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1. Statistical Integration of ‘Omics Data Increases Biological Knowledge Extracted from Metabolomics Data: Application to Intestinal Exposure to the Mycotoxin Deoxynivalenol

Author

Marie Tremblay-Franco, Cécile Canlet, Philippe Pinton, Yannick Lippi, Roselyne Gautier, Claire Naylies, Manon Neves, Isabelle P. Oswald, Laurent Debrauwer, and Imourana Alassane-Kpembi

Subjects
mycotoxin exposure 1, transcriptomics 2, metabolomics 3, statistical integration 4, Microbiology, QR1-502
Abstract

The effects of low doses of toxicants are often subtle and information extracted from metabolomic data alone may not always be sufficient. As end products of enzymatic reactions, metabolites represent the final phenotypic expression of an organism and can also reflect gene expression changes caused by this exposure. Therefore, the integration of metabolomic and transcriptomic data could improve the extracted biological knowledge on these toxicants induced disruptions. In the present study, we applied statistical integration tools to metabolomic and transcriptomic data obtained from jejunal explants of pigs exposed to the food contaminant, deoxynivalenol (DON). Canonical correlation analysis (CCA) and self-organizing map (SOM) were compared for the identification of correlated transcriptomic and metabolomic features, and O2-PLS was used to model the relationship between exposure and selected features. The integration of both ‘omics data increased the number of discriminant metabolites discovered (39) by about 10 times compared to the analysis of the metabolomic dataset alone (3). Besides the disturbance of energy metabolism previously reported, assessing correlations between both functional levels revealed several other types of damage linked to the intestinal exposure to DON, including the alteration of protein synthesis, oxidative stress, and inflammasome activation. This confirms the added value of integration to enrich the biological knowledge extracted from metabolomics.

Published
2021
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2. Intestinal toxicity of the type B trichothecene mycotoxin fusarenon-X: whole transcriptome profiling reveals new signaling pathways

Author

Imourana Alassane-Kpembi, Juliana Rubira Gerez, Anne-Marie Cossalter, Manon Neves, Joëlle Laffitte, Claire Naylies, Yannick Lippi, Martine Kolf-Clauw, Ana Paula L. Bracarense, Philippe Pinton, and Isabelle P. Oswald

Subjects
Medicine, Science
Abstract

Abstract The few data available on fusarenon-X (FX) do not support the derivation of health-based guidance values, although preliminary results suggest higher toxicity than other regulated trichothecenes. Using histo-morphological analysis and whole transcriptome profiling, this study was designed to obtain a global view of the intestinal alterations induced by FX. Deoxynivalenol (DON) served as a benchmark. FX induced more severe histological alterations than DON. Inflammation was the hallmark of the molecular toxicity of both mycotoxins. The benchmark doses for the up-regulation of key inflammatory genes by FX were 4- to 45-fold higher than the previously reported values for DON. The transcriptome analysis revealed that both mycotoxins down-regulated the peroxisome proliferator-activated receptor (PPAR) and liver X receptor - retinoid X receptor (LXR-RXR) signaling pathways that control lipid metabolism. Interestingly, several pathways, including VDR/RXR activation, ephrin receptor signaling, and GNRH signaling, were specific to FX and thus discriminated the transcriptomic fingerprints of the two mycotoxins. These results demonstrate that FX induces more potent intestinal inflammation than DON. Moreover, although the mechanisms of toxicity of both mycotoxins are similar in many ways, this study emphasize specific pathways targeted by each mycotoxin, highlighting the need for specific mechanism-based risk assessments of Fusarium mycotoxins.

Published
2017
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3. Acute Exposure to Zearalenone Disturbs Intestinal Homeostasis by Modulating the Wnt/β-Catenin Signaling Pathway

Author

Tarek Lahjouji, Aurora Bertaccini, Manon Neves, Sylvie Puel, Isabelle P. Oswald, and Laura Soler

Subjects
mycotoxins, zearalenone, intestine, pig, wnt/β-catenin, estrogen, Medicine
Abstract

The mycotoxin zearalenone (ZEN), which frequently contaminates cereal-based human food and animal feed, is known to have an estrogenic effect. The biological response associated with exposure to ZEN has rarely been reported in organs other than the reproductive system. In the intestine, several studies suggested that ZEN might stimulate molecular changes related to the activation of early carcinogenesis, but the molecular mechanisms behind these events are not yet known. In this study, we investigated gene expression and changes in protein abundance induced by acute exposure to ZEN in the jejunum of castrated male pigs using an explant model. Our results indicate that ZEN induces the accumulation of ERα but not ERβ, modulates Wnt/β-catenin and TGF-β signaling pathways, and induces molecular changes linked with energy sensing and the antimicrobial activity without inducing inflammation. Our results confirm that the intestine is a target for ZEN, inducing changes that promote cellular proliferation and could contribute to the onset of intestinal pathologies.

Published
2020
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4. Saccharomyces cerevisiae Boulardii Reduces the Deoxynivalenol-Induced Alteration of the Intestinal Transcriptome

Author

Imourana Alassane-Kpembi, Philippe Pinton, Jean-François Hupé, Manon Neves, Yannick Lippi, Sylvie Combes, Mathieu Castex, and Isabelle P. Oswald

Subjects
deoxynivalenol, Saccharomyces cerevisiae boulardii CNCM I-1079, intestine, transcriptome, inflammation, oxidative stress, lipid metabolism, Medicine
Abstract

Type B trichothecene mycotoxin deoxynivalenol (DON) is one of the most frequently occurring food contaminants. By inducing trans-activation of a number of pro-inflammatory cytokines and increasing the stability of their mRNA, trichothecene can impair intestinal health. Several yeast products, especially Saccharomyces cerevisiae, have the potential for improving the enteric health of piglets, but little is known about the mechanisms by which the administration of yeast counteracts the DON-induced intestinal alterations. Using a pig jejunum explant model, a whole-transcriptome analysis was performed to decipher the early response of the small intestine to the deleterious effects of DON after administration of S. cerevisiae boulardii strain CNCM I-1079. Compared to the control condition, no differentially expressed gene (DE) was observed after treatment by yeast only. By contrast, 3619 probes—corresponding to 2771 genes—were differentially expressed following exposure to DON, and 32 signaling pathways were identified from the IPA software functional analysis of the set of DE genes. When the intestinal explants were treated with S. cerevisiae boulardii prior to DON exposure, the number of DE genes decreased by half (1718 probes corresponding to 1384 genes). Prototypical inflammation signaling pathways triggered by DON, including NF-κB and p38 MAPK, were reversed, although the yeast demonstrated limited efficacy toward some other pathways. S. cerevisiae boulardii also restored the lipid metabolism signaling pathway, and reversed the down-regulation of the antioxidant action of vitamin C signaling pathway. The latter effect could reduce the burden of DON-induced oxidative stress. Altogether, the results show that S. cerevisiae boulardii reduces the DON-induced alteration of intestinal transcriptome, and point to new mechanisms for the healing of tissue injury by yeast.

Published
2018
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5. Exposure of intestinal explants to NX, but not to DON, enriches the secretome in mitochondrial proteins

Author

Laura Soler, Ingrid Miller, Chloé Terciolo, Karin Hummel, Katharina Nöbauer, Manon Neves, and Isabelle P. Oswald

Subjects
Intestines, Mitochondrial Proteins, Proteomics, Fusarium, Cell Survival, Swine, Health, Toxicology and Mutagenesis, Animals, General Medicine, Toxicology, Secretome
Abstract

NX is a type A trichothecene produced by Fusarium graminearum with limited information on its toxicity. NX is structurally similar to deoxynivalenol (DON), only differing by the lacking keto group at C8. Because of the structural similarity of the two toxins as well as their potential co-occurrence in food and feed, it is of interest to determine the toxicity of this new compound. In this study, we compared the protein composition of the extracellular media of pig intestinal explants (secretome) exposed to 10 µM of DON or NX for 4 h compared with controls. The combination of two complementary quantitative proteomic approaches (a gel-based and a gel-free approach) identified 18 and 23 differentially abundant proteins (DAPs) for DON and NX, respectively, compared to controls. Functional analysis suggested that, whereas DON toxicity was associated with decreased cell viability and cell destruction, NX toxicity was associated with an enrichment of mitochondrial proteins in the secretome. The presence of these proteins may be associated with the already known ability of NX to induce an intestinal inflammation. Overall, our results indicated that DON- and NX-induced changes in the extracellular proteome of intestinal explants are different. The increased leakage/secretion of mitochondrial proteins by NX may be a feature of NX toxicity.

Published
2022

6. Intestinal toxicity of the new type A trichothecenes, NX and 3ANX

Author

Sylvie Puel, J. David Miller, Laura Soler, Isabelle P. Oswald, Yannick Lippi, Manon Neves, Alix Pierron, Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Transcriptomic impact of Xenobiotics (E23 TRiX), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), 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)-Université Toulouse III - Paul Sabatier (UT3), 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)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), 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)-ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Carleton College, This research was supported in part by the ANR grant 'Newmyco' (ANR-15-CE21-0010), the ANR grant 'EmergingMyco' (ANR-18-CE34-0014) and the Ontario Ministry of Food and Agriculture (FS2015-2617/SF6115)., ANR-15-CE21-0010,Newmyco,Metabolome de deux contaminants fongiques du blé d'importance majeure: identification de nouveaux métabolites toxiques(2015), ANR-18-CE34-0014,EmergingMyco,Les mycotoxines émergentes : un nouveau risque pour l'Homme et les animaux ?(2018), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), and 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)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse)

Subjects
Fusarium, Environmental Engineering, Swine, Health, Toxicology and Mutagenesis, Cell, Explant, Trichothecenes, Type A, Transcriptome, 03 medical and health sciences, Immune system, medicine, Environmental Chemistry, Animals, Humans, Gut, Intestinal Mucosa, 030304 developmental biology, 0303 health sciences, biology, Cell growth, Chemistry, Gene Expression Profiling, 030302 biochemistry & molecular biology, Public Health, Environmental and Occupational Health, General Medicine, General Chemistry, biology.organism_classification, Pollution, Molecular biology, Deoxynivalenol, 3. Good health, Fusarium graminearum, medicine.anatomical_structure, Vacuolization, Apoptosis, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Toxicity, Caco-2 Cells, Trichothecenes
Abstract

International audience; NX and its acetylated form 3ANX are two new type A trichothecenes produced by Fusarium graminearum whose toxicity is poorly documented. The aim of this study was to obtain a general view of the intestinal toxicity of these toxins. Deoxynivalenol (DON), which differs from NX by the keto group at C8, served as a benchmark. The viability of human intestinal Caco-2 cells decreased after 24 h of exposure to 3 μM NX (−21.4%), 3 μM DON (−20.2%) or 10 μM 3ANX (−17.4%). Histological observations of porcine jejunal explants exposed for 4 h to 10 μM of the different toxins showed interstitial edema and cellular debris. Explants exposed to NX also displayed cell vacuolization, a broken epithelial barrier and high loss of villi. Whole transcriptome profiling revealed that NX, DON and 3ANX modulated 369, 146 and 55 genes, respectively. Functional analyses indicated that the three toxins regulate the same gene networks and signaling pathways mainly; cell proliferation, differentiation, apoptosis and growth, and particularly immune and pro-inflammatory responses. Greater transcriptional impacts were observed with NX than with DON. In conclusion, our data revealed that the three toxins have similar impacts on the intestine but of different magnitude: NX > DON ≫ 3ANX. NX and 3ANX should consequently be included in overall risk analysis linked to the presence of trichothecenes in our diet.

Published
2022

7. Effects of Fusarium metabolites beauvericin and enniatins alone or in mixture with deoxynivalenol on weaning piglets

Author

Isabelle P. Oswald, Barbara Novak, Caroline Emsenhuber, Dian Schatzmayr, Amanda Lopes Hasuda, Ana Paula Frederico Rodrigues Loureiro Bracarense, Viviane Mayumi Maruo, Manon Neves, Mahdi Ghanbari, Philippe Pinton, Silvia Wein, Biomin Research Center, State University of Londrina = Universidade Estadual de Londrina, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Universidade Federal do Tocantins (UFT), Universidade Federal do Tocantins, Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), This research was funded by Austrian Research Promotion Agency (FFG) via the research project Early Stage, grant number 879467 and by the French ANR project 'EmergingMyco' (ANR-18-CE34-0014). Amanda L. Hasuda received a fellowship from the Coordenaç˜ao de Aperfeiçoamento de Pessoal de Nível Superior-CAPES/Cofecub (Grant 0389/2019). This study was financed in part by the Coordenaç˜ao de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - FinanceCode 001., and ANR-18-CE34-0014,EmergingMyco,Les mycotoxines émergentes : un nouveau risque pour l'Homme et les animaux ?(2018)

Subjects
Fusarium, Swine, [SDV]Life Sciences [q-bio], Weaning, Gut microbiota, Gut flora, Toxicology, Weight Gain, Jejunum, 03 medical and health sciences, chemistry.chemical_compound, Eating, Animal science, Depsipeptides, medicine, Animals, Mycotoxin, 030304 developmental biology, 0303 health sciences, biology, 030306 microbiology, food and beverages, General Medicine, Mycotoxins, biology.organism_classification, Biomarker of effect, Beauvericin, 3. Good health, Gastrointestinal Microbiome, Intestines, medicine.anatomical_structure, chemistry, Liver, Fungal metabolites, Lymph, medicine.symptom, Trichothecenes, Weight gain, Histological alterations, Cyclic hexadepsipeptides, Food Science
Abstract

International audience; The impact of the Fusarium-derived metabolites beauvericin, enniatin B and B1 (EB) alone or in combination with deoxynivalenol (DON) was investigated in 28-29 days old weaning piglets over a time period of 14 days. The coapplication of EB and DON (EB + DON) led to a significant decrease in the weight gain of the animals. Liver enzyme activities in plasma were significantly decreased at day 14 in piglets receiving the EB + DON-containing diet compared to piglets receiving the control diet. All mycotoxin-contaminated diets led to moderate to severe histological lesions in the jejunum, the liver and lymph nodes. Shotgun metagenomics revealed a significant effect of EB-application on the gut microbiota. Our results provide novel insights into the harmful impact of emerging mycotoxins alone or with DON on the performance, gut health and immunological parameters in pigs.

Published
2021

9. Dietary exposure to the food contaminant deoxynivalenol triggers colonic breakdown by activating the mitochondrial and the death receptor pathways

Author

Delphine Payros, Philippe Pinton, Joëlle Laffitte, Corine Lencina, Isabelle P. Oswald, Ana Paula Frederico Rodrigues Loureiro Bracarense, Imourana Alassane-Kpembi, Sandrine Ménard, Manon Neves, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Recherche en Santé Digestive (IRSD ), 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), Université de Montréal (UdeM), Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), State University of Londrina = Universidade Estadual de Londrina, and Neuro-Gastroentérologie & Nutrition (ToxAlim-NGN)

Subjects
medicine.medical_specialty, Colon, [SDV]Life Sciences [q-bio], Inflammation, Food Contamination, Dietary Exposure, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Internal medicine, Medicine, Animals, Intestinal Mucosa, Rats, Wistar, Receptor, 030304 developmental biology, 0303 health sciences, biology, Tight junction, business.industry, Cytochrome c, Receptors, Death Domain, digestive system diseases, 3. Good health, Rats, Endocrinology, Apoptosis, Myeloperoxidase, biology.protein, 030211 gastroenterology & hepatology, Tumor necrosis factor alpha, medicine.symptom, business, Trichothecenes, Food Science, Biotechnology
Abstract

Scope The food contamination by mycotoxins is of increasing public health concerns. Deoxynivalenol (DON), a mycotoxin contaminating cereals has been associated with the exacerbation of inflammatory bowel diseases (IBD), thereby raising the question of its role in the development of IBD. Moreover, the effect of DON on the colon is poorly described. Methods and results Wistar rats exposed (1-4 weeks) to low doses of DON (2 or 9 mg.kg-1 feed) showed microscopic alterations of colonic tissue (dilated lymphatic vessels, luminal debris, and cubic and flattened enterocytes). Ingestion of DON also altered colonic functions by increasing paracellular permeability while reducing the expression of the tight junction proteins and increased apoptosis in colonic tissue. Pro-apoptotic factors Bax/Bak, cytochrome C and caspase 9 were upregulated whereas expression of anti-apoptotic protein Bcl2 tended to decrease for the mitochondrial pathway. An increased expression of FasR and caspase-8 was observed for the extrinsic pathway. An increase in the pro-inflammatory markers TNFα, IL-17 and myeloperoxidase was also observed. Conclusion These results indicate that the dietary exposure to low levels of DON in food targets the colon inducing a health-threatening breakdown of the colonic barrier, highlighting oral exposure to DON as a potential risk factor in triggering IBD. This article is protected by copyright. All rights reserved.

Published
2021

10. The food contaminant, deoxynivalenol, modulates the Thelper-Treg balance and increases inflammatory bowel diseases

Author

Edwin Fouché, Marie Tremblay-Franco, Delphine Payros, Philippe Pinton, Joëlle Laffitte, Manon Neves, Isabelle P. Oswald, Su Luo, Sandrine Ménard, Vassilia Theodorou, Selma P. Snini, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Neuro-Gastroentérologie & Nutrition (ToxAlim-NGN), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Analyse de Xénobiotiques, Identification, Métabolisme (E20 Metatoul-AXIOM), MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), 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)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), 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)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), 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)-ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Prévention et promotion de la cancérogénèse par les aliments (ToxAlim-PPCA), ANR-15-CE21-0001,CaDON,Cadmium et Deoxynivalenol dans les récoltes de blé dur: comprendre les évènements de contamination croisée et évaluer la toxicité du mélange.(2015), ANR-19-CE34-0014,Genofood,Exacerbation de la génotoxicité du microbiote intestinal par un contaminant alimentaire(2019), 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)-Université Toulouse III - Paul Sabatier (UT3), Metatoul AXIOM (E20 ), MetaboHUB-MetaToul, OSWALD, Isabelle, Cadmium et Deoxynivalenol dans les récoltes de blé dur: comprendre les évènements de contamination croisée et évaluer la toxicité du mélange. - - CaDON2015 - ANR-15-CE21-0001 - AAPG2015 - VALID, Exacerbation de la génotoxicité du microbiote intestinal par un contaminant alimentaire - - Genofood2019 - ANR-19-CE34-0014 - AAPG2019 - VALID, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-ToxAlim (ToxAlim), and This work was supported by grants from the French National Research Agency (projects CaDON 15-CE21-0001 and Genofood 19-CE34).

Subjects
0301 basic medicine, Male, Health, Toxicology and Mutagenesis, [SDV]Life Sciences [q-bio], Stimulation, 010501 environmental sciences, Toxicology, 01 natural sciences, T-Lymphocytes, Regulatory, Mycotoxin, biology, Dextran Sulfate, General Medicine, Colitis, 3. Good health, Intestine, Intestines, [SDV.TOX] Life Sciences [q-bio]/Toxicology, medicine.anatomical_structure, [SDV.TOX.TVM] Life Sciences [q-bio]/Toxicology/Vegetal toxicology and mycotoxicology, Myeloperoxidase, [SDV.TOX]Life Sciences [q-bio]/Toxicology, [SDV.TOX.TVM]Life Sciences [q-bio]/Toxicology/Vegetal toxicology and mycotoxicology, Spleen, Food Contamination, [SDV.TOX.TCA]Life Sciences [q-bio]/Toxicology/Toxicology and food chain, 03 medical and health sciences, Immune system, medicine, Animals, Secretion, Immune response, 0105 earth and related environmental sciences, Lamina propria, Innate immune system, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, business.industry, [SDV.BA.MVSA] Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Mycotoxins, medicine.disease, Inflammatory Bowel Diseases, Diet, Rats, Disease Models, Animal, 030104 developmental biology, De-epoxy-DON: DOM-1, [SDV.TOX.TCA] Life Sciences [q-bio]/Toxicology/Toxicology and food chain, Immunology, biology.protein, business, Trichothecenes, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

International audience; The incidence of inflammatory bowel diseases (IBD) is increasing in both Western and developing countries. IBD are multifactorial disorders involving complex interactions between genetic, immune, and environmental factors such as exposure to food contaminants. Deoxynivalenol (DON) is the most prevalent mycotoxin that contaminates staple food and induces intestinal breakdown and inflammatory response. To delineate the role of DON oral exposure in IBD, we used a Dextran sulfate sodium (DSS) colitis model in rats fed with a DON-contaminated diet or a control diet for 4 weeks. Colitis was induced in the 4th week by increasing concentrations of DSS in the drinking water (0, 2, 3 or 5%). DON exacerbated body weight loss and accelerated the appearance of symptoms in animals treated with DSS. DON increased morphological damage, pro-inflammatory markers (myeloperoxidase, CXCL-1 and IL-1β) and immune cell responses. In lamina propria of the rat with colitis, DON increased adaptive and innate immune responses after anti-CD3/28 or LPS stimulation, respectively. In the spleen, DON increased IFNγ secretion and reduced Treg populations. Interestingly, De-epoxy-DON (DOM-1) a detoxified form of DON did not have any consequences on colitis. These results suggest that DON is a risk factor in the onset of IBD.

Published
2020

11. Comparative sensitivity of proliferative and differentiated intestinal epithelial cells to the food contaminant, deoxynivalenol

Author

Manon Neves, Sylvie Puel, Yannick Lippi, Su Luo, Isabelle P. Oswald, Claire Naylies, Philippe Pinton, Chloé Terciolo, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Transcriptomic impact of Xenobiotics (E23 TRiX), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), 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)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), 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)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), 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)-ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), This work was supported, in part, by the Genofood ANR project (19-CE34). Su Luo was supported by the China Scholarship Council., ANR-19-CE34-0014,Genofood,Exacerbation de la génotoxicité du microbiote intestinal par un contaminant alimentaire(2019), and 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)-Université Toulouse III - Paul Sabatier (UT3)

Subjects
010504 meteorology & atmospheric sciences, Health, Toxicology and Mutagenesis, Cellular differentiation, Cytotoxicity, [SDV]Life Sciences [q-bio], Cell, 010501 environmental sciences, Biology, Toxicology, Intestinal barrier function, 01 natural sciences, Transcriptome, medicine, Humans, Viability assay, Cell proliferation, 0105 earth and related environmental sciences, Tight junction, Cell growth, Cell Differentiation, Epithelial Cells, General Medicine, Pollution, Intestinal epithelium, Intestinal cell renewal, Cell biology, Cell toxicity, medicine.anatomical_structure, Mycotoxin, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Stem cell, Caco-2 Cells, Trichothecenes, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

International audience; The intestinal epithelium is a functional and physical barrier formed by a cell monolayer that constantly differentiates from a stem cell in the crypt. This is the first target for food contaminants, especially mycotoxins. Deoxynivalenol (DON) is one of the most prevalent mycotoxins. This study compared the effects of DON (0-100 μM) on proliferative and differentiated intestinal epithelial cells. Three cell viability assays (LDH release, ATP content and neutral red uptake) indicated that proliferative Caco-2 cells are more sensitive to DON than differentiated ones. The establishment of transepithelial electrical resistance (TEER), as a read out of the differentiation process, was delayed in proliferative cells after exposure to 1 μM DON. Transcriptome analysis of proliferative and differentiated exposure to 0-3 μM DON for 24 h revealed 4862 differentially expressed genes (DEG) and indicated an effect of both the differentiation status and the DON treatment. KEGG enrichment analysis indicated involvement of metabolism, ECM receptors and tight junctions in the differentiation process, while ribosome biogenesis, mRNA surveillance, and the MAPK pathway were involved in the response to DON. The number of differentially expressed genes and the amplitude of the effect were higher in proliferative cells exposed to DON than that in differentiated cells. In conclusion, our study shows that proliferative cells are more susceptible than differentiated ones to DON and that the mycotoxin delays the differentiation process.

Published
2020

12. Acute Exposure to Zearalenone Disturbs Intestinal Homeostasis by Modulating the Wnt/β-Catenin Signaling Pathway

Author

Aurora Bertaccini, Sylvie Puel, Isabelle P. Oswald, Laura Soler, Tarek Lahjouji, Manon Neves, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), and This project received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 722634 as well as by the Agence Nationale de la Recherche (ANR) grant ExpoMycoPig (ANR-17-Carn012).

Subjects
pig, Male, Time Factors, Swine, Health, Toxicology and Mutagenesis, [SDV]Life Sciences [q-bio], lcsh:Medicine, Gene Expression, Toxicology, medicine.disease_cause, 0302 clinical medicine, Transforming Growth Factor beta, Gene expression, estrogen, Homeostasis, Reproductive system, Wnt Signaling Pathway, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, beta Catenin, 0303 health sciences, Wnt/β-catenin, Wnt signaling pathway, Receptors, Adipokine, 3. Good health, Cell biology, Jejunum, 030220 oncology & carcinogenesis, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Cytokines, medicine.symptom, Signal transduction, medicine.drug_class, Inflammation, Food Contamination, Biology, Article, 03 medical and health sciences, Wnt, mycotoxins, medicine, Animals, Castration, intestine, 030304 developmental biology, lcsh:R, fungi, zearalenone, Estrogen Receptor alpha, beta-catenin, Animal Feed, Estrogen, Carcinogenesis, Transforming growth factor
Abstract

The mycotoxin zearalenone (ZEN), which frequently contaminates cereal-based human food and animal feed, is known to have an estrogenic effect. The biological response associated with exposure to ZEN has rarely been reported in organs other than the reproductive system. In the intestine, several studies suggested that ZEN might stimulate molecular changes related to the activation of early carcinogenesis, but the molecular mechanisms behind these events are not yet known. In this study, we investigated gene expression and changes in protein abundance induced by acute exposure to ZEN in the jejunum of castrated male pigs using an explant model. Our results indicate that ZEN induces the accumulation of ER but not ER, modulates Wnt/&beta, catenin and TGF- signaling pathways, and induces molecular changes linked with energy sensing and the antimicrobial activity without inducing inflammation. Our results confirm that the intestine is a target for ZEN, inducing changes that promote cellular proliferation and could contribute to the onset of intestinal pathologies.

Published
2020

13. Co-occurrence of DON and emerging mycotoxins in worldwide finished pig feed and their combined toxicity in intestinal cells

Author

Barbara Novak, Abdullah Khan Khoshal, Isabelle P. Oswald, Gerd Schatzmayr, Timothy P. Jenkins, Manon Neves, Philippe Pinton, Pascal G.P. Martin, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), BIOMIN Research Center, Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), and Pinton, Philippe

Subjects
Fusarium, IPEC-1, Cell Survival, Swine, Health, Toxicology and Mutagenesis, emerging mycotoxins, global survey, Food Contamination, Toxicology, 01 natural sciences, DON, co-occurrence, combined toxicitty, finished pig feed, toxicity, Article, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, Animals, Food science, Mycotoxin, Toxicologie, 030304 developmental biology, 0303 health sciences, biology, 010401 analytical chemistry, Brevianamide F, food and beverages, Epithelial Cells, Mycotoxins, biology.organism_classification, Animal Feed, Beauvericin, 0104 chemical sciences, 3. Good health, Intestines, chemistry, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Penicillium, Toxicity, Emodin, combined toxicity, Enniatin
Abstract

Food and feed can be naturally contaminated by several mycotoxins, and concern about the hazard of exposure to mycotoxin mixtures is increasing. In this study, more than 800 metabolites were analyzed in 524 finished pig feed samples collected worldwide. Eighty-eight percent of the samples were co-contaminated with deoxynivalenol (DON) and other regulated/emerging mycotoxins. The Top 60 emerging/regulated mycotoxins co-occurring with DON in pig feed shows that 48%, 13%, 8% and 12% are produced by Fusarium, Aspergillus, Penicillium and Alternaria species, respectively. Then, the individual and combined toxicity of DON and the 10 most prevalent emerging mycotoxins (brevianamide F, cyclo-(L-Pro-L-Tyr), tryptophol, enniatins A1, B, B1, emodin, aurofusarin, beauvericin and apicidin) was measured at three ratios corresponding to pig feed contamination. Toxicity was assessed by measuring the viability of intestinal porcine epithelial cells, IPEC-1, at 48-h. BRV-F, Cyclo and TRPT did not alter cell viability. The other metabolites were ranked in the following order of toxicity: apicidin &gt, enniatin A1 &gt, DON &gt, beauvericin &gt, enniatin B &gt, enniatin B1 &gt, emodin &gt, aurofusarin. In most of the mixtures, combined toxicity was similar to the toxicity of DON alone. In terms of pig health, these results demonstrate that the co-occurrence of emerging mycotoxins that we tested with DON does not exacerbate toxicity.

Published
2019

14. Saccharomyces cerevisiae boulardii Reduces the Deoxynivalenol-Induced Alteration of the Intestinal Transcriptome

Author

Mathieu Castex, Manon Neves, Sylvie Combes, Yannick Lippi, Isabelle P. Oswald, Jean-François Hupé, Philippe Pinton, Imourana Alassane-Kpembi, ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre National Hospitalier et Universitaire Hubert Koutoukou Maga de Cotonou, Partenaires INRAE, Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Lallemand S.A.S., Transcriptomic impact of Xenobiotics (E23 TRiX), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Toulouse III - Paul Sabatier (UT3), 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)-Université Toulouse III - Paul Sabatier (UT3), 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)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Génétique Physiologie et Systèmes d'Elevage (GenPhySE ), École nationale supérieure agronomique de Toulouse [ENSAT]-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Plateforme Génome & Transcriptome (GET), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), 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)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), and Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
0301 basic medicine, Male, Swine, Health, Toxicology and Mutagenesis, p38 mitogen-activated protein kinases, [SDV]Life Sciences [q-bio], Saccharomyces cerevisiae, Trichothecene, deoxynivalenol, lcsh:Medicine, Ascorbic Acid, Toxicology, medicine.disease_cause, p38 Mitogen-Activated Protein Kinases, Article, Antioxidants, Transcriptome, 03 medical and health sciences, lipid, Gene expression, medicine, oxidative stress, Animals, [INFO]Computer Science [cs], Saccharomyces cerevisiae boulardii CNCM I-1079, intestine, [SDV.GEN]Life Sciences [q-bio]/Genetics, biology, lcsh:R, biology.organism_classification, Lipid Metabolism, saccharomyce cerevisiae boulardii CNCM 1-1079, transcriptome, inflammation, Yeast, 3. Good health, Cell biology, lipid metabolism, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, 030104 developmental biology, Jejunum, Signal transduction, Trichothecenes, Oxidative stress, Signal Transduction
Abstract

International audience; Type B trichothecene mycotoxin deoxynivalenol (DON) is one of the most frequently occurring food contaminants. By inducing trans-activation of a number of pro-inflammatory cytokines and increasing the stability of their mRNA, trichothecene can impair intestinal health. Several yeast products, especially Saccharomyces cerevisiae, have the potential for improving the enteric health of piglets, but little is known about the mechanisms by which the administration of yeast counteracts the DON-induced intestinal alterations. Using a pig jejunum explant model, a whole-transcriptome analysis was performed to decipher the early response of the small intestine to the deleterious effects of DON after administration of S. cerevisiae boulardii strain CNCM I-1079. Compared to the control condition, no differentially expressed gene (DE) was observed after treatment by yeast only. By contrast, 3619 probescorresponding to 2771 geneswere differentially expressed following exposure to DON, and 32 signaling pathways were identified from the IPA software functional analysis of the set of DE genes. When the intestinal explants were treated with S. cerevisiae boulardii prior to DON exposure, the number of DE genes decreased by half (1718 probes corresponding to 1384 genes). Prototypical inflammation signaling pathways triggered by DON, including NF-B and p38 MAPK, were reversed, although the yeast demonstrated limited efficacy toward some other pathways. S. cerevisiae boulardii also restored the lipid metabolism signaling pathway, and reversed the down-regulation of the antioxidant action of vitamin C signaling pathway. The latter effect could reduce the burden of DON-induced oxidative stress. Altogether, the results show that S. cerevisiae boulardii reduces the DON-induced alteration of intestinal transcriptome, and point to new mechanisms for the healing of tissue injury by yeast.

Published
2018

15. Intestinal toxicity of deoxynivalenol is limited by Lactobacillus rhamnosus RC007 in pig jejunum explants

Author

Maria Laura Gonzalez Pereyra, Joëlle Laffitte, Gisela Romina García, Cecilia Ana Dogi, Lilia Reneé Cavaglieri, Isabelle P. Oswald, Manon Neves, Philippe Pinton, Delphine Payros, National University of Río Cuarto = Universidad Nacional de Río Cuarto (UNRC), Consejo Nacional de Investigaciones Científicas y Técnicas, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), ANPCYT-PICT1606/12, ANR-13-CESA-0003,ImBio,Impacts d'une intoxication chronique par des bioinsecticides Bt k sur l'homéostasie intestinale et la réponse immunitaire: des insectes aux mammifères(2013), and ANR-15-CE21-0001,CaDON,Cadmium et Deoxynivalenol dans les récoltes de blé dur: comprendre les évènements de contamination croisée et évaluer la toxicité du mélange.(2015)

Subjects
0301 basic medicine, DEOXYNIVALENOL, Male, Swine, Health, Toxicology and Mutagenesis, [SDV]Life Sciences [q-bio], deoxynivalenol, Toxicology, TOXICITY, law.invention, mycotoxin, LACTOBACILLUS RHAMNOSUS, purl.org/becyt/ford/1 [https], Probiotic, fluids and secretions, law, INTESTINE, Transcellular, Phosphorylation, 2. Zero hunger, Lacticaseibacillus rhamnosus, food and beverages, General Medicine, 3. Good health, Jejunum, Paracellular transport, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Toxicity, Cytokines, Mitogen-Activated Protein Kinases, p38 mitogen-activated protein kinases, Feed additive, MYCOTOXIN, [SDV.TOX.TVM]Life Sciences [q-bio]/Toxicology/Vegetal toxicology and mycotoxicology, [SDV.TOX.TCA]Life Sciences [q-bio]/Toxicology/Toxicology and food chain, Biology, In Vitro Techniques, lactobacillus rhamnosus, Permeability, Microbiology, Andrology, 03 medical and health sciences, Lactobacillus rhamnosus, medicine, Animals, purl.org/becyt/ford/1.6 [https], intestine, Intestinal permeability, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Probiotics, toxicity, biology.organism_classification, medicine.disease, Animal Feed, 030104 developmental biology, Trichothecenes
Abstract

Probiotics have been explored to stimulate gut health in weaned pigs, when they started to consume solid diet where mycotoxins could be present. The aim of this study was to evaluate the effect of Lactobacillus rhamnosus RC007 on the intestinal toxicity of deoxynivalenol (DON) in an ex vivo model. Jejunal explants, obtained from 5-week-old crossbred castrated male piglets, were kept as control, exposed for 3 h to 10 μM DON, incubated for 4 h with 109 CFU/mL L. rhamnosus, or pre-incubated 1 h with 109L. rhamnosus and exposed to DON. Histological lesions were observed, para- and transcellular intestinal permeability was measured in Ussing chambers. The expression levels of mRNA encoding six inflammatory cytokines (CCL20, IL-10, IL-1β, TNFα, IL-8 and IL-22) were determined by RT-PCR. The expressions of the phosphorylated MAP kinases p42/p44 and p38 were assessed by immunoblotting. Exposure to DON induced histological changes, significantly increased the expression of CCL20, IL-1β, TNFα, IL-8, IL-22 and IL-10, increased the intestinal paracellular permeability and activated MAP kinases. Incubation with L. rhamnosus alone did not have any significant effect. By contrast, the pre-incubation with L. rhamnosus reduced all the effects of DON: the histological alterations, the pro-inflammatory response, the paracellular permeability and the phosphorylation of MAP kinases. Of note, L. rhamnosus did not adsorb DON and only slightly degrade the toxin. In conclusion, L. rhamnosus RC007 is a promising probiotic which, included as feed additive, can decrease the intestinal toxicity of DON. Fil: García, Gisela Romina. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Microbiología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina Fil: Payros, Delphine. Instituto National de Recherches Agronomiques. Centre de Recherches de Toulouse; Francia. Université Paul Sabatier; Francia Fil: Pinton, Philippe. Instituto National de Recherches Agronomiques. Centre de Recherches de Toulouse; Francia. Université Paul Sabatier; Francia Fil: Dogi, Cecilia Ana. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Microbiología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina Fil: Laffitte, Joëlle. Instituto National de Recherches Agronomiques. Centre de Recherches de Toulouse; Francia. Université Paul Sabatier; Francia Fil: Neves, Manon. Instituto National de Recherches Agronomiques. Centre de Recherches de Toulouse; Francia. Université Paul Sabatier; Francia Fil: Gonzalez Pereyra, Maria Laura. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Microbiología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina Fil: Cavaglieri, Lilia Reneé. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas, Fisicoquímicas y Naturales. Departamento de Microbiología e Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina Fil: Oswald, Isabelle P.. Instituto National de Recherches Agronomiques. Centre de Recherches de Toulouse; Francia. Université Paul Sabatier; Francia

Published
2017

16. Intestinal toxicity of the type B trichothecene mycotoxin fusarenon-X: whole transcriptome profiling reveals new signaling pathways

Author

Joëlle Laffitte, Anne-Marie Cossalter, Philippe Pinton, Yannick Lippi, Isabelle P. Oswald, Juliana R. Rubira Gerez, Claire Naylies, Ana Paula Frederico Rodrigues Loureiro Bracarense, Imourana Alassane-Kpembi, Manon Neves, Martine Kolf-Clauw, ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Hopital d'Instruction des Armées Camp Guezo, Department of Veterinary Preventive Medicine, Laboratory of Animal Pathology, Universidade Estadual de Londrina, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Hôpital d'Instruction des Armées Camp Guézo, Service de Santé des Armées, State University of Londrina = Universidade Estadual de Londrina, Plateforme Ezop (Ezop), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Biosynthèse & Toxicité des Mycotoxines (ToxAlim-BioToMyc), Transcriptomic impact of Xenobiotics (E23 TRiX), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), 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)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), 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)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Plateforme Génome & Transcriptome (GET), 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)-Université Toulouse III - Paul Sabatier (UT3), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Oswald, Isabelle P.

Subjects
Male, 0301 basic medicine, mycotoxine, Swine, Science, fusarenone x, [SDV]Life Sciences [q-bio], Peroxisome Proliferator-Activated Receptors, Trichothecene, toxicologie alimentaire, Peroxisome proliferator-activated receptor, Biology, Retinoid X receptor, Bioinformatics, Calcitriol receptor, Article, Cell Line, Tissue Culture Techniques, Transcriptome, 03 medical and health sciences, Fusarium, Animals, Castration, Liver X receptor, Liver X Receptors, chemistry.chemical_classification, Multidisciplinary, Gene Expression Profiling, food and beverages, Epithelial Cells, Mycotoxins, Lipid Metabolism, Microarray Analysis, 3. Good health, Cell biology, Gene expression profiling, Jejunum, Retinoid X Receptors, 030104 developmental biology, Gene Expression Regulation, chemistry, Receptors, Calcitriol, Medicine, Signal transduction, Trichothecenes, Signal Transduction
Abstract

Times Cited: 0Alassane-Kpembi, Imourana Gerez, Juliana Rubira Cossalter, Anne-Marie Neves, Manon Laffitte, Joelle Naylies, Claire Lippi, Yannick Kolf-Clauw, Martine Bracarense, Ana Paula L. Pinton, Philippe Oswald, Isabelle P.ANR-CESA project DONCo; PHC Stefanik [35813XM]The authors are grateful to the Bioinformatics platform from Toulouse Midi-Pyrenees genopole (GenoToul) for providing resources for the microarray analysis. This work was supported by the ANR-CESA project DON&Co and PHC Stefanik 35813XM.0; The few data available on fusarenon-X (FX) do not support the derivation of health-based guidance values, although preliminary results suggest higher toxicity than other regulated trichothecenes. Using histo-morphological analysis and whole transcriptome profiling, this study was designed to obtain a global view of the intestinal alterations induced by FX. Deoxynivalenol (DON) served as a benchmark. FX induced more severe histological alterations than DON. Inflammation was the hallmark of the molecular toxicity of both mycotoxins. The benchmark doses for the up-regulation of key inflammatory genes by FX were 4- to 45-fold higher than the previously reported values for DON. The transcriptome analysis revealed that both mycotoxins down-regulated the peroxisome proliferator-activated receptor (PPAR) and liver X receptor - retinoid X receptor (LXR-RXR) signaling pathways that control lipid metabolism. Interestingly, several pathways, including VDR/RXR activation, ephrin receptor signaling, and GNRH signaling, were specific to FX and thus discriminated the transcriptomic fingerprints of the two mycotoxins. These results demonstrate that FX induces more potent intestinal inflammation than DON. Moreover, although the mechanisms of toxicity of both mycotoxins are similar in many ways, this study emphasize specific pathways targeted by each mycotoxin, highlighting the need for specific mechanism-based risk assessments of Fusarium mycotoxins.

Published
2017

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