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56. Probiotics and Trained Immunity

Author

Cortes-Perez, Naima G., primary, de Moreno de LeBlanc, Alejandra, additional, Gomez-Gutierrez, Jorge G., additional, LeBlanc, Jean Guy, additional, and Bermúdez-Humarán, Luis G., additional

Published
2021
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59. Anti-Microbiota Vaccines Modulate the Tick Microbiome in a Taxon-Specific Manner

Author

Mateos-Hernández, Lourdes, primary, Obregón, Dasiel, additional, Wu-Chuang, Alejandra, additional, Maye, Jennifer, additional, Bornères, Jeremie, additional, Versillé, Nicolas, additional, de la Fuente, José, additional, Díaz-Sánchez, Sandra, additional, Bermúdez-Humarán, Luis G., additional, Torres-Maravilla, Edgar, additional, Estrada-Peña, Agustín, additional, Hodžić, Adnan, additional, Šimo, Ladislav, additional, and Cabezas-Cruz, Alejandro, additional

Published
2021
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60. Anti-microbiota vaccines modulate the tick microbiome in a taxon-specific manner

Author

Agence Nationale de la Recherche (France), Programa Nacional de Becas de Postgrado en el Exterior Don Carlos Antonio López (Paraguay), Mateos-Hernández, Lourdes, Obregón, Dasiel A., Wu-Chuang, Alejandra, Maye, Jennifer, Bornères, Jeremie, Versillé, Nicolas, Fuente, José de la, Díaz-Sánchez, Sandra, Bermúdez-Humarán, Luis G., Torres-Maravilla, Edgar, Estrada-Peña, Agustín, Hodžić, Adnan, Šimo, Ladislav, Cabezas-Cruz, Alejandro, Agence Nationale de la Recherche (France), Programa Nacional de Becas de Postgrado en el Exterior Don Carlos Antonio López (Paraguay), Mateos-Hernández, Lourdes, Obregón, Dasiel A., Wu-Chuang, Alejandra, Maye, Jennifer, Bornères, Jeremie, Versillé, Nicolas, Fuente, José de la, Díaz-Sánchez, Sandra, Bermúdez-Humarán, Luis G., Torres-Maravilla, Edgar, Estrada-Peña, Agustín, Hodžić, Adnan, Šimo, Ladislav, and Cabezas-Cruz, Alejandro

Abstract

The lack of tools for the precise manipulation of the tick microbiome is currently a major limitation to achieve mechanistic insights into the tick microbiome. Anti-tick microbiota vaccines targeting keystone bacteria of the tick microbiota alter tick feeding, but their impact on the taxonomic and functional profiles of the tick microbiome has not been tested. In this study, we immunized a vertebrate host model (Mus musculus) with live bacteria vaccines targeting keystone (i.e., Escherichia-Shigella) or non-keystone (i.e., Leuconostoc) taxa of tick microbiota and tested the impact of bacterial-specific antibodies (Abs) on the structure and function of tick microbiota. We also investigated the effect of these anti-microbiota vaccines on mice gut microbiota composition. Our results showed that the tick microbiota of ticks fed on Escherichia coli-immunized mice had reduced Escherichia-Shigella abundance and lower species diversity compared to ticks fed on control mice immunized with a mock vaccine. Immunization against keystone bacteria restructured the hierarchy of nodes in co-occurrence networks and reduced the resistance of the bacterial network to taxa removal. High levels of E. coli-specific IgM and IgG were negatively correlated with the abundance of Escherichia-Shigella in tick microbiota. These effects were not observed when Leuconostoc was targeted with vaccination against Leuconostoc mesenteroides. Prediction of functional pathways in the tick microbiome using PICRUSt2 revealed that E. coli vaccination reduced the abundance of lysine degradation pathway in tick microbiome, a result validated by qPCR. In contrast, the gut microbiome of immunized mice showed no significant alterations in the diversity, composition and abundance of bacterial taxa. Our results demonstrated that anti-tick microbiota vaccines are a safe, specific and an easy-to-use tool for manipulation of vector microbiome. These results guide interventions for the control of tick infestations and

Published
2021

63. Rewiring the altered tryptophan metabolism as a novel therapeutic strategy in inflammatory bowel diseases

Author

Michaudel, Chloé, Danne, Camille, Agus, Allison, Magniez, Aurélie, Aucouturier, Anne, Spatz, Madeleine, Lefevre, Antoine, Kirchgesner, Julien, Rolhion, Nathalie, Wang, Yazhou, Lavelle, Aonghus, Galbert, Chloé, Da Costa, Gregory, Poirier, Maxime, Lapière, Alexia, Planchais, Julien, Nádvorník, Petr, Illes, Peter, Oeuvray, Cyriane, Creusot, Laura, Michel, Marie-Laure, Benech, Nicolas, Bourrier, Anne, Nion-Larmurier, Isabelle, Landman, Cecilia, Richard, Mathias L, Emond, Patrick, Seksik, Philippe, Beaugerie, Laurent, Arguello, Rafael Rose, Moulin, David, Mani, Sridhar, Dvorák, Zdenek, Bermúdez-Humarán, Luis G, Langella, Philippe, and Sokol, Harry

Abstract

ObjectiveThe extent to which tryptophan (Trp) metabolism alterations explain or influence the outcome of inflammatory bowel diseases (IBDs) is still unclear. However, several Trp metabolism end-products are essential to intestinal homeostasis. Here, we investigated the role of metabolites from the kynurenine pathway.DesignTargeted quantitative metabolomics was performed in two large human IBD cohorts (1069 patients with IBD). Dextran sodium sulphate-induced colitis experiments in mice were used to evaluate effects of identified metabolites. In vitro, ex vivo and in vivo experiments were used to decipher mechanisms involved. Effects on energy metabolism were evaluated by different methods including Single Cell mEtabolism by profiling Translation inHibition.ResultsIn mice and humans, intestinal inflammation severity negatively correlates with the amount of xanthurenic (XANA) and kynurenic (KYNA) acids. Supplementation with XANA or KYNA decreases colitis severity through effects on intestinal epithelial cells and T cells, involving Aryl hydrocarbon Receptor (AhR) activation and the rewiring of cellular energy metabolism. Furthermore, direct modulation of the endogenous tryptophan metabolism, using the recombinant enzyme aminoadipate aminotransferase (AADAT), responsible for the generation of XANA and KYNA, was protective in rodent colitis models.ConclusionOur study identified a new mechanism linking Trp metabolism to intestinal inflammation and IBD. Bringing back XANA and KYNA has protective effects involving AhR and the rewiring of the energy metabolism in intestinal epithelial cells and CD4+T cells. This study paves the way for new therapeutic strategies aiming at pharmacologically correcting its alterations in IBD by manipulating the endogenous metabolic pathway with AADAT.

Published
2023
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67. Gut Microbiota Abrogates Anti-α-Gal IgA Response in Lungs and Protects against Experimental Aspergillus Infection in Poultry

Author

Mateos-Hernández, Lourdes, Risco-Castillo, Veronica, Torres-Maravilla, Edgar, Bermúdez-Humarán, Luis G., Alberdi, Pilar, Hodžić, Adnan, Hernández-Jarguin, Angelica, Rakotobe, Sabine, Galon, Clemence, Devillers, Elodie, de la Fuente, Jose, Guillot, Jacques, Cabezas-Cruz, Alejandro, Biologie moléculaire et immunologie parasitaires et fongiques (BIPAR), École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Dynamic Microbiology - EA 7380 (DYNAMIC), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est (UPE)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Instituto de Investigación en Recursos Cinegéticos (IREC), Institute of Parasitology [Vienna], University of Veterinary Medicine, Vienna, Universidad Autónoma de Tamaulipas, Center for Veterinary Health Sciences, Oklahoma State University [Stillwater] (OSU), École nationale vétérinaire d'Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Research Group Dynamyc , EA 7380, EnvA (DynamYc), École nationale vétérinaire d'Alfort (ENVA)-Université Paris-Est (UPE), and Oklahoma State University [Stillwater]

Subjects
[SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, alpha-Gal, Microbiota, α-Gal, Aspergillus fumigatus, granulomas, lcsh:R, cross-protective immunity, lcsh:Medicine, Cross-protective immunity, Article, Granulomas, microbiota, Aspergillosis, aspergillosis
Abstract

Naturally occurring human antibodies (Abs) of the isotypes IgM and IgG and reactive to the galactose-&alpha, 1,3-galactose (&alpha, Gal) epitope are associated with protection against infectious diseases, caused by pathogens expressing the glycan. Gut microbiota bacteria expressing &alpha, Gal regulate the immune response to this glycan in animals lacking endogenous &alpha, Gal. Here, we asked whether the production of anti-&alpha, Gal Abs in response to microbiota stimulation in birds, confers protection against infection by Aspergillus fumigatus, a major fungal pathogen that expresses &alpha, Gal in its surface. We demonstrated that the oral administration of Escherichia coli O86:B7 strain, a bacterium with high &alpha, Gal content, reduces the occurrence of granulomas in lungs and protects turkeys from developing acute aspergillosis. Surprisingly, the protective effect of E. coli O86:B7 was not associated with an increase in circulating anti-&alpha, Gal IgY levels, but with a striking reduction of anti-&alpha, Gal IgA in the lungs of infected turkeys. Subcutaneous immunization against &alpha, Gal did not induce a significant reduction of lung anti-&alpha, Gal IgA and failed to protect against an infectious challenge with A. fumigatus. Oral administration of E. coli O86:B7 was not associated with the upregulation of lung cytokines upon A. fumigatus infection. We concluded that the oral administration of bacteria expressing high levels of &alpha, Gal decreases the levels of lung anti-&alpha, Gal IgA, which are mediators of inflammation and lung damage during acute aspergillosis.

Published
2020
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68. Use of E. Coli strains expressing high level of alpha-gal to modulate immunity and provide protection against infectious diseases in animals

Author

Cabezas-Cruz, Alejandro, Mateos-Hernández, Lourdes, Holzer, Astrid Sibylle, Bermúdez-Humarán, Luis G., Risco-Castillo, Veronica, Fuente-García, José de Jesús de la, Torres-Maravilla, Edgar, and Guillot, Jacques

Abstract

The present invention concerns an E. coli strains expressing high level of α-Gal, in particular selected in the group consisting of E. coli Nissle 1917 strain, E. coli O111 strain, E. coli O86: B7 strain, and mixture thereof, as a probiotic and/or feed additive and/or oral vaccine in a non-human animal, in particular fish and poultry, to prevent and/or reduce an infectious disease caused by a pathogen expressing α-Gal on its surface., Institut National de Recherche Pour l'Agriculture, l'Alimentation et l'Environment, École Nationale Veterinarie d'Alfort, Universite Paris est Creteil Val de Marne, Consejo Superior de Investigaciones Científicas (CSIC), Biologické Centrum AV CR, A1 Solicitud de patente con informe sobre el estado de la técnica

Published
2020

70. Lactococci and lactobacilli as mucosal delivery vectors for therapeutic proteins and DNA vaccines

Author

Chatel Jean-Marc, Kharrat Pascale, Bermúdez-Humarán Luis G, and Langella Philippe

Subjects
Microbiology, QR1-502
Abstract

Abstract Food-grade Lactic Acid Bacteria (LAB) have been safely consumed for centuries by humans in fermented foods. Thus, they are good candidates to develop novel oral vectors, constituting attractive alternatives to attenuated pathogens, for mucosal delivery strategies. Herein, this review summarizes our research, up until now, on the use of LAB as mucosal delivery vectors for therapeutic proteins and DNA vaccines. Most of our work has been based on the model LAB Lactococcus lactis, for which we have developed efficient genetic tools, including expression signals and host strains, for the heterologous expression of therapeutic proteins such as antigens, cytokines and enzymes. Resulting recombinant lactococci strains have been tested successfully for their prophylactic and therapeutic effects in different animal models: i) against human papillomavirus type 16 (HPV-16)-induced tumors in mice, ii) to partially prevent a bovine β-lactoglobulin (BLG)-allergic reaction in mice and iii) to regulate body weight and food consumption in obese mice. Strikingly, all of these tools have been successfully transposed to the Lactobacillus genus, in recent years, within our laboratory. Notably, anti-oxidative Lactobacillus casei strains were constructed and tested in two chemically-induced colitis models. In parallel, we also developed a strategy based on the use of L. lactis to deliver DNA at the mucosal level, and were able to show that L. lactis is able to modulate the host response through DNA delivery. Today, we consider that all of our consistent data, together with those obtained by other groups, demonstrate and reinforce the interest of using LAB, particularly lactococci and lactobacilli strains, to develop novel therapeutic protein mucosal delivery vectors which should be tested now in human clinical trials.

Published
2011
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82. A Versatile New Model of Chemically Induced Chronic Colitis Using an Outbred Murine Strain

Author

Barone, Monica, Chain, Florian, Sokol, Harry, Brigidi, Patrizia, Bermúdez-Humarán, Luis G, Langella, Philippe, Martin, Rebeca, Università di Bologna [Bologna] (UNIBO), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Pierre et Marie Curie - Paris 6 (UPMC), Equipe de Recherche Labelisée (ERL) 1157, Avenir Team Gut Microbiota and Immunity, Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), University of Bologna, Barone, Monica, Chain, Florian, Sokol, Harry, Brigidi, Patrizia, Bermúdez-Humarán, Luis G., Langella, Philippe, and Martín, Rebeca

Subjects
Microbiology (medical), [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, murine IBD model, colitis, DNBS, Methods, CD-1 mice, gut inflammation, Coliti, Microbiology
Abstract

International audience; Murine colitis models are crucial tools for understanding intestinal homeostasis and inflammation. However, most current models utilize a highly inbred strain of mice, and often only one sex is employed to limit bias. This targeted approach, which in itself is biased, means that murine genetic diversity and sex-related differences are ignored, making it even more difficult to extend findings to humans, who are highly heterogeneous. Furthermore, most models do not examine the chronic form of colitis, an important fact taking into account the chronic nature of the inflammatory bowel diseases (IBD). Here, we attempted to create a more realistic murine colitis model by addressing these three issues. Using chemically induced chronic colon inflammation in an outbred strain of mice (RjOrl:SWISS [CD-1]), we (i) mimicked the relapsing nature of the disease, (ii) better represented normal genetic variability, and (iii) employed both female and male mice. Colitis was induced by intrarectal administration of dinitrobenzene sulfonic acid (DNBS). After a recovery period and 3 days before the mice were euthanized, colitis was reactivated by a second administration of DNBS. Protocol length was 24 days. Colitis severity was assessed using body mass, macroscopic scores, and histological scores. Myeloperoxidase (MPO) activity, cytokine levels, and lymphocyte populations were also characterized. Our results show that the intrarectal administration of DNBS effectively causes colitis in both female and male CD-1 mice in a dose-dependent manner, as reflected by loss of body mass, macroscopic scores and histological scores. Furthermore, colon cytokine levels and mesenteric lymph node characteristics indicate that this model involves immune system activation. Although some variables were sex-specific, most of the results support including both females and males in the model. Our ultimate goal is to make this model available to researchers for testing candidate anti-inflammatory agents, such as classical or next-generation probiotics; we also aim for the results to be more easily transferrable to human trials.

Published
2018
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85. Bile Salt Hydrolase Activities: A Novel Target to Screen Anti-Giardia Lactobacilli?

Author

Allain, Thibault, Chaouch, Soraya, Thomas, Myriam, Travers, Marie-Agnès, Valle, Isabelle, Langella, Philippe, Grellier, Philippe, Polack, Bruno, Florent, Isabelle, Bermúdez-Humarán, Luis G., MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Muséum national d'Histoire naturelle (MNHN), Laboratoire de Génétique et Pathologie (LGP), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Biologie moléculaire et immunologie parasitaires et fongiques (BIPAR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Molécules de Communication et Adaptation des Micro-Organismes (MCAM), Unité d'Ecologie et de Physiologie du Système Digestif, INRA, Unité d'écologie et de physiologie du système digestif, Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire d'Alfort (ENVA)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN), Thérapie des maladies du muscle strié, 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), École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé, Region Ile-de-France-DIM (Maladies Infectieuses, Parasitaires et Nosocomiales Emergentes) [120092], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, and KOHL, Linda

Subjects
[SDV] Life Sciences [q-bio], lactobacilli, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Lactobacillus gasseri, probiotics, [SDV]Life Sciences [q-bio], bile salt hydrolases, [CHIM]Chemical Sciences, Microbiology, ComputingMilieux_MISCELLANEOUS, Original Research, Giardia duodenalis, Lactobacillus johnsonii
Abstract

International audience; Giardia duodenalis is a protozoan parasite responsible for giardiasis, a disease characterized by intestinal malabsorption, diarrhea and abdominal pain in a large number of mammal species. Giardiasis is one of the most common intestinal parasitic diseases in the world and thus a high veterinary, and public health concern. It is well-established that some probiotic bacteria may confer protection against this parasite in vitro and in vivo and we recently documented the implication of bile-salt hydrolase (BSH)-like activities from strain La1 of Lactobacillus johnsonii as mediators of these effects in vitro. We showed that these activities were able to generate deconjugated bile salts that were toxic to the parasite. In the present study, a wide collection of lactobacilli strains from different ecological origins was screened to assay their anti-giardial effects. Our results revealed that the anti-parasitic effects of some of the strains tested were well-correlated with the expression of BSH-like activities. The two most active strains in vitro, La1 and Lactobacillus gasseri CNCM I-4884, were then tested for their capacity to influence G. duodenalis infection in a suckling mice model. Strikingly, only L. gasseri CNCM I-4884 strain was able to significantly antagonize parasite growth with a dramatic reduction of the trophozoites load in the small intestine. Moreover, this strain also significantly reduced the fecal excretion of Giardia cysts after 5 days of treatment, which could contribute to blocking the transmission of the parasite, in contrast of La1 where no effect was observed. This study represents a step toward the development of new prophylactic strategies to combat G. duodenalis infection in both humans and animals.

Published
2018
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86. Oral delivery of pancreatitis‐associated protein by Lactococcus lactis displays protective effects in dinitro‐benzenesulfonic‐acid‐induced colitis model and is able to modulate the composition of the microbiota

Author

Breyner, Natalia M., primary, Vilas Boas, Priscilla Bagano, additional, Fernandes, Gabriel, additional, Carvalho, Rodrigo D., additional, Rochat, Tatiana, additional, Michel, Marie‐Laure, additional, Chain, Florian, additional, Sokol, Harry, additional, Azevedo, Marcela, additional, Myioshi, Anderson, additional, Azevedo, Vasco A., additional, Langella, Philippe, additional, Bermúdez‐Humarán, Luis G., additional, and Chatel, Jean‐Marc, additional

Published
2019
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90. Phosphatidylglycerols are induced by gut dysbiosis and inflammation, and favorably modulate adipose tissue remodeling in obesity

Author

Kayser, Brandon D., primary, Lhomme, Marie, additional, Prifti, Edi, additional, Cunha, Carla Da, additional, Marquet, Florian, additional, Chain, Florian, additional, Naas, Isabelle, additional, Pelloux, Véronique, additional, Dao, Maria‐Carlota, additional, Kontush, Anatol, additional, Rizkalla, Salwa W., additional, Aron‐Wisnewsky, Judith, additional, Bermúdez‐Humarán, Luis G., additional, Oakley, Fiona, additional, Langella, Philippe, additional, Clément, Karine, additional, and Dugail, Isabelle, additional

Published
2019
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91. Heterologous production of human papillomavirus type-16 L1 protein by a lactic acid bacterium

Author

Bermúdez-Humarán Luis G, Langella Philippe, Kharrat Pascale, and Cortes-Perez Naima G

Subjects
Medicine, Biology (General), QH301-705.5, Science (General), Q1-390
Abstract

Abstract Background The expression of vaccine antigens in lactic acid bacteria (LAB) is a safe and cost-effective alternative to traditional expression systems. In this study, we investigated i) the expression of Human papillomavirus type 16 (HPV-16) L1 major capsid protein in the model LAB Lactococcus lactis and ii) the ability of the resulting recombinant strain to produce either capsomer-or virus-like particles (VLPs). Results and conclusion HPV-16 L1 gene was cloned into two vectors, pCYT and pSEC, designed for controlled intra- or extracellular heterologous expression in L. lactis, respectively. The capacity of L. lactis harboring either pCYT:L1 or pSEC:L1 plasmid to accumulate L1 in the cytoplasm and supernatant samples was confirmed by Western blot assays. Electron microscopy analysis suggests that, L1 protein produced by recombinant lactococci can self-assemble into structures morphologically similar to VLPs intracellularly. The presence of conformational epitopes on the L. lactis-derived VLPs was confirmed by ELISA using an anti-HPV16 L1 capsid antigen antibody. Our results support the feasibility of using recombinant food-grade LAB, such as L. lactis, for the production of L1-based VLPs and open the possibility for the development of a new safe mucosal vector for HPV-16 prophylactic vaccination.

Published
2009
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92. Increased gut permeability in cancer cachexia: mechanisms and clinical relevance.

Author

UCL - SSS/LDRI - Louvain Drug Research Institute, UCL - SSS/IREC/EDIN - Pôle d'endocrinologie, diabète et nutrition, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service d'endocrinologie et de nutrition, Bindels, Laure B., Neyrinck, Audrey M., Loumaye, Audrey, Catry, Emilie, Walgrave, Hannah, Cherbuy, Claire, Leclercq, Sophie, Van Hul, Matthias, Plovier, Hubert, Pachikian, Barbara D., Bermúdez-Humarán, Luis G, Langella, Philippe, Cani, Patrice D., Thissen, Jean-Paul, Delzenne, Nathalie M., UCL - SSS/LDRI - Louvain Drug Research Institute, UCL - SSS/IREC/EDIN - Pôle d'endocrinologie, diabète et nutrition, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service d'endocrinologie et de nutrition, Bindels, Laure B., Neyrinck, Audrey M., Loumaye, Audrey, Catry, Emilie, Walgrave, Hannah, Cherbuy, Claire, Leclercq, Sophie, Van Hul, Matthias, Plovier, Hubert, Pachikian, Barbara D., Bermúdez-Humarán, Luis G, Langella, Philippe, Cani, Patrice D., Thissen, Jean-Paul, and Delzenne, Nathalie M.

Abstract

Intestinal disorders often occur in cancer patients, in association with body weight loss, and this alteration is commonly attributed to the chemotherapy. Here, using a mouse model of cancer cachexia induced by ectopic transplantation of C26 cancer cells, we discovered a profound alteration in the gut functions (gut permeability, epithelial turnover, gut immunity, microbial dysbiosis) independently of any chemotherapy. These alterations occurred independently of anorexia and were driven by interleukin 6. Gut dysfunction was found to be resistant to treatments with an anti-inflammatory bacterium () or with gut peptides involved in intestinal cell renewal (teduglutide, a glucagon-like peptide 2 analogue). The translational value of our findings was evaluated in 152 colorectal and lung cancer patients with or without cachexia. The serum level of the lipopolysaccharide-binding protein, often presented as a reflection of the bacterial antigen load, was not only increased in cachectic mice and cancer patients, but also strongly correlated with the serum IL-6 level and predictive of death and cachexia occurrence in these patients. Altogether, our data highlight profound alterations of the intestinal homeostasis in cancer cachexia occurring independently of any chemotherapy and food intake reduction, with potential relevance in humans. In addition, we point out the lipopolysaccharide-binding protein as a new biomarker of cancer cachexia related to gut dysbiosis.

Published
2018

93. Heterologous expression of Brucella abortus GroEL heat-shock protein in Lactococcus lactis

Author

Langella Philippe, Oliveira Sérgio C, Le Loir Yves, Ribeiro Luciana A, Bermúdez-Humarán Luis G, Miyoshi Anderson, and Azevedo Vasco

Subjects
Microbiology, QR1-502
Abstract

Abstract Background Brucella abortus is a facultative intracellular pathogen that mainly infects cattle and humans. Current vaccines rely on live attenuated strains of B. abortus, which can revert to their pathogenic status and thus are not totally safe for use in humans. Therefore, the development of mucosal live vaccines using the food-grade lactic acid bacterium, Lactococcus lactis, as an antigen delivery vector, is an attractive alternative and a safer vaccination strategy against B. abortus. Here, we report the construction of L. lactis strains genetically modified to produce B. abortus GroEL heat-shock protein, a candidate antigen, in two cellular locations, intracellular or secreted. Results Only the secreted form of GroEL was stably produced in L. lactis, suggesting a detrimental effect of GroEL protein when intracellularly produced in this bacterium. Only trace amounts of mature GroEL were detected in the supernatant fraction of induced lactococcal cultures, and the GroEL precursor remained stacked in the cell fraction. Attempts to raise the secretion yields were made, but even when GroEL was fused to a synthetic propeptide, secretion of this antigen was not improved. Conclusion We found that L. lactis is able to produce, and to secrete, a stable form of GroEL into the extracellular medium. Despite the low secretion efficiency of GroEL, which suggest that this antigen interacts with the cell envelope of L. lactis, secretion seems to be the best way to achieve both production and protein yields, regardless of cellular location. The L. lactis strain secreting GroEL has potential for in vivo immunization.

Published
2006
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95. Protein secretion in Lactococcus lactis : an efficient way to increase the overall heterologous protein production

Author

Leclercq Sophie, Ribeiro Luciana A, Nouaille Sébastien, Bermúdez-Humarán Luis G, Miyoshi Anderson, Freitas Daniela A, Oliveira Sergio C, Azevedo Vasco, Le Loir Yves, Gabriel Jane E, Guimaraes Valeria D, Oliveira Maricê N, Charlier Cathy, Gautier Michel, and Langella Philippe

Subjects
Microbiology, QR1-502
Abstract

Abstract Lactococcus lactis, the model lactic acid bacterium (LAB), is a food grade and well-characterized Gram positive bacterium. It is a good candidate for heterologous protein delivery in foodstuff or in the digestive tract. L. lactis can also be used as a protein producer in fermentor. Many heterologous proteins have already been produced in L. lactis but only few reports allow comparing production yields for a given protein either produced intracellularly or secreted in the medium. Here, we review several works evaluating the influence of the localization on the production yields of several heterologous proteins produced in L. lactis. The questions of size limits, conformation, and proteolysis are addressed and discussed with regard to protein yields. These data show that i) secretion is preferable to cytoplasmic production; ii) secretion enhancement (by signal peptide and propeptide optimization) results in increased production yield; iii) protein conformation rather than protein size can impair secretion and thus alter production yields; and iv) fusion of a stable protein can stabilize labile proteins. The role of intracellular proteolysis on heterologous cytoplasmic proteins and precursors is discussed. The new challenges now are the development of food grade systems and the identification and optimization of host factors affecting heterologous protein production not only in L. lactis, but also in other LAB species.

Published
2005
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99. Increased gut permeability in cancer cachexia: mechanisms and clinical relevance

Author

Bindels, Laure B., primary, Neyrinck, Audrey M., additional, Loumaye, Audrey, additional, Catry, Emilie, additional, Walgrave, Hannah, additional, Cherbuy, Claire, additional, Leclercq, Sophie, additional, Van Hul, Matthias, additional, Plovier, Hubert, additional, Pachikian, Barbara, additional, Bermúdez-Humarán, Luis G., additional, Langella, Philippe, additional, Cani, Patrice D., additional, Thissen, Jean-Paul, additional, and Delzenne, Nathalie M., additional

Published
2018
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