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1. Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance

Author

Pellegrinelli, V., Rodriguez-Cuenca, S., Rouault, C., Figueroa-Juarez, E., Schilbert, H., Virtue, S., Moreno-Navarrete, J. M., Bidault, G., Vázquez-Borrego, M. C., Dias, A. R., Pucker, B., Dale, M., Campbell, M., Carobbio, S., Lin, Y. H., Vacca, M., Aron-Wisnewsky, J., Mora, S., Masiero, M. M., Emmanouilidou, A., Mukhopadhyay, S., Dougan, G., den Hoed, M., Loos, R. J. F., Fernández-Real, J. M., Chiarugi, D., Clément, K., and Vidal-Puig, A.

Published
2022
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3. Networks of gut bacteria relate to cardiovascular disease in a multi-ethnic population: the HELIUS study

Author

Warmbrunn, M V, primary, Boulund, U, additional, Aron-Wisnewsky, J, additional, de Goffau, M C, additional, Abeka, R E, additional, Davids, M, additional, Bresser, L R F, additional, Levin, E, additional, Clement, K, additional, Galenkamp, H, additional, Ferwerda, B, additional, van den Born, B J H, additional, Kurilshikov, A, additional, Fu, J, additional, Zwinderman, A H, additional, Soeters, M R, additional, van Raalte, D H, additional, Herrema, H, additional, Groen, A K, additional, and Nieuwdorp, M, additional

Published
2024
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13. Diagnostic approach to sleep disordered-breathing among patients with grade III obesity

Author

Perger, E, Aron-Wisnewsky, J, Arnulf, I, Oppert, J, Redolfi, S, Perger E., Aron-Wisnewsky J., Arnulf I., Oppert J. -M., Redolfi S., Perger, E, Aron-Wisnewsky, J, Arnulf, I, Oppert, J, Redolfi, S, Perger E., Aron-Wisnewsky J., Arnulf I., Oppert J. -M., and Redolfi S.

Abstract

Sleep apnea test (SAT) is a cost-effective approach to evaluate subjects without associated comorbidities suspected for obstructive sleep apnea (OSA), a disorder particularly common in obese subjects. The association of obesity with awake hypercapnia (carbon dioxide arterial pressure, PaCO2 ≥45 mmHg) defines the obesity-hypoventilation syndrome (OHS), which in turn results in increased morbidity and mortality compared to simple OSA. Isolated hypoventilation during sleep in obese patients (obesity-related sleep hypoventilation, ORSH) is now considered as an early stage of OHS. The aim of this study was to assess the performance of SAT in diagnosing OSA and predicting the presence of ORHS among patients with grade III obesity without awake hypercapnia. Methods: Over a 14-months period, patients with grade III obesity (body mass index≥40 kg/m2) presenting moderate-to-severe OSA (apnea-hypopnea index [AHI]≥15) upon SAT and normal awake PaCO2 at arterial blood gas analysis, systematically underwent in-lab nocturnal polysomnography combined with transcutaneous carbon dioxide pressure (PtcCO2) monitoring. Results: Among 48 patients included in the study, 16 (33%) presented an AHI<15 upon polysomnography and 14 (29%) had ORSH. The test revealed no difference in ORSH prevalence between patients with AHI <15 or ≥15 (31% vs. 25%). No SAT variables were independently associated with increased PtCO2. Conclusions: This study shows that SAT overestimates OSA severity and ORSH affects one third of patients with grade III obesity without awake hypercapnia and with moderate-to-severe OSA at SAT, suggesting how polysomnography combined with PtCO2 monitoring is the most appropriate diagnostic approach for OSA and ORSH in this population.

Published
2021

15. Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance

Author

Pellegrinelli, V, Rodriguez-Cuenca, S., Rouault, C., Figueroa-Juarez, E., Schilbert, H., Virtue, S., Moreno-Navarrete, J. M., Bidault, G., Vazquez-Borrego, M. C., Dias, A. R., Pucker, B., Dale, M., Campbell, M., Carobbio, S., Lin, Y. H., Vacca, M., Aron-Wisnewsky, J., Mora, S., Masiero, M. M., Emmanouilidou, Anastasia, Mukhopadhyay, S., Dougan, G., den Hoed, Marcel, Loos, R. J. F., Fernandez-Real, J. M., Chiarugi, D., Clement, K., Vidal-Puig, A., Pellegrinelli, V, Rodriguez-Cuenca, S., Rouault, C., Figueroa-Juarez, E., Schilbert, H., Virtue, S., Moreno-Navarrete, J. M., Bidault, G., Vazquez-Borrego, M. C., Dias, A. R., Pucker, B., Dale, M., Campbell, M., Carobbio, S., Lin, Y. H., Vacca, M., Aron-Wisnewsky, J., Mora, S., Masiero, M. M., Emmanouilidou, Anastasia, Mukhopadhyay, S., Dougan, G., den Hoed, Marcel, Loos, R. J. F., Fernandez-Real, J. M., Chiarugi, D., Clement, K., and Vidal-Puig, A.

Abstract

Resulting from impaired collagen turnover, fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance (IR). Prolidase, also known as peptidase D (PEPD), plays a vital role in collagen turnover by degrading proline-containing dipeptides but its specific functional relevance in AT is unknown. Here we show that in human and mouse obesity, PEPD expression and activity decrease in AT, and PEPD is released into the systemic circulation, which promotes fibrosis and AT IR. Loss of the enzymatic function of PEPD by genetic ablation or pharmacological inhibition causes AT fibrosis in mice. In addition to its intracellular enzymatic role, secreted extracellular PEPD protein enhances macrophage and adipocyte fibro-inflammatory responses via EGFR signalling, thereby promoting AT fibrosis and IR. We further show that decreased prolidase activity is coupled with increased systemic levels of PEPD that act as a pathogenic trigger of AT fibrosis and IR. Thus, PEPD produced by macrophages might serve as a biomarker of AT fibro-inflammation and could represent a therapeutic target for AT fibrosis and obesity-associated IR and type 2 diabetes. Obesity-associated AT fibro-inflammation and metabolic disturbances are linked to PEPD activity and PEPD extracellular levels.

Published
2022
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16. 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

23. 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

24. 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

28. A data integration multi-omics approach to study calorie restriction-induced changes in insulin sensitivity

Author

Dao, M. C., Sokolovska, N., Brazeilles, R., Affeldt, S., Pelloux, V., Prifti, E., Chilloux, J., Verger, E., Kayser, B. D., Aron-Wisnewsky, J., Ichou, F., Pujos-Guillot, E., Hoyles, L., Juste, C., Dore, J., Dumas, M. E., Rizkalla, S. W., Holmes, B. A., Zucker, Jean-Daniel, Clement, K., and Micro-Obes Consortium

Subjects
microbiota, insulin sensitivity, lifestyle factors, data integration, omics
Abstract

Background: The mechanisms responsible for calorie restriction (CR)-induced improvement in insulin sensitivity (IS) have not been fully elucidated. Greater insight can be achieved through deep biological phenotyping of subjects undergoing CR, and integration of big data. Materials and Methods: An integrative approach was applied to investigate associations between change in IS and factors from host, microbiota, and lifestyle after a 6-week CR period in 27 overweight or obese adults (ClinicalTrials.gov: NCT01314690). Partial least squares regression was used to determine associations of change (week 6 - baseline) between IS markers and lifestyle factors (diet and physical activity), subcutaneous adipose tissue (sAT) gene expression, metabolomics of serum, urine and feces, and gut microbiota composition. ScaleNet, a network learning approach based on spectral consensus strategy (SCS, developed by us) was used for reconstruction of biological networks. Results: A spectrum of variables from lifestyle factors (10 nutrients), gut microbiota (10 metagenomics species), and host multi-omics (metabolic features: 84 from serum, 73 from urine, and 131 from feces; and 257 sAT gene probes) most associated with IS were identified. Biological network reconstruction using SCS, highlighted links between changes in IS, serum branched chain amino acids, sAT genes involved in endoplasmic reticulum stress and ubiquitination, and gut metagenomic species (MGS). Linear regression analysis to model how changes of select variables over the CR period contribute to changes in IS, showed greatest contributions from gut MGS and fiber intake. Conclusion: This work has enhanced previous knowledge on links between host glucose homeostasis, lifestyle factors and the gut microbiota, and has identified potential biomarkers that may be used in future studies to predict and improve individual response to weight-loss interventions. Furthermore, this is the first study showing integration of the wide range of data presented herein, identifying 115 variables of interest with respect to IS from the initial input, consisting of 9,986 variables.

Published
2019

29. Prediction of long-term diabetes remission after rygb, sleeve gastrectomy, and adjustable gastric banding using DiaRem and Advanced-DiaRem scores

Author

Dicker, D., Golan, R., Aron-Wisnewsky, J., Zucker, Jean-Daniel, Sokolowska, N., Comaneshter, D. S., Yahalom, R., Vinker, S., Clement, K., and Rudich, A.

Subjects
Bariatric surgery, Diabetes remission, Prediction score
Abstract

Purpose DiaRem is a clinical scoring system designed to predict diabetes remission (DR) 1-year post-Roux-en-Y gastric bypass (RYGB). We examined long-term (2- and 5-year) postoperative DR prediction by DiaRem and an advanced-DiaRem (Ad-DiaRem) score following RYGB, sleeve gastrectomy (SG), and gastric banding (GB). Methods We accessed data from a computerized database of persons with type 2 diabetes and BMI >= 30 kg/m(2) who underwent RYGB, SG, or GB, and determined DR status 2- and 5-year postoperative according to preoperative DiaRem and the Ad-DiaRem calculated scores. Results Among 1459 patients with 5-year postoperative diabetes status data, 53.6% exhibited DR. For RYGB, Ad-DiaRem trended to exhibit mildly improved predictive capacity 5-year postoperatively compared to DiaRem: Areas under receiver operating characteristic [AUROC] curves were 0.85 (0.76-0.93) and 0.78 (0.69-0.88), respectively. The positive predictive values (PPVs) detecting >80% of those achieving DR (i.e., sensitivity >= 0.8) were 78.2% and 73.2%, respectively, and higher Ad-DiaRem scores more consistently associated with decreased DR rates. Following SG, both scores had an AUROC of 0.82, but Ad-DiaRem still had a higher PPV for predicting >80% of those with 5-year postoperative DR (76.2% and 71.0%). Predictive capacity parameters were comparatively lower, for both scores, when considering DR 5-year post-GB (AUROC: 0.73 for both scores, PPV: 66.3% and 64.3%, respectively). Conclusions Ad-DiaRem provides modest improvement compared to DiaRem in predicting long-term DR 5-years post-RYGB. Both scores similarly provide fair predictive capacity for 5-year postoperative DR after SG.

Published
2019

30. 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

36. Long-term Relapse of Type 2 Diabetes After Roux-en-Y Gastric Bypass: Prediction and clinical relevance

Author

Debedat, J., Sokolovska, N., Coupaye, M., Panunzi, S., Chakaroun, R., Genser, L., De Turenne, G., Bouillot, J. -L., Poitou, C., Oppert, J. -M., Bluher, M., Stumvoll, M., Mingrone, G., Ledoux, S., Zucker, J. -D., Clement, K., Aron-Wisnewsky, J., Mingrone G. (ORCID:0000-0003-2021-528X), Debedat, J., Sokolovska, N., Coupaye, M., Panunzi, S., Chakaroun, R., Genser, L., De Turenne, G., Bouillot, J. -L., Poitou, C., Oppert, J. -M., Bluher, M., Stumvoll, M., Mingrone, G., Ledoux, S., Zucker, J. -D., Clement, K., Aron-Wisnewsky, J., and Mingrone G. (ORCID:0000-0003-2021-528X)

Abstract

OBJECTIVE: Roux-en-Y gastric bypass (RYGB) induces type 2 diabetes remission (DR) in 60% of patients at 1 year, yet long-term relapse occurs in half of these patients. Scoring methods to predict DR outcomes 1 year after surgery that include only baseline parameters cannot accurately predict 5-year DR (5y-DR). We aimed to develop a new score to better predict 5y-DR. RESEARCH DESIGN AND METHODS: We retrospectively included 175 RYGB patients with type 2 diabetes with 5-year follow-up. Using machine learning algorithms, we developed a scoring method, 5-year Advanced-Diabetes Remission (5y-Ad-DiaRem), predicting longer-term DR postsurgery by integrating medical history, bioclinical data, and antidiabetic treatments. The scoring method was based on odds ratios and variables significantly different between groups. This score was further validated in three independent RYGB cohorts from three European countries. RESULTS: Compared with 5y-DR patients, patients who had relapsed after 5 years exhibited more severe type 2 diabetes at baseline, lost significantly less weight during the 1st year after RYGB, and regained more weight afterward. The 5y-Ad-DiaRem includes baseline (diabetes duration, number of antidiabetic treatments, and HbA1C) and 1-year follow-up parameters (glycemia, number of antidiabetic treatments, remission status, 1st-year weight loss). The 5y-Ad-DiaRem was accurate (area under the receiver operating characteristic curve [AUROC], 90%; accuracy, 85%) at predicting 5y-DR, performed better than the Diabetes Remission score (DiaRem) and the Advanced-DiaRem (AUROC, 81% and 84%; accuracy, 79% and 78%, respectively), and correctly reclassified 13 of 39 patients misclassified with the DiaRem. The 5y-Ad-DiaRem robustness was confirmed in the independent cohorts. CONCLUSIONS: The 5y-Ad-DiaRem accurately predicts 5y-DR and appears relevant to identify patients at risk for relapse. Using this score could help personalize patient care after the 1st year post-RYGB to maxim

Published
2018

37. The advanced-DiaRem score improves prediction of diabetes remission 1 year post-Roux-en-Y gastric bypass

Author

Aron-Wisnewsky, J., Sokolovska, N., Liu, Y. J., Comaneshter, D. S., Vinker, S., Pecht, T., Poitou, C., Oppert, J. M., Bouillot, J. L., Genser, L., Dicker, D., Zucker, Jean-Daniel, Rudich, A., and Clement, K.

Subjects
Bariatric surgery, Type 2 diabetesmellitus, Diabetes remission, Obese
Abstract

Aims/hypothesis Not all people with type 2 diabetes who undergo bariatric surgery achieve diabetes remission. Thus it is critical to develop methods for predicting outcomes that are applicable for clinical practice. The DiaRem score is relevant for predicting diabetes remission post-Roux-en-Y gastric bypass (RYGB), but it is not accurate for all individuals across the entire spectrum of scores. We aimed to develop an improved scoring system for predicting diabetes remission following RYGB (the Advanced-DiaRem [Ad-DiaRem]). Methods We used a retrospective French cohort (n = 1866) that included 352 individuals with type 2 diabetes followed for 1 year post-RYGB. We developed the Ad-DiaRemin a test cohort (n = 213) and examined its accuracy in independent cohorts from France (n = 134) and Israel (n = 99). Results Adding two clinical variables (diabetes duration and number of glucose-lowering agents) to the original DiaRem and modifying the penalties for each category led to improved predictive performance for Ad-DiaRem. Ad-DiaRem displayed improved area under the receiver operating characteristic curve and predictive accuracy compared with DiaRem (0.911 vs 0.856 and 0.841 vs 0.789, respectively; p = 0.03); thus correcting classification for 8% of those initially misclassified with DiaRem. With Ad-DiaRem, there were also fewer misclassifications of individuals with mid-range scores. This improved predictive performance was confirmed in independent cohorts. Conclusions/interpretation We propose the Ad-DiaRem, which includes two additional clinical variables, as an optimised tool with improved accuracy to predict diabetes remission 1 year post-RYGB. This tool might be helpful for personalised management of individuals with diabetes when considering bariatric surgery in routine care, ultimately contributing to precision medicine.

Published
2017

39. Decision-making in obesity without eating disorders: a systematic review and meta-analysis of Iowa gambling task performances

Author

Rotge, J. Y., Poitou, Christine, Fossati, P., Aron-Wisnewsky, J., Oppert, J.-M., Service de psychiatrie adulte [CHU Pitié-Salpêtière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Service de nutrition [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], HAL-UPMC, Gestionnaire, Service de Psychiatrie Adulte [CHU Pitié-Salpêtière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [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)-CHU Pitié-Salpêtrière [AP-HP], 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)-Sorbonne Université (SU)-Sorbonne Université (SU), Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP]

Subjects
[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Meta-analysis, [SCCO]Cognitive science, Obesity words, Iowa Gambling Task, [SCCO] Cognitive science, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Decision-making
Abstract

International audience; Background: There is evidence that obesity is associated with impairments in executive functions, such as deficits in decision-making, planning or problem solving, which might interfere with weight loss in obese individuals. We performed a systematic review and meta-analysis of decision-making abilities, as measured with the Iowa gambling task (IGT), in obesity without eating disorders.Methods: A systematic search was conducted to identify studies comparing IGT performances between groups of obese patients without eating disorders and groups of healthy control groups. The standardized mean differences were calculated for the total IGT scores and for the course of IGT scores. Meta-regression analyses were performed to explore the influence of clinical variables on standardized mean differences.Results: Total IGT scores were significantly lower in obese patients compared with normal-weight healthy controls. IGT performances did not differ between groups for the first trials of the task. Significant effect sizes for the last trials of the task were subjected to a high degree of heterogeneity.Conclusion: Risky decision-making is impaired in obesity. The clinical importance of non-food-related decision-making impairments remains to be assessed especially in terms of consequences in daily life or the achievement of weight loss.

Published
2017

40. Projet OBEPAR article 51: vers une amélioration de l'organisation et du financement du parcours de soins du patient candidat à la chirurgie bariatrique.

Author

Ledoux, S., Aron-Wisnewsky, J., Tissier, F., Blaizot van Wijk, P., Gourmelon, N., Hama, H., Oppert, J.-M., Czernichow, S., Garnier, V., and Obepar, Groupe

Abstract

Copyright of Obésité is the property of Lavoisier and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2020
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43. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology

Author

Dao, MC, Everard, A, Aron-Wisnewsky, J, Sokolovska, N, Prifti, E, Verger, EO, Kayser, BD, Levenez, F, Chilloux, J, Hoyles, L, MICRO-Obes Consortium, Dumas, M-E, Rizkalla, SW, Dore, J, Cani, PD, Clément, K, ProdInra, Migration, 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Catholique de Louvain = Catholic University of Louvain (UCL), MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Imperial College London, 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 (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Commission of the European Communities

Subjects
0301 basic medicine, Blood Glucose, Male, obesity, HOST, [SDV]Life Sciences [q-bio], GASTRIC BYPASS, Gut flora, Overweight, GLUCOSE, Feces, Weight loss, POPULATION, 2. Zero hunger, education.field_of_study, INSULIN-RESISTANCE, biology, Ecology, Gastroenterology, Middle Aged, [SDV] Life Sciences [q-bio], Treatment Outcome, Female, medicine.symptom, SENSITIVITY, Life Sciences & Biomedicine, Akkermansia muciniphila, EXPRESSION, Adult, Diet, Reducing, glucose metabolism, Population, 03 medical and health sciences, Insulin resistance, Verrucomicrobia, MICRO-Obes Consortium, medicine, Humans, education, Triglycerides, BARIATRIC SURGERY, Aged, ADIPOCYTE SIZE, Science & Technology, Gastroenterology & Hepatology, Akkermansia, 1103 Clinical Sciences, biology.organism_classification, medicine.disease, Obesity, Gastrointestinal Microbiome, METAGENOME, 030104 developmental biology, 1114 Paediatrics and Reproductive Medicine, intestinal bacteria, Insulin Resistance, Biomarkers
Abstract

International audience; Objectives :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

44. 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

50. Mucosal-associated invariant T cell alterations in obese and type 2 diabetic patients

Author

Magalhaes, I, Pingris, K, Poitou, C, Bessoles, S, Venteclef, N, Kiaf, B, Beaudoin, L, Da Silva, J, Allatif, O, Rossjohn, J, Kjer-Nielsen, L, McCluskey, J, Ledoux, S, Genser, L, Torcivia, A, Soudais, C, Lantz, O, Boitard, C, Aron-Wisnewsky, J, Larger, E, Clement, K, Lehuen, A, Magalhaes, I, Pingris, K, Poitou, C, Bessoles, S, Venteclef, N, Kiaf, B, Beaudoin, L, Da Silva, J, Allatif, O, Rossjohn, J, Kjer-Nielsen, L, McCluskey, J, Ledoux, S, Genser, L, Torcivia, A, Soudais, C, Lantz, O, Boitard, C, Aron-Wisnewsky, J, Larger, E, Clement, K, and Lehuen, A

Abstract

Obesity and type 2 diabetes (T2D) are associated with low-grade inflammation, activation of immune cells, and alterations of the gut microbiota. Mucosal-associated invariant T (MAIT) cells, which are innate-like T cells that recognize bacterial ligands, are present in blood and enriched in mucosal and inflamed tissues. Here, we analyzed MAIT cells in the blood and adipose tissues of patients with T2D and/or severe obesity. We determined that circulating MAIT cell frequency was dramatically decreased in both patient groups, and this population was even undetectable in some obese patients. Moreover, in both patient groups, circulating MAIT cells displayed an activated phenotype that was associated with elevated Th1 and Th17 cytokine production. In obese patients, MAIT cells were more abundant in adipose tissue than in the blood and exhibited a striking IL-17 profile. Bariatric surgery in obese patients not only improved their metabolic parameters but also increased circulating MAIT cell frequency at 3 months after surgery. Similarly, cytokine production by blood MAIT cells was strongly decreased after surgery. This study reveals profound MAIT cell abnormalities in patients harboring metabolic disorders, suggesting their potential role in these pathologies.

Published
2015

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