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Pancreatitis-Associated Protein (Pap) Produced by Different Lactic Acid Bacteria Can Protect Mice Inan Acute Colitis Model After Oral Delivery

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Pancreatitis-Associated Protein (Pap) Produced by Different Lactic Acid Bacteria Can Protect Mice Inan Acute Colitis Model After Oral Delivery Pancreatitis-associated protein (pap) produced by different lactic acid bacteria can protect mice inan acute colitis model after oral delivery. Priscilla Vilas Boas To cite this version: Priscilla Vilas Boas. Pancreatitis-associated protein (pap) produced by different lactic acid bacte- ria can protect mice in an acute colitis model after oral delivery.. Microbiology and Parasitology. Université Paris Saclay (COmUE); Universidade federal de Minas Gerais, 2018. English. NNT : 2018SACLS307. tel-02936771 HAL Id: tel-02936771 https://tel.archives-ouvertes.fr/tel-02936771 Submitted on 11 Sep 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. PANCREATITIS-ASSOCIATED PROTEIN (PAP) PRODUCED BY DIFFERENT LACTIC ACID BACTERIA CAN PROTECT MICE IN AN 307 S ACUTE COLITIS MODEL AFTER ORAL DELIVERY. 2018SACL : Thèse de doctorat de l'Université Paris-Saclay et de Universidade Federal de Minas Gerais NNT préparée à l’Úniversité Paris-Sud École doctorale n°581 : agriculture, alimentation, biologie, environnement et santé (ABIES) Spécialité de doctorat : sciences de la vie et de la santé Thèse présentée et soutenue à Ville Jouy-en-Josas, le 14 Septembre 2018, par Vilas Boas Priscilla Composition du Jury : LANGELLA Philippe Directeur de Recherche, INRA (MICALIS) Président GÓES-NETO Aristoteles Professeur, UFMG (Département de Biologie) Rapporteur CARVALHO Frédéric Chargé de Recherche, Université Clermont Auvergne Rapporteur BREYNER Natalia Post Doc, INRA (TOXALIM) Examinateur LANGELLA Philippe Directeur de Recherche, INRA (MICALIS) Examinateur CHATEL Jean-Marc DR2, INRA (MICALIS) Directeur de thèse AZEVEDO Vasco Professeur, UFMG (Département de Biologie) Co-Directeur de thèse UNIVERSIDADE FEDERAL DE MINAS GERAIS INSTITUTO DE CIÊNCIAS BIOLÓGICAS DEPARTAMENTO DE BIOLOGIA GERAL PROGRAMA DE PÓS-GRADUAÇÃO EM MICROBIOLOGIA PhD Thesis PANCREATITIS-ASSOCIATED PROTEIN (PAP) PRODUCED BY DIFFERENT LACTIC ACID BACTERIA CAN PROTECT MICE IN AN ACUTE COLITIS MODEL AFTER ORAL DELIVERY. Student: PRISCILLA CAROLINNE BAGANO VILAS BOAS Supervisors: VASCO ARISTON DE CARVALHO AZEVEDO JEAN-MARC CHATEL JOUY-EM-JOSAS / FRANCE SEPTEMBER – 2018 PRISCILLA CAROLINNE BAGANO VILAS BOAS PANCREATITIS-ASSOCIATED PROTEIN (PAP) PRODUCED BY DIFFERENT LACTIC ACID BACTERIA CAN PROTECT MICE IN AN ACUTE COLITIS MODEL AFTER ORAL DELIVERY. Thesis presented as partial requirement for the degree of Doctor in Microbiology, to the Department of General Biology at the Institute of Biological Sciences, Federal University of Minas Gerais and the degree of Doctor in “Sciences du Vivant” to the University of Paris-Saclay. Student: PRISCILLA CAROLINNE BAGANO VILAS BOAS Supervisors: VASCO ARISTON DE CARVALHO AZEVEDO JEAN-MARC CHATEL JOUY-EM-JOSAS / FRANCE SEPTEMBER – 2018 I dedicate this work to my niece Sophia, the light of my eyes and the joy of my days. ACKNOWLEDGEMENTS I would first like to thank my supervisors and co-supervisors for the opportunity to develop this work, for all the support and teachings. To all my colleagues from LGCM, INRA and LIB for all the help in the experiments and for all the knowledge that was shared. To all my family, especially my parents and brothers, for all unconditional love, for being the basis of my perseverance and for always having taught me that I am able to overcome all adversities. To Leandro for having encouraged me to start this PhD and never to have let me give up, even in times of greater difficulties. To all my friends who have always listened to me, advised me, wiped away my tears and smiled at me when I needed them most. “If you can’t fly then run, if you can’t run then walk, if you can’t walk then crawl, but whatever you do you have to keep moving forward” Martin Luther King, Jr. ABSTRACT…………………………………………………………………………….9 RESUMÉ……………………………………………………………………………...11 Abbreviations………………………………………………………………………..13 I THESIS PRESENTATION…………………………………………………………14 • COLLABORATIONS...............................................................................15 • THESIS OUTLINE..................................................................................15 II GENERAL INTRODUCTION..........................................................................16 III AIMS OF THE STUDY…………………………………………………………….48 • Main aim of the study…………………………………………………………49 • Specific aims of the study……………………………………………………49 IV CHAPTER 1 - Oral delivery of Pancreatitis-Associated Protein (PAP) by Lactococcus lactis displays protective effects in DNBS-induced colitis model and is able to modulate the composition of the microbiota………….50 1. GENERAL BACKGROUND AND STORY OF THE PROJECT………51 2. ACTORS IMPLIED IN THE PROJECT…………………………………52 3. GOALS…………………………………………………………………….53 3.1 General goals…………………………………………………………53 3.2 Specific goals…………………………………………………………53 4. INTRODUCTION…………………………………………………………53 5. MATERIALS AND METHODS…………………………………………..55 6. RESULTS…………………………………………………………………60 7. DISCUSSION……………………………………………………………..68 REFERENCES……………………………………………………………….72 V CHAPTER 2 - Comparison of the efficiency of Lactococcus lactis and Lactobacillus casei strains expressing pap in the protection of mice in an acute colitis model………………………………………………………………….77 1. GENERAL BACKGROUND AND STORY OF THE PROJECT….78 2. ACTORS IMPLIED IN THE PROJECT……………………………..79 3. GOALS………………………………………………………………...79 3.1 General goals……………………………………………………..80 3.2 Specific goals……………………………………………………..80 4. INTRODUCTION……………………………………………………..80 5. MATERIALS AND METHODS………………………………………82 6. RESULTS……………………………………………………………..90 7. DISCUSSION……………………………………………………….103 8. CONCLUSIONS…………………………………………………….108 REFERENCES………………………………………………………….109 VI CHAPTER 3 - Comparison between Lactococcus lactis strain delivering an eukaryotic expression plasmid for PAP expression by intestinal cells and L. lactis strain delivering PAP as a protein……………………………….115 1. GENERAL BACKGROUND AND STORY OF THE PROJECT..116 2. ACTORS IMPLIED IN THE PROJECT……………………………117 3. GOALS……………………………………………………………….117 3.1 General goals……………………………………………………117 3.2 Specific goals……………………………………………………118 4. INTRODUCTION……………………………………………………118 5. MATERIALS AND METHODS……………………………………..119 6. RESULTS……………………………………………………………121 7. DISCUSSION……………………………………………………….125 8. CONCLUSIONS…………………………………………………….127 REFERENCES………………………………………………………….128 VII GENERAL CONCLUSIONS…………………………………………………..132 VIII DIRECTIONS FOR FUTURE WORKS………………………………………137 REFERENCES FROM GENERAL INTRODUCTION…………………………..140 APPENDIX…………………………………………………………………………..164 ABSTRACT Inflammatory bowel disease (IBD) is a group of chronic, complex and relapsing inflammatory conditions of GIT that has been a global health problem, with an increasing incidence. IBD is a group of closely related but heterogeneous disease processes. It includes two main forms, Crohn's disease (CD) and ulcerative colitis (UC), which are characterized by alternating phases of clinical relapse and remission. One of the molecules that has been studied by our research group in the treatment of IBD is the Pancreatitis Associated Protein I (PAP). PAP is part of the proteins encoded by the regenerating islet-derived (REG) gene family, that many of them are associated with epithelial inflammation. PAP is expressed in the gastrointestinal, with their expression focused in the crypt base spreading from Paneth cells of jejunum and ileum and by the goblet cells and enterocytes in the colon, and is up-regulated in patients with inflammatory bowel disease. PAP has a variety of activities, which includes anti-apoptotic, anti-inflammatory, antibacterial effects and proliferative, maintaining host-bacterial homeostasis in the mammalian gut. Several new strategies using lactic acid bacteria (LAB) for the expression or ability to metabolize molecules capable of reducing inflammation in inflammatory bowel diseases have been studied in recent years. Some strains of LABs, such as Lactobacillus casei Shirota and Bacillus bifidus communis, have been considered as probiotics, which means “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host”. Here, we first sought to determine whether PAP delivered at intestinal membrane by recombinant Lactococcus lactis strain, LL-PAP, is able to modulate the microbiota community and reduce the chemically induced intestinal inflammation. After a DiNitro-BenzeneSulfonic-acid (DNBS) challenge, mice treated with LL-PAP showed a decrease in the colitis severity compared to those treated with the control L. lactis strain. This effect was characterized by: protection against weight loss; lower macroscopical and histological scores; and down-regulation of pro-inflammatory cytokines secreted by lymphocytes in Mesenteric Lymph Node (MLN). Moreover after 5 days of treatment LL-PAP was able to increase the diversity of the microbiota and relative abundance of Eubacterium plexicaudatum, a butyrate producer. Based on our findings, we hypothesize that a treatment with LL-PAP shift the microbiota preventing thus the 9 severity of colon inflammation in acute colitis model through increase of Eubacterium plexicaudatum,
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