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1. The colibactin-producing Escherichia coli alters the tumor microenvironment to immunosuppressive lipid overload facilitating colorectal cancer progression and chemoresistance

Author: Nilmara de Oliveira Alves, Guillaume Dalmasso, Darja Nikitina, Amaury Vaysse, Richard Ruez, Lea Ledoux, Thierry Pedron, Emma Bergsten, Olivier Boulard, Lora Autier, Sofian Allam, Laurence Motreff, Pierre Sauvanet, Diane Letourneur, Pragya Kashyap, Johan Gagnière, Denis Pezet, Catherine Godfraind, Michel Salzet, Emmanuel Lemichez, Mathilde Bonnet, Imène Najjar, Christophe Malabat, Marc Monot, Denis Mestivier, Nicolas Barnich, Pankaj Yadav, Isabelle Fournier, Sean Kennedy, Amel Mettouchi, Richard Bonnet, Iradj Sobhani, and Mathias Chamaillard
Subjects: Colibactin-producing Escherichia coli, land’s cycle, lipid droplet, right-sided colorectal cancer, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: ABSTRACTIntratumoral bacteria flexibly contribute to cellular and molecular tumor heterogeneity for supporting cancer recurrence through poorly understood mechanisms. Using spatial metabolomic profiling technologies and 16SrRNA sequencing, we herein report that right-sided colorectal tumors are predominantly populated with Colibactin-producing Escherichia coli (CoPEC) that are locally establishing a high-glycerophospholipid microenvironment with lowered immunogenicity. It coincided with a reduced infiltration of CD8+ T lymphocytes that produce the cytotoxic cytokines IFN-γ where invading bacteria have been geolocated. Mechanistically, the accumulation of lipid droplets in infected cancer cells relied on the production of colibactin as a measure to limit genotoxic stress to some extent. Such heightened phosphatidylcholine remodeling by the enzyme of the Land’s cycle supplied CoPEC-infected cancer cells with sufficient energy for sustaining cell survival in response to chemotherapies. This accords with the lowered overall survival of colorectal patients at stage III-IV who were colonized by CoPEC when compared to patients at stage I-II. Accordingly, the sensitivity of CoPEC-infected cancer cells to chemotherapies was restored upon treatment with an acyl-CoA synthetase inhibitor. By contrast, such metabolic dysregulation leading to chemoresistance was not observed in human colon cancer cells that were infected with the mutant strain that did not produce colibactin (11G5∆ClbQ). This work revealed that CoPEC locally supports an energy trade-off lipid overload within tumors for lowering tumor immunogenicity. This may pave the way for improving chemoresistance and subsequently outcome of CRC patients who are colonized by CoPEC.
Published: 2024
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2. Pasteurized Akkermansia muciniphila improves irritable bowel syndrome-like symptoms and related behavioral disorders in mice

Author: Maëva Meynier, Valentine Daugey, Geoffroy Mallaret, Sandie Gervason, Mathieu Meleine, Julie Barbier, Youssef Aissouni, Stéphane Lolignier, Mathilde Bonnet, Denis Ardid, Willem M. De Vos, Matthias Van Hul, Peter Suenaert, Amandine Brochot, Patrice D. Cani, and Frédéric A. Carvalho
Subjects: Pasteurized Akkermansia muciniphila, IBS, colonic hypersensitivity, anxiety-like disorders, memory impairment, neuroinhibition, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: ABSTRACTGut – brain communications disorders in irritable bowel syndrome (IBS) are associated with intestinal microbiota composition, increased gut permeability, and psychosocial disturbances. Symptoms of IBS are difficult to medicate, and hence much research is being made into alternative approaches. This study assesses the potential of a treatment with pasteurized Akkermansia muciniphila for alleviating IBS-like symptoms in two mouse models of IBS with different etiologies. Two clinically relevant animal models were used to mimic IBS-like symptoms in C57BL6/J mice: the neonatal maternal separation (NMS) paradigm and the Citrobacter rodentium infection model. In both models, gut permeability, colonic sensitivity, fecal microbiota composition and colonic IL-22 expression were evaluated. The cognitive performance and emotional state of the animals were also assessed by several tests in the C. rodentium infection model. The neuromodulation ability of pasteurized A. muciniphila was assessed on primary neuronal cells from mice dorsal root ganglia using a ratiometric calcium imaging approach. The administration of pasteurized A. muciniphila significantly reduced colonic hypersensitivity in both IBS mouse models, accompanied by a reinforcement of the intestinal barrier function. Beneficial effects of pasteurized A. muciniphila treatment have also been observed on anxiety-like behavior and memory defects in the C. rodentium infection model. Finally, a neuroinhibitory effect exerted by pasteurized A. muciniphila was observed on neuronal cells stimulated with two algogenic substances such as capsaicin and inflammatory soup. Our findings demonstrate novel anti-hyperalgesic and neuroinhibitory properties of pasteurized A. muciniphila, which therefore may have beneficial effects in relieving pain and anxiety in subjects with IBS.
Published: 2024
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3. Cytotoxic necrotizing factor 1 hinders colon tumorigenesis induced by colibactin-producing Escherichia coli in ApcMin/+ mice

Author: Héloïse Chat, Guillaume Dalmasso, Catherine Godfraind, Virginie Bonnin, Racha Beyrouthy, Mathilde Bonnet, Nicolas Barnich, Amel Mettouchi, Emmanuel Lemichez, Richard Bonnet, and Julien Delmas
Subjects: Colorectal cancer, Escherichia coli, colibactin, CNF-1, CoPEC, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: ABSTRACTColorectal cancer (CRC) patients are frequently colonized by colibactin-producing Escherichia coli (CoPEC) (>40%), which enhances tumorigenesis in mouse models of CRC. We observed that 50% of CoPEC also contains the cnf1 gene, which encodes cytotoxic necrotizing factor-1 (CNF1), an enhancer of the eukaryotic cell cycle. The impact of its co-occurrence with colibactin (Clb) has not yet been investigated. We evaluated the impact of CNF1 on colorectal tumorigenesis using human colonic epithelial HT-29 cells and CRC-susceptible ApcMin/+ mice inoculated with the CoPEC 21F8 clinical strain (Clb+Cnf+) or 21F8 isogenic mutants (Clb+Cnf-, Clb-Cnf+ and Clb-Cnf-). Infection with the Clb+Cnf- strain induced higher levels of inflammatory cytokines and senescence markers both in vitro and in vivo compared to those induced by infection with the Clb+Cnf+ strain. In contrast, the Clb+Cnf- and Clb+Cnf+ strains generated similar levels of DNA damage in HT-29 cells and in colonic murine tissues. Furthermore, the ApcMin/+ mice inoculated with the Clb+Cnf- strain developed significantly more tumors than the mice inoculated with the Clb+Cnf+ strain or the isogenic mutants, and the composition of their microbiota was changed. Finally, rectal administration of the CNF1 protein in ApcMin/+ mice inoculated with the Clb+Cnf- strain significantly decreased tumorigenesis and inflammation. Overall, this study provides evidence that CNF1 decreases the carcinogenic effects of CoPEC in ApcMin/+ mice by decreasing CoPEC-induced cellular senescence and inflammation.
Published: 2023
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4. Determination of biomarkers associated with neoadjuvant treatment response focusing on colibactin-producing Escherichia coli in patients with mid or low rectal cancer: a prospective clinical study protocol (MICARE)

Author: Nicolas Barnich, Philippe Rouanet, Marta Jarlier, Caroline Chevarin, Johan Gagniere, Mathilde Bonnet, Pierre-Emmanuel Colombo, Guillaume Carrier, Hélène de Forges, Christophe Taoum, Gwenaelle Roche, and Catherine Fiess
Subjects: Medicine
Abstract: Introduction The management of mid and low rectal cancer is based on neoadjuvant chemoradiotherapy (CRT) followed by standardised surgery. There is no biomarker in rectal cancer to aid clinicians in foreseeing treatment response. The determination of factors associated with treatment response might allow the identification of patients who require tailored strategies (eg, therapeutic de-escalation or intensification). Colibactin-producing Escherichia coli (CoPEC) has been associated with aggressive colorectal cancer and could be a poor prognostic factor. Currently, no study has evaluated the potential association between intestinal microbiota composition and tumour response to CRT in mid and low rectal cancer. The aim of this study is to assess the association between response to neoadjuvant CRT and faecal intestinal microbiota composition and/or CoPEC prevalence in patients with mid or low rectal cancer.Methods and analysis This is a non-randomised bicentric prospective clinical study with a recruitment capacity of 200 patients. Three stool samples will be collected from participants with histological-proven adenocarcinome of mid or low rectum who meet eligibility criteria of the study protocol: one before neoadjuvant treatment start, one in the period between CRT end and surgery and one the day before surgery. In each sample, CoPEC will be detected by culture in special media and molecular (PCR) approaches. The global microbiota composition will be also assessed by the bacterial 16S rRNA gene sequencing. Neoadjuvant CRT response and tumour regression grade will be described using the Dworak system at pathological examination. Clinical data and survival outcomes will also be collected and investigated.Ethics and dissemination MICARE was approved by the local ethics committee (Comité de Protection des Personnes Sud-Est II, 18 December 2019. Reference number 2019-A02493-54 and the institutional review board. Patients will be required to provide written informed consent. Results will be published in a peer reviewed journal.Trial registration number NCT04103567.
Published: 2022
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5. AhR/IL-22 pathway as new target for the treatment of post-infectious irritable bowel syndrome symptoms

Author: Maëva Meynier, Elodie Baudu, Nathalie Rolhion, Manon Defaye, Marjolène Straube, Valentine Daugey, Morgane Modoux, Ivan Wawrzyniak, Frédéric Delbac, Romain Villéger, Mathieu Méleine, Esther Borras Nogues, Catherine Godfraind, Nicolas Barnich, Denis Ardid, Philippe Poirier, Harry Sokol, Jean-Marc Chatel, Philippe Langella, Valérie Livrelli, Mathilde Bonnet, and Frédéric Antonio Carvalho
Subjects: post-infectious ibs, colonic-associated microbiota, citrobacter rodentium, tryptophan, ahr, il-22, lactococcus lactis, well-being disorders, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Alterations in brain/gut/microbiota axis are linked to Irritable Bowel Syndrome (IBS) physiopathology. Upon gastrointestinal infection, chronic abdominal pain and anxio-depressive comorbidities may persist despite pathogen clearance leading to Post-Infectious IBS (PI-IBS). This study assesses the influence of tryptophan metabolism, and particularly the microbiota-induced AhR expression, on intestinal homeostasis disturbance following gastroenteritis resolution, and evaluates the efficacy of IL-22 cytokine vectorization on PI-IBS symptoms. The Citrobacter rodentium infection model in C57BL6/J mice was used to mimic Enterobacteria gastroenteritis. Intestinal homeostasis was evaluated as low-grade inflammation, permeability, mucosa-associated microbiota composition, and colonic sensitivity. Cognitive performances and emotional state of animals were assessed using several tests. Tryptophan metabolism was analyzed by targeted metabolomics. AhR activity was evaluated using a luciferase reporter assay method. One Lactococcus lactis strain carrying an eukaryotic expression plasmid for murine IL-22 (L. lactisIL−22) was used to induce IL-22 production in mouse colonic mucosa. C. rodentium-infected mice exhibited persistent colonic hypersensitivity and cognitive impairments and anxiety-like behaviors after pathogen clearance. These post-infectious disorders were associated with low-grade inflammation, increased intestinal permeability, decrease of Lactobacillaceae abundance associated with the colonic layer, and increase of short-chain fatty acids (SCFAs). During post-infection period, the indole pathway and AhR activity were decreased due to a reduction of tryptophol production. Treatment with L. lactisIL−22 restored gut permeability and normalized colonic sensitivity, restored cognitive performances and decreased anxiety-like behaviors. Data from the video-tracking system suggested an upgrade of welfare for mice receiving the L.lactisIL−22 strain. Our findings revealed that AhR/IL-22 signaling pathway is altered in a preclinical PI-IBS model. IL-22 delivering alleviate PI-IBS symptoms as colonic hypersensitivity, cognitive impairments, and anxiety-like behaviors by acting on intestinal mucosa integrity. Thus, therapeutic strategies targeting this pathway could be developed to treat IBS patients suffering from chronic abdominal pain and associated well-being disorders.
Published: 2022
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6. Nebulized hypertonic saline 3% for 1 versus 3 days in hospitalized bronchiolitis: a blinded non-inferiority randomized controlled trial

Author: Gaëlle Beal, Catherine Barbier, Sophie Thoret, Amandine Rubio, Mathilde Bonnet, Roseline Mazet, Anne Ego, and Isabelle Pin
Subjects: Bronchiolitis, Hypertonic saline, Children, Pediatrics, RJ1-570
Abstract: Abstract Background The use and optimal duration of treatment with nebulized hypertonic saline (HS) in infants hospitalized for acute bronchiolitis is unclear. The objective was to compare the efficacy of 1 versus 3 days of nebulized 3% HS at 72 h of treatment. We conducted a blinded non-inferiority randomized controlled trial including infants aged less than 12 months old, hospitalized for a moderate bronchiolitis. Methods Nebulisations of 3% HS for 1 day were followed by either the continuation of 3% HS (HS3d group) or switched to 0.9% normal isotonic saline (HS1d group) for 2 days Randomization was performed according to a predefined list with a 1:1 ratio, obtained with a random generator number with blocks.. Main outcome was mean Wang clinical severity score (CSS) after 72 h of treatment. Results One hundred sixteen infants (HS1d n = 59 and HS3d n = 57), were included over two epidemic seasons from 2014 to 2016, but recruitement did not reach the planned sample size. The difference for the Wang CSS score in the HS3d vs HS1d group was 0.71 [IC 90% 0.1; 1.3], above the precluded value of 0.4 set in the protocol defining the non-inferiority of shorter treatment duration. Clinical remission was more rapidly obtained in the HS3d than in HS1d (2.3 ± 1.6 vs 2.9 ± 1.4 days, p = 0.04), with a non-significant tendency for less need of nutritional support and supplemental oxygen in HS3d group. Clinical worsening and treatment intolerance were similar in the 2 groups. Conclusions Despite being underpowered, results seem not to be in favour of reducing the duration of nebulised HS treatment from 3 to 1 day in acute moderate bronchiolitis. Trial registration Clinical trials NCT 02538458, October 2014.
Published: 2019
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7. Efficient and reproducible experimental infections of rats with Blastocystis spp.

Author: Manon Defaye, Céline Nourrisson, Elodie Baudu, Ivan Warwzyniak, Virginie Bonnin, Mathilde Bonnet, Nicolas Barnich, Denis Ardid, Frédéric Delbac, Frédéric Antonio Carvalho, and Philippe Poirier
Subjects: Medicine, Science
Abstract: Although Blastocystis spp. infect probably more than 1 billion people worldwide, their clinical significance is still controversial and their pathophysiology remains poorly understood. In this study, we describe a protocol for an efficient and reproducible model of chronic infection in rats, laying the groundwork for future work to evaluate the pathogenic potential of this parasite. In our experimental conditions, we were unable to infect rats using vacuolar forms of an axenically cultivated ST4 isolate, but we successfully established chronic infections of 4 week-old rats after oral administration of both ST3 and ST4 purified cysts isolated from human stool samples. The infection protocol was also applied to 4 week-old C57BL/9, BALB/C and C3H mice, but any mouse was found to be infected by Blastocystis. Minimal cyst inoculum required for rat infection was higher with ST3 (105) than with ST4 (102). These results were confirmed by co-housing experiments highlighting a higher contagious potential of ST4 in rats compared to ST3. Finally, experiments mimicking fecal microbiota transfer from infected to healthy animals showed that Blastocystis spp. could easily infect a new host, even though its intestinal microbiota is not disturbed. In conclusion, our results provide a well-documented and robust rat model of Blastocystis chronic infection, reproducing "natural" infection. This model will be of great interest to study host parasite interactions and to better evaluate clinical significance of Blastocystis.
Published: 2018
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8. Predictive factors associated with pemetrexed acute toxicity

Author: Mathilde Bonnet, Anne Jouinot, Pascaline Boudou-Rouquette, Vanessa Seif, Clémentine Villeminey, Jennifer Arrondeau, Michel Vidal, Rui Batista, Marie Wislez, Benoit Blanchet, François Goldwasser, and Audrey Thomas-Schoemann
Subjects: Pharmacology, Pharmacology (medical), General Medicine
Published: 2023
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9. Impact of time to diagnosis on the occurrence of cardiogenic shock in MIS-C post-COVID-19 infection

Author: Saïd Bichali, Mathilde Bonnet, Marie-Emilie Lampin, Jean-Benoit Baudelet, Héloïse Reumaux, Olivia Domanski, Thameur Rakza, Alexandre Delarue, Morgan Recher, Jérôme Soquet, Francois Dubos, Stéphane Leteurtre, Ali Houeijeh, and Francois Godart
Subjects: Pediatrics, Perinatology and Child Health
Abstract: In multisystem inflammatory syndrome in children (MIS-C), diagnostic delay could be associated with severity. This study aims to measure the time to diagnosis in MIS-C, assess its impact on the occurrence of cardiogenic shock, and specify its determinants.A single-center prospective cohort observational study was conducted between May 2020 and July 2022 at a tertiary care hospital. Children meeting the World Health Organization MIS-C criteria were included. A long time to diagnosis was defined as six days or more. Data on time to diagnosis were collected by two independent physicians. The primary outcome was the occurrence of cardiogenic shock. Logistic regression and receiver operating characteristic curve analysis were used for outcomes, and a Cox proportional hazards model was used for determinants.Totally 60 children were assessed for inclusion, and 31 were finally analyzed [52% males, median age 8.8 (5.7-10.7) years]. The median time to diagnosis was 5.3 (4.2-6.2) days. In univariable analysis, age above the median, time to diagnosis, high C-reactive protein, and high N-terminal pro-B-type natriuretic peptide (NT-proBNP) were associated with cardiogenic shock [odds ratio (OR) 6.13 (1.02-36.9), 2.79 (1.15-6.74), 2.08 (1.05-4.12), and 1.70 (1.04-2.78), respectively]. In multivariable analysis, time to diagnosis ≥ 6 days was associated with cardiogenic shock [adjusted OR (aOR) 21.2 (1.98-227)]. Time to diagnosis ≥ 6 days had a sensitivity of 89% and a specificity of 77% in predicting cardiogenic shock; the addition of age 8 years and NT-proBNP at diagnosis ≥ 11,254 ng/L increased the specificity to 91%. Independent determinants of short time to diagnosis were age 8.8 years [aHR 0.34 (0.13-0.88)], short distance to tertiary care hospital [aHR 0.27 (0.08-0.92)], and the late period of the COVID-19 pandemic [aHR 2.48 (1.05-5.85)].Time to diagnosis ≥ 6 days was independently associated with cardiogenic shock in MIS-C. Early diagnosis and treatment are crucial to avoid the use of inotropes and limit morbidity, especially in older children.
Published: 2023
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10. ISID0844 - Improvement of in vivo survival of mesenchymal stromal cells in immunodeficient mice

Author: Mathilde Bonnet des Claustres
Published: 2023
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11. Supplementary Table 1 from Colonization of the Human Gut by E. coli and Colorectal Cancer Risk

Author: Arlette Darfeuille-Michaud, Denis Pezet, Richard Bonnet, Pierre Déchelotte, Bruno Pereira, Damien Dubois, Claude Darcha, Pierre Sauvanet, Emmanuel Buc, and Mathilde Bonnet
Abstract: PDF file - 47K, Table A: The presence of mucosa-associated or internalized E. coli in the tissues of colon 542 cancer patients according to clinical characteristics.
Published: 2023
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12. Supplementary Figures 1 - 3 from Colonization of the Human Gut by E. coli and Colorectal Cancer Risk

Author: Arlette Darfeuille-Michaud, Denis Pezet, Richard Bonnet, Pierre Déchelotte, Bruno Pereira, Damien Dubois, Claude Darcha, Pierre Sauvanet, Emmanuel Buc, and Mathilde Bonnet
Abstract: PDF file - 1963K, Figure A: TNM stage in relation to the mucosal proliferative index measured by Ki-67 immunostaining. Figure B: Colonization of the mucosa or tumor by E. coli in relation to the presence of B2 phylotype E. coli strains. Figure C: Colonization of the mucosa or tumor by E. coli in relation to the presence of cyclomodulin-encoded genes.
Published: 2023
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13. Supplementary Figure Legend from Colonization of the Human Gut by E. coli and Colorectal Cancer Risk

Author: Arlette Darfeuille-Michaud, Denis Pezet, Richard Bonnet, Pierre Déchelotte, Bruno Pereira, Damien Dubois, Claude Darcha, Pierre Sauvanet, Emmanuel Buc, and Mathilde Bonnet
Abstract: PDF file - 20K
Published: 2023
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14. Data from Colonization of the Human Gut by E. coli and Colorectal Cancer Risk

Author: Arlette Darfeuille-Michaud, Denis Pezet, Richard Bonnet, Pierre Déchelotte, Bruno Pereira, Damien Dubois, Claude Darcha, Pierre Sauvanet, Emmanuel Buc, and Mathilde Bonnet
Abstract: Purpose: The intestinal microbiota is potentially involved in the development of colorectal carcinoma via various mechanisms. Escherichia coli are commensal bacteria of the human gut microbiota, but some pathogenic strains have acquired the ability to induce chronic inflammation and/or produce toxins, such as cyclomodulin, which could participate in the carcinogenesis process. Here, we analyzed the E. coli population associated with mucosa of patients with colon cancer in relation to clinicopathologic characteristics. We assessed carcinogenic properties of a colon cancer–associated E. coli strain in multiple intestinal neoplasia (Min) mice.Experimental design: Mucosa-associated or internalized E. coli were quantified and characterized from tumors and mucosa of patients with colon cancer and the healthy mucosa of diverticulosis controls. Min mice were inoculated with a colon cancer–associated E. coli strain (11G5). The number of colonic polyps was evaluated at 7 weeks after infection.Results: An increased level of mucosa-associated and internalized E. coli was observed in the tumors compared with normal tissue. A relationship between poor prognostic factors for colon cancer (tumor–node–metastasis stage) and colonization of mucosa by E. coli was observed. Pathogenic cyclomodulin-positive E. coli strains were more prevalent on mucosa of patients with stages III/IV than those with stage I colon cancer. Proliferative index and E. coli colonization level of the mucosa distant from the tumor significantly correlated. Min mice infected with the E. coli strain 11G5 displayed a marked increase in the number of visible colonic polyps compared with controls.Conclusion: These findings support that pathogenic E. coli could be a cofactor in pathogenesis of colorectal cancer. Clin Cancer Res; 20(4); 859–67. ©2013 AACR.
Published: 2023
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15. Determination of biomarkers associated with neoadjuvant treatment response focusing on colibactin-producing Escherichia coli in patients with mid or low rectal cancer: a prospective clinical study protocol (MICARE)

Author: Christophe Taoum, Guillaume Carrier, Marta Jarlier, Gwenaelle Roche, Johan Gagniere, Catherine Fiess, Helene De forges, Caroline Chevarin, Pierre-Emmanuel Colombo, Nicolas Barnich, Philippe Rouanet, Mathilde Bonnet, Institut du Cancer de Montpellier (ICM), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Service de Chirurgie Digestive et Hépatobiliaire [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, and ROSSI, Sabine
Subjects: MICROBIOLOGY, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, General Medicine, GASTROENTEROLOGY, ONCOLOGY, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, RADIOTHERAPY
Abstract: IntroductionThe management of mid and low rectal cancer is based on neoadjuvant chemoradiotherapy (CRT) followed by standardised surgery. There is no biomarker in rectal cancer to aid clinicians in foreseeing treatment response. The determination of factors associated with treatment response might allow the identification of patients who require tailored strategies (eg, therapeutic de-escalation or intensification). Colibactin-producingEscherichia coli(CoPEC) has been associated with aggressive colorectal cancer and could be a poor prognostic factor. Currently, no study has evaluated the potential association between intestinal microbiota composition and tumour response to CRT in mid and low rectal cancer. The aim of this study is to assess the association between response to neoadjuvant CRT and faecal intestinal microbiota composition and/or CoPEC prevalence in patients with mid or low rectal cancer.Methods and analysisThis is a non-randomised bicentric prospective clinical study with a recruitment capacity of 200 patients. Three stool samples will be collected from participants with histological-proven adenocarcinome of mid or low rectum who meet eligibility criteria of the study protocol: one before neoadjuvant treatment start, one in the period between CRT end and surgery and one the day before surgery. In each sample, CoPEC will be detected by culture in special media and molecular (PCR) approaches. The global microbiota composition will be also assessed by the bacterial 16S rRNA gene sequencing. Neoadjuvant CRT response and tumour regression grade will be described using the Dworak system at pathological examination. Clinical data and survival outcomes will also be collected and investigated.Ethics and disseminationMICARE was approved by the local ethics committee (Comité de Protection des Personnes Sud-Est II, 18 December 2019. Reference number 2019-A02493-54 and the institutional review board. Patients will be required to provide written informed consent. Results will be published in a peer reviewed journal.Trial registration numberNCT04103567.
Published: 2022
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16. Implication du pharmacien hospitalier dans le parcours des patients sous anticancéreux oraux en oncologie digestive

Author: Vincent Leclerc, Marie-Pauline Gagaille, Clémence Hollande, Sabrina Sidali, Samantha Martins, Julie Devictor, Mohamed Bouattour, Nathalie Pons-Kerjean, and Mathilde Bonnet
Subjects: Pharmacology (medical)
Published: 2023
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17. ESDR290 - Strategies to improve in vivo survival of Mesenchymal Stromal Cells after injection in immunodeficient mice

Author: Hovnanian Alain, Sonia Gaucher, Juliette Peltzer, Matthias Titeux, and Mathilde Bonnet des Claustres
Published: 2022
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18. Hyper inflammatory syndrome following COVID-19 mRNA vaccine in children: A national post-authorization pharmacovigilance study

Author: Naïm Ouldali, Haleh Bagheri, Francesco Salvo, Denise Antona, Antoine Pariente, Claire Leblanc, Martine Tebacher, Joëlle Micallef, Corinne Levy, Robert Cohen, Etienne Javouhey, Brigitte Bader-Meunier, Caroline Ovaert, Sylvain Renolleau, Veronique Hentgen, Isabelle Kone-Paut, Nina Deschamps, Loïc De Pontual, Xavier Iriart, Christelle Gras-Le Guen, François Angoulvant, Alexandre Belot, Aurelie Donzeau, Layal El Aridi, Sophie Lety, Bertrand Leboucher, Agnes Baur, Lucas Jeusset, Maelle Selegny, Cristian Fedorczuk, Marion Lajus, Philippe Bensaid, Yacine Laoudi, Charlotte Pons, Anne-Cécile Robert, Camille Beaucourt, Muriel Richard, Etienne Goisque, Olivier Brissaud, Pierre Segretin, Julie Molimard, Marie-Clothilde Orecel, Gregoire Benoit, Lucille Bongiovanni, Margaux Guerder, Robin Pouyau, Jean-Marie De Guillebon De Resnes, Ellia Mezgueldi, Fleur Cour-Andlauer, Come Horvat, Pierre Poinsot, Cecile Frachette, Antoine Ouziel, Yves Gillet, Catherine Barrey, Jacques Brouard, Florence Villedieu, Vathanaksambath Ro, Narcisse Elanga, Vincent Gajdos, Romain Basmaci, Hadile Mutar, Sébastien Rouget, Elodie Nattes, Isabelle Hau, Sandra Biscardi, Houmam El Jurdi, Camille Jung, Denis Semama, Frederic Huet, Anne-Marie Zoccarato, Mayssa Sarakbi, Guillaume Mortamet, Cécile Bost-Bru, Joachim Bassil, Caroline Vinit, Véronique Hentgen, Pascal Leroux, Valérie Bertrand, Caroline Parrod, Irina Craiu, Philippe Durand, Pierre Tissiere, Caroline Claude, Guillaume Morelle, Tamazoust Guiddir, Charlotte Borocco, Frédérique Delion, Camille Guillot, Stéphane Leteurtre, François Dubos, Mylene Jouancastay, Alain Martinot, Valentine Voeusler, Jeanne Languepin, Nathalie Garrec, Arnaud Chalvon Demersay, Aurélie Morand, Emmanuelle Bosdure, Noémie Vanel, Fabrice Ughetto, Fabrice Michel, Marie Caujolle, Renaud Blonde, Jacqueline Nguyen, Olivier Vignaud, Caroline Masserot-Lureau, François Gouraud, Carine Araujo, Tara Ingrao, Sanaa Naji, Mohammed Sehaba, Christine Roche, Aurelia Carbasse, Christophe Milesi, Mustapha Mazeghrane, Sandrine Haupt, Cyril Schweitzer, Benedicte Romefort, Elise Launay, Christèle Gras-Le Guen, Ahmed Ali, Nathalie Blot, Antoine Tran, Anne Rancurel, Mickael Afanetti, Sophie Odorico, Deborah Talmud, Anais Chosidow, Anne-Sophie Romain, Emmanuel Grimprel, Marie Pouletty, Jean Gaschignard, Olivier Corseri, Albert Faye, Isabelle Melki, Camille Ducrocq, Cherine Benzoïd, Johanna Lokmer, Stéphane Dauger, Maryline Chomton, Anna Deho, Fleur Lebourgeois, Fabrice Lesage, Florence Moulin, Laurent Dupic, Yael Pinhas, Agathe Debray, Martin Chalumeau, Véronique Abadie, Pierre Frange, Jeremie F Cohen, Slimane Allali, William Curtis, Zahra Belhadjer, Johanne Auriau, Mathilde Méot, Lucile Houyel, Damien Bonnet, Christophe Delacourt, Brigitte Bader Meunier, Pierre Quartier, Youssef Shaim, Laurence Baril, Samuel Crommelynck, Baptiste Jacquot, Philippe Blanc, Natacha Maledon, Blandine Robert, Camille Loeile, Clémence Cazau, Gauthier Loron, Simona Gaga, Cécile Vittot, Loubna El Nabhani, François Buisson, Muriel Prudent, Hugues Flodrops, Fadhila Mokraoui, Simon Escoda, Laurent Bonnemains, Sarah-Louisa Mahi, Clara Mertes, Joelle Terzic, Julie Helms, Charlotte Idier, Soraya Chenichene, Nicoleta Magdolena Ursulescu, Gladys Beaujour, Abdelhak Hakim, Alice Miquel, Agnès Rey, Arnaud Wiedermann, Anne Charbonneau, Agnès Veauvy-Juven, Alexandrine Ferry, Alexis Mandelcwajg, Alix Rousseau, Amandine Prenant, Anne-Laure Bourneuf, Anne Filleron, Audrey Robine, Arthur Félix, Aude Parizel, Aurélie Labarre, Aymeric Cantais, Barbara Ros, Basile Coulon, Blandine Biot, Bérengère Dalichoux, Benjamin Fournier, Benoit Cagnard, Blandine Vanel, David Brossier, Bruno Ménager, Bruno Ozanne, Carole Marie-Jeanne, Camille Bergerot, Camille Chavy, Camille Guidon, Candice Fabre, Caroline Galeotti, Catherine Baker, Claire Ballot-Schmit, Céline Belleau, Céline Charasse, Caroline Favel, Chadia Toumi, Charlène Ferrandiz, Charlotte Couturier, Charlotte Pouchoux, Maryline Chomton-Cailliez, Charlotte Kevorkian-Verguet, Clément Brunet, Céline Manteau, Clémence Mougey, Coline Santy, Coralie Fitament, Charlotte Petriat, Charlotte Rebelle, Cyril Charron, Maxime Dartus, David Toulorge, Cécile Guillou-Debuisson, Dorann Bartebin, Valérie Klein, E Broustal, E Desselas, Elodie Marteau, Emmanuelle Bouvrot, Elise Delacroix, Edeline Coinde, Loubna Elnabhani, Elsa Amouyal, Emilie Chaillou, Emeline Gabilly-Bernard, Emilie Ruiz, Emilie Thibault, Emilie Robin, Etienne Darrieux, Eva Blondel, Floriane Socchi, François Cazassus, Fanny Bajolle, Fatma Lacin, Fouad Madhi, Franck Zekre, François Guerin, Gerald Boussicault, Henri Ginies, Gnansounou Magloire, Guilhem Arnold, Ines Coulognon, Iona Sicard-Cras, Jean-Emmanuel Kahn, Jeanne Bordet, Jeanne-Lise Fausser, Jean-François Baleine, Josephine Brice, Julie Gendras, Kaan Pekin, Karine Norbert, Clément Karsenty, Léa Savary, Laurence Martinat, Léa Lesniewski, Lorelei Charbonnier, Louise Alexandre, Lucas Percheron, Marie Vincenti, Manon Lanzini, Margot Grisval, Marianne Mercy, Marie-Emilie Lampin, Marie Desgranges, Marie Duperril, Marie-Clothilde Orcel, Marion Audier, Marion Favier, Mathieu Carpentier, Mathilde Balcean, Mathilde Bonnet, Maurine Jouret, Marie Delattre, Michael Levy, Michael Valensi, Mickael Shum, Morgane Dumortier, Morgane Gelin, Morgane Nemmouchi, Morgane Williaume, M Sebaha, Nicoleta Genetay-Stanescu, Nathan Giroux, Nicolas Crassard, Neil Derridj, Noemie Lachaume, Oscar Werner, Olivier Guilluy, Olivier Richer, Olivier Tirel, Aurianne Pauvert, Paul Casha, Noémie Perez, Pauline Gras, Pierre-Louis Leger, Marion Pinchou, Pierre Mornand, Prisca Largo, Ramona-Christina Ibanez, Charlotte Roulland, Salam Hadah Albarazi, Said Bichali, Sarah Faton, Amandine Schott, Sébastien Walser, Severine Guillaume, Solene Vincent, Sophie Galene-Gromez, Stanislas Kozisek, Thierry Maugard, Thierry Blanc, Thierry Navarro, Thomas Lauvray, Tamas Kovacs, Valérie Launay, Véronique Despert, Victoria Lhostis, Virginie Gall, Xavier Micaelli, Yasmine Benadjaoud, Zied Matoussi, Hélène Géniaux, Anthony Facile, Tessa Pietri, Pascale Palassin, Sylvine Pinel, Laurent Chouchana, Delphine Callot, Charlène Boulay, Hôpital Robert Debré, CHU Sainte Justine [Montréal], Association Clinique et Thérapeutique Infantile du Val de Marne (ACTIV), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Santé publique France - French National Public Health Agency [Saint-Maurice, France], Les Hôptaux universitaires de Strasbourg (HUS), CHU Strasbourg, CHU Marseille, Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHI Créteil, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression (PI3), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence pour les Maladies Rhumatologiques Auto-Immunes et Systémiques [CHU Necker] (RAISE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital de la Timone [CHU - APHM] (TIMONE), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Evaluation thérapeutique et pharmacologie périnatale et pédiatrique (EA_7323), Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier de Versailles André Mignot (CHV), Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses [CH Versailles] (CeRéMAIA - Hôpital André Mignot), Hôpital Bicêtre, Université Paris-Saclay, CH de Saint-Malo [Broussais], Hôpital Jean Verdier [AP-HP], Institut de rythmologie et modélisation cardiaque [Pessac] (IHU Liryc), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des rhumatismes inflammatoires et maladies auto-immunes systémiques rares de l’enfant / National Referee Centre for Rheumatic and AutoImmune and Systemic Diseases in Children [Lyon] (RAISE), European Society for Paediatric Infectious Diseases, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPC), CHU Toulouse [Toulouse], Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques - EA 7426 (PI3), Centre de Référence pour les Maladies Rhumatologiques Auto-Immunes et Systémiques [Paris] (Institut IMAGINE/RAISE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Imagine [Paris Necker] (2I), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), HESAM Université (HESAM)-HESAM Université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPC), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Health data- and model- driven Knowledge Acquisition (HeKA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE)
Subjects: Oncology, [SDV]Life Sciences [q-bio], Health Policy, Multisystem inflammatory syndrome in children, Internal Medicine, COVID-19 mRNA vaccine, BNT162b2, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, SARS-COV-2, Hyper-inflammatory syndrome, Child
Abstract: International audience; BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is the most severe clinical entity associated with pediatric SARS-CoV-2 infection with a putative role of the spike protein into the immune system activation. Whether COVID-19 mRNA vaccine can induce this complication in children is unknown. We aimed to assess the risk of hyper-inflammatory syndrome following COVID-19 mRNA vaccine in children. METHODS: We conducted a post-authorization national population-based surveillance using the French enhanced pharmacovigilance surveillance system for COVID-19 vaccines. All cases of suspected hyper-inflammatory syndrome following COVID-19 mRNA vaccine in 12-17-year-old children between June 15(th), 2021 and January 1(st), 2022, were reported. Cases were reviewed according to WHO criteria for MIS-C. The reporting rate of this syndrome was compared to the MIS-C rate per 1,000,000 12-17-year-old children infected by SARS-CoV-2. FINDINGS: Up to January 2022, 8,113,058 COVID-19 mRNA vaccine doses were administered to 4,079,234 12-17-year-old children. Among them, 12 presented a hyper-inflammatory syndrome with multisystemic involvement. Main clinical features included male predominance (10/12, 83%), cardiac involvement (10/12, 83%), digestive symptoms (10/12, 83%), coagulopathy (7/12, 58%), cytolytic hepatitis (6/12, 50%), and shock (5/12, 42%). 4/12 (33%) required intensive care unit transfer, and 3/12 (25%) hemodynamic support. All cases recovered. In eight cases, no evidence of previous SARS-CoV-2 infection was found. The reporting rate was 1.5 (95%CI [0.8; 2.6]) per 1,000,000 doses injected, i.e. 2.9 (95%CI [1.5; 5.1]) per 1,000,000 12-17-year-old vaccinated children. As a comparison, 113 MIS-C (95%CI [95; 135]) occurred per 1,000,000 12-17-year-old children infected by SARS-CoV-2. INTERPRETATION: Very few cases of hyper-inflammatory syndrome with multi-organ involvement occurred following COVID-19 mRNA vaccine in 12-17-year-old children. The low reporting rate of this syndrome, compared to the rate of post-SARS-CoV-2 MIS-C in the same age-group, largely supports the vaccination in a context of an important circulation of SARS-CoV-2. FUNDING: ESPID Fellowship Award; Grandir-Fonds de Solidarité Pour L'enfance.
Published: 2022
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19. Duality of Netherton syndrome manifestations and response to ixekizumab

Author: Michel De La Brassinne, Alain Hovnanian, Guy Bricteux, C. Barbieux, Mathilde Bonnet des Claustres, Martine Bagot, and Emmanuelle Bourrat
Subjects: Algebra, Ixekizumab, business.industry, Medicine, Duality (optimization), Netherton syndrome, Dermatology, business, medicine.disease
Published: 2021
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20. Qualification and impact of a video-assisted control system in a chemotherapy compounding unit

Author: Marie-Pauline Gagaille, Vincent Leclerc, Jeanne Allard, Florent Marty, Bleuenn Treguier, Mathilde Bonnet, and Nathalie Pons-Kerjean
Subjects: General Pharmacology, Toxicology and Pharmaceutics
Published: 2023
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21. Interactions entre les AOD et les anticancéreux : on fait le point !

Author: Mathilde Bonnet, Emmanuelle De Raucourt, Nathalie Pons-Kerjean, Marie-Pauline Gagaille, and Vincent Leclerc
Subjects: Pharmacology (medical)
Published: 2023
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22. Microangiopathy associated with gemcitabine: a drug interaction with nab-paclitaxel? A case series and literature review

Author: Jeanne Allard, Mathilde Bonnet, Lucie Laurent, Mohamed Bouattour, Marie-Pauline Gagaille, and Vincent Leclerc
Subjects: Pharmacology, Paclitaxel, Thrombotic Microangiopathies, General Medicine, Adenocarcinoma, Deoxycytidine, Gemcitabine, Pancreatic Neoplasms, Mice, Albumins, Antineoplastic Combined Chemotherapy Protocols, Animals, Humans, Pharmacology (medical), Drug Interactions
Abstract: Gemcitabine and nab-paclitaxel association can be used in first- or second-line treatment for metastatic pancreatic adenocarcinoma. Here, we report five cases of supposed gemcitabine-induced thrombotic microangiopathy (G-TMA), four of them with nab-paclitaxel. We assumed that nab-paclitaxel could be responsible for a potential drug interaction with gemcitabine, increasing the risk of thrombotic microangiopathy occurrence.Clinicians reported cases of supposed G-TMA that were declared to the Pharmacovigilance center. We collected the patients' data (clinical and biological characteristics), calculated an incidence rate of G-TMA in our center, and a Naranjo score for each patient. We also reviewed literature on a potential drug interaction between nab-paclitaxel and gemcitabine.Four patients were treated with nab-paclitaxel/gemcitabine and one with gemcitabine alone. The time onset of supposed G-TMA was 2 to 11 months. Patients developed anemia, thrombocytopenia, and renal failure. The incidence rate of supposed G-TMA was 2.7% in our center compared to 0.31% (Meyler's Side Effect of Drugs) and 0.01% in the gemcitabine's summary of product characteristics. Literature review outlined an increase of gemcitabine's plasmatic concentrations induced by nab-paclitaxel (Drugs® website) and a potentiation of gemcitabine's effect by nab-paclitaxel in murine models. This study showed that nab-paclitaxel inhibits cytidine deaminase's activity (responsible for gemcitabine's metabolism) and increases gemcitabine's active metabolite concentrations (gemcitabine triphosphate) in tumor tissues.High incidence rate of G-TMA was observed in our cohort due to a potential drug interaction between nab-paclitaxel and gemcitabine with an increased risk of developing G-TMA. Additional pharmacological and pharmaco-epidemiological investigations are mandatory to explore this hypothesis.
Published: 2022

23. Correction to 'Hyper inflammatory syndrome following COVID-19 mRNA vaccine in children: A national post-authorization pharmacovigilance study'

Author: Naïm Ouldali, Haleh Bagheri, Francesco Salvo, Denise Antona, Antoine Pariente, Claire Leblanc, Martine Tebacher, Joëlle Micallef, Corinne Levy, Robert Cohen, Etienne Javouhey, Brigitte Bader-Meunier, Caroline Ovaert, Sylvain Renolleau, Veronique Hentgen, Isabelle Kone-Paut, Nina Deschamps, Loïc De Pontual, Xavier Iriart, Christelle Gras-Le Guen, Francois Angoulvant, Alexandre Belot, Aurelie Donzeau, Layal El Aridi, Sophie Lety, Bertrand Leboucher, Agnes Baur, Lucas Jeusset, Maelle Selegny, Cristian Fedorczuk, Marion Lajus, Philippe Bensaid, Yacine Laoudi, Charlotte Pons, Anne-Cécile Robert, Camille Beaucourt, Muriel Richard, Etienne Goisque, Olivier Brissaud, Pierre Segretin, Julie Molimard, Marie-Clothilde Orecel, Gregoire Benoit, Lucille Bongiovanni, Margaux Guerder, Robin Pouyau, Jean-Marie De Guillebon De Resnes, Ellia Mezgueldi, Fleur Cour-Andlauer, Come Horvat, Pierre Poinsot, Cecile Frachette, Antoine Ouziel, Yves Gillet, Catherine Barrey, Jacques Brouard, Florence Villedieu, Vathanaksambath Ro, Narcisse Elanga, Vincent Gajdos, Romain Basmaci, Hadile Mutar, Sébastien Rouget, Elodie Nattes, Isabelle Hau, Sandra Biscardi, Houmam El Jurdi, Camille Jung, Denis Semama, Frederic Huet, Anne-Marie Zoccarato, Mayssa Sarakbi, Guillaume Mortamet, Cécile Bost-Bru, Joachim Bassil, Caroline Vinit, Véronique Hentgen, Pascal Leroux, Valérie Bertrand, Caroline Parrod, Irina Craiu, Philippe Durand, Pierre Tissiere, Caroline Claude, Guillaume Morelle, Tamazoust Guiddir, Charlotte Borocco, Frédérique Delion, Camille Guillot, Stéphane Leteurtre, François Dubos, Mylene Jouancastay, Alain Martinot, Valentine Voeusler, Jeanne Languepin, Nathalie Garrec, Arnaud Chalvon Demersay, Aurélie Morand, Emmanuelle Bosdure, Noémie Vanel, Fabrice Ughetto, Fabrice Michel, Marie Caujolle, Renaud Blonde, Jacqueline Nguyen, Olivier Vignaud, Caroline Masserot-Lureau, François Gouraud, Carine Araujo, Tara Ingrao, Sanaa Naji, Mohammed Sehaba, Christine Roche, Aurelia Carbasse, Christophe Milesi, Mustapha Mazeghrane, Sandrine Haupt, Cyril Schweitzer, Benedicte Romefort, Elise Launay, Christèle Gras-Le Guen, Ahmed Ali, Nathalie Blot, Antoine Tran, Anne Rancurel, Mickael Afanetti, Sophie Odorico, Deborah Talmud, Anais Chosidow, Anne-Sophie Romain, Emmanuel Grimprel, Marie Pouletty, Jean Gaschignard, Olivier Corseri, Albert Faye, Isabelle Melki, Camille Ducrocq, Cherine Benzoïd, Johanna Lokmer, Stéphane Dauger, Maryline Chomton, Anna Deho, Fleur Lebourgeois, Fabrice Lesage, Florence Moulin, Laurent Dupic, Yael Pinhas, Agathe Debray, Martin Chalumeau, Véronique Abadie, Pierre Frange, Jeremie F Cohen, Slimane Allali, William Curtis, Zahra Belhadjer, Johanne Auriau, Mathilde Méot, Lucile Houyel, Damien Bonnet, Christophe Delacourt, Brigitte Bader Meunier, Pierre Quartier, Youssef Shaim, Laurence Baril, Samuel Crommelynck, Baptiste Jacquot, Philippe Blanc, Natacha Maledon, Blandine Robert, Camille Loeile, Clémence Cazau, Gauthier Loron, Simona Gaga, Cécile Vittot, Loubna El Nabhani, François Buisson, Muriel Prudent, Hugues Flodrops, Fadhila Mokraoui, Simon Escoda, Laurent Bonnemains, Sarah-Louisa Mahi, Clara Mertes, Joelle Terzic, Julie Helms, Charlotte Idier, Soraya Chenichene, Nicoleta Magdolena Ursulescu, Gladys Beaujour, Abdelhak Hakim, Alice Miquel, Agnès Rey, Arnaud Wiedermann, Anne Charbonneau, Agnès Veauvy-Juven, Alexandrine Ferry, Alexis Mandelcwajg, Alix Rousseau, Amandine Prenant, Anne-Laure Bourneuf, Anne Filleron, Audrey Robine, Arthur Félix, Aude Parizel, Aurélie Labarre, Aymeric Cantais, Barbara Ros, Basile Coulon, Blandine Biot, Bérengère Dalichoux, Benjamin Fournier, Benoit Cagnard, Blandine Vanel, David Brossier, Bruno Ménager, Bruno Ozanne, Carole Marie-Jeanne, Camille Bergerot, Camille Chavy, Camille Guidon, Candice Fabre, Caroline Galeotti, Catherine Baker, Claire Ballot-Schmit, Céline Belleau, Céline Charasse, Caroline Favel, Chadia Toumi, Charlène Ferrandiz, Charlotte Couturier, Charlotte Pouchoux, Maryline Chomton-Cailliez, Charlotte Kevorkian-Verguet, Clément Brunet, Céline Manteau, Clémence Mougey, Coline Santy, Coralie Fitament, Charlotte Petriat, Charlotte Rebelle, Cyril Charron, Maxime Dartus, David Toulorge, Cécile Guillou-Debuisson, Dorann Bartebin, Valérie Klein, E Broustal, E. Desselas, Elodie Marteau, Emmanuelle Bouvrot, Elise Delacroix, Edeline Coinde, Loubna Elnabhani, Elsa Amouyal, Emilie Chaillou, Emeline Gabilly-Bernard, Emilie Ruiz, Emilie Thibault, Emilie Robin, Etienne Darrieux, Eva Blondel, Floriane Socchi, François Cazassus, Fanny Bajolle, Fatma Lacin, Fouad Madhi, Franck Zekre, François Guerin, Gerald Boussicault, Henri Ginies, Gnansounou Magloire, Guilhem Arnold, Ines Coulognon, Iona Sicard-Cras, Jean-Emmanuel Kahn, Jeanne Bordet, Jeanne-Lise Fausser, Jean-François Baleine, Josephine Brice, Julie Gendras, Kaan Pekin, Karine Norbert, Clément Karsenty, Léa Savary, Laurence Martinat, Léa Lesniewski, Lorelei Charbonnier, Louise Alexandre, Lucas Percheron, Marie Vincenti, Manon Lanzini, Margot Grisval, Marianne Mercy, Marie-Emilie Lampin, Marie Desgranges, Marie Duperril, Marie-Clothilde Orcel, Marion Audier, Marion Favier, Mathieu Carpentier, Mathilde Balcean, Mathilde Bonnet, Maurine Jouret, Marie Delattre, Michael Levy, Michael Valensi, Mickael Shum, Morgane Dumortier, Morgane Gelin, Morgane Nemmouchi, Morgane Williaume, M. Sebaha, Nicoleta Genetay-Stanescu, Nathan Giroux, Nicolas Crassard, Neil Derridj, Noemie Lachaume, Oscar Werner, Olivier Guilluy, Olivier Richer, Olivier Tirel, Aurianne Pauvert, Paul Casha, Noémie Perez, Pauline Gras, Pierre-Louis Leger, Marion Pinchou, Pierre Mornand, Prisca Largo, Ramona-Christina Ibanez, Charlotte Roulland, Salam Hadah Albarazi, Said Bichali, Sarah Faton, Amandine Schott, Sébastien Walser, Severine Guillaume, Solene Vincent, Sophie Galene-Gromez, Stanislas Kozisek, Thierry Maugard, Thierry Blanc, Thierry Navarro, Thomas Lauvray, Tamas Kovacs, Valérie Launay, Véronique Despert, Victoria Lhostis, Virginie Gall, Xavier Micaelli, Yasmine Benadjaoud, Zied Matoussi, Hélène Géniaux, Anthony Facile, Tessa Pietri, Pascale Palassin, Sylvine Pinel, Laurent Chouchana, Delphine Callot, and Charlène Boulay
Subjects: Oncology, Health Policy, Internal Medicine
Published: 2022
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24. Probiotics/Synbiotics to Reduce Infectious Complications after Colorectal Surgery: A Systematic Review and Meta-Analysis of Randomised Controlled Trials

Author: Bruno Pereira, Bob-Valéry Occéan, Chadli Dziri, Karem Slim, Julie Veziant, Mathilde Bonnet, CHU Lille, Groupe francophone de Réhabilitation Améliorée après Chirurgie (GRACE), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Medical Simulation Center (MSC), Unité de Biostatistiques [CHU Clermont-Ferrand], Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de Chirurgie Digestive et Hépatobiliaire [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], and Molé, Christine
Subjects: Nutrition and Dietetics, Anastomotic Leak, meta-analysis, surgery, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, probiotics, Urinary Tract Infections, postoperative complications, Humans, Surgical Wound Infection, synbiotics, Colorectal Surgery, colorectal, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Randomized Controlled Trials as Topic, Food Science
Abstract: International audience; Aim: The aims of this systematic review and meta-analysis were to assess to what extent probiotics/synbiotics reduce infectious complications after colorectal surgery and whether probiotics or synbiotics should be considered as perioperative measures preventing or reducing infectious complications after CRS and should be included in enhanced recovery programmes (ERP). Secondary aims were to answer practical questions precisely on the best formulation and the type and timing of probiotics or synbiotics in CRS. Method: This systematic review and quantitative meta-analysis were conducted in accordance with PRISMA 2020 guidelines. Inclusion criteria were randomised trials comparing perioperative probiotics/synbiotics with a placebo or standard care in elective colorectal surgery. Exclusion criteria were non-randomised trials. Overall infectious complications and surgical site infections (SSIs including both deep abdominal infections and wound (skin or under the skin) infections) were the primary outcomes. Secondary outcomes were pulmonary and urinary infections, wound infections, and anastomotic leaks. The databases consulted were Medline, Cochrane Database of Systematic Reviews, Scopus, and Clinical Trials Register. Risk of bias was assessed according to the GRADE approach. The analysis calculated the random effects estimates risk ratio (RR) for each outcome. Results: 21 trials were included; 15 evaluated probiotics, and 6 evaluated synbiotics. There were significantly fewer infectious complications (risk ratio (RR) 0.59 [0.47-0.75], I 2 = 15%) and fewer SSI (RR 0.70 [0.52-0.95], I 2 = 0%) in the probiotic or synbiotic group. There were also significantly fewer pulmonary infections (RR 0.35 [0.20-0.63]) and urinary infections RR 0.41 [0.19-0.87]) as opposed to anastomotic leaks (RR 0.83 [0.47-1.48]) and wound infections (RR 0.74 [0.53-1.03]). Sensitivity analyses showed no significant difference between probiotics and synbiotics in reducing postoperative infections (RR 0.55 [0.42-0.73] versus RR 0.69 [0.42-1.13], p = 0.46). Conclusions: Based on the finding of this study, probiotics/synbiotics reduce infectious complications after colorectal surgery. The effect size was more pronounced for pulmonary and urinary infections. From a practical aspect, some of the questions related to formulations and duration of probiotics or synbiotics need to be answered before including them definitively in enhanced recovery after colorectal surgery programmes.
Published: 2022
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25. Gut microbiota as potential biomarker and/or therapeutic target to improve the management of cancer: focus on colibactin-producing Escherichia coli in colorectal cancer

Author: Nicolas Barnich, Mathilde Bonnet, Julie Veziant, Romain Villeger, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Ecologie et biologie des interactions (EBI), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Ministere de la Recherche et de la Technologie, Ligue nationale contre le cancer [63/03], INRAE (USC-2018), INSERM, ANR-16-IDEX-0001,CAP 20-25,CAP 20-25(2016), Chirurgie digestive, hépato-biliaire et endocrinienne [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Université Clermont Auvergne, CPER 2016, Molé, Christine, and CAP 20-25 - - CAP 20-252016 - ANR-16-IDEX-0001 - IDEX - VALID
Subjects: 0301 basic medicine, intestinal microbiota, Cancer Research, Colorectal cancer, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, Gut flora, E. coli, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, cancer, Escherichia coli, RC254-282, anti-cancer treatment, biology, business.industry, Melanoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cancer, CoPEC, dysbiosis, medicine.disease, biology.organism_classification, 3. Good health, Biomarker, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, biomarker, Sarcoma, prognosis, colibactin, business, Dysbiosis
Abstract: Simple Summary Gut microbiota is emerging as new diagnostic and prognostic marker and/or therapeutic target to improve the management of cancer. This review aims to summarize microbial signatures that have been associated with digestive and other cancers. We report the clinical relevance of these microbial markers to predict the response to cancer therapy. Among these biomarkers, colibactin-producing E. coli are prevalent in the colonic mucosa of patients with colorectal cancer and they promote colorectal carcinogenesis in several pre-clinical models. Here we discuss the promising use of colibactin-producing E. coli as a new predictive factor and a therapeutic target in colon cancer management. Abstract The gut microbiota is crucial for physiological development and immunological homeostasis. Alterations of this microbial community called dysbiosis, have been associated with cancers such colorectal cancers (CRC). The pro-carcinogenic potential of this dysbiotic microbiota has been demonstrated in the colon. Recently the role of the microbiota in the efficacy of anti-tumor therapeutic strategies has been described in digestive cancers and in other cancers (e.g., melanoma and sarcoma). Different bacterial species seem to be implicated in these mechanisms: F. nucleatum, B. fragilis, and colibactin-associated E. coli (CoPEC). CoPEC bacteria are prevalent in the colonic mucosa of patients with CRC and they promote colorectal carcinogenesis in susceptible mouse models of CRC. In this review, we report preclinical and clinical data that suggest that CoPEC could be a new factor predictive of poor outcomes that could be used to improve cancer management. Moreover, we describe the possibility of using these bacteria as new therapeutic targets.
Published: 2021
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26. Netherton syndrome subtypes share IL-17/IL-36 signature with distinct IFN-α and allergic responses

Author: Claire, Barbieux, Mathilde, Bonnet des Claustres, Matthias, Fahrner, Evgeniya, Petrova, Lam C, Tsoi, Olivier, Gouin, Florent, Leturcq, Pascale, Nicaise-Roland, Christine, Bole, Vivien, Béziat, Emmanuelle, Bourrat, Oliver, Schilling, Johann E, Gudjonsson, and Alain, Hovnanian
Subjects: Netherton Syndrome, Interleukin-17, Hypersensitivity, Proteinase Inhibitory Proteins, Secretory, Humans, Interferon-alpha, Serine Peptidase Inhibitor Kazal-Type 5, Epidermis, Skin Diseases, Skin
Abstract: Netherton syndrome (NS) is a rare recessive skin disorder caused by loss-of-function mutations in SPINK5 encoding the protease inhibitor LEKTI (lymphoepithelial Kazal-type-related inhibitor). NS patients experience severe skin barrier defects, display inflammatory skin lesions, and have superficial scaling with atopic manifestations. They present with typical ichthyosis linearis circumflexa (NS-ILC) or scaly erythroderma (NS-SE).We used a combination of several molecular profiling methods to comprehensively characterize the skin, immune cells, and allergic phenotypes of NS-ILC and NS-SE patients.We studied a cohort of 13 patients comprising 9 NS-ILC and 4 NS-SE.Integrated multiomics revealed abnormal epidermal proliferation and differentiation and IL-17/IL-36 signatures in lesion skin and in blood in both NS endotypes. Although the molecular profiles of NS-ILC and NS-SE lesion skin were very similar, nonlesion skin of each disease subtype displayed distinctive molecular features. Nonlesion and lesion NS-SE epidermis showed activation of the type I IFN signaling pathway, while lesion NS-ILC skin differed from nonlesion NS-ILC skin by increased complement activation and neutrophil infiltration. Serum cytokine profiling and immunophenotyping of circulating lymphocytes showed a TThis study confirms IL-17/IL-36 as the predominant signaling axes in both NS endotypes and unveils molecular features distinguishing NS-ILC and NS-SE. These results identify new therapeutic targets and could pave the way for precision medicine of NS.
Published: 2021

27. Emerging drugs for the treatment of epidermolysis bullosa

Author: Araksya Izmiryan, Alain Hovnanian, Matthias Titeux, Mathilde Bonnet des Claustres, and Hélène Ragot
Subjects: medicine.medical_specialty, Genetic enhancement, 030226 pharmacology & pharmacy, Severity of Illness Index, Cell therapy, 03 medical and health sciences, 0302 clinical medicine, Drug Development, Medicine, Animals, Humans, Pharmacology (medical), skin and connective tissue diseases, Pharmacology, Heterogeneous group, integumentary system, business.industry, Drug Repositioning, medicine.disease, Dermatology, Drug repositioning, 030220 oncology & carcinogenesis, Drug Design, Epidermolysis bullosa, business, Epidermolysis Bullosa
Abstract: Epidermolysis Bullosa (EB) form a heterogeneous group of rare, sometimes life-threatening inherited skin diseases characterized by skin and mucosal blistering after mild trauma from birth. They display a wide range of disease severity, with multiple local and systemic complications with no satisfactory treatment.Approaches aiming to restore the functional expression of the defective protein such asA cure for all forms of EB will remain challenging, but it is anticipated that treatments for EB will rely on precision medicine, involving a combination of complementary approaches. Treatments aiming to restore the function of the defective genes will be combined with symptom-relief therapies to address the specific features of the different forms of EB and each patient complications. A growing number of biotech and pharmaceutical companies have shown an increasing interest in the treatment of EB and as a result, have implemented numerous clinical trials. Therefore, we anticipate the emergence of effective treatments in the near future.
Published: 2020

28. Secukinumab Therapy for Netherton Syndrome

Author: Corinne Brunner, Barbara Meier-Schiesser, Nicole Knöpfel, Claire Barbieux, Mathilde Bonnet des Claustres, Alain Hovnanian, Davide Donghi, Agnes Schwieger-Briel, Lisa Weibel, Isabelle Luchsinger, Martin Theiler, Michael Buettcher, University of Zurich, Weibel, Lisa, Université Paris Cité, Equipe HAL, Différentiation et rôle pathogénique des lymphocytes T auxiliaires folliculaires dans la marche atopique - - Tfh-Atopy2017 - ANR-17-CE14-0025 - AAPG2017 - VALID, Développement d'une nouvelle biothérapie ciblant les mécanismes inflammatoires du syndrome de Netherton - - TARGET-NS2019 - ANR-19-CE17-0017 - AAPG2019 - VALID, University Children’s Hospital Zurich, Genetic skin diseases : from disease mechanism to therapies (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Bellinzona Regional Hospital [Bellinzona], Children’s Hospital Lucerne, Partenaires INRAE, University hospital of Zurich [Zurich], Service de génétique moléculaire [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This study was supported by the ANR-17-CE14-0025-03 Tfh-Atopy project and ANR-19-CE17-0017-01 TARGET-NS (Drs Hovnanian and Barbieux) funded by the French National Research Agency and Imagine cross-laboratory project (Dr Bonnet des Claustres) funded by the Imagine Institute., ANR-17-CE14-0025,Tfh-Atopy,Différentiation et rôle pathogénique des lymphocytes T auxiliaires folliculaires dans la marche atopique(2017), and ANR-19-CE17-0017,TARGET-NS,Développement d'une nouvelle biothérapie ciblant les mécanismes inflammatoires du syndrome de Netherton(2019)
Subjects: Compassionate Use Trials, Male, Erythema, MESH: Interleukin-17, Severity of Illness Index, MESH: Netherton Syndrome, 030207 dermatology & venereal diseases, 0302 clinical medicine, MESH: Child, Child, Skin, MESH: Compassionate Use Trials, Interleukin-17, Dermatology Life Quality Index, Phenotype, MESH: Young Adult, 030220 oncology & carcinogenesis, Female, Interleukin 17, medicine.symptom, Adult, medicine.medical_specialty, 610 Medicine & health, Dermatology, MESH: Onychomycosis, MESH: Phenotype, Antibodies, Monoclonal, Humanized, 2708 Dermatology, Young Adult, 03 medical and health sciences, MESH: Skin, MESH: Severity of Illness Index, Ichthyosis linearis circumflexa, Onychomycosis, medicine, Humans, Netherton syndrome, 10220 Clinic for Surgery, MESH: Pruritus, Adverse effect, MESH: Humans, Chemokine CCL20, business.industry, Pruritus, MESH: Quality of Life, MESH: Adult, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, MESH: Chemokine CCL20, medicine.disease, MESH: Male, MESH: Dermatologic Agents, MESH: Antibodies, Monoclonal, Humanized, Netherton Syndrome, Quality of Life, Secukinumab, Dermatologic Agents, business, MESH: Female, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Case series
Abstract: International audience; ImportanceNetherton syndrome (NS) is a rare, severe genetic disorder of cornification with high morbidity. Treatment for NS has been notoriously difficult. Recent studies showed an upregulated helper T cell (TH) 17/interleukin 23 (IL-23) pathway in NS, suggesting the possibility of treatment strategies that target IL-17.ObjectiveTo evaluate the clinical response of NS to treatment with the IL-17 antagonist secukinumab.Design, Setting, and ParticipantsThis case series study reports the experience of compassionate use therapy with secukinumab in 4 patients with severe NS, including 2 children, from December 1, 2018, to December 1, 2019, with 3 patients still undergoing treatment at the time of final analysis. Data were analyzed from December 1, 2018, to December 1, 2019.Main Outcomes and MeasuresExpression of IL-17 in the skin was evaluated by immunohistochemical analysis, and serum cytokine concentrations were measured using a commercially available assay. Treatment response was assessed using the Ichthyosis Area and Severity Index (IASI) total score, including measures of erythema and scaling, the Dermatology Life Quality Index (DLQI), and the 5-D itch scale.ResultsIn all 4 patients (age range, 9-27 years; 3 male and 1 female), immunostaining with an IL-17A antibody showed an increased number of positive cells in lesional skin. Cytokine assessment in serum samples revealed increased levels of CCL20. Treatment duration with secukinumab was 3 to 12 months at the time of this report. After 3 months of therapy, IASI scores were reduced by 44% to 88%, DLQI scores were reduced by 40% to 76%, and 5-D itch scale scores were reduced by 27% to 62%. This outcome was sustained at the 6-month follow-up. Two patients with an erythrodermic phenotype showed marked improvement of all parameters. A refractory palmoplantar eczematous eruption occurred in 2 patients, and a candidal nail infection developed in 2 patients. No severe adverse events were reported.Conclusions and RelevanceThis initial case series reporting the use of anti–IL-17 therapy in NS demonstrated marked cutaneous improvement, particularly in 2 pediatric patients with erythrodermic phenotypes. Further studies are needed to evaluate the long-term benefit of this potential treatment modality.
Published: 2020
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29. Transgenic Kallikrein 14 Mice Display Major Hair Shaft Defects Associated with Desmoglein 3 and 4 Degradation, Abnormal Epidermal Differentiation, and IL-36 Signature

Author: Mathilde Bonnet des Claustres, Alain Hovnanian, Florent Leturcq, Claire Barbieux, Olivier Gouin, Evgeniya Petrova, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CCSD, Accord Elsevier, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Université de Paris (UP)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Stratum granulosum, Mice, Transgenic, Dermatology, Biology, Biochemistry, Desmoglein, 03 medical and health sciences, 0302 clinical medicine, Loss of Function Mutation, KLK7, medicine, Animals, Humans, Netherton syndrome, education, Molecular Biology, Involucrin, education.field_of_study, integumentary system, Desmoglein 3, KLK5, Cell Biology, medicine.disease, Immunity, Innate, Recombinant Proteins, Cell biology, [SDV] Life Sciences [q-bio], Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Netherton Syndrome, 030220 oncology & carcinogenesis, Proteolysis, Serine Peptidase Inhibitor Kazal-Type 5, Female, Kallikreins, Epidermis, Desmogleins, Filaggrin, Hair, Interleukin-1
Abstract: Netherton syndrome is a rare autosomal recessive skin disease caused by loss-of-function mutations in SPINK5 encoding LEKTI protein that results in unopposed activity of epidermal kallikrein-related peptidases (KLKs), mainly KLK5, KLK7, and KLK14. Although the function of KLK5 and KLK7 has been previously studied, the role of KLK14 in skin homeostasis and its contribution to Netherton syndrome pathogenesis remains unknown. We generated a transgenic murine model overexpressing human KLK14 (TghKLK14) in stratum granulosum. TghKLK14 mice revealed increased proteolytic activity in the granular layers and in hair follicles. Their hair did not grow and displayed major defects with hyperplastic hair follicles when hKLK14 was overexpressed. TghKLK14 mice displayed abnormal epidermal hyperproliferation and differentiation. Ultrastructural analysis revealed cell separation in the hair cortex and increased thickness of Huxley's layer. Desmoglein (Dsg) 2 staining was increased, whereas Dsg3 and Dsg4 were markedly reduced. In vitro studies showed that hKLK14 directly cleaves recombinant human DSG3 and recombinant human DSG4, suggesting that their degradation contributes to hair abnormalities. Their skin showed an inflammatory signature, with enhanced expression of IL-36 family members and their downstream targets involved in innate immunity. This in vivo study identifies KLK14 as an important contributor to hair abnormalities and skin inflammation seen in Netherton syndrome.
Published: 2020
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30. The IL-22 pathway as target to relieve visceral pain and animal well-being

Author: Maeva Meynier, Elodie Baudu, Manon Defaye, Wawzyniak, Y., Frederic Delbac, Nicolas Barnich, Ardid, D., Philippe Poirier, Romain Villeger, Chatel, J. M., Livrelli, V., Mathilde Bonnet, Frederic carvalho, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Laboratoire Microorganismes : Génome et Environnement (LMGE), and Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2020

31. Fecal dysbiosis associated with colonic hypersensitivity and behavioral alterations in chronically Blastocystis-infected rats

Author: Céline Nourrisson, Denis Ardid, Elodie Baudu, Ivan Wawrzyniak, Nicolas Barnich, Amandine Lashermes, Agathe Gelot, Julie Barbier, Virginie Bonnin, Frédéric Delbac, Manon Defaye, Maeva Meynier, Mathieu Meleine, Catherine Godfraind, Benoit Chassaing, Mathilde Bonnet, Philippe Poirier, Frederic A. Carvalho, Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Laboratoire de Parasitologie et Mycologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Georgia State University, University System of Georgia (USG), Mucosal microbiota in chronic inflammatory diseases [Paris], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Service d'Anatomie Pathologique [CHU Clermont-Ferrand], This work was supported by co-financing from the Region Auvergne-Rhône-Alpes and FEDER in 2015 ('Thématiques émergentes'). Manon Defaye and Elodie Baudu received grants from the Auvergne-Rhône-Alpes Region. This work was supported by the « Ministère de la Recherche et de la Technologie », Inserm and University Clermont Auvergne [UMR1107, UMR1071], INRA [USC-2018], CNRS [UMR6023]., Region Auvergne-Rhone-Alpes European Union (EU) Region Auvergne-Rhone-AlpesRegion Bourgogne-Franche-ComteRegion Hauts-de-FranceRegion Nouvelle-Aquitaine Ministere de la Recherche et de la Technologie Institut National de la Sante et de la Recherche Medicale (Inserm) University Clermont Auvergne UMR1107UMR1071INRA USC-2018Centre National de la Recherche Scientifique (CNRS)UMR6023, Bodescot, Myriam, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université de Paris (UP), Service d'Anatomopathologie [Clermont-Ferrand], CHU Clermont-Ferrand, and Interactions microbiote/mucus dans les maladies inflammatoires chroniques = Mucosal microbiota in chronic inflammatory diseases
Subjects: 0301 basic medicine, Elevated plus maze, Intestinal parasite, lcsh:Medicine, Blastocystis Infections, Gut flora, medicine.disease_cause, Microbiology, Article, 03 medical and health sciences, Colonic Diseases, Feces, 0302 clinical medicine, medicine, Animals, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Risk factor, Rats, Wistar, lcsh:Science, Irritable bowel syndrome, Blastocystis, Multidisciplinary, biology, Behavior, Animal, business.industry, Microbiota, lcsh:R, Gastroenterology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, biology.organism_classification, medicine.disease, Fatty Acids, Volatile, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Rats, Disease Models, Animal, 030104 developmental biology, ROC Curve, Area Under Curve, Immunology, Dysbiosis, 030211 gastroenterology & hepatology, lcsh:Q, Serine Proteases, business, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology
Abstract: Background: Infectious gastroenteritis is a risk factor for the development of post-infectious Irritable Bowel Syndrome (PI-IBS). Recent clinical studies reported a higher prevalence of the intestinal parasite Blastocystis in IBS patients. Using a rat model, we investigated the possible association between Blastocystis infection, colonic hypersensitivity (CHS), behavioral disturbances and gut microbiota changes. Methods: Rats were orally infected with Blastocystis subtype 4 (ST4) cysts, isolated from human stool samples. Colonic sensitivity was assessed by colorectal distension and animal behavior with an automatic behavior recognition system (PhenoTyper), the Elevated Plus Maze test and the Forced Swimming tests. Feces were collected at different time points after infection to study microbiota composition by 16 S rRNA amplicon sequencing and for short-chain fatty acid (SFCA) analysis. Results: Blastocystis-infected animals had non-inflammatory CHS with increased serine protease activity. Infection was also associated with anxiety- and depressive-like behaviors. Analysis of fecal microbiota composition showed an increase in bacterial richness associated with altered microbiota composition. These changes included an increase in the relative abundance of Oscillospira and a decrease in Clostridium, which seem to be associated with lower levels of SCFAs in the feces from infected rats. Conclusions: Our findings suggest that experimental infection of rats with Blastocystis mimics IBS symptoms with the establishment of CHS related to microbiota and metabolic shifts.
Published: 2020
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32. Autophagy of Intestinal Epithelial Cells Inhibits Colorectal Carcinogenesis Induced by Colibactin-Producing Escherichia coli in Apc Mice

Author: Laurène Salesse, Mathilde Bonnet, Catherine Godfraind, Denis Pezet, Cécily Lucas, Nicolas Barnich, Anaïs Larabi, Hang Thi Thu Nguyen, My Hanh Thi Hoang, Pierre Sauvanet, Guillaume Dalmasso, Johan Gagnière, Philip Rosenstiel, Richard Bonnet, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de Neuropathologie, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Clinique Saint-Luc, CHU Clermont-Ferrand, Department of Digestive Surgery, University Medical Hospital, Institute of Clinical Molecular Biology, Kiel University, CCSD, Accord Elsevier, and ANR-16-IDEX-0001,CAP 20-25,CAP 20-25(2016)
Subjects: 0301 basic medicine, Carcinogenesis, Colon, DNA repair, DNA damage, Adenomatous Polyposis Coli Protein, ATG5, Autophagy-Related Proteins, Mice, Transgenic, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Autophagy, Escherichia coli, Animals, Humans, Intestinal Mucosa, RNA, Small Interfering, ATG16L1, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, Hepatology, Gastroenterology, Epithelial Cells, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, HCT116 Cells, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Gene Expression Regulation, Neoplastic, Reverse transcription polymerase chain reaction, Disease Models, Animal, 030104 developmental biology, Real-time polymerase chain reaction, Gene Knockdown Techniques, Polyketides, Colonic Neoplasms, Host-Pathogen Interactions, Cancer research, 030211 gastroenterology & hepatology, Tumor necrosis factor alpha, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Peptides, HeLa Cells
Abstract: Background & Aims Colibactin-producing Escherichia coli (CoPEC) colonize the colonic mucosa of a higher proportion of patients with vs without colorectal cancer (CRC) and promote colorectal carcinogenesis in susceptible mouse models of CRC. Autophagy degrades cytoplasmic contents, including intracellular pathogens, via lysosomes and regulates intestinal homeostasis. We investigated whether inhibiting autophagy affects colorectal carcinogenesis in susceptible mice infected with CoPEC. Methods Human intestinal epithelial cells (IECs) (HCT-116) were infected with a strain of CoPEC (11G5 strain) isolated from a patient or a mutant strain that does not produce colibactin (11G5ΔclbQ). Levels of ATG5, ATG16L1, and SQSTM1 (also called p62) were knocked down in HCT-116 cells using small interfering RNAs. ApcMin/+ mice and ApcMin/+ mice with IEC-specific disruption of Atg16l1 (ApcMin/+/Atg16l1ΔIEC) were infected with 11G5 or 11G5ΔclbQ. Colonic tissues were collected from mice and analyzed for tumor size and number and by immunohistochemical staining, immunoblot, and quantitative reverse transcription polymerase chain reaction for markers of autophagy, DNA damage, cell proliferation, and inflammation. We analyzed levels of messenger RNAs (mRNAs) encoding proteins involved in autophagy in colonic mucosal tissues from patients with sporadic CRC colonized with vs without CoPEC by quantitative reverse-transcription polymerase chain reaction. Results Patient colonic mucosa with CoPEC colonization had higher levels of mRNAs encoding proteins involved in autophagy than colonic mucosa without these bacteria. Infection of cultured IECs with 11G5 induced autophagy and DNA damage repair, whereas infection with 11G5ΔclbQ did not. Knockdown of ATG5 in HCT-116 cells increased numbers of intracellular 11G5, secretion of interleukin (IL) 6 and IL8, and markers of DNA double-strand breaks but reduced markers of DNA repair, indicating that autophagy is required for bacteria-induced DNA damage repair. Knockdown of ATG5 in HCT-116 cells increased 11G5-induced senescence, promoting proliferation of uninfected cells. Under uninfected condition, ApcMin/+/Atg16l1ΔIEC mice developed fewer and smaller colon tumors than ApcMin/+ mice. However, after infection with 11G5, ApcMin/+/Atg16l1ΔIEC mice developed more and larger tumors, with a significant increase in mean histologic score, than infected ApcMin/+ mice. Increased levels of Il6, Tnf, and Cxcl1 mRNAs, decreased level of Il10 mRNA, and increased markers of DNA double-strand breaks and proliferation were observed in the colonic mucosa of 11G5-infected ApcMin/+/Atg16l1ΔIEC mice vs 11G5-infected ApcMin/+ mice. Conclusion Infection of IECs and susceptible mice with CoPEC promotes autophagy, which is required to prevent colorectal tumorigenesis. Loss of ATG16L1 from IECs increases markers of inflammation, DNA damage, and cell proliferation and increases colorectal tumorigenesis in 11G5-infected ApcMin/+ mice. These findings indicate the importance of autophagy in response to CoPEC infection, and strategies to induce autophagy might be developed for patients with CRC and CoPEC colonization.
Published: 2020
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33. Colibactin‐positive Escherichia coli induce a procarcinogenic immune environment leading to immunotherapy resistance in colorectal cancer

Author: Al Hassan Casse, Guillaume Carrier, Pierre Sauvanet, Souad Naimi, Franck Pagès, Nicolas Barnich, Mathilde Bonnet, Romain Villeger, Elisabeth Billard, Arnaud Briat, Denis Pezet, Amélie Lopès, Gwenaëlle Roche, Julie Veziant, Bruno Dumas, Sanofi [Vitry-sur-Seine], SANOFI Recherche, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Chirurgie Digestive et Hépatobiliaire [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Laboratoire d’immunologie [Hôpital Européen Georges Pompidou - APHP], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CIFRE grant [2015/622], Ligue contre le cancer 63/03 [2018], ANR-16-IDEX-0001,CAP 20-25,CAP 20-25(2016), European Project: AV001826/AV0010859,CPER, École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP)
Subjects: Cancer Research, Lymphocyte T, Neutrophils, Colorectal cancer, medicine.medical_treatment, Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, Microenvironnement immunitaire, Cancer colorectal, Mice, 0302 clinical medicine, T-cell, Tumor Microenvironment, Mesenteric lymph nodes, biology, Colibactin, Colibactine, 3. Good health, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Colonic Neoplasms, Female, Immunotherapy, medicine.symptom, T cell, CD3, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Immune system, Escherichia coli, medicine, Animals, Humans, Lymphocyte Count, business.industry, E. coli, medicine.disease, digestive system diseases, Mice, Inbred C57BL, Immune microenvironment, Drug Resistance, Neoplasm, Polyketides, Cancer research, biology.protein, Peptides, business, CD8, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Colibactin-producing E. coli (CoPEC) are frequently detected in colorectal cancer (CRC) and exhibit procarcinogenic properties. Because increasing evidence show the role of immune environment and especially of antitumor T-cells in CRC development, we investigated the impact of CoPEC on these cells in human CRC and in the APC(Min/+) mice colon. T-cell density was evaluated by immunohistochemistry in human tumors known for their CoPEC status. APC(min/+) mice were chronically infected with a CoPEC strain (11G5). Immune cells (neutrophils and T-cell populations) were then quantified by immunofluorescent staining of the colon. The quantification of lymphoid populations was also performed in the mesenteric lymph nodes (MLNs). Here, we show that the colonization of CRC patients by CoPEC is associated with a decrease of tumor-infiltrating T lymphocytes (CD3(+) T-cells). Similarly, we demonstrated, in mice, that CoPEC chronic infection decreases CD3(+) and CD8(+) T-cells and increases colonic inflammation. In addition, we noticed a significant decrease in antitumor T-cells in the MLNs of CoPEC-infected mice compared to that of controls. Moreover, we show that CoPEC infection decreases the antimouse PD-1 immunotherapy efficacy in MC38 tumor model. Our findings suggest that CoPEC could promote a procarcinogenic immune environment through impairment of antitumor T-cell response, leading to tumoral resistance to immunotherapy. CoPEC could thus be a new biomarker predicting the anti-PD-1 response in CRC.
Published: 2020
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34. Microbial markers in colorectal cancer detection and/or prognosis

Author: Delphine Boucher, Elisabeth Billard, Johan Gagnière, Nicolas Barnich, Mathilde Bonnet, Julie Veziant, Romain Villeger, Amélie Lopès, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Centre Hospitalier Universitaire Clermont Ferrand, CHU Clermont-Ferrand, Service Chirurgie Disgestive, Centre Hospitalier Universitaire Estaing, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Inserm, Universite Clermont Auvergne UMR 1071, INRA (USC), Conseil regional Auvergne-Rhones-Alpes, and FDER/CPER
Subjects: 0301 basic medicine, Oncology, Colorectal cancer, Microbiota, F. nucleatum, Colibactin-producing E. coli, Prognostic markers, Diagnostic markers, Dysbiosis, Carcinogenesis, diagnostic, Review, Gut flora, marqueur, medicine.disease_cause, Feces, 0302 clinical medicine, Early Detection of Cancer, biology, Gastroenterology, General Medicine, Prognosis, 3. Good health, cancer colorectal, 030220 oncology & carcinogenesis, Metabolome, escherichia coli, Colorectal Neoplasms, Treatment response, medicine.medical_specialty, Adenoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sensitivity and Specificity, 03 medical and health sciences, microbiote, Internal medicine, medicine, Humans, business.industry, Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, digestive system diseases, Gastrointestinal Microbiome, Hépatologie et Gastroentérologie, 030104 developmental biology, colibactine, Hépatology and Gastroenterology, business, Biomarkers
Abstract: International audience; Colorectal cancer (CRC) is the second leading cause of cancer worldwide. CRC is still associated with a poor prognosis among patients with advanced disease. On the contrary, due to its slow progression from detectable precancerous lesions, the prognosis for patients with early stages of CRC is encouraging. While most robust methods are invasive and costly, actual patient-friendly screening methods for CRC suffer of lack of sensitivity and specificity. Therefore, the development of sensitive, non-invasive and cost-effective methods for CRC detection and prognosis are necessary for increasing the chances of a cure. Beyond its beneficial functions for the host, increasing evidence suggests that the intestinal microbiota is a key factor associated with carcinogenesis. Many clinical studies have reported a disruption in the gut microbiota balance and an alteration in the faecal metabolome of CRC patients, suggesting the potential use of a microbial-based test as a non-invasive diagnostic and/or prognostic tool for CRC screening. This review aims to discuss the microbial signatures associated with CRC known to date, including dysbiosis and faecal metabolome alterations, and the potential use of microbial variation markers for non-invasive early diagnosis and/or prognostic assessment of CRC and advanced adenomas. We will finally discuss the possible use of these markers as predicators for treatment response and their limitations.
Published: 2018
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35. Formulation of a 3-months Stability Oral Viscous Budesonide Gel and Development of an Indicating Stability HPLC Method

Author: Thomas Storme, Clara Roessle, Samira Benakouche, Marine Dermu, Marc Bellaiche, Véronique Vasseur, Tarik Abarou, and Mathilde Bonnet
Subjects: Pharmacology, Budesonide, Chromatography, paediatric, budesonide, business.industry, Pharmacy, RM1-950, medicine.disease, 03 medical and health sciences, eosinophilic esophagitis, 0302 clinical medicine, 030220 oncology & carcinogenesis, medicine, 030211 gastroenterology & hepatology, Pharmacology (medical), Therapeutics. Pharmacology, HD9665-9675, Eosinophilic esophagitis, business, Hplc method, high-performance liquid chromatography (hplc), Pharmaceutical industry, medicine.drug
Abstract: Background Eosinophilic Esophagitis is an increasing pathology which can cause stomach symptom like dysphagia, vomiting, food blockage. The treatment consists in dietary therapy and topical corticosteroid therapy to avoid the important number of side effects of the oral corticosteroids. There is presently no available topical form adapted for treating esophageal pathology. Methods The aim of this work was to develop an oral viscous budesonide gel (OVBG). A focus on palatability was made in order to use OVBG in children. A stability indicating HLPC method able to quantify budesonide contained in our OVBG has been developed. Results Previous work of Hefner and Al. showed that xanthan gum had a longer esophageal mucosal contact time than sucralose. This encouraged the development of a xanthan gum-based formulation. This OVBG has also the advantage to facilitate compliance thanks to its taste and pleasant texture. The stability length of the preparation can be extended over a 3-months period, stored in a refrigerator at 2–8 °C. Conclusions An adapted pediatric formulation with a 3-months stability was developed. Furthermore, the formulation can be easily reproduced in community pharmacy. Regarding the increasing number of patients concerned OVBG is a good answer to a real clinical need.
Published: 2018

36. Transgenic kallikrein 14 mice display major hair defects associated with desmoglein 3 and 4 degradation and an inflammatory signature

Author: Hovnanian Alain, Evgeniya Petrova, Mathilde Bonnet des Claustres, Florent Leturcq, Claire Barbieux, and Olivier Gouin
Published: 2019
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37. IMPACTS OF ADDITIVE FOOD E171 (TITANIUM DIOXIDE) ON THE GUT MICROBIOTA AND COLORECTAL CARCINOGENESIS IN APCMIN/+ MURINE MODEL

Author: Sandrine Brugiroux, Thomas Sauvaitre, Gwenaelle Roche, Célia Ledieu, Caroline Chevarin, Catherine Godfraind, Christophe Massard, Komla Oscar Awitor, Nicolas Barnich, Mathilde Bonnet, Delphine Boucher, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Institut Universitaire de Technologie - Clermont-Ferrand (IUT Clermont-Ferrand), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), OUERTANI, jeannette, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), IUT de Clermont-Ferrand (IUT de Clermont-Ferrand), Université Clermont Auvergne (UCA), and Massard, Christophe
Subjects: [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience; Background and aim: Contaminant molecules could play a key role in the initiation and/or promotion of colorectal cancer (CRC) which is the second leading cause of cancer worldwide. Among the different pollutants, titanium dioxide (TiO2) is a white natural metal oxide which is particularly monitored. It is one of the most widely used engineered nanomaterials in daily consumer products, including food. Long-term inhalation studies with TiO2 nanoparticles (NPs) in rats reported development of lung tumors leading to classify this compound as a possible carcinogen for humans by International Agency for Research on Cancer. The food additive TiO2, referred to as E171 in the European Union, is commonly used as a whitening and brightening agent in sugar confectionary, sauces, ice creams and pastries. The gastro-intestinal tract may be an important absorption route for TiO2 NPs and additive E171 could be involved in the CRC etiology. Thus, this project aimed to assess the impact of chronic exposure of food additive E171 in CRC development using APCmin/+ mouse model which spontaneously develop intestinal tumors. Because intestinal microbiota play a role in colorectal carcinogenesis, carcinogenic properties of TiO2 will be evaluated in association with microbiota dysbiosis.Methods: Additive E171 composition was characterized by X-ray diffraction (XRD) and thermogravimetric analysis (TGA). APCmin/+ mice were chronically exposed (twice per week) to E171 (1 and 10 mg/kg of body weight (BW)) or vehicle (water) for 28 days via intragastric gavage. Micro-inflammation was assessed by the quantification of fecal lipocalin-2 (LCN-2) marker. At the end of the experimental protocol, macroscopic and histologic examinations of colon were performed and colonic mucosa-associated microbiota was analyzed by quantitative PCR.Results: As shown by the TGA analysis, the E171 compound is purely mineral and the size of NPs administrated to mice in this study did not exceed 28 nm (XRD analysis). No significant body weight loss was observed between mice groups suggesting no toxicity in our experimental conditions. However macroscopic and histological observations showed a more advanced tumor development in mice receiving the additive E171 (at a dose of 10 mg/kg of BW) compared to control animals. At the end of the experiment, high level of fecal LCN-2 concentration correlated with increase of tumoral volume. Mice with adenocarcinoma within this group also exhibit an increase of Bacteroides and Akkermansia as well as a higher prevalence of Escherichia coli and a decrease of Bifidobacterium.Conclusion: Additive E171 promotes colonic tumorigenesis and induces change in gut microbiota composition. Underlying carcinogenic mechanisms focusing on microbiota dysbiosis implication are in progress. This study supports the carcinogenic properties of TiO2 in the context of colorectal cancer.
Published: 2019

38. Nebulized hypertonic saline 3% for 1 versus 3 days in hospitalized bronchiolitis: a blinded non-inferiority randomized controlled trial

Author: Mathilde Bonnet, Anne Ego, Catherine Barbier, Roseline Mazet, Amandine Rubio, Sophie Thoret, Isabelle Pin, Gaëlle Beal, Department of Pediatrics [Chambéry], Centre Hospitalier Métropole Savoie [Chambéry], Department of Pediatrics [Grenoble], CHU Grenoble, Centre d'Investigation Clinique [Grenoble] (CIC Grenoble ), CHU Grenoble-Hôpital Michallon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Department of Pharmacy [Grenoble], Public Health Department [Grenoble], CHU Grenoble-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Techniques pour l'Evaluation et la Modélisation des Actions de la Santé (TIMC-IMAG-ThEMAS), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), This study was supported by grant from Fondation Agir pour les Maladies Chroniques (AMPC) and from Grenoble-Alpes University Hospital., and Bodescot, Myriam
Subjects: Male, Randomization, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Drug Administration Schedule, law.invention, 03 medical and health sciences, 0302 clinical medicine, Non inferiority, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Hypertonic saline, Randomized controlled trial, Double-Blind Method, law, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 030225 pediatrics, medicine, Humans, 030212 general & internal medicine, Prospective Studies, Children, Saline Solution, Hypertonic, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, Nutritional Support, Nebulizers and Vaporizers, Remission Induction, lcsh:RJ1-570, Infant, lcsh:Pediatrics, medicine.disease, 3. Good health, Clinical trial, Oxygen, Treatment Outcome, Sample size determination, Bronchiolitis, Acute Bronchiolitis, Anesthesia, Pediatrics, Perinatology and Child Health, Acute Disease, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Female, Saline Solution, business, Child, Hospitalized, Research Article
Abstract: Background The use and optimal duration of treatment with nebulized hypertonic saline (HS) in infants hospitalized for acute bronchiolitis is unclear. The objective was to compare the efficacy of 1 versus 3 days of nebulized 3% HS at 72 h of treatment. We conducted a blinded non-inferiority randomized controlled trial including infants aged less than 12 months old, hospitalized for a moderate bronchiolitis. Methods Nebulisations of 3% HS for 1 day were followed by either the continuation of 3% HS (HS3d group) or switched to 0.9% normal isotonic saline (HS1d group) for 2 days Randomization was performed according to a predefined list with a 1:1 ratio, obtained with a random generator number with blocks.. Main outcome was mean Wang clinical severity score (CSS) after 72 h of treatment. Results One hundred sixteen infants (HS1d n = 59 and HS3d n = 57), were included over two epidemic seasons from 2014 to 2016, but recruitement did not reach the planned sample size. The difference for the Wang CSS score in the HS3d vs HS1d group was 0.71 [IC 90% 0.1; 1.3], above the precluded value of 0.4 set in the protocol defining the non-inferiority of shorter treatment duration. Clinical remission was more rapidly obtained in the HS3d than in HS1d (2.3 ± 1.6 vs 2.9 ± 1.4 days, p = 0.04), with a non-significant tendency for less need of nutritional support and supplemental oxygen in HS3d group. Clinical worsening and treatment intolerance were similar in the 2 groups. Conclusions Despite being underpowered, results seem not to be in favour of reducing the duration of nebulised HS treatment from 3 to 1 day in acute moderate bronchiolitis. Trial registration Clinical trials NCT 02538458, October 2014.
Published: 2019
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39. 1152 AUTOPHAGY INHIBITS COLORECTAL CARCINOGENESIS INDUCED BY COLIBACTIN-PRODUCING ESCHERICHIA COLI

Author: Denis Pezet, Anaïs Larabi, Hang Thi Thu Nguyen, Nicolas Barnich, Catherine Godfraind, Cécily Lucas, My Hanh Thi Hoang, Philip Rosenstiel, Johan Gagnière, Guillaume Dalmasso, Pierre Sauvanet, Richard Bonnet, Laurène Salesse, and Mathilde Bonnet
Subjects: Hepatology, Chemistry, Colibactin, Autophagy, Gastroenterology, medicine, Cancer research, Colorectal carcinogenesis, medicine.disease_cause, Escherichia coli
Published: 2020
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40. Prognostic value of a combination of innovative factors (gut microbiota, sarcopenia, obesity, metabolic syndrome) to predict surgical/oncologic outcomes following surgery for sporadic colorectal cancer: a prospective cohort study protocol (METABIOTE)

Author: Karine Poirot, Bruno Pereira, Lucie Cassagnes, Denis Pezet, Mathilde Bonnet, Caroline Chevarin, Pierre Sauvanet, Benoit Chassaing, Frédéric Robin, Catherine Godfraind, Johan Gagnière, Nicolas Barnich, Julie Veziant, CHU Clermont-Ferrand, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Chirurgie Digestive et Hépatobiliaire [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Georgia State University, University System of Georgia (USG), Télécom ParisTech, Laboratoire de Neuropathologie, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Clinique Saint-Luc, Department of Digestive Surgery, University Medical Hospital, Unité de biostatistiques, ANR-16-IDEX-0001,CAP 20-25,CAP 20-25(2016), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), OUERTANI, jeannette, and CAP 20-25 - - CAP 20-252016 - ANR-16-IDEX-0001 - IDEX - VALID
Subjects: obesity, medicine.medical_specialty, postoperative outcomes, Colorectal cancer, colorectal cancer, Gut flora, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, metabolic syndrome, sarcopenia, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Informed consent, medicine, Humans, Prospective Studies, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, gut microbiota, biology, business.industry, prognostic factors, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Medicine, Length of Stay, medicine.disease, biology.organism_classification, Survival Analysis, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Obesity, Gastrointestinal Microbiome, 3. Good health, Surgery, Clinical trial, Treatment Outcome, pathogenicE, coli, Oncology, pathogenicE. coli, 030220 oncology & carcinogenesis, Sarcopenia, Body Composition, 030211 gastroenterology & hepatology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Metabolic syndrome, Colorectal Neoplasms, business
Abstract: IntroductionColorectal cancer (CRC) is still associated with poor prognosis, especially in patients with advanced disease. Development of new prognostic tools replacing or supplementing those routinely used is definitely needed, with the aim to optimise and personalise treatment strategies. Gut microbiota composition and body composition profile (obesity, sarcopenia and metabolic syndrome) have recently been reported separately as new relevant prognostic factors for postoperative surgical and oncologic outcomes following CRC surgery. However interactions that exist between these factors have been poorly studied. The purpose of this translational prospective cohort study (METABIOTE) is to investigate potential interactions between gut microbiota, body composition profile and postoperative outcomes and recurrence in patients undergoing surgery for non-metastatic sporadic CRC.Methods and analysisThis single-centre project aims to prospectively enrol 300 consecutive patients undergoing surgery for non-metastatic sporadic CRC at the University Hospital of Clermont-Ferrand, France for the identification of specific microbial signatures (from tumour, colonic mucosa and stools samples) associated with particular metabolic profiles that could impact postoperative morbidity and oncologic outcomes, using microbiological, molecular and imaging approaches. The primary outcome is the 5-year overall survival (OS). Other outcomes are 5-year CRC-related OS, 5-year disease-free survival, 30-day postoperative morbidity, 90-day postoperative mortality and length of hospital stay.Ethics and disseminationThis study protocol was reviewed and approved by an independent French regional review board (n°2018-A00352-53, ‘Comité de Protection des Personnes Ile de France VII’ on 4 July 2018, declared to the competent French authority (‘Agence Nationale de Sécurité du Médicament et des produits de santé’, France), and registered on the Clinical Trials web-based platform (NCT 03843905). Oral and written informed consent will be obtained from each included patient. Study results will be reported to the scientific community at conferences and in peer-reviewed scientific journals.Trial registration numberNCT03843905..
Published: 2020
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41. Deciphering the immune microenvironment of a tissue by digital imaging and cognition network

Author: Elisabeth Billard, E. Boulcourt-Sambou, C. Larois, Nicolas Barnich, Mathilde Bonnet, Amélie Lopès, Gwenaëlle Roche, Bruno Dumas, Al Hassan Casse, S. Naimi, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Sanofi [Vitry-sur-Seine], SANOFI Recherche, Ministere de la Recherche et de la Technologie, Inserm, Université Clermont-Auvergne [UMR1071], INRA [USC-2018], CIFRE, Sanofi RD [2015/622], Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Cassé, Al Hassan, Dumas, Bruno, and Lopès, Amélie
Subjects: 0301 basic medicine, démarche préclinique, Myeloid, Colorectal cancer, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Immune microenvironment, T cell, méthode de coloration, Fluorescent Antibody Technique, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Immunofluorescence, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Article, Flow cytometry, Mice, 03 medical and health sciences, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, intestin, Tumor Microenvironment, medicine, Animals, Intestinal Mucosa, immunofluorescence, lcsh:Science, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, intestine, Cell localization, Multidisciplinary, medicine.diagnostic_test, colon, lcsh:R, cellule immunitaire, indirect fluorescent antibody techn, immune-defense cell, medicine.disease, Cell biology, algorithme d'apprentissage, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, 030104 developmental biology, medicine.anatomical_structure, Colonic Neoplasms, lcsh:Q, Algorithms
Abstract: Evidence has highlighted the importance of immune cells in various gut disorders. Both the quantification and localization of these cells are essential to the understanding of the complex mechanisms implicated in these pathologies. Even if quantification can be assessed (e.g., by flow cytometry), simultaneous cell localization and quantification of whole tissues remains technically challenging. Here, we describe the use of a computer learning-based algorithm created in the Tissue Studio interface that allows for a semi-automated, robust and rapid quantitative analysis of immunofluorescence staining on whole colon sections according to their distribution in different tissue areas. Indeed, this algorithm was validated to characterize gut immune microenvironment. Its application to the preclinical colon cancer APCMin/+ mouse model is illustrated by the simultaneous counting of total leucocytes and T cell subpopulations, in the colonic mucosa, lymphoid follicles and tumors. Moreover, we quantify T cells in lymphoid follicles for which quantification is not possible with classical methods. Thus, this algorithm is a new and robust preclinical research tool, for investigating immune contexture exemplified by T cells but it is also applicable to other immune cells such as other myeloid and lymphoid populations or other cellular phenomenon along mouse gut.
Published: 2018
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42. Efficient and reproducible experimental infections of rats with Blastocystis spp

Author: Frédéric Delbac, Manon Defaye, Philippe Poirier, Nicolas Barnich, Virginie Bonnin, Mathilde Bonnet, Frederic A. Carvalho, Elodie Baudu, Ivan Warwzyniak, Denis Ardid, Céline Nourrisson, Laboratoire Microorganismes : Génome et Environnement - Clermont Auvergne (LMGE), Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Neuro-Dol - Clermont Auvergne (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), CHU Gabriel Montpied (CHU), CHU Clermont-Ferrand, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), FEDER in 2015 'Thématiques émergentes', Région Auvergne-Rhone-Alpes, Ministère de la Recherche et de la Technologie, Université Clermont Auvergne [UMR1071, UMR1107), INRA [USC-2018], CNRS [UMR6023], Inserm, Carvalho, Frédéric Antonio, Poirier, Philippe, Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CHU Gabriel Montpied [Clermont-Ferrand], Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de la Recherche Agronomique (INRA), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), and Barnich, Nicolas
Subjects: 0301 basic medicine, modèle animal, [SDV]Life Sciences [q-bio], lcsh:Medicine, Blastocystis Infections, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], souris, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Feces, blastocyste, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Medicine and Health Sciences, Parasite hosting, Cyst, rat, modèle pour les maladies humaines, lcsh:Science, blastocyst stage, Protozoans, Gastrointestinal tract, Mice, Inbred BALB C, Mice, Inbred C3H, Multidisciplinary, biology, axenic culture, Eukaryota, Pathophysiology, animal models, 3. Good health, [SDV] Life Sciences [q-bio], Separation Processes, Experimental Organism Systems, Anatomy, Research Article, mice, Colon, Mouse Models, Research and Analysis Methods, Microbiology, culture axenique, 03 medical and health sciences, Model Organisms, medicine, Parasitic Diseases, Animals, Humans, Clinical significance, Animal Models of Disease, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Distillation, Blastocystis, Host (biology), lcsh:R, Organisms, Biology and Life Sciences, biology.organism_classification, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Parasitic Protozoans, Rats, Mice, Inbred C57BL, Gastrointestinal Tract, Chronic infection, Disease Models, Animal, Animal Models of Infection, 030104 developmental biology, Animal Studies, lcsh:Q, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Parasitic Intestinal Diseases, Digestive System
Abstract: Although Blastocystis spp. infect probably more than 1 billion people worldwide, their clinical significance is still controversial and their pathophysiology remains poorly understood. In this study, we describe a protocol for an efficient and reproducible model of chronic infection in rats, laying the groundwork for future work to evaluate the pathogenic potential of this parasite. In our experimental conditions, we were unable to infect rats using vacuolar forms of an axenically cultivated ST4 isolate, but we successfully established chronic infections of 4 week-old rats after oral administration of both ST3 and ST4 purified cysts isolated from human stool samples. The infection protocol was also applied to 4 week-old C57BL/9, BALB/C and C3H mice, but any mouse was found to be infected by Blastocystis. Minimal cyst inoculum required for rat infection was higher with ST3 (105) than with ST4 (102). These results were confirmed by co-housing experiments highlighting a higher contagious potential of ST4 in rats compared to ST3. Finally, experiments mimicking fecal microbiota transfer from infected to healthy animals showed that Blastocystis spp. could easily infect a new host, even though its intestinal microbiota is not disturbed. In conclusion, our results provide a well-documented and robust rat model of Blastocystis chronic infection, reproducing "natural" infection. This model will be of great interest to study host parasite interactions and to better evaluate clinical significance of Blastocystis.
Published: 2018
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43. List of Contributors

Author: A. Ahmet Başaran, Anna Ardevol, Vanessa Areco, Ahmet E. Atay, Merve Bacanlı, Rafael Bañares, Nurşen Başaran, Georg Bauer, John Anthony Bauer, Mayte Blay, Mathilde Bonnet, Araní Casillas-Ramírez, Raja Chakraborty, Carolina Ciacci, Saverio A. Ciampi, Alexander D. Clark, Ana Laura Colín-González, Martha L. Contreras-Zentella, Paula Cordero-Pérez, Mario Dell’Agli, Bennur Esen, Anabel Fernández-Iglesias, Samuel Fernández-Tomé, Jakub Fichna, Marília O. Fonseca Goulart, Marco Fumagalli, Johan Gagnière, Juan C. Garcia Pagan, Davis E. Garrison, Peter J. Giannone, Emel S. Gokmen, Jordi Gracia-Sancho, Ignazio Grattagliano, Feng He, Blanca Hernández-Ledesma, Rolando Hernández-Muñoz, Diana Hide, Chia-Chien Hsieh, Victor Antony Santiago Jesudoss, Mónica B. Jiménez-Castro, Mandar S. Joshi, Hyeyoung Kim, Min-Hyun Kim, Lars-Oliver Klotz, Koyamangalath Krishnan, Erica Lafoz, Virginia R. Lemon, Po Sing Leung, Lin Li, Ana Marchionatti, Francesca Marciano, Sandra G. Medina-Escobedo, José Miranda-Bautista, Paula Mosińska, Fabiana A. Moura, Craig A. Nankervis, Marisela Olguín-Martínez, Victoria Palau, Carmen Peralta, Adriana Pérez, Montserrat Pinent, Piero Portincasa, Valeria Rodríguez, Ilaria Russo, Maciej Salaga, Josepa Salvadó, Lourdes Sánchez-Sevilla, Enrico Sangiovanni, Abel Santamaría, Brandon Schanbacher, Saikat Sen, Bodo Speckmann, Holger Steinbrenner, Michael R. Stenger, Bill Stone, Partiban Subramanian, David C. Sypert, Ximena Terra, Nori Tolosa de Talamoni, Dinesh M. Tripathi, Pietro Vajro, Javier Vaquero, Karthikkumar Venkatachalam, Sundari Victor Antony Santiago, Marina Vilaseca, Stella Lucia Volpe, Zan Xu, and Li Zuo
Published: 2017
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44. Molecular Mechanism Underlying the Actions of Antioxidant Molecules in Digestive Disorders

Author: Mathilde Bonnet and Johan Gagnière
Subjects: 0301 basic medicine, Cell signaling, Antioxidant, medicine.medical_treatment, Oxidative phosphorylation, Metabolism, Biology, medicine.disease_cause, Cell biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Biochemistry, 030220 oncology & carcinogenesis, medicine, Molecular mechanism, Digestive tract, Mitochondria targeted antioxidant, Oxidative stress
Abstract: The gastrointestinal (GI) tract is a major site for the generation of prooxidant molecules. Reactive oxygen/nitrogen species (ROS/RNS) are produced during normal physiological metabolism and are essential signaling molecules involved in cell proliferation and/or in defenses against pathogens. However, excessive production of ROS and RNS and/or their inefficient elimination lead to oxidative and nitrosative stress. Therefore, oxidative stress has been implicated in numerous human GI diseases. To target these mechanisms in digestive tract pathologies, considerable research has been improved into the development of effective antioxidant therapies using natural derivatives or new synthetic molecules. Here we reviewed new mechanisms implicated in antioxidant responses. Understanding these new mechanisms allows designing new molecules or news associations of antioxidant molecules that could represent innovative therapeutic strategies to improve the care of patients with digestive diseases.
Published: 2017
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45. Tetraspanin 8 (TSPAN 8) as a potential target for radio-immunotherapy of colorectal cancer

Author: Alexandre Pichard, Isabelle Navarro-Teulon, Tiffany Witkowski, Yingying Zhu, Françoise Degoul, Sophie Besse, Eric Rubinstein, Mercedes Quintana, Paule Opolon, Elisabeth Miot-Noirault, Lydia Maigne, Arnaud Briat, Claude Boucheix, Aurélie Maisonial-Besset, Giovanna Fois, Mathilde Bonnet, Odile Berthier-Vergnes, Jean-Pierre Pouget, Jean-Michel Chezal, Olivia Bawa, Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Laboratoire de Physique de Clermont (LPC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut André Lwoff - Biologie intégrée de la cellule, virus et cancer (IALBICVC), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Imagerie Moléculaire et Thérapie Vectorisée (IMTV), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Cancéropôle CLARA-ITMO ' Technologies pour la Santé ', Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Plateforme histo-cyto-pathologies (PHCP), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Rayet, Béatrice, Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de la Recherche Agronomique (INRA), and Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Immunoconjugates, Colorectal cancer, Tetraspanins, medicine.medical_treatment, TSPAN8, Lutetium, Mice, 0302 clinical medicine, Tetraspanin, Medicine, Tissue Distribution, Molecular Targeted Therapy, Mice, Inbred BALB C, dosimetry, Indium Radioisotopes, Antibodies, Monoclonal, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Radioimmunotherapy, [PHYS.PHYS.PHYS-MED-PH]Physics [physics]/Physics [physics]/Medical Physics [physics.med-ph], Female, [INFO.INFO-MO] Computer Science [cs]/Modeling and Simulation, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Colorectal Neoplasms, Research Paper, Biodistribution, medicine.drug_class, Mice, Nude, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Monoclonal antibody, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Animals, Humans, neoplasms, [PHYS.PHYS.PHYS-MED-PH] Physics [physics]/Physics [physics]/Medical Physics [physics.med-ph], business.industry, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Xenograft Model Antitumor Assays, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, digestive system diseases, 030104 developmental biology, Cancer research, radioimmunotherapy, Radiopharmaceuticals, business, Nuclear medicine, Ex vivo
Abstract: Tetraspanin 8 (TSPAN8) overexpression is correlated with poor prognosis in human colorectal cancer (CRC). A murine mAb Ts29.2 specific for human TSPAN8 provided significant efficiency for immunotherapy in CRC pre-clinical models. We therefore evaluate the feasability of targeting TSPAN8 in CRC with radiolabeled Ts29.2. Staining of tissue micro-arrays with Ts29.2 revealed that TSPAN8 espression was restricted to a few human healthy tissues. DOTA-Ts29.2 was radiolabeled with 111In or 177Lu with radiochemical purities >95%, specific activity ranging from 300 to 600 MBq/mg, and radioimmunoreactive fractions >80%. The biodistribution of [111In]DOTA-Ts29.2 in nude mice bearing HT29 or SW480 CRC xenografts showed a high specificity of tumor localization with high tumor/blood ratios (HT29: 4.3; SW480-TSPAN8: 3.9 at 72h and 120h post injection respectively). Tumor-specific absorbed dose calculations for [177Lu]DOTA-Ts29.2 was 1.89 Gy/MBq, establishing the feasibility of using radioimmunotherapy of CRC with this radiolabeled antibody. A significant inhibition of tumor growth in HT29 tumor-bearing mice treated with [177Lu]DOTA-Ts29.2 was observed compared to control groups. Ex vivo experiments revealed specific DNA double strand breaks associated with cell apoptosis in [177Lu]DOTA-Ts29.2 treated tumors compared to controls. Overall, we provide a proof-of-concept for the use of [111In/177Lu]DOTA-Ts29.2 that specifically target in vivo aggressive TSPAN8-positive cells in CRC.
Published: 2017
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46. Interactions between microsatellite instability and human gut colonization by Escherichia coli in colorectal cancer

Author: Richard Bonnet, Allison Agus, Anne-Sophie Jarrousse, Pierre Déchelotte, Nancy Uhrhammer, Denis Pezet, Virginie Bonnin, Pierre Sauvanet, Emilie Cardamone, Johan Gagnière, Nicolas Barnich, Mathilde Bonnet, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Département de Pathologie, Université libre de Bruxelles (ULB)-Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB), Département Oncogénétique, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER-UNICANCER, Ministere de la Recherche et de la Technologie, Inserm and Universite d'AuvergneUMR1071, INRAUSC-2018, Conseil Regional d'Auvergne, 'Robert Debre pour la recherche medicale', association 'Nuovo Soldati Foundation for Cancer Research, 'Inserm Region' 358013, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Université Libre de Bruxelles [Bruxelles] (ULB)-Institut Jules Bordet, and Centre Jean Perrin - Centre Régional de Lutte contre le Cancer d'Auvergne
Subjects: 0301 basic medicine, Genome instability, microsatellite, Colorectal cancer, interaction, Biology, MLH1, medicine.disease_cause, microsatellites, 03 medical and health sciences, Pathogenic Escherichia coli, medicine, Escherichia coli, neoplasms, Genetics, instabilité, Microsatellite instability, General Medicine, stability, medicine.disease, biology.organism_classification, Phenotype, digestive system diseases, 3. Good health, 030104 developmental biology, colonisation intestinale, cancer colorectal, DNA mismatch repair, escherichia coli, colorectal neoplasm, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Recent studies suggest that colonization of colonic mucosa by pathogenic Escherichia coli could be involved in the development of colorectal cancer (CRC), especially through the production of genotoxins such as colibactin and/or by interfering with the DNA mismatch repair (MMR) pathway that leads to microsatellite instability (MSI). The present study, performed on 88 CRC patients, revealed a significant increase in E. coli colonization in the MSI CRC phenotype. In the same way, E. coli persistence and internalization were increased in vitro in MMR-deficient cells. Moreover, we demonstrated that colibactin-producing E. coli induce inhibition of the mutL homologue 1 (MLH1) MMR proteins, which could lead to genomic instability. However, colibactin-producing E. coli were more frequently identified in microsatellite stable (MSS) CRC. The present study suggests differences in the involvement of colibactin-producing E. coli in colorectal carcinogenesis according to the CRC phenotype. Further host–pathogen interactions studies should take into account CRC phenotypes.
Published: 2017
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47. 32 Impact of colibactin-producing escherichia coli on immune microenvironment in preclinical colorectal cancer models

Author: Elisabeth Miot-Noirault, Julie Veziant, Al Hassan Casse, Elisabeth Billard, S. Naimi, Nicolas Barnich, Gwenaëlle Roche, Mathilde Bonnet, Bruno Dumas, and Amélie Lopès
Subjects: Cancer Research, medicine.diagnostic_test, T cell, CD3, Inflammation, Biology, medicine.disease_cause, Molecular biology, Flow cytometry, medicine.anatomical_structure, Immune system, Oncology, medicine, biology.protein, IL-2 receptor, medicine.symptom, Lymph node, Escherichia coli
Abstract: Introduction Increasing evidence link the immune microenvironment, microbiota and colorectal cancer (CRC). E. coli pks + are more frequently detected on CRC patient mucosa and exhibit procarcinogenic properties in CRC murine models. Aim of this work was to evaluate the impact of chronical infection by colibactin-producing E. coli on immune cells in APC min/+ mice colon. Material and methods Min mice were per os inoculated with a CRC E. coli pks + strain (11 G5), non-pathogenic E. coli (K-12) or PBS. Induction of oxidative stress and inflammation during the infection was evaluated using optical in vivo imaging (IVIS spectrum). After 7 weeks, number and volume of polyps were evaluated and colonic samples were histologically analysed. Immunofluorescent staining of immune cells (neutrophils and T cell populations) was performed to quantify positive cells in three interesting colon areas: mucosa, lymphoid follicle and tumour using an innovative algorithm created with Tissue Studio software. In parallel, quantification of immune cells (lymphoid populations) was performed in mesenteric lymph node (MLNs) by flow cytometry. Results and discussions Using optical imaging, we detected a significant increase of oxidative stress and inflammation in the gut after thirty days of 11 G5 infection. However, using our specific algorithm and CD45 immunostaining, we observed a significant increase of lymphoid follicle size in the gut of mice infected with the 11 G5 strains. Interestingly, follicle size was positively correlated with tumour volume suggesting an association between pro-carcinogenic properties of 11 G5 strain and gut immune response. In addition, we observed an increase of neutrophils on the mucosa and lymphoid follicle of 11 G5 infected mice. These results can be linked to our in vivo optical imaging observations. Moreover we observed a trend to decrease of CD3 + T cells on mucosa and tumour for the 11 G5 group, suggesting a possible link between E. coli pks +and anti-tumour T cells. Finally we noticed a significant decrease of CD4 + CD25 + anti-inflammatory T cells in MLNs of 11 G5 infected mice, negatively correlated with gut bacteria colonisation. Conclusion Here we report a potential immunomodulatory effect on gut microenvironment by pks+E. coli, which could be associated with its carcinogenic effect. Our results suggest that gut lymphoid follicle and immune cells such as neutrophils and T cells could be involved in this process. This work shows a link between immune microenvironment, pathogenic E. coli and tumour development.
Published: 2018
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48. Intestinal Microbiota: A Novel Target to Improve Anti-Tumor Treatment?

Author: Amélie Lopès, Elisabeth Billard, Romain Villeger, Guillaume Carrier, Nicolas Barnich, Johan Gagnière, Mathilde Bonnet, Julie Veziant, Emilie Vazeille, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Sanofi [Vitry-sur-Seine], SANOFI Recherche, Institut du Cancer de Montpellier (ICM), CHU Clermont-Ferrand, Ministere de la Recherche et de la Technologie Universite Clermont-Auvergne UMR1071INRA USC-2018Ligue nationale contre le cancerFrench government IDEX-ISITE initiative of the University of Clermont Auvergne 16-IDEX-0001-CAP 20-25CIFRE grant 2015/622CPER EPICURE 2016 Institut National de la Sante et de la Recherche Medicale (Inserm), OUERTANI, jeannette, and ANR-16-IDEX-0001,CAP 20-25,CAP 20-25(2016)
Subjects: intestinal microbiota, 0301 basic medicine, Colorectal cancer, medicine.medical_treatment, Antibiotics, anticancer treatment, microbiome, Review, Gut flora, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, chemotherapy, lcsh:Chemistry, surgery, 0302 clinical medicine, Neoplasms, lcsh:QH301-705.5, Spectroscopy, biology, General Medicine, Prognosis, Combined Modality Therapy, 3. Good health, Computer Science Applications, Treatment Outcome, 030220 oncology & carcinogenesis, Adjuvant, medicine.drug_class, Catalysis, Inorganic Chemistry, 03 medical and health sciences, medicine, Animals, Humans, cancer, Microbiome, Physical and Theoretical Chemistry, Molecular Biology, radiotherapy, business.industry, Organic Chemistry, Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Immunotherapy, medicine.disease, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Gastrointestinal Microbiome, Radiation therapy, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, probiotics, Cancer research, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, adjuvant therapies, business
Abstract: International audience; Recently, preclinical and clinical studies targeting several types of cancer strongly supported the key role of the gut microbiota in the modulation of host response to anti-tumoral therapies such as chemotherapy, immunotherapy, radiotherapy and even surgery. Intestinal microbiome has been shown to participate in the resistance to a wide range of anticancer treatments by direct interaction with the treatment or by indirectly stimulating host response through immunomodulation. Interestingly, these effects were described on colorectal cancer but also in other types of malignancies. In addition to their role in therapy efficacy, gut microbiota could also impact side effects induced by anticancer treatments. In the first part of this review, we summarized the role of the gut microbiome on the efficacy and side effects of various anticancer treatments and underlying mechanisms. In the second part, we described the new microbiota-targeting strategies, such as probiotics and prebiotics, antibiotics, fecal microbiota transplantation and physical activity, which could be effective adjuvant therapies developed in order to improve anticancer therapeutic efficiency.
Published: 2019
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49. Su1976 – Impacts of Additive Food E171 (Titanium Dioxide) on the Gut Microbiota and Colorectal Carcinogenesis in ApcMIN/+ Murine Model

Author: Oscar Komla Awitor, Caroline Chevarin, Célia Ledieu, Delphine Boucher, Gwenaëlle Roche, Thomas Sauvaitre, Nicolas Barnich, Mathilde Bonnet, Sandrine Brugiroux, Christophe Massard, and Catherine Godfraind
Subjects: Hepatology, biology, Chemistry, Gastroenterology, Cancer, Context (language use), Akkermansia, Pharmacology, Gut flora, biology.organism_classification, medicine.disease, medicine, media_common.cataloged_instance, European union, Dysbiosis, Carcinogen, media_common, Bifidobacterium
Abstract: Background and aim: Contaminant molecules could play a key role in the initiation and/or promotion of colorectal cancer (CRC) which is the second leading cause of cancer worldwide. Among the different pollutants, titanium dioxide (TiO2) is a white natural metal oxide which is particularly monitored. It is one of the most widely used engineered nanomaterials in daily consumer products, including food. Long-term inhalation studies with TiO2 nanoparticles (NPs) in rats reported development of lung tumors leading to classify this compound as a possible carcinogen for humans by International Agency for Research on Cancer. The food additive TiO2, referred to as E171 in the European Union, is commonly used as a whitening and brightening agent in sugar confectionary, sauces, ice creams and pastries. The gastro-intestinal tract may be an important absorption route for TiO2 NPs and additive E171 could be involved in the CRC etiology. Thus, this project aimed to assess the impact of chronic exposure of food additive E171 in CRC development using APCmin/+ mouse model which spontaneously develop intestinal tumors. Because intestinal microbiota play a role in colorectal carcinogenesis, carcinogenic properties of TiO2 will be evaluated in association with microbiota dysbiosis. Methods: Additive E171 composition was characterized by X-ray diffraction (XRD) and thermogravimetric analysis (TGA). APCmin/+ mice were chronically exposed (twice per week) to E171 (1 and 10 mg/kg of body weight (BW)) or vehicle (water) for 28 days via intragastric gavage. Micro-inflammation was assessed by the quantification of fecal lipocalin-2 (LCN-2) marker. At the end of the experimental protocol, macroscopic and histologic examinations of colon were performed and colonic mucosa-associated microbiota was analyzed by quantitative PCR. Results: As shown by the TGA analysis, the E171 compound is purely mineral and the size of NPs administrated to mice in this study did not exceed 28 nm (XRD analysis). No significant body weight loss was observed between mice groups suggesting no toxicity in our experimental conditions. However macroscopic and histological observations showed a more advanced tumor development in mice receiving the additive E171 (at a dose of 10 mg/kg of BW) compared to control animals. At the end of the experiment, high level of fecal LCN-2 concentration correlated with increase of tumoral volume. Mice with adenocarcinoma within this group also exhibit an increase of Bacteroides and Akkermansia as well as a higher prevalence of Escherichia coli and a decrease of Bifidobacterium. Conclusion: Additive E171 promotes colonic tumorigenesis and induces change in gut microbiota composition. Underlying carcinogenic mechanisms focusing on microbiota dysbiosis implication are in progress. This study supports the carcinogenic properties of TiO2 in the context of colorectal cancer.
Published: 2019
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50. Corrigendum to: Formulation of a 3-months Stability Oral Viscous Budesonide Gel and Development of an Indicating Stability HPLC Method

Author: Marc Bellaiche, Samira Benakouche, Véronique Vasseur, Clara Roessle, Mathilde Bonnet, Marine Dermu, Thomas Storme, and Tarik Abarou
Subjects: Pharmacology, Budesonide, Chromatography, Chemistry, medicine, Pharmacology (medical), Pharmacy, Therapeutics. Pharmacology, RM1-950, HD9665-9675, Hplc method, Pharmaceutical industry, medicine.drug
Published: 2019

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