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1. Gut mucosa alterations and loss of segmented filamentous bacteria in type 1 diabetes are associated with inflammation rather than hyperglycaemia

Author

Philippe J. Sansonetti, Matthieu Rouland, Maria Rescigno, Lucie Cagninacci, Nathalie Vergnolle, Sandra Guilmeau, Juliette Mouriès, Latif Rachdi, Lucie Beaudoin, Azadeh Saffarian, Agnès Lehuen, Dalale Gueddouri, Anne-Françoise Burnol, Ute Christine Rogner, Asmaa Tazi, Ophélie Rouxel, Léo Bertrand, Thierry Pedron, Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Pathogénie microbienne moléculaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humanitas University [Milan] (Hunimed), Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), LabEx Inflamex, This work was supported by Agence Nationale de la Recherche (ANR-11-IDEX-0005-02 Laboratory of Excellence INFLAMEX and ANR-17-CE14-0002-01 Diab1MAIT), Fondation pour la Recherche Médicale (DEQ20140329520 and EQU201903007779), the INSERM crosscutting program on microbiota and the European Foundation for the Study of Diabetes–Juvenile Diabetes Research Foundation–MR, OR and LBer were supported by the French Ministry of Research., ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), ANR-17-CE14-0002,Diab1MAIT,Rôle des cellules MAIT dans le diabète de type 1 chez l'homme et la souris(2017), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Fondation pour la Recherche Medicale (DEQ20140329520 and EQU201903007779), European Foundation for the Study of Diabetes-Juvenile Diabetes Research Foundation-MR, OR and LBer are supported by the French Ministry of Research, and the INSERM crosscutting program on microbiota is supported by the French Ministry of Research

Subjects
0301 basic medicine, endocrine system diseases, medicine.medical_treatment, Segmented filamentous bacteria, intestinal microbiology, Inflammation, Gut flora, digestive system, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Diabetes Mellitus, medicine, Animals, Intestinal Mucosa, Autoimmune disease, Bacteria, biology, Insulin, digestive, oral, and skin physiology, Gastroenterology, Interleukin, Epithelial Cells, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, biology.organism_classification, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Gastrointestinal Microbiome, 3. Good health, Disease Models, Animal, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Diabetes Mellitus, Type 1, 030104 developmental biology, Hyperglycemia, 030220 oncology & carcinogenesis, Immunology, mucosal immunity, Cytokines, Dysbiosis, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

ObjectiveType 1 diabetes (T1D) is an autoimmune disease caused by the destruction of pancreatic β-cells producing insulin. Both T1D patients and animal models exhibit gut microbiota and mucosa alterations, although the exact cause for these remains poorly understood. We investigated the production of key cytokines controlling gut integrity, the abundance of segmented filamentous bacteria (SFB) involved in the production of these cytokines, and the respective role of autoimmune inflammation and hyperglycaemia.DesignWe used several mouse models of autoimmune T1D as well as mice rendered hyperglycaemic without inflammation to study gut mucosa and microbiota dysbiosis. We analysed cytokine expression in immune cells, epithelial cell function, SFB abundance and microbiota composition by 16S sequencing. We assessed the role of anti-tumour necrosis factor α on gut mucosa inflammation and T1D onset.ResultsWe show in models of autoimmune T1D a conserved loss of interleukin (IL)-17A, IL-22 and IL-23A in gut mucosa. Intestinal epithelial cell function was altered and gut integrity was impaired. These defects were associated with dysbiosis including progressive loss of SFB. Transfer of diabetogenic T-cells recapitulated these gut alterations, whereas induction of hyperglycaemia with no inflammation failed to do so. Moreover, anti-inflammatory treatment restored gut mucosa and immune cell function and dampened diabetes incidence.ConclusionOur results demonstrate that gut mucosa alterations and dysbiosis in T1D are primarily linked to inflammation rather than hyperglycaemia. Anti-inflammatory treatment preserves gut homeostasis and protective commensal flora reducing T1D incidence.

Published
2021
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2. Mucosal-associated invariant T cells in autoimmune and immune-mediated diseases

Author

Agnès Lehuen, Ophélie Rouxel, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'excellence Inflamex, Sorbonne Paris Cité, and Lehuen, Agnès

Subjects
0301 basic medicine, mediated-immune diseases, [SDV.IMM] Life Sciences [q-bio]/Immunology, Autoimmune diseases, Immunology, Inflammation, Mucosal associated invariant T cell, Biology, Mucosal-Associated Invariant T Cells, Proinflammatory cytokine, Pathogenesis, 03 medical and health sciences, Immune system, medicine, Immunology and Allergy, Animals, Humans, INSERM 1016, MAIT Cells, Cell Biology, 3. Good health, 030104 developmental biology, Immune System Diseases, mucosal-associated invariant T cells Correspondence Agn es Lehuen, inflammation, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, innate T cells, Homing (hematopoietic), Tissue inflammation
Abstract

International audience; Autoimmune and inflammatory diseases have complex etiologies not fully understood. Both innate and adaptive immune cells are involved in the pathogenesis of these diseases. Mucosal-associated invariant T (MAIT) cells express an invariant TCRa chain (Va7.2-Ja33 in humans and Va19-Ja33 in mice) and recognize the conserved MHC-I-related molecule MR1 presenting bacterial metabolites derived from the synthesis of vitamin B. MAIT cells harbor tissue homing properties and produce inflammatory cytokines, suggesting that MAIT cells may play a key role in autoimmune and inflammatory diseases. In this review, we described the current knowledge on MAIT cells in these pathologies, based on patients analyses as well as mouse models. While most of the studies support a deleterious role of MAIT cells in tissue inflammation and destruction, a few reports suggest a protective role of MAIT cells. MAIT cells could represent a new biomarker of disease progression, and a better knowledge of their function might open new avenues for therapeutic strategies based on their manipulation.

Published
2018
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3. Intestinal invalidation of the glucose transporter GLUT2 delays tissue distribution of glucose and reveals an unexpected role in gut homeostasis

Author

Charlotte Schmitt, Chloé Melchior, Ophélie Rouxel, Thomas Aranias, Danielle Chateau, Guillaume Gourcerol, Armelle Leturque, Alexandra Grosfeld, Agnès Lehuen, Edith Brot-Laroche, Maude Le Gall, Patricia Serradas, Nathalie Kapel, Anne-Judith Waligora-Dupriet, Thomas Viel, Bertrand Tavitian, Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Service d'Hépato-Gastroentérologie [Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), LabEx Inflamex, Service de coprologie fonctionnelle, CHU Pitié-Salpêtrière [APHP], Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de physiologie digestive, urinaire, respiratoire et de l'exercice [CHU Rouen], Nutrition et obésités: approches systémiques (UMR-S 1269) (Nutriomics), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), HAL UPMC, Gestionnaire, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Charles Nicolle [Rouen]-CHU Rouen, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), and Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie)

Subjects
Blood Glucose, 0301 basic medicine, Malabsorption, OGTT, oral glucose tolerance test, Glucose Transport Proteins, Facilitative, Gut flora, Glucose homeostasis, Mice, 0302 clinical medicine, Glucagon-Like Peptide 1, PET-CT, Positron Emission Tomography-Computed Tomography, Homeostasis, Tissue Distribution, Sodium-Glucose Transporter 1, Intestinal Mucosa, IEC, intestinal epithelial cells, ComputingMilieux_MISCELLANEOUS, Glucose Transporter Type 2, Mice, Knockout, 2. Zero hunger, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, biology, Microbiota, GLP-1, glucagon-like peptide-1, GLUT1-7, glucose transporter 1–7, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Glucose-galactose malabsorption, IPGTT, intraperitoneal glucose tolerance test, Original Article, medicine.medical_specialty, lcsh:Internal medicine, endocrine system, Calorie restriction, Intestinal adaptation, 030209 endocrinology & metabolism, digestive system, DPP-IV, dipeptidyl-peptidase IV, 03 medical and health sciences, Internal medicine, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, lcsh:RC31-1245, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 2FDG, 2-deoxy-2-[18F]fluoro-d-glucose, ITT, insulin tolerance test, Glucose transporter, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, biology.organism_classification, medicine.disease, IL, interleukin, SGLT1, sodium-glucose transporter 1, Glucose, 030104 developmental biology, Endocrinology, Intestinal Absorption, biology.protein, GLUT2, GLP-1
Abstract

Objective Intestinal glucose absorption is orchestrated by specialized glucose transporters such as SGLT1 and GLUT2. However, the role of GLUT2 in the regulation of glucose absorption remains to be fully elucidated. Methods We wanted to evaluate the role of GLUT2 on glucose absorption and glucose homeostasis after intestinal-specific deletion of GLUT2 in mice (GLUT2ΔIEC mice). Results As anticipated, intestinal GLUT2 deletion provoked glucose malabsorption as visualized by the delay in the distribution of oral sugar in tissues. Consequences of intestinal GLUT2 deletion in GLUT2ΔIEC mice were limiting body weight gain despite normal food intake, improving glucose tolerance, and increasing ketone body production. These features were reminiscent of calorie restriction. Other adaptations to intestinal GLUT2 deletion were reduced microvillus length and altered gut microbiota composition, which was associated with improved inflammatory status. Moreover, a reduced density of glucagon-like peptide-1 (GLP-1) positive cells was compensated by increased GLP-1 content per L-cell, suggesting a preserved enteroendocrine function in GLUT2ΔIEC mice. Conclusions Intestinal GLUT2 modulates glucose absorption and constitutes a control step for the distribution of dietary sugar to tissues. Consequently, metabolic and gut homeostasis are improved in the absence of functional GLUT2 in the intestine, thus mimicking calorie restriction., Highlights • Intestinal GLUT2 deletion induces moderate malabsorption and ketone body production. • Loss of intestinal GLUT2 modulates gut microbiota. • Intestinal GLUT2 plays a role in gut permeability and inflammatory status. • Intestinal GLUT2 modulates enteroendocrine L-cell function.

Published
2017
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4. Regulatory role of natural killer T cells in diabetes

Author

Ophélie Rouxel, Céline Tard, Agnès Lehuen, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), and Bos, Mireille

Subjects
Immune regulation, Cellular differentiation, 030232 urology & nephrology, Autoimmunity, 030230 surgery, Systemic inflammation, medicine.disease_cause, Mice, 03 medical and health sciences, Immune system, 0302 clinical medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, lcsh:QH301-705.5, lcsh:R5-920, Type 1 diabetes, biology, Microbiota, Diabetes, Interleukin, Cell Differentiation, NKT, General Medicine, medicine.disease, Natural killer T cell, 3. Good health, Metabolism, Diabetes Mellitus, Type 1, lcsh:Biology (General), Diabetes Mellitus, Type 2, CD1D, Immunology, biology.protein, Cytokines, Natural Killer T-Cells, medicine.symptom, lcsh:Medicine (General)
Abstract

International audience; Type 1 and type 2 diabetes are growing public health problems. Despite having different pathophysiologies, both diseases are associated with defects in immune regulation. Invariant natural killer T (iNKT) cells are innate-like T cells that recognize glycolipids presented by CD1d. These cells not only play a key role in the defense against pathogens, but also exert potent immunoregulatory functions. The regulatory role of iNKT cells in the prevention of type 1 diabetes has been demonstrated in murine models and analyzed in diabetic patients. The decreased frequency of iNKT cells in non-obese diabetic mice initially suggested the regulatory role of this cell subset. Increasing the frequency or the activation of iNKT cells with agonists protects non-obese diabetic mice from the development of diabetes. Several mechanisms mediate iNKT regulatory functions. They can rapidly produce immunoregulatory cytokines, interleukin (IL)-4 and IL-10. They induce tolerogenic dendritic cells, thereby inducing the anergy of autoreactive anti-islet T cells and increasing the frequency of T regulatory cells (Treg cells). Synthetic agonists are able to activate iNKT cells and represent potential therapeutic treatment in order to prevent type 1 diabetes. Growing evidence points to a role of immune system in glucose intolerance and type 2 diabetes. iNKT cells are resident cells of adipose tissue and their local and systemic frequencies are reduced in obese patients, suggesting their involvement in local and systemic inflammation during obesity. With the discovery of potential continuity between type 1 and type 2 diabetes in some patients, the role of iNKT cells in these diseases deserves further investigation.

Published
2016
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