard, V., Gravier, R., Gravil, B., Gregoire, M., Gregoire, S., Grelot, P., Gresillon, D., Grisolia, C., Gros, G., Grosman, A., Grua, P., Guerin, O., Guigon, R., Guilhem, D., Guillerminet, B., Guirlet, R., Guiziou, L., Gunn, J., Hacquin, S., Harris, J., Haste, G., Hatchressian, J.C., Hemsworth, R., Hennequin, P., Hennion, F., Hennion, V., Henry, D., Hernandez, C., Hertout, P., Hess, W., Hesse, M., Heuraux, S., Hillairet, J., Hoang, G.T., Hogan, J., Hong, S.H., Honore, C., Horton, L., Horton, W.W., Houlberg, W.A., Hourtoule, J., Houry, M., Houy, P., How, J., Hron, M., Hutter, T., Huynh, P., Huysmans, G., Idmtal, J., Imbeaux, F., Isler, R., Jaben, C., Jacquinot, J., Jacquot, C., Jager, B., Jaunet, M., Javon, C., Jelea, A., Jequier, F., Jie, Y.X., Jimenez, R., Joffrin, E., Johner, J., Jourd'heuil, L., Y. Journeaux, J, Joyer, P., Ju, M., Jullien, F., Junique, F., Kaye, S.M., Kazarian, F., Khodja, H., Klepper, C., Kocan, M., Koski, J., Krivenski, V., Krylov, A., Kupfer, K., Kuus, H., Labit, B., Laborde, L., Lacroix, B., Ladurelle, L., Lafon, D., Lamaison, V., Laporte, P., Lasalle, J., Latu, G., Laugier, F., Laurent, L., Lausenaz, Y., Laviron, C., Layet, J.M., Le Bris, A., Le Coz, F., Le Niliot, C., Leclert, G., Lecoustey, P., Ledyankinc, A., Leloup, C., Lennholm, M., Leroux, F., Y. Li, Y, Libeyre, P., Linez, F., Lipa, M., Lippmann, S., Litaudon, X., Liu, W.D., Loarer, T., Lott, F., Lotte, P., Lowry, C., Luciani, J.F., Lutjens, H., Luty, J., Lutz, T., Lyraud, C., Maas, A., Macor, A., Madeleine, S., Magaud, P., Maget, P., Magne, R., Mahdavi, A., Mahe, F., Mailloux, J., Mandl, W., Manenc, L., Marandet, Y., Marbach, G., Marechal, J.L., Martin, C., Martin, G., Martin, V., Martinez, A., Martins, J.P., Maschke, E., Masse, L., Masset, R., Massmann, P., Mattioli, M., Mayaux, G., Mayoral, M.L., Mazon, D., McGrath, R., Mercier, C., Meslin, B., Meunier, L., Meyer, O., Michelot, Y., Million, L., Millot, P., Minguella, G., Minot, F., Mioduszewski, P., Misguich, J.H., Miskane, F., Missirlian, M., Mitteau, R., Moerel, F., Mollard, P., Monakhov, I., Moncada, V., Moncel, L., Monier-Garbet, P., Moreau, D., Moreau, F., Moreau, P., Morera, J.P., Moret, J.M., Moulin, B., Moulin, D., Mourgues, F., Moustier, M., Nakach, R., Nannini, M., Nanobashvili, I., Nardon, E., Navarra, P., Nehme, H., Nguyen, C., Nguyen, F., Nicollet, S., Nygren, R., Ogorodnikova, O., Olivain, J., Orlandelli, P., Ottaviani, M., Ouvrier-Buffet, P., Ouyang, Z., Owen, L., Pacella, D., Pain, M., Pamela, J., Pamela, S., Panek, R., Panzarella, A., Paris, R., Parisot, T., Park, S.H., Parlange, F., Parrat, H., Pastor, G., Pastor, P., Pastor, T., Patris, R., Paume, M., Payan, J., Pecquet, A.L., Pegourie, B., Petrov, Y., Petrzilka, V., Peysson, Y., Piat, D., Picchiottino, J.M., Pierre, J., Platz, P., Portafaix, C., Prou, M., Pugno, R., Putchy, L., Qin, C.M., Quallis, L., Quemeneur, A., Quet, P., Rabaglino, E., Raharijaona, J.J., Ramette, J., Ravenel, N., Rax, J.M., Reichle, R., Renard, B., Renner, H., Reuss, J.D., Reux, C., Reverdin, C., Rey, G., Reynaud, P., Riband, P.H., Richou, M., Rigollet, F., Rimini, F., Riquet, D., Rochard, F., Rodriguez, L., Romanelli, M., Romannikov, A., Rosanvallon, S., Roth, J., Rothan, B., Roubin, J.P., Roubin, P., Roupillard, G., Roussel, P., Ruggieri, R., Sabathier, F., Sabbagh, S.A., Sabot, R., Saha, S.K., Saint-Laurent, F., Salasca, S., Salmon, T., Salvador, J., Samaille, F., Samain, A., Santagiustina, A., Saoutic, B., Sarazin, Y., Schild, T., Schlosser, J., Schneider, M., Schneider, K., Schunke, B., Schwander, F., Schwob, J.L., Sebelin, E., Segui, J.L., Seigneur, A., Shepard, T., Shigin, P., Signoret, J., Simoncini, J., Simonet, F., Simonin, A., Sirinelli, A., Sledziewski, Z., Smits, F., Soler, K., Sonato, P.G., Song, S.D., Sonnendrucker, E., Sourd, F., Spitz, P., Spuig, P., Stamm, R., Stephan, Y., Stirling, W., Stockel, J., Stott, P., Sthal, K.S., Surle, F., Svensson, L., Tachon, J., Talvard, M., Tamain, P., Tavian, L., Tena, M., Theis, J.M., Thomas, C.E., Thomas, P., Thonnat, M., Tobin, S., Tokar, M., Tonon, G., Torossian, A., Torre, A., Trainham, R.C., Travere, J.M., Tresset, G., Trier, E., Truc, A., Tsitrone, E., Turck, B., Turco, F., Turlur, S., Uckan, T., Udintsev, V., Urguijo, G., Utzel, N., Vallet, J.C., Valter, J., Van Houtte, D., Van Rompuy, T., Vatry, A., Verga, A., Vermare, L., Vezard, D., Viallet, H., Villecroze, F., Villedieu, E., Villegas, D., Vincent, E., Voitsekovitch, I., von Hellermann, M., Voslamber, D., Voyer, D., Vulliez, K., Wachter, C., Wagner, T., Waller, V., Wang, G., Wang, Z., Watkins, J., Weisse, J., White, R., Wijnands, T., Witrant, E., Worms, J., Xiao, W., Yu, D., Zabeo, L., Zabiego, M., Zani, L., Zhuang, G., Zou, X.L., Zucchi, E., Zunino, K., and Zwingmann, W.

Published
2009

21. Development of RF heating and current drive systems for long pulse operation on Tore Supra

Author

Agarici, G., Allibert, J. P., Ane, J.M., Arslanbekov, R., Artaud, J.F., Balme, S., Basiuk, V., Bayetti, P., Baylor, L., Becoulet, A., Benkadda, M., Berger-By, G., Bdrio, S., Bibet, P., Bizarro, J.P., Boeddeker, S., Bon-Mardion, G., Bottereau, J.M., Bottiglioni, F., Brémond, S., Brugnetti, R., Budny, R. V., Buravand, Y., Capes, H., Capitain, J.J., Carbonnier, J.L., Carrasco, J., Chappuis, P., Chatelier, E., Chatelier, M., Chatenet, Jh., Cherigier, F., Ciazynski, D., Clairet, F., Colas, L., Cordier, J.J., Côté, A., Couturier, B., Crenn, J.P., Cristofani, P., Deck, C., Decool, P., Gentile, B. De, Cal, E de La, Demarthe, H., Michelis, C. De, Deschumps, P., Desgranges, C., Devynck, P., Doceul, L., Doloc, C., Dougnac, M., Druetta, M., Dubois, M., Duch~teau, J.L., Dupas, L., Edery, D., Elbèze, D., Escande, D., Farjon, J.L., Ferron, R., Fois, M., Forrest, C., Fraboulet, D., 6), V. Fuchs, Fumelli, M, Gagey, B., Garampon, L., Garbet, X., Gauthier, E., Geraud, A., Gervais, F., Ghendrih, P., Gil, C., Giruzzi, G., Goniche, M., Gravier, R., Gravil, B., Gregoire, M., Gresillon, D., Grisolia, C., Grosman, A., Guilhem, D., Guillerminet, B., Guirlet, R., Guiziou, L., Harris, J., Hennequin, P., Hennion, F., Hertout, P., Hess, W.R., Hesse, M., Hoang, G.T., Hogan, J., Houlberg, W.A., Hutter, T., Jacquot, C., Jager, B., Joffrm, E., Johner, J., Journeaux, J.Y., Joyer, P., Klepper, C., Kazarian, F., Kuus, H., Ladurelle, L., Lafon, D., Laporte, P., Lasalle, J., Laurent, L., Lavirnn, C., Leclert, G., Ledyankine, A., Libeyre, P., Lipa, M, Litaudon, X., Loarer, T., Lore, P., Luciani, J.F., Lutz, T., Magaud, P., Mahdi, W., Martin, G., Martinez, A., Maschke, E.K, Masset, R., Mattioli, M., Mayaux, G., Meslm, B., Michelot, Y., Mioduszewski, P., Misguich, J., Mitteau, R., Mollard, P., Monier-Garbet, P., Moreau, D., Moreau, F., Moreau, P., Morera, J.P., Moulin, B., Moulm, D., Moustier, M., Nakach, R, Nguyen, F., Nygren, R., Ouvrier-Buffet, P., Owen, L., Pain, M., Pamela, J., Parlange, F, Pastor, G., Patris, R., Panme, M., Pecquet, A.L., Pdgouri, B., Peysson, Y., Piat, D., Platz, P., Portafaix, C., Prou, M., Quemeneur, A., Rey, G., Rothan, B., Ruggieri, R., 16), S a Sabbagh, Sabot, R., Samaille, F., Saoutic, B., Sarazm, Y., Sebelin, E., Schlosser, J., Segui, J.L., Soler, K., Sonato, Pg., Spuig, M., Stephan, Y., Theis, J. M., Tokar, M., Tonon, G., Torossian, A., Truc, A., Tsitrone, E, Turck, B., Turlur, S., Vallet, J.C., Vanhoutte, D., Verga, A., Viallet, H, Voitsekovitch, I., Weisse, J., White, R., Wijnands, T., Zabiego, M., Zou, X.L., Centre de Physique Théorique - UMR 6207 (CPT), and Université de la Méditerranée - Aix-Marseille 2-Université de Provence - Aix-Marseille 1-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Power transmission, Materials science, Steady state (electronics), Plasma parameters, business.industry, Electrical engineering, Pulse duration, Tore Supra, Reliability (semiconductor), [PHYS.PHYS.PHYS-PLASM-PH]Physics [physics]/Physics [physics]/Plasma Physics [physics.plasm-ph], Dielectric heating, Current (fluid), business, ComputingMilieux_MISCELLANEOUS
Abstract

Significant results on steady state control of the plasma parameters have been obtained with RF systems on Tore Supra. A sustained effort is under way to improve power transmission reliability. Developments of sources and antennas are in progress for future operation on Tore Supra with pulse length in the range of several hundreds of seconds.

Published
2008

22. 1363 CHARACTERIZATION OF THE GUT MICROBIOTA BY QUANTITATIVE METAGENOMICS: A PROMISING TOOL FOR RISK STRATIFICATION IN NAFLD PATIENTS

Author

Ratziu, V., primary, Pichaud, M., additional, Fedchuk, L., additional, Levenez, F., additional, Quinquis, B., additional, Galleron, N., additional, Batto, J.-M., additional, Pons, N., additional, Le Chatelier, E., additional, Almeida, M., additional, Kennedy, S., additional, Doré, J., additional, Ehrlich, S.D., additional, and Rimbaud, P., additional

Published
2013
Full Text
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26. The pAMβ1 CopF repressor regulates plasmid copy number by controlling transcription of the repE gene.

Author

Le Chatelier, E., Ehrlich, S. D., and Jannière, L.

Subjects
PLASMIDS, GRAM-positive bacteria, TRANSCRIPTION factors, GENES, PROTEINS
Abstract

pAMβ1 is a low-copy-number, promiscuous plasmid from Gram-positive bacteria that replicates by a unidirectional theta-type mode. Its replication is initiated by an original mechanism, involving the positive rate-limiting RepE protein. Here we show that the pAMβ1-encoded CopF protein is involved in negative regulation of the plasmid copy number. CopF represses ∼10-fold the transcription initiated at the promoter of the repE gene and binds to a 31 bp segment which is located immediately upstream of the -35 box of the repE promoter. We propose that CopF inhibits initiation of transcription at the repE promoter by binding to its operator. [ABSTRACT FROM AUTHOR]

Published
1994
Full Text
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28. TORE SUPRA TEAM MEMBERS 1988-2008

Author

Abgrall, R., Achard, M. H., Adam, J., Agarici, G., Agostini, E., Airaj, M., Albajar-Vinas, F., Allegretti, L., Allibert, J. P., Alliez, J. C., Allouche, A., Andreoletti, J., Ane, J. M., Angelino, P., Aniel, T., Antar, G., Arcis, N., Argouarch, A., Arnas, C., Arnoux, G., Arslanbekov, R., Artaud, J. F., Asp, E., Assas, S., Atttuel, G., Aymar, R., Azeroual, A., Balme, S., Barana, O., Bareyt, B., Basiuk, V., Basko, M., Bayetti, P., Baylor, L., Beaumont, B., Becherer, R., Becoulet, A., Becoulet, M., Begrambekov, L., Benkadda, S., Benoit, F., Bergeaud, V., Berger-By, G., Berio, S., Bernascolle, P., Bernier, N., Berroukeche, M., Bertrand, B., Bessette, D., Beyer, P., Bibet, P., Bizzaro, J., Blanchard, P., Blum, J., Boddeker, S., Boilson, D., Mardion, G. Bon, Bonnel, P., Bonnin, X., Boscary, J., Bosia, G., Bottereau, J. M., Bottiglioni, F., Bottollier-Curtet, H., Bouchand, C., Bouligand, G., Bouquey, F., Bourdelle, C., Bregeon, R., Bremond, F., Bremond, S., Breton, C., Breton, M., Brosset, C., Brugnetti, R., Bruneau, J. L., Bucalossi, J., Budny, R. V., Buravand, Y., Bush, C., Bussac, M. N., Cambe, A., Capes, H., Capitain, J. J., Cara, P., Carbonnier, J. L., Carpentier, S., Carrasco, J., Casati, A., Chaibi, O., Chamouard, C., Chantant, M., Chappuis, P., Chatain, D., Chatelier, E., Chatelier, M., Chatenet, J. H., Chen, X. P., Cherigier, L., Chevet, G., Chiarazzo, L., Ciazynski, D., Ciraolo, G., Cismondi, F., Clairet, F., Clary, J., Clement, C., Colas, L., Commaux, N., Corbel, E., Cordier, J. J., Corre, Y., Costanzo, L., Cote, A., Coulon, J. P., Courtois, L., Courtois, X., Couturier, B., Crenn, J. P., Cristofani, P., Crouseilles, N., Czarny, O., Rosa, P. Da Silva, Darbos, C., Darmet, G., Davi, M., Daviot, R., Esch, H., Gentile, B., Haas, J. C., La Cal, E., Michelis, C., Deck, C., Decker, J., Decool, P., Degond, P., Renaud Dejarnac, Delchambre, E., Delmas, E., Delpech, L., Demarthe, H., Dentan, M., Depret, G., Deschamps, P., Desgranges, C., Devynck, P., Doceul, L., Dolgetta, N., Doloc, C., Dong, Y., Dore, P., Douai, D., Dougnac, H., Drawin, H. W., Druaux, J., Druetta, M., Dubois, F., Dubois, M., Dubuit, N., Duchateau, J. L., Wit, T. Dudok, Dufour, E., Dumont, R., Dunand, G., Dupas, L., Duran, Y., Durocher, A., Edery, D., Ekedahl, A., Elbeze, D., Eriksson, L. G., Escande, D., Escarguel, A., Escourbiac, F., Evans, T., Faisse, F., Falchetto, G., Fall, T., Farge, M., Farjon, J. L., Faudot, E., Fazilleau, P., Fedorczak, N., Fenzi-Bonizec, C., Ferron, J. R., Fidone, I., Figarella, C., Fleurence, E., Fleury, I., Fois, M., Forrest, C., Foster, C. A., Fouquet, S., Fourment, C., Fraboulet, D., Francois, P., Franel, B., Frigione, D., Froissard, P., Fubiani, G., Fuchs, V., Fumelli, M., Gagey, B., Galindo, V., Gambier, D., Garampon, L., Garbet, X., Garbil, R., Garcia, J., Gardarein, J. L., Gargiulo, L., Garibaldi, P., Garin, P., Gauthier, E., Geraud, A., Gerbaud, T., Gervais, F., Geynet, M., Ghendrih, P., Gianakon, T., Giannella, R., Gil, C., Girard, J. P., Giruzzi, G., Godbert-Mouret, L., Gomez, P., Goniche, M., Gordeev, A., Granata, G., Grandgirard, V., Gravier, R., Gravil, B., Gregoire, M., Gregoire, S., Grelot, P., Gresillon, D., Grisolia, C., Gros, G., Grosman, A., Grua, P., Guerin, O., Guigon, R., Guilhem, D., Guillerminet, B., Guirlet, R., Guiziou, L., Gunn, J., Hacquin, S., Harris, J., Haste, G., Hatchressian, J. C., Hemsworth, R., Hennequin, P., Hennion, F., Hennion, V., Henry, D., Hernandez, C., Hertout, P., Hess, W., Hesse, M., Heuraux, S., Hillairet, J., Hoang, G. T., Hogan, J., Hong, S. H., Honore, C., Horton, L., Horton, W. W., Houlberg, W. A., Hourtoule, J., Houry, M., Houy, P., How, J., Hron, M., Hutter, T., Huynh, P., Huysmans, G., Idmtal, J., Imbeaux, F., Isler, R., Jaben, C., Jacquinot, J., Jacquot, C., Jager, B., Jaunet, M., Javon, C., Jelea, A., Jequier, F., Jie, Y. X., Jimenez, R., Joffrin, E., Johner, J., Jourd Heuil, L., Journeaux, J. Y., Joyer, P., Ju, M., Jullien, F., Junique, F., Kaye, S. M., Kazarian, F., Khodja, H., Klepper, C., Kocan, M., Koski, J., Krivenski, V., Krylov, A., Kupfer, K., Kuus, H., Labit, B., Laborde, L., Lacroix, B., Ladurelle, L., Lafon, D., Lamaison, V., Laporte, P., Lasalle, J., Latu, G., Laugier, F., Laurent, L., Lausenaz, Y., Laviron, C., Layet, J. M., Le Bris, A., Le Coz, F., Le Niliot, C., Lebris, A., Leclert, G., Lecoustey, P., Ledyankinc, A., Leloup, C., Lennholm, M., Leroux, F., Li, Y. Y., Libeyre, P., Linez, F., Lipa, M., Lippmann, S., Litaudon, X., Liu, W. D., Loarer, T., Lott, F., Lotte, P., Lowry, C., Luciani, J. F., Luetjens, H., Luty, J., Lutz, T., Lyraud, C., Maas, A., Macor, A., Madeleine, S., Magaud, P., Maget, P., Magne, R., Mahdavi, A., Mahe, F., Mailloux, J., Mandl, W., Manenc, L., Marandet, Y., Marbach, G., Marechal, J. L., Martin, C., Martin, G., Martin, V., Martinez, A., Martins, J. P., Maschke, E., Masse, L., Masset, R., Massmann, P., Mattioli, M., Mayaux, G., Mayoral, M. L., Mazon, D., Mcgrath, R., Mercier, C., Meslin, B., Meunier, L., Meyer, O., Michelot, Y., Million, L., Millot, P., Minguella, G., Minot, F., Mioduszewski, P., Misguich, J. H., Miskane, F., Missirlian, M., Mitteau, R., Moerel, F., Mollard, P., Monakhov, I., Moncada, V., Moncel, L., Monier-Garbet, P., Moreau, D., Moreau, F., Moreau, P., Morera, J. P., Moret, J. M., Moulin, B., Moulin, D., Mourgues, F., Moustier, M., Nakach, R., Nannini, M., Nanobashvili, I., Nardon, E., Navarra, P., Nehme, H., Nguyen, C., Nguyen, F., Nicollet, S., Nygren, R., Ogorodnikova, O., Olivain, J., Orlandelli, P., Ottaviani, M., Ouvrier-Buffet, P., Ouyang, Z., Owen, L., Pacella, D., Pain, M., Pamela, J., Pamela, S., Panek, R., Panzarella, A., Paris, R., Parisot, T., Park, S. H., Parlange, F., Parrat, H., Pastor, G., Pastor, P., Pastor, T., Patris, R., Paume, M., Payan, J., Pecquet, A. L., Pegourie, B., Petrov, Y., Petrzilka, V., Peysson, Y., Piat, D., Picchiottino, J. M., Pierre, J., Platz, P., Portafaix, C., Prou, M., Pugno, R., Putchy, L., Qin, C. M., Quallis, L., Quemeneur, A., Quet, P., Rabaglino, E., Raharijaona, J. J., Ramette, J., Ravenel, N., Rax, J. M., Reichle, R., Renard, B., Renner, H., Reuss, J. D., Reux, C., Reverdin, C., Rey, G., Reynaud, P., Riband, P. H., Richou, M., Rigollet, F., Rimini, F., Riquet, D., Rochard, F., Rodriguez, L., Romanelli, M., Romannikov, A., Rosanvallon, S., Roth, J., Rothan, B., Roubin, J. P., Roubin, P., Roupillard, G., Roussel, P., Ruggieri, R., Sabathier, F., Sabbagh, S. A., Sabot, R., Saha, S. K., Saint-Laurent, F., Salasca, S., Salmon, T., Salvador, J., Samaille, F., Samain, A., Santagiustina, A., Saoutic, B., Sarazin, Y., Schild, T., Schlosser, J., Schneider, M., Schneider, K., Schunke, B., Schwander, F., Schwob, J. L., Sebelin, E., Segui, J. L., Seigneur, A., Shepard, T., Shigin, P., Signoret, J., Simoncini, J., Simonet, F., Simonin, A., Sirinelli, A., Sledziewski, Z., Smits, F., Soler, K., Sonato, P. G., Song, S. D., Sonnendrucker, E., Sourd, F., Spitz, P., Spuig, P., Stamm, R., Stephan, Y., Stirling, W., Stockel, J., Stott, P., Sthal, K. Strom, Surle, F., Svensson, L., Tachon, J., Talvard, M., Tamain, P., Tavian, L., Tena, M., Theis, J. M., Thomas, C. E., Thomas, P., Thonnat, M., Tobin, S., Tokar, M., Tonon, G., Torossian, A., Torre, A., Trainham, R. C., Travere, J. M., Tresset, G., Trier, E., Truc, A., Tsitrone, E., Turck, B., Turco, F., Turlur, S., Uckan, T., Udintsev, V., Urguijo, G., Utzel, N., Vallet, J. C., Valter, J., Houtte, D., Rompuy, T., Vatry, A., Verga, A., Vermare, L., Vezard, D., Viallet, H., Villecroze, F., Villedieu, E., Villegas, D., Vincent, E., Voitsekovitch, I., Hellermann, M., Voslamber, D., Voyer, D., Vulliez, K., Wachter, C., Wagner, T., Waller, V., Wang, G., Wang, Z., Watkins, J., Weisse, J., White, R., Wijnands, T., Witrant, E., Worms, J., Xiao, W., Yu, D., Zabeo, L., Zabiego, M., Zani, L., Zhuang, G., Zou, X. L., Zucchi, E., Zunino, K., Zwingmann, W., and Tore Supra, Team

29. Lower-hybrid current drive experiments in TORE SUPRA

Author

Moreau, D., Agarici, G., Agostini, E., Ané, J. M., Augé, N., Balme, S., Basiuk, V., Bareyt, B., Bayetti, P., Beaumont, B., Becherer, R., Bécoulet, A., Benkadda, M., Berger-By, G., Bessette, D., Bibet, P., João P. S. Bizarro, Bon-Mardion, G., Bonnel, P., Bottereau, J. M., Bottiglioni, F., Brugnetti, R., Bruneau, J. L., Buravand, Y., Capes, H., Capitain, J. J., Carrasco, J., Chappuis, P., Chatain, D., Chatelier, E., Chatelier, M., Ciazynski, D., Cordier, J. J., Coston, J. F., Coulon, J. P., Couturier, B., Crenn, J. P., Deck, C., Gentile, B., Demarthe, H., Michelis, C., Deschamps, P., Devynck, P., Doceul, L., Dougnac, M., Drawin, H. W., Dubois, M., Duchâteau, J. L., Dupas, L., Edery, D., Elbèze, D., Evans, T., Fall, T., Farjon, J. L., Fidone, I., Fois, M., Foster, C. A., Fumelli, M., Gagey, B., Garbet, X., Gauthier, E., Géraud, A., Gervais, F., Ghendrih, P., Gil, C., Giruzzi, G., Goniche, M., Gravier, R., Gravil, B., Grégoire, M., Grésillon, D., Grisolia, C., Grosman, A., Guilhem, D., Guillerminet, B., Hennequin, P., Hennion, F., Hertout, P., Hess, W. R., Hesse, M., Hoang, G. T., Horton, L., Hubbard, A., Hutter, T., Idmtal, J., Jacquot, C., Jager, B., Javon, C., Jequier, F., Joffrin, E., Johner, J., Journeaux, J. Y., Joyer, P., Kupfer, K., Kuus, H., Lafon, D., Lasalle, J., Laurent, L., Laviron, C., Leclert, G., Lecoustey, P., Leloup, C., Libeyre, P., Lipa, M., Litaudon, X., Loarer, T., Lotte, P., Magaud, P., Magne, R., Martin, G., Martinez, A., Maschke, E. K., Mattioli, M., Mayaux, G., Mioduszewski, P., Misguich, J., Monier-Garbet, P., Morera, J. P., Moret, J. M., Moulin, B., Moulin, D., Mourgues-Millot, F., Moustier, M., Nakach, R., Nguyen, F., Olivain, J., POuvrier-Buffet, Pamela, J., Panzarella, A., Parlange, F., Pastor, G., Patris, R., Paume, M., Pecquet, A. L., Pégourié, B., Peysson, Y., Piat, D., Picchiottino, J. M., Pierre, J., Platz, P., Portafaix, C., Poutchy, F., Prou, M., Quemeneur, A., Rax, J. M., Rey, G., Riband, P., Rigaud, D., Rodriguez, L., Rothan, B., Roubin, J. P., Roussel, P., Saha, S. K., Samaille, F., Samain, A., Saoutic, B., Schlosser, J., Seigneur, A., Segui, J. L., Shepard, T., Soler, K., Stirling, W., Tachon, J., Talvard, M., Tonon, G., Torossian, A., Truc, A., Turck, B., Uckan, T., Vallet, J. C., Houtte, D., Weisse, J., and Zou, X. L.

30. THEORY AND EXPERIMENTS ON RF PLASMA-HEATING, CURRENT DRIVE AND PROFILE CONTROL IN TORE-SUPRA

Author

Moreau, D., Agarici, G., Allibert, Jp, Ane, Jm, Arslanbekov, R., Balme, S., Bareyt, B., Basiuk, V., Bayetti, P., Beaumont, B., Becherer, R., Becoulet, A., Benkadda, M., Bergerby, G., Bessette, D., Bibet, P., Bizarro, Jp, Bonmardion, G., Bonnel, P., Bottereau, Jm, Bottiglioni, F., Bremond, S., Brugnetti, R., Budny, Rv, Buravand, Y., Capes, H., Capitain, Jj, Carbonnier, Jl, Carrasco, J., Chappuis, P., Chatain, D., Chatelier, E., Chatelier, M., Chatenet, Jh, Chen, Xp, Chinardet, J., Ciazynski, D., Clairet, F., Colas, L., Cordier, Jj, Cote, A., Coulon, Jp, Couturier, B., Crenn, Jp, Cristofani, P., Deck, C., Decool, P., Degentile, B., Demarthe, H., Dehas, Jc, Demichelis, C., Deschamps, P., Desgranges, C., Devynck, P., Doceul, L., Doloc, C., Dougnac, M., Drawin, Hw, Druetta, M., Dubois, M., Duchateau, Jl, Dewit, Td, Dupas, L., Edery, D., Elbeze, D., Escande, D., Farjon, Jl, Fidone, I., Fois, M., Foster, Ca, Fraboulet, D., Fuchs, V., Fumelli, M., Gagey, B., Garampon, L., Garbet, X., Gauthier, E., Geraud, A., Gervais, F., Ghendrih, P., Gil, C., Giruzzi, G., Goniche, M., Gravier, R., Gravil, B., Gregoire, M., Gresillon, D., Grisolia, C., Grosman, A., Guilhem, D., Guillerminet, B., Guirlet, R., Guiziou, L., Harris, G., Harris, J., Harvey, R., Haste, G., Hennequin, P., Hennion, F., Hertout, P., Hess, Wr, Hesse, M., Hoang, Gt, Hogans, J., Hutter, T., Idmtal, J., Jacquot, C., Jager, B., Jequier, F., Joffrin, E., Johner, J., Journeaux, Jy, Joyer, P., Stanley Kaye, Klepper, C., Kazarian, F., Kupfer, K., Kuus, H., Lafon, D., Laporte, P., Lasalle, J., Laurent, L., Laviron, C., Leclert, G., Lecoustey, P., Ledyankine, A., Leloup, C., Li, Yy, Libeyre, P., Lipa, M., Lippmann, S., Litaudon, X., Liu, Wd, Loarer, T., Lotte, P., Luciani, Jf, Mcgrath, R., Magaud, P., Magne, R., Martin, G., Martinez, A., Maschke, Ek, Masset, R., Mattioli, M., Mayaux, G., Michelot, Y., Mioduszewski, P., Misguich, J., Mollard, P., Moniergarvet, P., Moreau, F., Morera, Jp, Moulin, B., Moulin, D., Moustier, M., Nakach, R., Nguyen, F., Ouvrierbuffet, P., Owen, L., Pain, M., Pamela, J., Parlange, F., Pastor, G., Patris, R., Paume, M., Payan, J., Pecquet, Al, Pegourie, B., Peysson, Y., Piat, D., Picchiottino, Jm, Platz, P., Portafaix, C., Prou, M., Quemeneur, A., Rax, Jm, Rey, C., Riband, P., Rothan, B., Roussel, P., Sabbagh, Sa, Saha, Sk, Samaille, F., Samain, A., Saoutic, B., Schlosser, J., Seigneur, A., Segui, Jl, Smits, F., Soler, K., Stephan, Y., Tachon, J., Talvard, M., Theis, Jm, Thomas, Ce, Tobin, S., Tonon, G., Torossian, A., Truc, A., Tsitrone, E., Turck, B., Turlur, S., Uckan, T., Urquijo, G., Vallet, Jc, Valter, J., Vanhoutte, D., Verga, A., Vezard, D., Viallet, H., Watkins, J., Weisse, J., White, R., Wijnands, T., Zabiego, M., and Zou, Xl

31. Multifaceted modes of action of the anticancer probiotic Enterococcus hirae

Author

Marion Leduc, Didier Raoult, Laura Mondragón, Kristina Iribarren, Anne-Gaëlle Goubet, Diane Derrien, Satoru Yonekura, Noélie Bossut, Valerio Iebba, Nicola Segata, Guo Chen, Ivo G. Boneca, Lisa Derosa, Adrien Joseph, Fabrice Andre, Sylvère Durand, Aurélie Fluckiger, Maryam Tidjani Alou, Fanny Aprahamian, Richard J. Wheeler, Maryse Moya-Nilges, Eugenie Pizzato, Bo Qu, Guido Kroemer, Oliver Kepp, Nicolas Pons, Romain Daillère, Fabien Lemaitre, Laurence Zitvogel, Department of Radiology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France, Faculté de Médecine Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Shanghai Jiao Tong University [Shanghai], Institut Gustave Roussy (IGR), 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 de Paris (UP), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, UMR 1015 Immunologie des tumeurs et immunothérapie contre le cancer (ITIC), Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Institut Pasteur [Paris], MetaGenoPolis (MGP (US 1367)), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Trento [Trento], Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université de Paris (UP), 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), Karolinska University Hospital [Stockholm], Fondation pour la Recherche Médicale, Ligue contre le Cancer (équipes labellisées), Leducq Foundation, Seerave Foundation, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), SIRIC Cancer Research and Personalized Medicine (CARPEM), Fondation ARC pour la Recherche sur le Cancer, Région Ile-de-France, Chancellerie des universités de Paris (Legs Poix), FRM, European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR), Gustave Roussy Odyssea, Fondation Carrefour, High-end Foreign Expert Program in China: GDW20171100085 and GDW20181100051, Institut National du Cancer (INCA) France, Inserm (HTE), Institut Universitaire de France, ANR-10-COHO-0004,CANTO,Etude des toxicités chroniques des traitements anticancéreux chez les patientes porteuses cancer(2010), ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), European Project: 680969,H2020,H2020-HCO-2015,ERA-CVD(2015), European Project: 825410, H2020-EU.3.1., H2020-EU.3.1.2.,ONCOBIOME (2019), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), 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), Ligue Nationale Contre le Cancer (LNCC), Institut Pasteur [Paris] (IP), Université Paris Cité (UPCité), Goubet, A. -G., Wheeler, R., Fluckiger, A., Qu, B., Lemaitre, F., Iribarren, K., Mondragon, L., Tidjani Alou, M., Pizzato, E., Durand, S., Derosa, L., Aprahamian, F., Bossut, N., Moya-Nilges, M., Derrien, D., Chen, G., Leduc, M., Joseph, A., Pons, N., Le Chatelier, E., Segata, N., Yonekura, S., Iebba, V., Kepp, O., Raoult, D., Andre, F., Kroemer, G., Boneca, I. G., Zitvogel, L., Daillere, R., 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 (UPC), Université Paris Cité (UPC), Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université Paris-Saclay, Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), and European Project: 825410,ONCOBIOME

Subjects
0301 basic medicine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], microbiome, law.invention, Probiotic, Mice, 0302 clinical medicine, Cancer immunotherapy, Enterococcus hirae, law, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Neoplasms, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, CD137, 3. Good health, Bifidobacterium animalis, Anti-Bacterial Agents, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, immunotherapy, Immunotherapy, microbiota, cancer, tumor, probiotic, intratumoral IFNγ, Biology, Article, Microbiology, 03 medical and health sciences, Memory T Cells, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine, Animals, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Microbiome, Molecular Biology, Probiotics, Autophagy, Cell Biology, biology.organism_classification, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Gastrointestinal Microbiome, Mice, Inbred C57BL, 030104 developmental biology, Dysbiosis
Abstract

International audience; A deviated repertoire of the gut microbiome predicts resistance to cancer immunotherapy. Enterococcus hirae compensated cancer-associated dysbiosis in various tumor models. However, the mechanisms by which E. hirae restored the efficacy of cyclophosphamide administered with concomitant antibiotics remain ill defined. Here, we analyzed the multifaceted modes of action of this anticancer probiotic. Firstly, E. hirae elicited emigration of thymocytes and triggered systemic and intratumoral IFN gamma-producing and CD137-expressing effector memory T cell responses. Secondly, E. hirae activated the autophagy machinery in enterocytes and mediated ATG4B-dependent anticancer effects, likely as a consequence of its ability to increase local delivery of polyamines. Thirdly, E. hirae shifted the host microbiome toward a Bifidobacteria-enriched ecosystem. In contrast to the live bacterium, its pasteurized cells or membrane vesicles were devoid of anticancer properties. These pleiotropic functions allow the design of optimal immunotherapies combining E. hirae with CD137 agonistic antibodies, spermidine, or Bifidobacterium animalis. We surmise that immunological, metabolic, epithelial, and microbial modes of action of the live E. hirae cooperate to circumvent primary resistance to therapy.

Published
2021

32. Transient colonizing microbes promote gut dysbiosis and functional impairment.

Author

Lee S, Meslier V, Bidkhori G, Garcia-Guevara F, Etienne-Mesmin L, Clasen F, Park J, Plaza Oñate F, Cai H, Le Chatelier E, Pons N, Pereira M, Seifert M, Boulund F, Engstrand L, Lee D, Proctor G, Mardinoglu A, Blanquet-Diot S, Moyes D, Almeida M, Ehrlich SD, Uhlen M, and Shoaie S

Subjects
Humans, Sweden, Longitudinal Studies, Metagenome, Adult, Bioreactors microbiology, Fermentation, Dysbiosis microbiology, Gastrointestinal Microbiome, Metagenomics methods, Bacteria classification, Bacteria genetics, Bacteria isolation & purification, Feces microbiology
Abstract

Species composition of the healthy adult gut microbiota tends to be stable over time. Destabilization of the gut microbiome under the influence of different factors is the main driver of the microbial dysbiosis and subsequent impacts on host physiology. Here, we used metagenomics data from a Swedish longitudinal cohort, to determine the stability of the gut microbiome and uncovered two distinct microbial species groups; persistent colonizing species (PCS) and transient colonizing species (TCS). We validated the continuation of this grouping, generating gut metagenomics data for additional time points from the same Swedish cohort. We evaluated the existence of PCS/TCS across different geographical regions and observed they are globally conserved features. To characterize PCS/TCS phenotypes, we performed bioreactor fermentation with faecal samples and metabolic modeling. Finally, using chronic disease gut metagenome and other multi-omics data, we identified roles of TCS in microbial dysbiosis and link with abnormal changes to host physiology., (© 2024. The Author(s).)

Published
2024
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33. Global compositional and functional states of the human gut microbiome in health and disease.

Author

Lee S, Portlock T, Le Chatelier E, Garcia-Guevara F, Clasen F, Oñate FP, Pons N, Begum N, Harzandi A, Proffitt C, Rosario D, Vaga S, Park J, von Feilitzen K, Johansson F, Zhang C, Edwards LA, Lombard V, Gauthier F, Steves CJ, Gomez-Cabrero D, Henrissat B, Lee D, Engstrand L, Shawcross DL, Proctor G, Almeida M, Nielsen J, Mardinoglu A, Moyes DL, Ehrlich SD, Uhlen M, and Shoaie S

Subjects
Humans, Machine Learning, Fusobacterium nucleatum genetics, Bacteria classification, Bacteria genetics, Gastrointestinal Microbiome genetics, Metagenome, Metagenomics methods
Abstract

The human gut microbiota is of increasing interest, with metagenomics a key tool for analyzing bacterial diversity and functionality in health and disease. Despite increasing efforts to expand microbial gene catalogs and an increasing number of metagenome-assembled genomes, there have been few pan-metagenomic association studies and in-depth functional analyses across different geographies and diseases. Here, we explored 6014 human gut metagenome samples across 19 countries and 23 diseases by performing compositional, functional cluster, and integrative analyses. Using interpreted machine learning classification models and statistical methods, we identified Fusobacterium nucleatum and Anaerostipes hadrus with the highest frequencies, enriched and depleted, respectively, across different disease cohorts. Distinct functional distributions were observed in the gut microbiomes of both westernized and nonwesternized populations. These compositional and functional analyses are presented in the open-access Human Gut Microbiome Atlas, allowing for the exploration of the richness, disease, and regional signatures of the gut microbiota across different cohorts., (© 2024 Lee et al.; Published by Cold Spring Harbor Laboratory Press.)

Published
2024
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34. Privacy-Preserving Federated Survival Support Vector Machines for Cross-Institutional Time-To-Event Analysis: Algorithm Development and Validation.

Author

Späth J, Sewald Z, Probul N, Berland M, Almeida M, Pons N, Le Chatelier E, Ginès P, Solé C, Juanola A, Pauling J, and Baumbach J

Abstract

Background: Central collection of distributed medical patient data is problematic due to strict privacy regulations. Especially in clinical environments, such as clinical time-to-event studies, large sample sizes are critical but usually not available at a single institution. It has been shown recently that federated learning, combined with privacy-enhancing technologies, is an excellent and privacy-preserving alternative to data sharing., Objective: This study aims to develop and validate a privacy-preserving, federated survival support vector machine (SVM) and make it accessible for researchers to perform cross-institutional time-to-event analyses., Methods: We extended the survival SVM algorithm to be applicable in federated environments. We further implemented it as a FeatureCloud app, enabling it to run in the federated infrastructure provided by the FeatureCloud platform. Finally, we evaluated our algorithm on 3 benchmark data sets, a large sample size synthetic data set, and a real-world microbiome data set and compared the results to the corresponding central method., Results: Our federated survival SVM produces highly similar results to the centralized model on all data sets. The maximal difference between the model weights of the central model and the federated model was only 0.001, and the mean difference over all data sets was 0.0002. We further show that by including more data in the analysis through federated learning, predictions are more accurate even in the presence of site-dependent batch effects., Conclusions: The federated survival SVM extends the palette of federated time-to-event analysis methods by a robust machine learning approach. To our knowledge, the implemented FeatureCloud app is the first publicly available implementation of a federated survival SVM, is freely accessible for all kinds of researchers, and can be directly used within the FeatureCloud platform., (©Julian Späth, Zeno Sewald, Niklas Probul, Magali Berland, Mathieu Almeida, Nicolas Pons, Emmanuelle Le Chatelier, Pere Ginès, Cristina Solé, Adrià Juanola, Josch Pauling, Jan Baumbach. Originally published in JMIR AI (https://ai.jmir.org), 29.03.2024.)

Published
2024
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35. Perturbation and resilience of the gut microbiome up to 3 months after β-lactams exposure in healthy volunteers suggest an important role of microbial β-lactamases.

Author

d'Humières C, Delavy M, Alla L, Ichou F, Gauliard E, Ghozlane A, Levenez F, Galleron N, Quinquis B, Pons N, Mullaert J, Bridier-Nahmias A, Condamine B, Touchon M, Rainteau D, Lamazière A, Lesnik P, Ponnaiah M, Lhomme M, Sertour N, Devente S, Docquier JD, Bougnoux ME, Tenaillon O, Magnan M, Ruppé E, Grall N, Duval X, Ehrlich D, Mentré F, Denamur E, Rocha EPC, Le Chatelier E, and Burdet C

Subjects
Adult, Humans, beta-Lactamases genetics, beta-Lactams pharmacology, Healthy Volunteers, Anti-Bacterial Agents, Bacteria genetics, Feces microbiology, Gastrointestinal Microbiome genetics, Resilience, Psychological
Abstract

Background: Antibiotics notoriously perturb the gut microbiota. We treated healthy volunteers either with cefotaxime or ceftriaxone for 3 days, and collected in each subject 12 faecal samples up to day 90. Using untargeted and targeted phenotypic and genotypic approaches, we studied the changes in the bacterial, phage and fungal components of the microbiota as well as the metabolome and the β-lactamase activity of the stools. This allowed assessing their degrees of perturbation and resilience., Results: While only two subjects had detectable concentrations of antibiotics in their faeces, suggesting important antibiotic degradation in the gut, the intravenous treatment perturbed very significantly the bacterial and phage microbiota, as well as the composition of the metabolome. In contrast, treatment impact was relatively low on the fungal microbiota. At the end of the surveillance period, we found evidence of resilience across the gut system since most components returned to a state like the initial one, even if the structure of the bacterial microbiota changed and the dynamics of the different components over time were rarely correlated. The observed richness of the antibiotic resistance genes repertoire was significantly reduced up to day 30, while a significant increase in the relative abundance of β-lactamase encoding genes was observed up to day 10, consistent with a concomitant increase in the β-lactamase activity of the microbiota. The level of β-lactamase activity at baseline was positively associated with the resilience of the metabolome content of the stools., Conclusions: In healthy adults, antibiotics perturb many components of the microbiota, which return close to the baseline state within 30 days. These data suggest an important role of endogenous β-lactamase-producing anaerobes in protecting the functions of the microbiota by de-activating the antibiotics reaching the colon. Video Abstract., (© 2024. The Author(s).)

Published
2024
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36. Unveiling Candida albicans intestinal carriage in healthy volunteers: the role of micro- and mycobiota, diet, host genetics and immune response.

Author

Delavy M, Sertour N, Patin E, Le Chatelier E, Cole N, Dubois F, Xie Z, Saint-André V, Manichanh C, Walker AW, Quintana-Murci L, Duffy D, d'Enfert C, Bougnoux ME, and Consortium MI

Subjects
Humans, Genome-Wide Association Study, Diet, Immunity, Candida albicans physiology, Gastrointestinal Microbiome physiology
Abstract

Candida albicans is a commensal yeast present in the gut of most healthy individuals but with highly variable concentrations. However, little is known about the host factors that influence colonization densities. We investigated how microbiota, host lifestyle factors, and genetics could shape C. albicans intestinal carriage in 695 healthy individuals from the Milieu Intérieur cohort. C. albicans intestinal carriage was detected in 82.9% of the subjects using quantitative PCR. Using linear mixed models and multiway-ANOVA, we explored C. albicans intestinal levels with regard to gut microbiota composition and lifestyle factors including diet. By analyzing shotgun metagenomics data and C. albicans qPCR data, we showed that Intestinimonas butyriciproducens was the only gut microbiota species whose relative abundance was negatively correlated with C. albicans concentration. Diet is also linked to C. albicans growth, with eating between meals and a low-sodium diet being associated with higher C. albicans levels. Furthermore, by Genome-Wide Association Study, we identified 26 single nucleotide polymorphisms suggestively associated with C. albicans colonization. In addition, we found that the intestinal levels of C. albicans might influence the host immune response, specifically in response to fungal challenge. We analyzed the transcriptional levels of 546 immune genes and the concentration of 13 cytokines after whole blood stimulation with C. albicans cells and showed positive associations between the extent of C. albicans intestinal levels and NLRP3 expression, as well as secreted IL-2 and CXCL5 concentrations. Taken together, these findings open the way for potential new interventional strategies to curb C. albicans intestinal overgrowth.

Published
2023
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37. Four functional profiles for fibre and mucin metabolism in the human gut microbiome.

Author

Labarthe S, Plancade S, Raguideau S, Plaza Oñate F, Le Chatelier E, Leclerc M, and Laroche B

Subjects
Humans, Mucins, Dysbiosis, Metagenome, Dietary Fiber, Inflammation, Metagenomics methods, Gastrointestinal Microbiome genetics, Microbiota genetics
Abstract

Background: With the emergence of metagenomic data, multiple links between the gut microbiome and the host health have been shown. Deciphering these complex interactions require evolved analysis methods focusing on the microbial ecosystem functions. Despite the fact that host or diet-derived fibres are the most abundant nutrients available in the gut, the presence of distinct functional traits regarding fibre and mucin hydrolysis, fermentation and hydrogenotrophic processes has never been investigated., Results: After manually selecting 91 KEGG orthologies and 33 glycoside hydrolases further aggregated in 101 functional descriptors representative of fibre and mucin degradation pathways in the gut microbiome, we used nonnegative matrix factorization to mine metagenomic datasets. Four distinct metabolic profiles were further identified on a training set of 1153 samples, thoroughly validated on a large database of 2571 unseen samples from 5 external metagenomic cohorts and confirmed with metatranscriptomic data. Profiles 1 and 2 are the main contributors to the fibre-degradation-related metagenome: they present contrasted involvement in fibre degradation and sugar metabolism and are differentially linked to dysbiosis, metabolic disease and inflammation. Profile 1 takes over Profile 2 in healthy samples, and unbalance of these profiles characterize dysbiotic samples. Furthermore, high fibre diet favours a healthy balance between profiles 1 and profile 2. Profile 3 takes over profile 2 during Crohn's disease, inducing functional reorientations towards unusual metabolism such as fucose and H2S degradation or propionate, acetone and butanediol production. Profile 4 gathers under-represented functions, like methanogenesis. Two taxonomic makes up of the profiles were investigated, using either the covariation of 203 prevalent genomes or metagenomic species, both providing consistent results in line with their functional characteristics. This taxonomic characterization showed that profiles 1 and 2 were respectively mainly composed of bacteria from the phyla Bacteroidetes and Firmicutes while profile 3 is representative of Proteobacteria and profile 4 of methanogens., Conclusions: Integrating anaerobic microbiology knowledge with statistical learning can narrow down the metagenomic analysis to investigate functional profiles. Applying this approach to fibre degradation in the gut ended with 4 distinct functional profiles that can be easily monitored as markers of diet, dysbiosis, inflammation and disease. Video Abstract., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Published
2023
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38. Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide.

Author

Andrikopoulos P, Aron-Wisnewsky J, Chakaroun R, Myridakis A, Forslund SK, Nielsen T, Adriouch S, Holmes B, Chilloux J, Vieira-Silva S, Falony G, Salem JE, Andreelli F, Belda E, Kieswich J, Chechi K, Puig-Castellvi F, Chevalier M, Le Chatelier E, Olanipekun MT, Hoyles L, Alves R, Helft G, Isnard R, Køber L, Coelho LP, Rouault C, Gauguier D, Gøtze JP, Prifti E, Froguel P, Zucker JD, Bäckhed F, Vestergaard H, Hansen T, Oppert JM, Blüher M, Nielsen J, Raes J, Bork P, Yaqoob MM, Stumvoll M, Pedersen O, Ehrlich SD, Clément K, and Dumas ME

Subjects
Adult, Humans, Causality, Kidney, Methylamines, Endocrinology
Abstract

The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk., (© 2023. Springer Nature Limited.)

Published
2023
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39. A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers.

Author

Fidelle M, Rauber C, Alves Costa Silva C, Tian AL, Lahmar I, de La Varende AM, Zhao L, Thelemaque C, Lebhar I, Messaoudene M, Pizzato E, Birebent R, Mbogning Fonkou MD, Zoppi S, Reni A, Dalban C, Leduc M, Ferrere G, Durand S, Ly P, Silvin A, Mulder K, Dutertre CA, Ginhoux F, Yonekura S, Roberti MP, Tidjani-Alou M, Terrisse S, Chen J, Kepp O, Schippers A, Wagner N, Suárez-Gosálvez J, Kobold S, Fahrner JE, Richard C, Bosq J, Lordello L, Vitali G, Galleron N, Quinquis B, Le Chatelier E, Blanchard L, Girard JP, Jarry A, Gervois N, Godefroy E, Labarrière N, Koschny R, Daillère R, Besse B, Truntzer C, Ghiringhelli F, Coatnoan N, Mhanna V, Klatzmann D, Drubay D, Albiges L, Thomas AM, Segata N, Danlos FX, Marabelle A, Routy B, Derosa L, Kroemer G, and Zitvogel L

Subjects
Animals, Humans, Mice, Bacteria immunology, Cell Movement, Fecal Microbiota Transplantation, Interleukin-17 metabolism, Th17 Cells immunology, Gastrointestinal Tract immunology, Gastrointestinal Tract microbiology, Anti-Bacterial Agents adverse effects, Cell Adhesion Molecules metabolism, Drug Resistance, Neoplasm, Gastrointestinal Microbiome immunology, Immune Checkpoint Inhibitors therapeutic use, Immune Tolerance drug effects, Immunologic Surveillance, Integrins metabolism, Mucoproteins metabolism, Neoplasms immunology, Neoplasms therapy
Abstract

Antibiotics (ABX) compromise the efficacy of programmed cell death protein 1 (PD-1) blockade in cancer patients, but the mechanisms underlying their immunosuppressive effects remain unknown. By inducing the down-regulation of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the ileum, post-ABX gut recolonization by Enterocloster species drove the emigration of enterotropic α4β7 + CD4 + regulatory T 17 cells into the tumor. These deleterious ABX effects were mimicked by oral gavage of Enterocloster species, by genetic deficiency, or by antibody-mediated neutralization of MAdCAM-1 and its receptor, α4β7 integrin. By contrast, fecal microbiota transplantation or interleukin-17A neutralization prevented ABX-induced immunosuppression. In independent lung, kidney, and bladder cancer patient cohorts, low serum levels of soluble MAdCAM-1 had a negative prognostic impact. Thus, the MAdCAM-1-α4β7 axis constitutes an actionable gut immune checkpoint in cancer immunosurveillance.

Published
2023
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40. In Vitro Modelling of Oral Microbial Invasion in the Human Colon.

Author

Etienne-Mesmin L, Meslier V, Uriot O, Fournier E, Deschamps C, Denis S, David A, Jegou S, Morabito C, Quinquis B, Thirion F, Plaza Oñate F, Le Chatelier E, Ehrlich SD, Blanquet-Diot S, and Almeida M

Abstract

Recent advances in the human microbiome characterization have revealed significant oral microbial detection in stools of dysbiotic patients. However, little is known about the potential interactions of these invasive oral microorganisms with commensal intestinal microbiota and the host. In this proof-of-concept study, we proposed a new model of oral-to-gut invasion by the combined use of an in vitro model simulating both the physicochemical and microbial (lumen- and mucus-associated microbes) parameters of the human colon (M-ARCOL), a salivary enrichment protocol, and whole-metagenome shotgun sequencing. Oral invasion of the intestinal microbiota was simulated by injection of enriched saliva in the in vitro colon model inoculated with a fecal sample from the same healthy adult donor. The mucosal compartment of M-ARCOL was able to retain the highest species richness levels over time, while species richness levels decreased in the luminal compartment. This study also showed that oral microorganisms preferably colonized the mucosal microenvironment, suggesting potential oral-to-intestinal mucosal competitions. This new model of oral-to-gut invasion can provide useful mechanistic insights into the role of oral microbiome in various disease processes. IMPORTANCE Here, we propose a new model of oral-to-gut invasion by the combined use of an in vitro model simulating both the physicochemical and microbial (lumen- and mucus-associated microbes) parameters of the human colon (M-ARCOL), a salivary enrichment protocol, and whole-metagenome shotgun sequencing. Our study revealed the importance of integrating the mucus compartment, which retained higher microbial richness during fermentation, showed the preference of oral microbial invaders for the mucosal resources, and indicated potential oral-to-intestinal mucosal competitions. It also underlined promising opportunities to further understand mechanisms of oral invasion into the human gut microbiome, define microbe-microbe and mucus-microbe interactions in a compartmentalized fashion, and help to better characterize the potential of oral microbial invasion and their persistence in the gut.

Published
2023
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41. Both Disease Activity and HLA-B27 Status Are Associated With Gut Microbiome Dysbiosis in Spondyloarthritis Patients.

Author

Berland M, Meslier V, Berreira Ibraim S, Le Chatelier E, Pons N, Maziers N, Thirion F, Gauthier F, Plaza Oñate F, Furet JP, Leboime A, Said-Nahal R, Levenez F, Galleron N, Quinquis B, Langella P, Ehrlich SD, and Breban M

Subjects
Adult, Humans, HLA-B27 Antigen genetics, Dysbiosis microbiology, Gastrointestinal Microbiome genetics, Spondylarthritis genetics, Spondylarthritis complications, Microbiota
Abstract

Objective: Gut microbiome dysbiosis has previously been reported in spondyloarthritis (SpA) patients and could be critically involved in the pathogenesis of this disorder. The objectives of this study were to further characterize the microbiota structure in SpA patients and to investigate the relationship between dysbiosis and disease activity in light of the putative influence of the genetic background., Methods: Shotgun sequencing was performed on fecal DNA isolated from stool samples from 2 groups of adult volunteers: SpA patients (n = 102) and healthy controls (n = 63). A subset of the healthy controls comprised the age-matched siblings of patients whose HLA-B27 status was known. Changes in gut microbiota composition were assessed based on species diversity, enterotypes, and taxonomic and functional differences., Results: Dysbiosis was confirmed in SpA patients as compared to healthy controls. The restriction of microbiota diversity was detected in patients with the most active disease, and the abundance of several bacterial species was correlated with Bath Ankylosing Spondylitis Disease Activity Index score. Among healthy controls, significant differences in microbiota composition were also detected between the HLA-B27-positive and the HLA-B27-negative siblings of SpA patients. We highlighted a decreased abundance of several species of bacteria in SpA patients, especially those bacteria belonging to the Clostridiales order. Among the few species of bacteria showing increased abundance, Ruminococcus gnavus was one of the top differentiating species., Conclusion: These findings reveal that genetic background and level of disease activity are likely to influence the composition of the gut microbiota of patients with SpA. It may be appropriate for further research on chronic arthritis to focus on these key parameters., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Published
2023
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42. Impairment of gut microbial biotin metabolism and host biotin status in severe obesity: effect of biotin and prebiotic supplementation on improved metabolism.

Author

Belda E, Voland L, Tremaroli V, Falony G, Adriouch S, Assmann KE, Prifti E, Aron-Wisnewsky J, Debédat J, Le Roy T, Nielsen T, Amouyal C, André S, Andreelli F, Blüher M, Chakaroun R, Chilloux J, Coelho LP, Dao MC, Das P, Fellahi S, Forslund S, Galleron N, Hansen TH, Holmes B, Ji B, Krogh Pedersen H, Le P, Le Chatelier E, Lewinter C, Mannerås-Holm L, Marquet F, Myridakis A, Pelloux V, Pons N, Quinquis B, Rouault C, Roume H, Salem JE, Sokolovska N, Søndertoft NB, Touch S, Vieira-Silva S, Galan P, Holst J, Gøtze JP, Køber L, Vestergaard H, Hansen T, Hercberg S, Oppert JM, Nielsen J, Letunic I, Dumas ME, Stumvoll M, Pedersen OB, Bork P, Ehrlich SD, Zucker JD, Bäckhed F, Raes J, and Clément K

Subjects
Humans, Mice, Animals, Prebiotics, Biotin pharmacology, Mice, Inbred C57BL, Obesity metabolism, Inflammation, Gastrointestinal Microbiome, Obesity, Morbid surgery, Diabetes Mellitus, Type 2, Vitamin B Complex pharmacology
Abstract

Objectives: Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome's functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation., Design: We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice., Results: Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration., Conclusion: Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity., Trial Registration Number: NCT02059538., Competing Interests: Competing interests: KC is a consultant for Danone Research, Ysopia and CONFO therapeutics for work not associated with this study. KC held a collaborative research contract with Danone Research in the context of MetaCardis project. FB is a shareholder of Implexion pharma AB. MB received lecture and/or consultancy fees from AstraZeneca, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis and Sanofi., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2022
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43. Low-dose IL-2 shapes a tolerogenic gut microbiota that improves autoimmunity and gut inflammation.

Author

Tchitchek N, Nguekap Tchoumba O, Pires G, Dandou S, Campagne J, Churlaud G, Fourcade G, Hoffmann TW, Strozzi F, Gaal C, Bonny C, Le Chatelier E, Erlich SD, Sokol H, and Klatzmann D

Subjects
Animals, Autoimmunity, Dextran Sulfate toxicity, Humans, Inflammation therapy, Interleukin-2 pharmacology, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Autoimmune Diseases, Gastrointestinal Microbiome
Abstract

Gut microbiota dysbiosis is associated with inflammatory bowel diseases and with cardiometabolic, neurological, and autoimmune diseases. Gut microbiota composition has a direct effect on the immune system, and vice versa, and it has a particular effect on Treg homeostasis. Low-dose IL-2 (IL-2LD) stimulates Tregs and is a promising treatment for autoimmune and inflammatory diseases. We aimed to evaluate the impact of IL-2LD on gut microbiota and correlatively on the immune system. We used 16S ribosomal RNA profiling and metagenomics to characterize gut microbiota of mice and humans treated or not with IL-2LD. We performed fecal microbiota transplantation (FMT) from IL-2LD-treated to naive recipient mice and evaluated its effects in models of gut inflammation and diabetes. IL-2LD markedly affected gut microbiota composition in mice and humans. Transfer of an IL-2-tuned microbiota by FMT protected C57BL/6J mice from dextran sulfate sodium-induced colitis and prevented diabetes in NOD mice. Metagenomic analyses highlighted a role for several species affected by IL-2LD and for microbial pathways involved in the biosynthesis of amino acids, short-chain fatty acids, and L-arginine. Our results demonstrate that IL-2LD induced changes in gut microbiota that are involved in the immunoregulatory effects of IL-2LD and suggest a crosstalk between Tregs and gut microbiota. These results provide potentially novel insight for understanding the mode of action of Treg-directed therapies.

Published
2022
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44. Diet Supplementation with NUTRIOSE, a Resistant Dextrin, Increases the Abundance of Parabacteroides distasonis in the Human Gut.

Author

Thirion F, Da Silva K, Plaza Oñate F, Alvarez AS, Thabuis C, Pons N, Berland M, Le Chatelier E, Galleron N, Levenez F, Vergara C, Chevallier H, Guérin-Deremaux L, Doré J, and Ehrlich SD

Subjects
Bacteroidetes, Diet, Feces microbiology, Female, Humans, Dextrins pharmacology, Dietary Supplements
Abstract

Scope: An imbalance of the gut microbiota ("dysbiosis") is associated with numerous chronic diseases, and its modulation is a promising novel therapeutic approach. Dietary supplementation with soluble fiber is one of several proposed modulation strategies. This study aims at confirming the impact of the resistant dextrin NUTRIOSE (RD), a soluble fiber with demonstrated beneficial health effects, on the gut microbiota of healthy individuals., Methods and Results: Fifty healthy women are enrolled and supplemented daily with either RD (n = 24) or a control product (n = 26) during 6 weeks. Characterization of the fecal metagenome with shotgun sequencing reveals that RD intake dramatically increases the abundance of the commensal bacterium Parabacteroides distasonis. Furthermore, presence in metagenomes of accessory genes from P. distasonis, coding for susCD (a starch-binding membrane protein complex) is associated with a greater increase of the species. This suggests that response to RD might be strain-dependent., Conclusion: Supplementation with RD can be used to specifically increase P. distasonis in gut microbiota of healthy women. The magnitude of the response may be associated with fiber-metabolizing capabilities of strains carried by subjects. Further research will seek to confirm that P. distasonis directly modulates the clinical effects observed in other studies., (© 2022 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH GmbH.)

Published
2022
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45. A Natural Polyphenol Exerts Antitumor Activity and Circumvents Anti-PD-1 Resistance through Effects on the Gut Microbiota.

Author

Messaoudene M, Pidgeon R, Richard C, Ponce M, Diop K, Benlaifaoui M, Nolin-Lapalme A, Cauchois F, Malo J, Belkaid W, Isnard S, Fradet Y, Dridi L, Velin D, Oster P, Raoult D, Ghiringhelli F, Boidot R, Chevrier S, Kysela DT, Brun YV, Falcone EL, Pilon G, Oñate FP, Gitton-Quent O, Le Chatelier E, Durand S, Kroemer G, Elkrief A, Marette A, Castagner B, and Routy B

Subjects
Animals, Bacteria, Fecal Microbiota Transplantation, Humans, Mice, Polyphenols pharmacology, Polyphenols therapeutic use, Gastrointestinal Microbiome
Abstract

Several approaches to manipulate the gut microbiome for improving the activity of cancer immune-checkpoint inhibitors (ICI) are currently under evaluation. Here, we show that oral supplementation with the polyphenol-rich berry camu-camu (CC; Myrciaria dubia) in mice shifted gut microbial composition, which translated into antitumor activity and a stronger anti-PD-1 response. We identified castalagin, an ellagitannin, as the active compound in CC. Oral administration of castalagin enriched for bacteria associated with efficient immunotherapeutic responses (Ruminococcaceae and Alistipes) and improved the CD8+/FOXP3+CD4+ ratio within the tumor microenvironment. Moreover, castalagin induced metabolic changes, resulting in an increase in taurine-conjugated bile acids. Oral supplementation of castalagin following fecal microbiota transplantation from ICI-refractory patients into mice supported anti-PD-1 activity. Finally, we found that castalagin binds to Ruminococcus bromii and promoted an anticancer response. Altogether, our results identify castalagin as a polyphenol that acts as a prebiotic to circumvent anti-PD-1 resistance., Significance: The polyphenol castalagin isolated from a berry has an antitumor effect through direct interactions with commensal bacteria, thus reprogramming the tumor microenvironment. In addition, in preclinical ICI-resistant models, castalagin reestablishes the efficacy of anti-PD-1. Together, these results provide a strong biological rationale to test castalagin as part of a clinical trial. This article is highlighted in the In This Issue feature, p. 873., (©2022 The Authors; Published by the American Association for Cancer Research.)

Published
2022
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46. Long-term diosmectite use does not alter the gut microbiota in adults with chronic diarrhea.

Author

Da Silva K, Guilly S, Thirion F, Le Chatelier E, Pons N, Roume H, Quinquis B, Ehrlich SD, Bekkat N, Mathiex-Fortunet H, Sokol H, and Doré J

Subjects
Adolescent, Adult, Bacteria classification, Bacteria genetics, Chronic Disease therapy, Female, Humans, Male, Middle Aged, Young Adult, Diarrhea drug therapy, Feces microbiology, Gastrointestinal Microbiome drug effects, Gastrointestinal Microbiome genetics, Metagenome, Silicates therapeutic use
Abstract

Background: Diosmectite, a natural colloidal clay, has been used worldwide for a number of approved indications, including the treatment of chronic functional diarrhea. Here, we used high-resolution whole metagenome shotgun sequencing to assess the impact of a 5 weeks administration of diosmectite (3 g/sachet, 3 sachets/day) on the fecal microbiota of 35 adults with functional chronic diarrhea., Results: Gut microbiota was not impacted by diosmectite administration. In particular, richness remained stable and no microbial species displayed a significant evolution. Segregating patients either by diosmectite response (non responder, early responder, late responder) or by nationality (Great-Britain or Netherlands) yielded the same results., Conclusion: We concluded that no microbiota-related physiological alterations are expected upon long-term treatment with diosmectite., Trial Registration: Clinicaltrials.gov NCT03045926., (© 2022. The Author(s).)

Published
2022
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47. Alteration of Gut Microbiome in Patients With Schizophrenia Indicates Links Between Bacterial Tyrosine Biosynthesis and Cognitive Dysfunction.

Author

Thirion F, Speyer H, Hansen TH, Nielsen T, Fan Y, Le Chatelier E, Fromentin S, Berland M, Plaza Oñate F, Pons N, Galleron N, Levenez F, Markó L, Birkner T, Jørgensen T, Forslund SK, Vestergaard H, Hansen T, Nordentoft M, Mors O, Benros ME, Pedersen O, and Ehrlich SD

Abstract

Background: Schizophrenia (SCZ) is a heterogeneous neuropsychiatric disorder for which current treatment has insufficient efficacy and severe adverse effects. The modifiable gut microbiome might be a potential target for intervention to improve neurobiological functions through the gut-microbiome-brain axis., Methods: In this case-control study, gut microbiota of 132 patients with SCZ and increased waist circumference were compared with gut microbiota of two age- and sex-matched control groups, composed of 132 healthy individuals and 132 individuals with metabolic syndrome. Shotgun sequencing was used to characterize fecal samples at the taxonomic and functional levels. Cognition of the patients with SCZ was evaluated using the Brief Assessment of Cognition instrument., Results: SCZ gut microbiota differed significantly from those of healthy control subjects and individuals with metabolic syndrome in terms of richness and global composition. SCZ gut microbiota were notably enriched in Flavonifractor plautii , Collinsella aerofaciens , Bilophila wadsworthia , and Sellimonas intestinalis , while depleted in Faecalibacterium prausnitzii , Ruminococcus lactaris , Ruminococcus bicirculans , and Veillonella rogosae . Functional potential of the gut microbiota accounted for 11% of cognition variability. In particular, the bacterial functional module for synthesizing tyrosine, a precursor for dopamine, was in SCZ cases positively associated with cognitive score (ρ = 0.34, q ≤ .1)., Conclusions: Overall, this study shows that the gut microbiome of patients with SCZ differs greatly from that of healthy control subjects or individuals with metabolic syndrome. Cognitive function of patients with SCZ is associated with the potential for gut bacterial biosynthesis of tyrosine, a precursor for dopamine, suggesting that gut microbiota might be an intervention target for alleviation of cognitive dysfunction in SCZ., (© 2022 The Authors.)

Published
2022
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48. Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer.

Author

Derosa L, Routy B, Thomas AM, Iebba V, Zalcman G, Friard S, Mazieres J, Audigier-Valette C, Moro-Sibilot D, Goldwasser F, Silva CAC, Terrisse S, Bonvalet M, Scherpereel A, Pegliasco H, Richard C, Ghiringhelli F, Elkrief A, Desilets A, Blanc-Durand F, Cumbo F, Blanco A, Boidot R, Chevrier S, Daillère R, Kroemer G, Alla L, Pons N, Le Chatelier E, Galleron N, Roume H, Dubuisson A, Bouchard N, Messaoudene M, Drubay D, Deutsch E, Barlesi F, Planchard D, Segata N, Martinez S, Zitvogel L, Soria JC, and Besse B

Subjects
Akkermansia, B7-H1 Antigen, Humans, Programmed Cell Death 1 Receptor, Retrospective Studies, Tumor Microenvironment, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung metabolism, Lung Neoplasms drug therapy, Lung Neoplasms genetics
Abstract

Aside from PD-L1 expression, biomarkers of response to immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) are needed. In a previous retrospective analysis, we documented that fecal Akkermansia muciniphila (Akk) was associated with clinical benefit of ICI in patients with NSCLC or kidney cancer. In the current study, we performed shotgun-metagenomics-based microbiome profiling in a large cohort of patients with advanced NSCLC (n = 338) treated with first- or second-line ICIs to prospectively validate the predictive value of fecal Akk. Baseline stool Akk was associated with increased objective response rates and overall survival in multivariate analyses, independent of PD-L1 expression, antibiotics, and performance status. Intestinal Akk was accompanied by a richer commensalism, including Eubacterium hallii and Bifidobacterium adolescentis, and a more inflamed tumor microenvironment in a subset of patients. However, antibiotic use (20% of cases) coincided with a relative dominance of Akk above 4.8% accompanied with the genus Clostridium, both associated with resistance to ICI. Our study shows significant differences in relative abundance of Akk that may represent potential biomarkers to refine patient stratification in future studies., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Published
2022
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49. Microbiome and metabolome features of the cardiometabolic disease spectrum.

Author

Fromentin S, Forslund SK, Chechi K, Aron-Wisnewsky J, Chakaroun R, Nielsen T, Tremaroli V, Ji B, Prifti E, Myridakis A, Chilloux J, Andrikopoulos P, Fan Y, Olanipekun MT, Alves R, Adiouch S, Bar N, Talmor-Barkan Y, Belda E, Caesar R, Coelho LP, Falony G, Fellahi S, Galan P, Galleron N, Helft G, Hoyles L, Isnard R, Le Chatelier E, Julienne H, Olsson L, Pedersen HK, Pons N, Quinquis B, Rouault C, Roume H, Salem JE, Schmidt TSB, Vieira-Silva S, Li P, Zimmermann-Kogadeeva M, Lewinter C, Søndertoft NB, Hansen TH, Gauguier D, Gøtze JP, Køber L, Kornowski R, Vestergaard H, Hansen T, Zucker JD, Hercberg S, Letunic I, Bäckhed F, Oppert JM, Nielsen J, Raes J, Bork P, Stumvoll M, Segal E, Clément K, Dumas ME, Ehrlich SD, and Pedersen O

Subjects
Humans, Longitudinal Studies, Metabolome, Middle Aged, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Microbiota
Abstract

Previous microbiome and metabolome analyses exploring non-communicable diseases have paid scant attention to major confounders of study outcomes, such as common, pre-morbid and co-morbid conditions, or polypharmacy. Here, in the context of ischemic heart disease (IHD), we used a study design that recapitulates disease initiation, escalation and response to treatment over time, mirroring a longitudinal study that would otherwise be difficult to perform given the protracted nature of IHD pathogenesis. We recruited 1,241 middle-aged Europeans, including healthy individuals, individuals with dysmetabolic morbidities (obesity and type 2 diabetes) but lacking overt IHD diagnosis and individuals with IHD at three distinct clinical stages-acute coronary syndrome, chronic IHD and IHD with heart failure-and characterized their phenome, gut metagenome and serum and urine metabolome. We found that about 75% of microbiome and metabolome features that distinguish individuals with IHD from healthy individuals after adjustment for effects of medication and lifestyle are present in individuals exhibiting dysmetabolism, suggesting that major alterations of the gut microbiome and metabolome might begin long before clinical onset of IHD. We further categorized microbiome and metabolome signatures related to prodromal dysmetabolism, specific to IHD in general or to each of its three subtypes or related to escalation or de-escalation of IHD. Discriminant analysis based on specific IHD microbiome and metabolome features could better differentiate individuals with IHD from healthy individuals or metabolically matched individuals as compared to the conventional risk markers, pointing to a pathophysiological relevance of these features., (© 2022. The Author(s).)

Published
2022
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50. Rifaximin-α reduces gut-derived inflammation and mucin degradation in cirrhosis and encephalopathy: RIFSYS randomised controlled trial.

Author

Patel VC, Lee S, McPhail MJW, Da Silva K, Guilly S, Zamalloa A, Witherden E, Støy S, Manakkat Vijay GK, Pons N, Galleron N, Huang X, Gencer S, Coen M, Tranah TH, Wendon JA, Bruce KD, Le Chatelier E, Ehrlich SD, Edwards LA, Shoaie S, and Shawcross DL

Subjects
Adult, Aged, Double-Blind Method, Female, Gastrointestinal Agents metabolism, Gastrointestinal Agents pharmacology, Gastrointestinal Agents therapeutic use, Hepatic Encephalopathy physiopathology, Humans, Inflammation epidemiology, Inflammation prevention & control, Liver Cirrhosis epidemiology, Liver Cirrhosis physiopathology, Male, Middle Aged, Mucins drug effects, Ontario epidemiology, Placebos, Rifaximin metabolism, Rifaximin therapeutic use, Hepatic Encephalopathy drug therapy, Inflammation drug therapy, Liver Cirrhosis drug therapy, Mucins metabolism, Rifaximin pharmacology
Abstract

Background & Aims: Rifaximin-α is efficacious for the prevention of recurrent hepatic encephalopathy (HE), but its mechanism of action remains unclear. We postulated that rifaximin-α reduces gut microbiota-derived endotoxemia and systemic inflammation, a known driver of HE., Methods: In a placebo-controlled, double-blind, mechanistic study, 38 patients with cirrhosis and HE were randomised 1:1 to receive either rifaximin-α (550 mg BID) or placebo for 90 days., Primary Outcome: 50% reduction in neutrophil oxidative burst (OB) at 30 days., Secondary Outcomes: changes in psychometric hepatic encephalopathy score (PHES) and neurocognitive functioning, shotgun metagenomic sequencing of saliva and faeces, plasma and faecal metabolic profiling, whole blood bacterial DNA quantification, neutrophil toll-like receptor (TLR)-2/4/9 expression and plasma/faecal cytokine analysis., Results: Patients were well-matched: median MELD (11 rifaximin-α vs. 10 placebo). Rifaximin-α did not lead to a 50% reduction in spontaneous neutrophil OB at 30 days compared to baseline (p = 0.48). However, HE grade normalised (p = 0.014) and PHES improved (p = 0.009) after 30 days on rifaximin-α. Rifaximin-α reduced circulating neutrophil TLR-4 expression on day 30 (p = 0.021) and plasma tumour necrosis factor-α (TNF-α) (p <0.001). Rifaximin-α suppressed oralisation of the gut, reducing levels of mucin-degrading sialidase-rich species, Streptococcus spp, Veillonella atypica and parvula, Akkermansia and Hungatella. Rifaximin-α promoted a TNF-α- and interleukin-17E-enriched intestinal microenvironment, augmenting antibacterial responses to invading pathobionts and promoting gut barrier repair. Those on rifaximin-α were less likely to develop infection (odds ratio 0.21; 95% CI 0.05-0.96)., Conclusion: Rifaximin-α led to resolution of overt and covert HE, reduced the likelihood of infection, reduced oralisation of the gut and attenuated systemic inflammation. Rifaximin-α plays a role in gut barrier repair, which could be the mechanism by which it ameliorates bacterial translocation and systemic endotoxemia in cirrhosis., Clinical Trial Number: ClinicalTrials.gov NCT02019784., Lay Summary: In this clinical trial, we examined the underlying mechanism of action of an antibiotic called rifaximin-α which has been shown to be an effective treatment for a complication of chronic liver disease which effects the brain (termed encephalopathy). We show that rifaximin-α suppresses gut bacteria that translocate from the mouth to the intestine and cause the intestinal wall to become leaky by breaking down the protective mucus barrier. This suppression resolves encephalopathy and reduces inflammation in the blood, preventing the development of infection., Competing Interests: Conflict of interest Dr V Patel and Ms A Zamalloa have delivered paid lectures for Norgine Pharmaceuticals Ltd. Professor Shawcross has participated in advisory boards for Norgine Pharmaceuticals Ltd, EnteroBiotix, Kaleido Biosciences, Mallinckrodt and Shionogi and has delivered paid lectures for Norgine Pharmaceuticals Ltd, Falk Pharma and Alfa Sigma. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Published
2022
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