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1. Effects of a Lacticaseibacillus Mix on Behavioural, Biochemical, and Gut Microbial Outcomes of Male Mice following Chronic Restraint Stress

Author

Vivien Letenneur, Magali Monnoye, Catherine Philippe, Sophie Holowacz, Sylvie Rabot, Patricia Lepage, Elsa Jacouton, and Laurent Naudon

Subjects
psychobiotics, microbiota–gut–brain-axis, chronic stress, anxiety behaviour, Nutrition. Foods and food supply, TX341-641
Abstract

The effect of supplementation with Lactobacillus strains to prevent the consequences of chronic stress on anxiety in mouse strains sensitive to stress and the consequences on gut microbiota have been relatively unexplored. Thus, we administered a Lacticaseibacillus casei LA205 and Lacticaseibacillus paracasei LA903 mix to male BALB/cByJrj mice two weeks before and during 21-day chronic restraint stress (CRS) (non-stressed/solvent (NS-PBS), non-stressed/probiotics (NS-Probio), CRS/solvent (S-PBS), CRS/probiotics (S-Probio)). CRS resulted in lower body weight and coat state alteration, which were attenuated by the probiotic mix. S-Probio mice showed less stress-associated anxiety-like behaviours than their NS counterpart, while no difference was seen in PBS mice. Serum corticosterone levels were significantly higher in the S-Probio group than in other groups. In the hippocampus, mRNA expression of dopamine and serotonin transporters was lower in S-Probio than in S-PBS mice. Few differences in bacterial genera proportions were detected, with a lower relative abundance of Alistipes in S-Probio vs. S-PBS. CRS was accompanied by a decrease in the proportion of caecal acetate in S-PBS mice vs. NS-PBS, but not in the intervention groups. These data show that the probiotic mix could contribute to better coping with chronic stress, although the precise bacterial mechanism is still under investigation.

Published
2023
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2. Occurrence of Neonatal Necrotizing Enterocolitis in Premature Neonates and Gut Microbiota: A Case–Control Prospective Multicenter Study

Author

Julio Aires, Zehra Esra Ilhan, Lancelot Nicolas, Laurent Ferraris, Johanne Delannoy, Maxime Bredel, Anne Chauvire-Drouard, Frédéric Barbut, Jean-Christophe Rozé, Patricia Lepage, Marie-José Butel, and ClosNEC Study Group

Subjects
necrotizing enterocolitis, NEC, multicenter study, gut microbiota, UPEC, uropathogenic Escherichia coli, Biology (General), QH301-705.5
Abstract

Background: Necrotizing enterocolitis (NEC) is still one of the leading causes of neonatal death. The present study reports the data from a French case–control prospective multicenter study. Methods: A total of 146 preterm neonates (PNs) with or without NEC were included. Bacterial 16S rRNA gene sequencing was performed on stool samples (n = 103). Specific culture media were used to isolate Escherichia coli, Clostridium butyricum, and Clostridium neonatale, and strains were phenotypically characterized. Results: The gut microbiota of PNs was dominated by Firmicutes and Proteobacteria, and five enterotypes were identified. The microbiota composition was similar between NEC cases and PN controls. However, differences were observed in the relative abundance of Lactobacillus genus, which was significantly lower in the NEC group, whereas that of the Clostridium cluster III was significantly higher (p < 0.05). Within enterotypes, several phylotypes were significantly more abundant in NEC cases (p < 0.05). Regarding perinatal factors, a statistical association was found between the gut microbiota and cesarean delivery and antifungal therapy. In NEC cases and PN controls, the carriage rates and virulence genes of uropathogenic E. coli were equivalent based on culture. No correlation was found between E. coli, C. butyricum, and C. neonatale carriages, beta-lactam resistance, and antibiotic treatment. Conclusions: At disease onset, our data support a microbiota dysbiosis between NEC and control infants at the genus level. In addition, it provides valuable information on bacterial antimicrobial susceptibility.

Published
2023
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3. Parasites and diet as main drivers of the Malagasy gut microbiome richness and function

Author

Stanislas Mondot, Philippe Poirier, Ahmed Abou-Bacar, Valentin Greigert, Julie Brunet, Céline Nourrisson, Milijaona Randrianarivelojosia, Jean-Louis Razafindrakoto, Eugene Morel, Rivo S. Rakotomalala, Marion Leclerc, Karine Le Roux, Céline Monot, Patricia Lepage, and Ermanno Candolfi

Subjects
Medicine, Science
Abstract

Abstract Interactions between the prokaryotic microbiome and eukaryotic parasites in the vertebrate gut may affect overall host health and disease. While intertropical areas exhibit a high rate of parasites carriers, such interactions are understudied in these populations. Our objectives were to (1) describe the gut microbiome of individuals living in Madagascar, (2) identify potential associations between bacterial taxa and parasites colonizing the digestive tract and (3) highlight main determinants of the gut microbiota composition in this developing country. Metadata (socioeconomic, diet, clinical) and fecal samples were collected from 219 volunteers from North-West Madagascar (Mahajanga). Fecal microbiome was assessed through 16S rRNA gene sequencing and metabolomics, and related to dietary habits and parasites carriage. We highlight important Malagasy gut microbiome peculiarities. Out of three detected enterotypes, only one is similar to that observed in Westernized countries (Ruminococcus-driven). Functions associated with the two others (Clostridium sensu stricto-driven and Escherichia/Shigella-driven) are mostly directed toward amino acids biosynthesis and degradation, respectively. Diet and protozoan carriage were the main drivers of microbiota composition. High protozoan carriage was associated with higher diversity, richness and microbial functionalities. The gut microbiome of Malagasy strongly differs from that of Westernized countries. Asymptomatic protozoan carriage and dietary habits are the external factors with the deepest impact on gut microbiome. Further studies are needed to understand whether gut microbial richness constitute a predilection niche for protozoans colonization, due to their gazing features, or whether the parasites themselves induce a higher bacterial richness.

Published
2021
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4. Very Preterm Children Gut Microbiota Comparison at the Neonatal Period of 1 Month and 3.5 Years of Life

Author

Gaël Toubon, Marie-José Butel, Jean-Christophe Rozé, Patricia Lepage, Johanne Delannoy, Pierre-Yves Ancel, Marie-Aline Charles, Julio Aires, for the EPIFLORE Study Group, Clotilde Rousseau, Joel Dore, Ziad Al Nabhani, Karine Le Roux, Celine Monot, Laetitia MartinMarchand, Melanie Durox, Alexandre Lapillonne, Jean-Charles Picaud, Farid Boudred, Delphine Mitanchez, Valerie Biran, Laurent Storme, Olivier Claris, Gilles Cambonie, Cyril Flamant, Anne Sauret, Odile Dicky, Geraldine Favrais, Jean-Michel Hascoet, Geraldine Gascoin, Gerard Thiriez, Luc Desfrere, Xavier Durrmeyer, and Clement Chollat

Subjects
prematurity, gut microbiota, DOHaD, children, enterotypes, Microbiology, QR1-502
Abstract

Prematurity is a risk factor for dysbiosis of the gut microbiota due to particular birth conditions and frequent prolonged hospitalization of neonates. Although gut microbiota colonization after birth and its establishment during the hospitalization period have been studied in preterm infants, data on gut microbiota following discharge, particularly during early childhood, are scarce. The present study investigated the relationship between gut microbiota at 1 month after birth (hospitalization period) and 3.5 years of age in 159 preterm children belonging to the French EPIFLORE prospective observational cohort study. Analysis using bacterial 16S rRNA gene sequencing showed that the gut microbiota of preterm neonates at 1 month was highly variable and characterized by six distinct enterotypes. In contrast, the gut microbiota of the same children at 3.5 years of age showed less variability, with only two discrete enterotypes. An absence of association between enterotypes at 1 month and 3.5 years of age was observed. While the alpha diversity of gut microbiota significantly increased between 1 month and 3.5 years of age, for both alpha and beta diversities, there was no correlation between the 1-month and 3.5-years time points. Comparison at 3.5 years between children born either preterm (n = 159) or full-term (n = 200) showed no differences in terms of enterotypes, but preterm children harbored a lower Shannon diversity index and a different overall composition of microbiota than full-term children. This study suggests that the characteristics of the early gut microbiota of preterm children are not predictive of the microbial community composition at 3.5 years of age. However, the impact of gestational age is still noticeable on the gut microbiota up to 3.5 years of age.

Published
2022
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5. Gut Microbiota Diversity of Preterm Neonates Is Associated With Clostridioides Difficile Colonization

Author

Jeanne Couturier, Patricia Lepage, Sarah Jolivet, Johanne Delannoy, Victoria Mesa, Pierre-Yves Ancel, Jean-Christophe Rozé, Marie-José Butel, Frédéric Barbut, and Julio Aires

Subjects
Clostridioides (Clostridium) difficile, colonization, preterm neonates, gut microbiota, microbial diversity, 16S rRNA gene sequencing, Microbiology, QR1-502
Abstract

In adults, Clostridioides difficile infections are associated with alterations of the intestinal bacterial populations. Although preterm neonates (PN) are frequently colonized by C. difficile, limited data are available regarding the relationship between C. difficile and the intestinal microbiota of this specific population. Therefore, we studied the intestinal microbiota of PN from two multicenter cohorts using high-throughput sequencing of the bacterial 16S rRNA gene. Our results showed that alpha diversity was significantly higher in children colonized by C. difficile than those without colonization. Beta diversity significantly differed between the groups. In multivariate analysis, C. difficile colonization was significantly associated with the absence of postnatal antibiotherapy and higher gestational age. Taxa belonging to the Lachnospiraceae, Enterobacteriaceae, Oscillospiraceae families and Veillonella sp. were positively associated with C. difficile colonization, whereas Bacteroidales and Bifidobacterium breve were negatively associated with C. difficile colonization. After adjustment for covariables, Clostridioides, Rothia, Bifidobacterium, Veillonella, Eisenbergiella genera and Enterobacterales were more abundant in the gut microbiota of colonized children. There was no significant association between C. difficile colonization and necrotizing enterocolitis in PN. Our results suggest that C. difficile colonization in PN is related to the establishment of physiological microbiota.

Published
2022
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6. Exposure to anti-seizure medications impact growth of gut bacterial species and subsequent host response

Author

Zehra Esra Ilhan, Vincent Brochard, Nicolas Lapaque, Stéphane Auvin, and Patricia Lepage

Subjects
Epilepsy, Antiepileptic drugs, Microbiome, Pharmaco-resistance, Drug formulations, Seizures, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Anti-seizure medications (ASMs) are the first line of treatment for seizure control in children with epilepsy. Cumulative evidence suggests an imbalanced gut microbiota in refractory epilepsy patients. We systematically investigated the differential antimicrobial impacts of nine ASM active ingredients, seven common excipients of ASMs, and four syrup formulations on core early-life gut microbiota strains. Additionally, we evaluated the toxicity and gene expression profiles of HT-29 colon epithelial cells when exposed to active ingredients with or without bacterial supernatants. The physicochemical structure of ASM active ingredients and bacterial phylogeny were found to be related to ASM toxicity. Carbamazepine, lamotrigine, and topiramate reduced the growth of more than ten strains along with syrup excipient propyl-paraben. Various artificial sweeteners present in ASM formulations stimulated the growth of gut bacterial strains. The active ingredients that were more toxic to bacterial strains also exhibited toxicity towards HT-29 cells, yet Bifidobacterium longum supernatant reduced cytotoxic effects of carbamazepine and lamotrigine. Akkermansia muciniphila or mixed community supernatants reduced the expression of drug resistance genes in HT-29 cell lines. In summary, our results indicate that several ASM active ingredients and their excipients regulate the growth of gut bacterial strains in a species-specific manner. Interactions between ASMs and gut epithelial cells might be modulated by gut microbial metabolites.

Published
2022
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7. High engraftment capacity of frozen ready-to-use human fecal microbiota transplants assessed in germ-free mice

Author

Magali Berland, Julie Cadiou, Florence Levenez, Nathalie Galleron, Benoît Quinquis, Florence Thirion, Franck Gauthier, Emmanuelle Le Chatelier, Florian Plaza Oñate, Carole Schwintner, Sylvie Rabot, Patricia Lepage, Dusko Ehrlich, Joël Doré, and Catherine Juste

Subjects
Medicine, Science
Abstract

Abstract The number of indications for fecal microbiota transplantation is expected to rise, thus increasing the needs for production of readily available frozen or freeze-dried transplants. Using shotgun metagenomics, we investigated the capacity of two novel human fecal microbiota transplants prepared in maltodextrin-trehalose solutions (abbreviated MD and TR for maltodextrin:trehalose, 3:1, w/w, and trehalose:maltodextrin 3:1, w/w, respectively), to colonize a germ-free born mouse model. Gavage with frozen-thawed MD or TR suspensions gave the taxonomic profiles of mouse feces that best resembled those obtained with the fresh inoculum (Spearman correlations based on relative abundances of metagenomic species around 0.80 and 0.75 for MD and TR respectively), while engraftment capacity of defrosted NaCl transplants most diverged (Spearman correlations around 0.63). Engraftment of members of the family Lachnospiraceae and Ruminoccocaceae was the most challenging in all groups of mice, being improved with MD and TR transplants compared to NaCl, but still lower than with the fresh preparation. Improvement of engraftment of this important group in maintaining health represents a challenge that could benefit from further research on fecal microbiota transplant manufacturing.

Published
2021
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8. Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer

Author

Clélia Coutzac, Jean-Mehdi Jouniaux, Angelo Paci, Julien Schmidt, Domenico Mallardo, Atmane Seck, Vahe Asvatourian, Lydie Cassard, Patrick Saulnier, Ludovic Lacroix, Paul-Louis Woerther, Aurore Vozy, Marie Naigeon, Laetitia Nebot-Bral, Mélanie Desbois, Ester Simeone, Christine Mateus, Lisa Boselli, Jonathan Grivel, Emilie Soularue, Patricia Lepage, Franck Carbonnel, Paolo Antonio Ascierto, Caroline Robert, and Nathalie Chaput

Subjects
Science
Abstract

The gut microbiota has been reported to regulate the efficacy of cancer therapy. Here, the authors show that short-chain fatty acids, which are generated through bacterial fermentation, increases immune tolerance leading to resistance to anti-CTLA-4 immunotherapy in mice and patients with metastatic melanoma.

Published
2020
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9. Late weaning is associated with increased microbial diversity and Faecalibacterium prausnitzii abundance in the fecal microbiota of piglets

Author

Francesca Romana Massacci, Mustapha Berri, Gaetan Lemonnier, Elodie Guettier, Fany Blanc, Deborah Jardet, Marie Noelle Rossignol, Marie-José Mercat, Joël Doré, Patricia Lepage, Claire Rogel-Gaillard, and Jordi Estellé

Subjects
Piglet, Gut microbiota, Age, Weaning, Diversity, F. Prausnitzii, Veterinary medicine, SF600-1100, Microbiology, QR1-502
Abstract

Abstract Background In pig production systems, weaning is a crucial period characterized by nutritional, environmental, and social stresses. Piglets transition from a milk-based diet to a solid, more complex plant-based diet, and their gut physiology must adapt accordingly. It is well established that piglets weaned later display improved health, better wean-to-finish growth performance, and lower mortality rates. The aim of this study was to evaluate the impact of weaning age on fecal microbiota diversity and composition in piglets. Forty-eight Large White piglets were divided into 4 groups of 12 animals that were weaned at different ages: 14 days (early weaning), 21 days (a common weaning age in intensive pig farming), 28 days (idem), and 42 days (late weaning). Microbiota composition was assessed in each group by sequencing the 16S rRNA gene using fecal samples taken on the day of weaning, 7 days later, and at 60 days of age. Results In each group, there were significant differences in fecal microbiota composition before and after weaning (p

Published
2020
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10. A Guide for Ex Vivo Handling and Storage of Stool Samples Intended for Fecal Microbiota Transplantation

Author

Sebastian D. Burz, Anne-Laure Abraham, Fernanda Fonseca, Olivier David, Audrey Chapron, Fabienne Béguet-Crespel, Stéphanie Cénard, Karine Le Roux, Orlane Patrascu, Florence Levenez, Carole Schwintner, Hervé M. Blottière, Christel Béra-Maillet, Patricia Lepage, Joël Doré, and Catherine Juste

Subjects
Medicine, Science
Abstract

Abstract Owing to the growing recognition of the gut microbiota as a main partner of human health, we are expecting that the number of indications for fecal microbiota transplantation (FMT) will increase. Thus, there is an urgent need for standardization of the entire process of fecal transplant production. This study provides a complete standardized procedure to prepare and store live and ready-to-use transplants that meet the standard requirements of good practices to applied use in pharmaceutical industry. We show that, if time before transformation to transplants would exceed 24 hours, fresh samples should not be exposed to temperatures above 20 °C, and refrigeration at 4 °C can be a safe solution. Oxygen-free atmosphere was not necessary and simply removing air above collected samples was sufficient to preserve viability. Transplants prepared in maltodextrin-trehalose solutions, stored in a -80 °C standard freezer and then rapidly thawed at 37 °C, retained the best revivification potential as proven by 16S rRNA profiles, metabolomic fingerprints, and flow cytometry assays over a 3-month observation period. Maltodextrin-trehalose containing cryoprotectants were also efficient in preserving viability of lyophilized transplants, either in their crude or purified form, an option that can be attractive for fecal transplant biobanking and oral formulation.

Published
2019
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11. Impact and consequences of intensive chemotherapy on intestinal barrier and microbiota in acute myeloid leukemia: the role of mucosal strengthening

Author

Thomas Hueso, Kenneth Ekpe, Camille Mayeur, Anna Gatse, Marie Joncquel-Chevallier Curt, Guillaume Gricourt, Christophe Rodriguez, Charles Burdet, Guillaume Ulmann, Christel Neut, Salah-Eddine Amini, Patricia Lepage, Bruno Raynard, Christophe Willekens, Jean-Baptiste Micol, Stéphane De Botton, Ibrahim Yakoub-Agha, Frédéric Gottrand, Jean-Luc Desseyn, Muriel Thomas, Paul-Louis Woerther, and David Seguy

Subjects
intestinal barrier, microbiota, chemotherapy, acute leukemia, mucus, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Induction chemotherapy (7 + 3 regimen) remains the gold standard for patients with acute myeloid leukemia (AML) but is responsible for gut damage leading to several complications such as bloodstream infection (BSI). We aimed to investigate the impact of induction chemotherapy on the intestinal barrier of patients with AML and in wild-type mice. Next, we assessed the potential benefit of strengthening the mucosal barrier in transgenic mice releasing a recombinant protein able to reinforce the mucus layer (Tg222). In patients, we observed a decrease of plasma citrulline, which is a marker of the functional enterocyte mass, of short-chain fatty acids and of fecal bacterial load, except for Escherichia coli and Enterococcus spp., which became dominant. Both the α and β-diversities of fecal microbiota decreased. In wild-type mice, citrulline levels decreased under chemotherapy along with an increase of E. coli and Enterococcus spp load associated with concomitant histologic impairment. By comparison with wild-type mice, Tg222 mice, 3 days after completing chemotherapy, had higher citrulline levels, a faster healing epithelium, and preserved α-diversity of their intestinal microbiota. This was associated with reduced bacterial translocations. Our results highlight the intestinal damage and the dysbiosis induced by the 7 + 3 regimen. As a proof of concept, our transgenic model suggests that strengthening the intestinal barrier is a promising approach to limit BSI and improve AML patients’ outcome.

Published
2020
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12. The gut microbiota drives the impact of bile acids and fat source in diet on mouse metabolism

Author

Sarah Just, Stanislas Mondot, Josef Ecker, Katrin Wegner, Eva Rath, Laura Gau, Theresa Streidl, Genevieve Hery-Arnaud, Sinah Schmidt, Till Robin Lesker, Valentin Bieth, Andreas Dunkel, Till Strowig, Thomas Hofmann, Dirk Haller, Gerhard Liebisch, Philippe Gérard, Sascha Rohn, Patricia Lepage, and Thomas Clavel

Subjects
Metabolic diseases, Diet-induced obesity, Gut microbiota, Germ-free mice, Bile acids, Dietary fat, Microbial ecology, QR100-130
Abstract

Abstract Background As the gut microbiota contributes to metabolic health, it is important to determine specific diet-microbiota interactions that influence host metabolism. Bile acids and dietary fat source can alter phenotypes of diet-induced obesity, but the interplay with intestinal microorganisms is unclear. Here, we investigated metabolic consequences of diets enriched in primary bile acids with or without addition of lard or palm oil, and studied gut microbiota structure and functions in mice. Results In combination with bile acids, dietary lard fed to male C57BL/6N mice for a period of 8 weeks enhanced fat mass accumulation in colonized, but not in germ-free mice when compared to palm oil. This was associated with impaired glucose tolerance, lower fasting insulin levels, lower counts of enteroendocrine cells, fatty liver, and elevated amounts of hepatic triglycerides, cholesteryl esters, and monounsaturated fatty acids. Lard- and bile acid-fed mice were characterized by shifts in dominant gut bacterial communities, including decreased relative abundances of Lachnospiraceae and increased occurrence of Desulfovibrionaceae and the species Clostridium lactatifermentans and Flintibacter butyricus. Metatranscriptomic analysis revealed shifts in microbial functions, including lipid and amino acid metabolism. Conclusions Caution is required when interpreting data from diet-induced obesity models due to varying effects of dietary fat source. Detrimental metabolic consequences of a diet enriched with lard and primary bile acids were dependent on microbial colonization of the host and were linked to hepatic lipid rearrangements and to alterations of dominant bacterial communities in the cecum.

Published
2018
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13. A Data Integration Multi-Omics Approach to Study Calorie Restriction-Induced Changes in Insulin Sensitivity

Author

Maria Carlota Dao, Nataliya Sokolovska, Rémi Brazeilles, Séverine Affeldt, Véronique Pelloux, Edi Prifti, Julien Chilloux, Eric O. Verger, Brandon D. Kayser, Judith Aron-Wisnewsky, Farid Ichou, Estelle Pujos-Guillot, Lesley Hoyles, Catherine Juste, Joël Doré, Marc-Emmanuel Dumas, Salwa W. Rizkalla, Bridget A. Holmes, Jean-Daniel Zucker, Karine Clément, The MICRO-Obes Consortium, Aurélie Cotillard, Sean P. Kennedy, Nicolas Pons, Emmanuelle Le Chatelier, Mathieu Almeida, Benoit Quinquis, Nathalie Galleron, Jean-Michel Batto, Pierre Renault, Stanislav Dusko Ehrlich, Hervé Blottière, Marion Leclerc, Tomas de Wouters, and Patricia Lepage

Subjects
data integration, insulin sensitivity, lifestyle factors, microbiota, omics, Physiology, QP1-981
Abstract

Background: The mechanisms responsible for calorie restriction (CR)-induced improvement in insulin sensitivity (IS) have not been fully elucidated. Greater insight can be achieved through deep biological phenotyping of subjects undergoing CR, and integration of big data.Materials and Methods: An integrative approach was applied to investigate associations between change in IS and factors from host, microbiota, and lifestyle after a 6-week CR period in 27 overweight or obese adults (ClinicalTrials.gov: NCT01314690). Partial least squares regression was used to determine associations of change (week 6 – baseline) between IS markers and lifestyle factors (diet and physical activity), subcutaneous adipose tissue (sAT) gene expression, metabolomics of serum, urine and feces, and gut microbiota composition. ScaleNet, a network learning approach based on spectral consensus strategy (SCS, developed by us) was used for reconstruction of biological networks.Results: A spectrum of variables from lifestyle factors (10 nutrients), gut microbiota (10 metagenomics species), and host multi-omics (metabolic features: 84 from serum, 73 from urine, and 131 from feces; and 257 sAT gene probes) most associated with IS were identified. Biological network reconstruction using SCS, highlighted links between changes in IS, serum branched chain amino acids, sAT genes involved in endoplasmic reticulum stress and ubiquitination, and gut metagenomic species (MGS). Linear regression analysis to model how changes of select variables over the CR period contribute to changes in IS, showed greatest contributions from gut MGS and fiber intake.Conclusion: This work has enhanced previous knowledge on links between host glucose homeostasis, lifestyle factors and the gut microbiota, and has identified potential biomarkers that may be used in future studies to predict and improve individual response to weight-loss interventions. Furthermore, this is the first study showing integration of the wide range of data presented herein, identifying 115 variables of interest with respect to IS from the initial input, consisting of 9,986 variables.Clinical Trial Registration:clinicaltrials.gov (NCT01314690).

Published
2019
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14. Host–microbe interactions in distal airways: relevance to chronic airway diseases

Author

Clémence Martin, Pierre-Régis Burgel, Patricia Lepage, Claire Andréjak, Jacques de Blic, Arnaud Bourdin, Jacques Brouard, Pascal Chanez, Jean-Charles Dalphin, Gaetan Deslée, Antoine Deschildre, Philippe Gosset, Lhousseine Touqui, and Daniel Dusser

Subjects
Diseases of the respiratory system, RC705-779
Abstract

This article is the summary of a workshop, which took place in November 2013, on the roles of microorganisms in chronic respiratory diseases. Until recently, it was assumed that lower airways were sterile in healthy individuals. However, it has long been acknowledged that microorganisms could be identified in distal airway secretions from patients with various respiratory diseases, including cystic fibrosis (CF) and non-CF bronchiectasis, chronic obstructive pulmonary disease, asthma and other chronic airway diseases (e.g. post-transplantation bronchiolitis obliterans). These microorganisms were sometimes considered as infectious agents that triggered host immune responses and contributed to disease onset and/or progression; alternatively, microorganisms were often considered as colonisers, which were considered unlikely to play roles in disease pathophysiology. These concepts were developed at a time when the identification of microorganisms relied on culture-based methods. Importantly, the majority of microorganisms cannot be cultured using conventional methods, and the use of novel culture-independent methods that rely on the identification of microorganism genomes has revealed that healthy distal airways display a complex flora called the airway microbiota. The present article reviews some aspects of current literature on host–microbe (mostly bacteria and viruses) interactions in healthy and diseased airways, with a special focus on distal airways.

Published
2015
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15. Dietary Protein Intake Level Modulates Mucosal Healing and Mucosa-Adherent Microbiota in Mouse Model of Colitis

Author

Sandra Vidal-Lletjós, Mireille Andriamihaja, Anne Blais, Marta Grauso, Patricia Lepage, Anne-Marie Davila, Roselyne Viel, Claire Gaudichon, Marion Leclerc, François Blachier, and Annaïg Lan

Subjects
dietary protein level, colitis, epithelial repair, mucosa-adherent microbiota, Nutrition. Foods and food supply, TX341-641
Abstract

Mucosal healing after an inflammatory flare is associated with lasting clinical remission. The aim of the present work was to evaluate the impact of the amount of dietary protein on epithelial repair after an acute inflammatory episode. C57BL/6 DSS-treated mice received isocaloric diets with different levels of dietary protein: 14% (P14), 30% (P30) and 53% (P53) for 3 (day 10), 6 (day 13) and 21 (day 28) days after the time of colitis maximal intensity. While the P53 diet worsened the DSS- induced inflammation both in intensity and duration, the P30 diet, when compared to the P14 diet, showed a beneficial effect during the epithelial repair process by accelerating inflammation resolution, reducing colonic permeability and increasing epithelial repair together with epithelial hyperproliferation. Dietary protein intake also impacted mucosa-adherent microbiota composition after inflammation since P30 fed mice showed increased colonization of butyrate-producing genera throughout the resolution phase. This study revealed that in our colitis model, the amount of protein in the diet modulated mucosal healing, with beneficial effects of a moderately high-protein diet, while very high-protein diet displayed deleterious effects on this process.

Published
2019
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16. Extensive expression differences along porcine small intestine evidenced by transcriptome sequencing.

Author

Núria Mach, Mustapha Berri, Diane Esquerré, Claire Chevaleyre, Gaëtan Lemonnier, Yvon Billon, Patricia Lepage, Isabelle P Oswald, Joël Doré, Claire Rogel-Gaillard, and Jordi Estellé

Subjects
Medicine, Science
Abstract

The aim of this study was to analyse gene expression along the small intestine (duodenum, jejunum, ileum) and in the ileal Peyer's patches in four young pigs with no clinical signs of disease by transcriptome sequencing. Multidimensional scaling evidenced that samples clustered by tissue type rather than by individual, thus prefiguring a relevant scenario to draw tissue-specific gene expression profiles. Accordingly, 1,349 genes were found differentially expressed between duodenum and jejunum, and up to 3,455 genes between duodenum and ileum. Additionally, a considerable number of differentially expressed genes were found by comparing duodenum (7,027 genes), jejunum (6,122 genes), and ileum (6,991 genes) with ileal Peyer's patches tissue. Functional analyses revealed that most of the significant differentially expressed genes along small intestinal tissues were involved in the regulation of general biological processes such as cell development, signalling, growth and proliferation, death and survival or cell function and maintenance. These results suggest that the intrinsic large turnover of intestinal tissues would have local specificities at duodenum, ileum and jejunum. In addition, in concordance with their biological function, enteric innate immune pathways were overrepresented in ileal Peyer's patches. The reported data provide an expression map of the cell pathway variation in the different small intestinal tissues. Furthermore, expression levels measured in healthy individuals could help to understand changes in gene expression that occur in dysbiosis or pathological states.

Published
2014
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17. Azithromycin promotes relapse by disrupting immune and metabolic networks after allogeneic stem cell transplantation

Author

Nicolas Vallet, Sophie Le Grand, Louise Bondeelle, Bénédicte Hoareau, Aurélien Corneau, Delphine Bouteiller, Simon Tournier, Lucille Derivry, Armelle Bohineust, Marie Tourret, Delphine Gibert, Ethan Mayeur, Raphael Itzykson, Kim Pacchiardi, Brian Ingram, Stéphane Cassonnet, Patricia Lepage, Régis Peffault de Latour, Gérard Socié, Anne Bergeron, and David Michonneau

Subjects
Neoplasms, Immunology, Hematopoietic Stem Cell Transplantation, Humans, Cell Biology, Hematology, Azithromycin, Biochemistry, Metabolic Networks and Pathways, Stem Cell Transplantation
Abstract

Administration of azithromycin after allogeneic hematopoietic stem cell transplantation for hematologic malignancies has been associated with relapse in a randomized phase 3 controlled clinical trial. Studying 240 samples from patients randomized in this trial is a unique opportunity to better understand the mechanisms underlying relapse, the first cause of mortality after transplantation. We used multi-omics on patients’ samples to decipher immune alterations associated with azithromycin intake and post-transplantation relapsed malignancies. Azithromycin was associated with a network of altered energy metabolism pathways and immune subsets, including T cells biased toward immunomodulatory and exhausted profiles. In vitro, azithromycin exposure inhibited T-cell cytotoxicity against tumor cells and impaired T-cell metabolism through glycolysis inhibition, down-regulation of mitochondrial genes, and up-regulation of immunomodulatory genes, notably SOCS1. These results highlight that azithromycin directly affects immune cells that favor relapse, which raises caution about long-term use of azithromycin treatment in patients at high risk of malignancies. The ALLOZITHRO trial was registered at www.clinicaltrials.gov as #NCT01959100.

Published
2022

18. Parasites and diet as main drivers of the Malagasy gut microbiome richness and function

Author

Valentin Greigert, Ermanno Candolfi, Patricia Lepage, Céline Monot, Stanislas Mondot, Céline Nourrisson, Karine Le Roux, Marion Leclerc, Philippe Poirier, Jean-Louis Razafindrakoto, Eugene Morel, Rivo Solotiana Rakotomalala, Milijaona Randrianarivelojosia, Julie Brunet, Ahmed Abou-Bacar, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), 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), Laboratoire de Parasitologie et Mycologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Institut de Parasitologie et de Pathologie Tropicale (IPPTS), Université de Strasbourg (UNISTRA), Université de Toliara, Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP), CHU PZaga [Mahajanga, Madagascar], and CHU Mahavoky Atsimo [Mahajanga, Madagascar]

Subjects
Adult, Male, Science, Niche, Zoology, Gut flora, Article, Microbial ecology, Feces, 03 medical and health sciences, parasitic diseases, Madagascar, Animals, Humans, Metabolomics, Parasites, Colonization, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Microbiome, 030304 developmental biology, 2. Zero hunger, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, 0303 health sciences, Multidisciplinary, biology, 030306 microbiology, Feeding Behavior, biology.organism_classification, Diet, Gastrointestinal Microbiome, Carriage, Medicine, Female, Enterotype, Species richness, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

Interactions between the prokaryotic microbiome and eukaryotic parasites in the vertebrate gut may affect overall host health and disease. While intertropical areas exhibit a high rate of parasites carriers, such interactions are understudied in these populations. Our objectives were to (1) describe the gut microbiome of individuals living in Madagascar, (2) identify potential associations between bacterial taxa and parasites colonizing the digestive tract and (3) highlight main determinants of the gut microbiota composition in this developing country. Metadata (socioeconomic, diet, clinical) and fecal samples were collected from 219 volunteers from North-West Madagascar (Mahajanga). Fecal microbiome was assessed through 16S rRNA gene sequencing and metabolomics, and related to dietary habits and parasites carriage. We highlight important Malagasy gut microbiome peculiarities. Out of three detected enterotypes, only one is similar to that observed in Westernized countries (Ruminococcus-driven). Functions associated with the two others (Clostridium sensu stricto-driven and Escherichia/Shigella-driven) are mostly directed toward amino acids biosynthesis and degradation, respectively. Diet and protozoan carriage were the main drivers of microbiota composition. High protozoan carriage was associated with higher diversity, richness and microbial functionalities. The gut microbiome of Malagasy strongly differs from that of Westernized countries. Asymptomatic protozoan carriage and dietary habits are the external factors with the deepest impact on gut microbiome. Further studies are needed to understand whether gut microbial richness constitute a predilection niche for protozoans colonization, due to their gazing features, or whether the parasites themselves induce a higher bacterial richness.

Published
2021

19. Mucosal Healing and Bacterial Composition in Response to Enteral Nutrition Vs Steroid-based Induction Therapy—A Randomised Prospective Clinical Trial in Children With Crohn’s Disease

Author

Patricia Lepage, Stanislas Mondot, Joël Doré, Jacques Schmitz, Frank M. Ruemmele, Olivier Goulet, Bénédicte Pigneur, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Sorbonne Paris Cité (COMUE) (USPC), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris Saclay (COmUE), MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), ProdInra, Migration, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Randomization, Adolescent, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Gut flora, Gastroenterology, 03 medical and health sciences, Enteral Nutrition, 0302 clinical medicine, Crohn Disease, Adrenal Cortex Hormones, Internal medicine, medicine, Humans, Child, Adverse effect, Neoadjuvant therapy, Crohn's disease, Mucous Membrane, biology, business.industry, Remission Induction, Mucous membrane, General Medicine, medicine.disease, biology.organism_classification, DNA Fingerprinting, Gastrointestinal Microbiome, 3. Good health, [SDV] Life Sciences [q-bio], Clinical trial, 030104 developmental biology, medicine.anatomical_structure, Parenteral nutrition, Female, 030211 gastroenterology & hepatology, business
Abstract

AimsExclusive enteral nutrition [EEN] is as efficacious as corticosteroids [CS] to induce remission in Crohn’s disease [CD], without their adverse effects. EEN seems to be more efficient than steroids to induce mucosal healing, but the underlying molecular mechanisms are only sparsely understood. We aimed in the present work to study the anti-inflammatory effects of EEN with Modulen IBD® vs CS in active paediatric CD, and to assess its modulatory effects on the intestinal microbiota as compared with steroids.Materials and MethodsNineteen patients with new-onset active CD (Harvey-Bradshaw index [HBI] >5), aged from 6 to 17 years, were included in this prospective randomised induction trial with CS [n = 6] or EEN [n = 13]. Patients were assessed at Weeks 0 and 8 using clinical parameters HBI, endoscopic findings (Crohn’s Disease Endoscopic Index of Severity [CDEIS] score) and analysis of faecal microbiota composition.ResultsAt 8 weeks, clinical remission [HBI ConclusionsBoth steroid and EEN induced clinical remission. However, patients with EEN-induced remission showed a higher rate of mucosal healing and this was associated with a different gut microbiota compositional shift in these children.

Published
2018

20. Assessment of Neonatal Intensive Care Unit Practices and Preterm Newborn Gut Microbiota and 2-Year Neurodevelopmental Outcomes

Author

Marie-José Butel, Pierre-Yves Ancel, Josef Neu, Julio Aires, Karine Le Roux, Jean-Christophe Rozé, Clotilde Rousseau, Emmanuel Montassier, Matthieu Resche-Rigon, Céline Monot, Patricia Lepage, Marine Butin, Laetitia Marchand-Martin, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Equipe 1 : EPOPé - Épidémiologie Obstétricale, Périnatale et Pédiatrique (CRESS - U1153), 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)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM), Hopital Saint-Louis [AP-HP] (AP-HP), Physiopathologie et Pharmacotoxicologie Placentaire Humaine (U1139), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hospices Civils de Lyon (HCL), PremUp Foundation, Institut de Recherche pour le Développement (IRD)-CHI Créteil-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Paris (UP), University of Central Florida [Orlando] (UCF), ANR-12-BSV3-0025,EPIFLORE,Ecosystème intestinal du grand et très grand prématuré: analyse du microbiote, implications cliniques à court et long term(2012), 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)-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), and Institut de Recherche pour le Développement (IRD)-CHI Créteil-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris-Saclay-Université Paris Cité (UPCité)

Subjects
Male, Pediatrics, medicine.medical_specialty, Neonatal intensive care unit, [SDV]Life Sciences [q-bio], Population, INFANTS, Infant, Premature, Diseases, 03 medical and health sciences, NECROTIZING ENTEROCOLITIS, 0302 clinical medicine, Intensive Care Units, Neonatal, Intensive care, Humans, Medicine, Prospective Studies, education, Original Investigation, 030304 developmental biology, 0303 health sciences, education.field_of_study, business.industry, Research, Confounding, Infant, Newborn, Infant, Gestational age, General Medicine, Odds ratio, Gastrointestinal Microbiome, 3. Good health, Online Only, Neurodevelopmental Disorders, Child, Preschool, Infant, Extremely Premature, Infant Care, Cohort, Dysbiosis, Female, business, 030217 neurology & neurosurgery, Cohort study
Abstract

Key Points Question What are the long-term outcomes associated with dysbiosis of gut microbiota in very preterm newborns? Findings In this cohort study of 577 very preterm newborns across 24 neonatal intensive care units from a French nationwide cohort, gut microbiota at week 4 after birth showed 6 bacterial patterns that varied according to gestational age, perinatal characteristics, individual treatments, and neonatal intensive care unit strategies. Three clusters were associated with 2-year outcomes after adjustment for these confounders. Meaning Modifying strategies associated with alterations in microbiota, such as promoting enteral nutrition, reducing sedation use, promoting early extubation, or skin-to-skin practice, may be correlated with outcomes in preterm newborns., Importance In very preterm newborns, gut microbiota is highly variable with major dysbiosis. Its association with short-term health is widely studied, but the association with long-term outcomes remains unknown. Objective To investigate in preterm newborns the associations among practice strategies in neonatal intensive care units (NICUs), gut microbiota, and outcomes at 2 years. Design, Setting, and Participants EPIFLORE is a prospective observational cohort study that includes a stool sample collection during the fourth week after birth. Preterm newborns of less than 32 weeks of gestational age (GA) born in 2011 were included from 24 NICUs as part of the French nationwide population-based cohort, EPIPAGE 2. Data were collected from May 2011 to December 2011 and analyzed from September 2016 to December 2018. Exposures Eight NICU strategies concerning sedation, ventilation, skin-to-skin practice, antibiotherapy, ductus arteriosus, and breastfeeding were assessed. A NICU was considered favorable to a practice if the percentage of that practice in the NICU was more than the expected percentage. Main Outcomes and Measures Gut microbiota was analyzed by 16S ribosomal RNA gene sequencing and characterized by a clustering-based method. The 2-year outcome was defined by death or neurodevelopmental delay using a Global Ages and Stages questionnaire score. Results Of 577 newborns included in the study, the mean (SD) GA was 28.3 (2.0) weeks, and 303 (52.5%) were male. Collected gut microbiota was grouped into 5 discrete clusters. A sixth cluster included nonamplifiable samples owing to low bacterial load. Cluster 4 (driven by Enterococcus [n = 63]), cluster 5 (driven by Staphylococcus [n = 52]), and cluster 6 (n = 93) were significantly associated with lower mean (SD) GA (26.7 [1.8] weeks and 26.8 [1.9] weeks, respectively) and cluster 3 (driven by Escherichia/Shigella [n = 61]) with higher mean (SD) GA (29.4 [1.6] weeks; P = .001). Cluster 3 was considered the reference. After adjustment for confounders, no assisted ventilation at day 1 was associated with a decreased risk of belonging to cluster 5 or cluster 6 (adjusted odds ratio [AOR], 0.21 [95% CI, 0.06-0.78] and 0.19 [95% CI, 0.06-0.62], respectively) when sedation (AOR, 10.55 [95% CI, 2.28-48.87] and 4.62 [1.32-16.18], respectively) and low volume of enteral nutrition (AOR, 10.48 [95% CI, 2.48-44.29] and 7.28 [95% CI, 2.03-26.18], respectively) was associated with an increased risk. Skin-to-skin practice was associated with a decreased risk of being in cluster 5 (AOR, 0.14 [95% CI, 0.04-0.48]). Moreover, clusters 4, 5, 6 were significantly associated with 2-year nonoptimal outcome (AOR, 6.17 [95% CI, 1.46-26.0]; AOR, 4.53 [95% CI, 1.02-20.1]; and AOR, 5.42 [95% CI, 1.36-21.6], respectively). Conclusions and Relevance Gut microbiota of very preterm newborns at week 4 is associated with NICU practices and 2-year outcomes. Microbiota could be a noninvasive biomarker of immaturity., This cohort study of 577 very preterm newborns across 24 neonatal intensive care units from a French nationwide cohort investigates associations among practice strategies, gut microbiota, and outcomes at 2 years.

Published
2020

21. Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer

Author

Julien Schmidt, Ludovic Lacroix, Atmane Seck, Aurore Vozy, Patrick Saulnier, Jonathan Grivel, Nathalie Chaput, Jean Mehdi Jouniaux, Ester Simeone, Franck Carbonnel, Paolo A. Ascierto, Laetitia Nebot-Bral, M. Naigeon, Domenico Mallardo, L. Boselli, Paul Louis Woerther, Caroline Robert, Lydie Cassard, Patricia Lepage, Angelo Paci, Clélia Coutzac, Mélanie Desbois, Christine Mateus, V. Asvatourian, Emilie Soularue, Micalis Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France, Laboratoire d’Immunomonitoring en Oncologie (LIO), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), 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), Faculté de Médecine Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Institut Gustave Roussy (IGR), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, IRCCS Istituto Nazionale dei Tumori [Milano], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Instituto Nazionale Tumori-Fondazione 'G. Pascale', Direction de la recherche [Gustave Roussy], Fondation Gustave Roussy Direction Générale de l’offre de Soins, DGOS: TRANSLA 12-174 Institut National de la Santé et de la Recherche Médicale, Inserm Centre National de la Recherche Scientifique, CNRS: INCa-DGOS-INSERM_12551, ANR-10IBHU-0001 Fondation Gustave Roussy Institut National Du Cancer, INCa: 2012-1-RT-14-IGR-01 Fondation pour la Recherche Médicale, FRM AstraZeneca Sanofi GlaxoSmithKline Australia, GSK, The authors thank Dr. Patrick Gonin from the PlatForm for Preclinical Evaluation (PFEP). Fundings: This study was funded by Gustave Roussy Cancer Campus, Fondation Gustave Roussy, the Institut national de la santé et de la recherche médicale (INSERM), the Centre national de la recherche scientifique (CNRS), SIRIC SOCRATE (INCa DGOS INSERM 6043), SIRIC SOCRATE 2.0 (INCa-DGOS-INSERM_12551), MMO program: ANR-10IBHU-0001), Direction General de l’Offre de Soins (DGOS, TRANSLA 12-174), Institut National du Cancer (INCa, 2012-062 N_ Canceropole: 2012-1-RT-14-IGR-01). Dr. Clélia Coutzac was supported by fellowships from Fondation pour la Recherche Medicale (FRM) from 2015 to 2016., N.C. reports research grants from Cytune Pharma, GSK, Sanofi, has participated in advisory boards for AstraZeneca and has been a speaker for Sanofi and AstraZeneca. C.R. has participated in advisory boards for Roche, GSK, Merck, Novartis, Amgen, BMS and Novartis. Franck Carbonnel received boards or lecture fees from enterome, Amgen, Astra, MSD, BMS, Janssen, Pfizer, Abbvie, Mayoly Spindler, Takeda, Pileje, Roche. E. Soularue has participated in advisory board for Novartis. L.L. has participated in advisory boards for Roche, Astrazeneca, BMS, Genomic Health, Illumina, Qiagen, Novartis Thermofisher and has been a speaker for Amgen, AstraZeneca, Dyn, Vela diagnostics, Luye Pharma, and Roche. P.A.A. has/had a consultant/advisory role for Bristol Myers-Squibb, Roche-Genentech, Merck Sharp & Dohme, Array, Novartis, Amgen, Merck Serono, Pierre Fabre, Incyte, NewLink Genetics, Genmab, Medimmune, AstraZeneca, Syndax, SunPharma, Sanofi, Idera. He also received Research funds from Bristol Myers-Squibb, Roche-Genentech, Array. The other authors have no conflicts of interest to declare., and ANR-10-IBHU-0001,MMO (IHU-CANCER),Institut de Médecine Personnalisée du Cancer(2010)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], T-Lymphocytes, medicine.medical_treatment, General Physics and Astronomy, Pharmacology, Gut flora, T-Lymphocytes, Regulatory, Immune tolerance, Tumour biomarkers, Mice, 0302 clinical medicine, Neoplasms, RNA, Ribosomal, 16S, CTLA-4 Antigen, lcsh:Science, Cancer, Mice, Inbred BALB C, Multidisciplinary, biology, Chemistry, hemic and immune systems, 3. Good health, Butyrates, 030220 oncology & carcinogenesis, B7-1 Antigen, Science, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, chemical and pharmacologic phenomena, Butyrate, digestive system, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immune system, Biomarkers, Tumor, medicine, Animals, Humans, CD86, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Dendritic Cells, General Chemistry, Immunotherapy, Fatty Acids, Volatile, biology.organism_classification, Ipilimumab, Gastrointestinal Microbiome, 030104 developmental biology, CTLA-4, lcsh:Q, B7-2 Antigen, Propionates, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Biomarkers, CD80
Abstract

Gut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity., The gut microbiota has been reported to regulate the efficacy of cancer therapy. Here, the authors show that short-chain fatty acids, which are generated through bacterial fermentation, increases immune tolerance leading to resistance to anti-CTLA-4 immunotherapy in mice and patients with metastatic melanoma.

Published
2020

22. Nutritional strategies and gut microbiota composition as risk factors for necrotizing enterocolitis in very-preterm infants

Author

Jean-Christophe Rozé, Pierre-Yves Ancel, Patricia Lepage, Laetitia Martin-Marchand, Ziad Al Nabhani, Johanne Delannoy, Jean-Charles Picaud, Alexandre Lapillonne, Julio Aires, Mélanie Durox, Dominique Darmaun, Josef Neu, Marie-José Butel, Farid Boudred, Delphine Mitanchez, Charlotte Casper, Valerie Biran, Laurent Storme, Olivier Claris, Gilles Cambonie, Jacques Sizun, Anne Sauret, Odile Dicky, Emmanuel Lopez, Jean-Michel Hascoet, Geraldine Gascoin, Rachel Vieux, Blandine de Lauzon, Luc Desfrere, Clement Chollat, Marie-Jose Butel, Clotilde Rousseau, Joel Doré, Karine Le Roux, Céline Monot, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), AP-HP Hôpitaux Universitaires Paris Centre, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Ecosystème intestinal, probiotiques, antibiotiques (EA 4065), Department of Neonatal Medicine, University Hospital, Paris Descartes Univ, Risks Pregnancy Dept, Paris, France, Partenaires INRAE, Paris Descartes Univ, EA Intestinal Ecosyst Probiot Antibiot 4065, Fac Pharm, Paris, France, University of Florida [Gainesville] (UF), French Institute of Public Health Research/Institute of Public Health, French Health Ministry, NIH and Medical Research, National Institute of Cancer, National Solidarity Fund for Autonomy, National Research Agency [ANR-11-EQPX-0038, ANR-12-SV, ANR-12-BSV3-0025001/EPIFLORE], PremUp Foundation, and Nestec Research Center (Vers-chez-les-Blanc, Switzerland)

Subjects
Time Factors, Neonatal intensive care unit, breastfeeding, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), Enteral administration, Gastroenterology, 0302 clinical medicine, Risk Factors, RNA, Ribosomal, 16S, Odds Ratio, Prospective Studies, 030212 general & internal medicine, speed of increasing enteral nutrition, 2. Zero hunger, Enterocolitis, education.field_of_study, Nutrition and Dietetics, Infant Formula, 3. Good health, Breast Feeding, Necrotizing enterocolitis, France, medicine.symptom, clostridia, Infant, Premature, Staphylococcus aureus, medicine.medical_specialty, Population, preterm infant, 03 medical and health sciences, Enteral Nutrition, Enterocolitis, Necrotizing, Intensive Care Units, Neonatal, 030225 pediatrics, Intensive care, Internal medicine, medicine, Humans, education, Clostridium, necrotizing enterocolitis, Bacteria, Milk, Human, business.industry, Infant, Newborn, Editorials, medicine.disease, digestive system diseases, Gastrointestinal Microbiome, Parenteral nutrition, Case-Control Studies, Intensive Care, Neonatal, business, Breast feeding
Abstract

International audience; Background: The pathophysiology of necrotizing enterocolitis (NEC) remains poorly understood. Objective: We assessed the relation between feeding strategies, intestinal microbiota composition, and the development of NEC. Design: We performed a prospective nationwide population-based study, EPIPAGE 2 (Etude Epidemiologique sur les Petits Ages Ges-tationnels), including preterm infants born at,32 wk of gestation in France in 2011. From individual characteristics observed during the first week of life, we calculated a propensity score for the risk of NEC (Bell's stage 2 or 3) after day 7 of life. We analyzed the relation between neonatal intensive care unit (NICU) strategies concerning the rate of progression of enteral feeding, the direct-breastfeeding policy, and the onset of NEC using general linear mixed models to account for clustering by the NICU. An ancillary propensitymatched case-control study, EPIFLORE (Etude Epidemiologique de la flore), in 20 of the 64 NICUs, analyzed the intestinal microbiota by culture and 16S ribosomal RNA gene sequencing. Results: Among the 3161 enrolled preterm infants, 106 (3.4%; 95% CI: 2.8%, 4.0%) developed NEC. Individual characteristics were significantly associated with NEC. Slower and intermediate rates of progression of enteral feeding strategies were associated with a higher risk of NEC, with an adjusted OR of 2.3 (95% CI: 1.2, 4.5; P = 0.01) and 2.0 (95% CI: 1.1, 3.5; P = 0.02), respectively. Less favorable and intermediate direct-breastfeeding policies were associated with higher NEC risk as well, with an adjusted OR of 2.5 (95% CI: 1.1, 5.8; P = 0.03) and 2.3 (95% CI: 1.1, 4.8; P = 0.02), respectively. Microbiota analysis performed in 16 cases and 78 controls showed an association between Clostridium neonatale and Staphylococcus aureus with NEC (P = 0.001 and P = 0.002). Conclusions: A slow rate of progression of enteral feeding and a less favorable direct-breastfeeding policy are associated with an increased risk of developing NEC. For a given level of risk assessed by propensity score, colonization by C. neonatale and/or S. aureus is significantly associated with NEC. This trial (EPIFLORE study) was registered at clinicaltrials.gov as NCT01127698.

Published
2017

23. Mucosal healing progression after acute colitis in mice

Author

Anne Blais, Sandra Vidal-Lletjós, François Blachier, Anne-Marie Davila, Mireille Andriamihaja, Claire Gaudichon, Patricia Lepage, Marta Grauso, Marion Leclerc, Annaïg Lan, Physiologie de la Nutrition et du Comportement Alimentaire (PNCA), AgroParisTech-Institut National de la Recherche Agronomique (INRA), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, SocieteFrancaise de Nutrition, Association Francois Aupetit, and INRA-Universite Paris-Saclay (ALIAS program)

Subjects
Male, Pathology, medicine.medical_specialty, Colon, Context (language use), Inflammation, Permeability, Acute colitis, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, RNA, Ribosomal, 16S, medicine, Animals, Humans, Regeneration, Intestinal Mucosa, Colitis, Barrier function, Cell Proliferation, Dextran sodium sulfate-induced colitis, Goblet cell, business.industry, Dextran Sulfate, Gastroenterology, Interleukin, General Medicine, Basic Study, medicine.disease, Gastrointestinal Microbiome, Colon luminal environment, 3. Good health, Mice, Inbred C57BL, Disease Models, Animal, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Dysbiosis, Colitis, Ulcerative, 030211 gastroenterology & hepatology, Epithelial repair, Inflammation Mediators, medicine.symptom, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

International audience; BACKGROUNDMucosal healing has become a therapeutic goal to achieve stable remission in patients with inflammatory bowel diseases. To achieve this objective, overlapping actions of complex cellular processes, such as migration, proliferation, and differentiation, are required. These events are longitudinally and tightly controlled by numerous factors including a wide range of distinct regulatory proteins. However, the sequence of events associated with colon mucosal repair after colitis and the evolution of the luminal content characteristics during this process have been little studied.AIMTo document the evolution of colon mucosal characteristics during mucosal healing using a mouse model with chemically-induced colitis.METHODSC57BL/6 male mice were given 3.5% dextran sodium sulfate (DSS) in drinking water for 5 d. They were euthanized 2 (day 7), 5 (day 10), 8 (day 13), and 23 (day 28) d after DSS removal. The colonic luminal environment and epithelial repair processes during the inflammatory flare and colitis resolution were analyzed with reference to a non-DSS treated control group, euthanized at day 0. Epithelial repair events were assessed histo-morphologically in combination with functional permeability tests, expression of key inflammatory and repairing factors, and evaluation of colon mucosa-adherent microbiota composition by 16S rRNA sequencing.RESULTSThe maximal intensity of colitis was concomitant with maximal alterations of intestinal barrier function and histological damage associated with goblet cell depletion in colon mucosa. It was recorded 2 d after termination of the DSS-treatment, followed by a progressive return to values similar to those of control mice. Although signs of colitis were severe (inflammatory cell infiltrate, crypt disarray, increased permeability) and associated with colonic luminal alterations (hyperosmolarity, dysbiosis, decrease in short-chain fatty acid content), epithelial healing processes were launched early during the inflammatory flare with increased gene expression of certain key epithelial repair modulators, including transforming growth factor-β, interleukin (Il)-15, Il-22, Il-33, and serum amyloid A. Whereas signs of inflammation progressively diminished, luminal colonic environment alterations and microscopic abnormalities of colon mucosa persisted long after colitis induction.CONCLUSIONThis study shows that colon repair can be initiated in the context of inflamed mucosa associated with alterations of the luminal environment and highlights the longitudinal involvement of key modulators.

Published
2019

24. A Guide for Ex Vivo Handling and storage of stool samples Intended for Fecal Microbiota transplantation

Author

Florence Levenez, Stéphanie Cenard, Anne-Laure Abraham, Audrey Chapron, Orlane Patrascu, Hervé M. Blottière, Joël Doré, Patricia Lepage, Fabienne Béguet-Crespel, Catherine Juste, Christel Béra-Maillet, Karine Le Roux, Olivier David, Fernanda Fonseca, Sebastian D. Burz, Carole Schwintner, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Génie et Microbiologie des Procédés Alimentaires (GMPA), MaaT Pharma [Lyon], Ile-de-France region (AIMA A1410003 Z), and from AAP Prematuration Idex, Paris-Saclay University (funding agreement 2015-04491)., ANR-15-CE14-0021,FunAMetaGen,Analyse fonctionnelle d'espèces métagénomiques présélectionnées comme étant potentiellement prédictives de la progression de la NAFLD, pour une meilleure prise en charge médicale des patients(2015), MaaT Pharma, ANR-15-CE14-0021,FunAMetaGen,Analyse fonctionnelle d’espèces métagénomiques présélectionnées comme étant potentiellement prédictives de la progression de la NAFLD, pour une meilleure prise en charge médicale des patients(2015), and Juste, Catherine

Subjects
0301 basic medicine, Cryoprotectant, Science, [SDV]Life Sciences [q-bio], Observation period, Guidelines as Topic, Biologics, Biology, Article, Specimen Handling, Feces, 03 medical and health sciences, Human health, Cryoprotective Agents, 0302 clinical medicine, Polysaccharides, Humans, Food science, Clinical microbiology, Multidisciplinary, Trehalose, Fecal bacteriotherapy, Fecal Microbiota Transplantation, 3. Good health, 030104 developmental biology, Medicine, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, Ex vivo
Abstract

Owing to the growing recognition of the gut microbiota as a main partner of human health, we are expecting that the number of indications for fecal microbiota transplantation (FMT) will increase. Thus, there is an urgent need for standardization of the entire process of fecal transplant production. This study provides a complete standardized procedure to prepare and store live and ready-to-use transplants that meet the standard requirements of good practices to applied use in pharmaceutical industry. We show that, if time before transformation to transplants would exceed 24hours, fresh samples should not be exposed to temperatures above 20°C, and refrigeration at 4°C can be a safe solution. Oxygen-free atmosphere was not necessary and simply removing air above collected samples was sufcient to preserve viability. Transplants prepared in maltodextrin-trehalose solutions, stored in a -80°C standard freezer and then rapidly thawed at 37°C, retained the best revivifcation potential as proven by 16S rRNA profles, metabolomic fngerprints, and fow cytometry assays over a 3-month observation period. Maltodextrin-trehalose containing cryoprotectants were also efcient in preserving viability of lyophilized transplants, either in their crude or purifed form, an option that can be attractive for fecal transplant biobanking and oral formulation. Te human intestinal microbiota ensures several essential functions that support maintenance of health and well-being. One of them is the prevention of colonization with allochtonous microbes including pathogens, also known as barrier efect or competitive exclusion. Tis is dependent on the maintenance of ecological homeostasis of the gut ecosystem1 . Another well-established function of the intestinal microbiota is its contribution to immune maturation and maintenance of a balanced immune tolerance and reactivity. It is mediated by a constant and intimate crosstalk between intestinal microbiota and the gut associated lymphoid tissues2 . Here again, a balanced microbiota-host crosstalk is dependent on the maintenance of ecological homeostasis of the gut ecosystem. In healthy adults, microbiota composition is individual specifc and for a given person, it remains fairly stable over time3 . Upon mild stress such as exposure to specifc nutrients or diverse conditions of modern daily life or clinical practices, including antibiotics, the intestinal microbiota can be temporarily altered but will eventually return to its original composition; it is resilient4 . Nonetheless, marked alterations of dietary habits, environmental exposures, drug therapy or surgical interventions will induce alterations of the intestinal microbiota that may exceed the resilience capacity5,6 and lead to onset of dysbiosis, i.e. distorted intestinal microbiota composition. Dysbiosis is now acknowledged as a common feature of numerous non-infectious diseases of modern societies, which have had a constant increase in incidence since the middle of the past century. Obesity is one of these

Published
2019

25. Gut bacteria are critical for optimal muscle function: a potential link with glucose homeostasis

Author

Kevin Nay, Maxence Jollet, Frédéric Derbré, Vincent Ollendorff, Christelle Koechlin-Ramonatxo, Luz Lefeuvre-Orfila, Anne Bonnieu, Bénédicte Goustard, Barbara Vernus, Mahendra Mariadassou, Claude Bendavid, Olivier Rué, Patricia Lepage, Maria Pontones, Narjes Baati, Dynamique Musculaire et Métabolisme (DMEM), Institut National de la Recherche Agronomique (INRA)-Université de Montpellier (UM), Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de la Recherche Agronomique (INRA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Institut National de la Recherche Agronomique (INRA), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Laboratoire Mouvement Sport Santé (M2S), Université de Rennes (UR)-École normale supérieure - Rennes (ENS Rennes)-Université de Brest (UBO)-Université de Rennes 2 (UR2)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Conseil Régional de Bretagne, Centre National d’Etudes Spatiales, INRA-Département AlimH, Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA), École normale supérieure - Cachan (ENS Cachan)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Brest (UBO)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Jonchère, Laurent

Subjects
0301 basic medicine, Male, mitochondrial biogenesis, Physiology, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Gut flora, chemistry.chemical_compound, Mice, 0302 clinical medicine, Glucose homeostasis, Homeostasis, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, biology, Glycogen, dysbiosis, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Anti-Bacterial Agents, medicine.anatomical_structure, muscle fatigue, medicine.symptom, maximal aerobic velocity, Muscle Contraction, medicine.medical_specialty, 030209 endocrinology & metabolism, Inflammation, digestive system, Extensor digitorum longus muscle, 03 medical and health sciences, Physiology (medical), Internal medicine, medicine, Animals, Muscle, Skeletal, Muscle fatigue, Skeletal muscle, biology.organism_classification, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Gastrointestinal Microbiome, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Glucose, chemistry, contractile properties, Energy Metabolism, Dysbiosis, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

International audience; Gut microbiota is involved in the development of several chronic diseases, including diabetes, obesity, and cancer, through its interactions with the host organs. It has been suggested that the cross talk between gut microbiota and skeletal muscle plays a role in different pathological conditions, such as intestinal chronic inflammation and cachexia. However, it remains unclear whether gut microbiota directly influences skeletal muscle function. In this work, we studied the impact of gut microbiota modulation on mice skeletal muscle function and investigated the underlying mechanisms. We determined the consequences of gut microbiota depletion after treatment with a mixture of a broad spectrum of antibiotics for 21 days and after 10 days of natural reseeding. We found that, in gut microbiota-depleted mice, running endurance was decreased, as well as the extensor digitorum longus muscle fatigue index in an ex vivo contractile test. Importantly, the muscle endurance capacity was efficiently normalized by natural reseeding. These endurance changes were not related to variation in muscle mass, fiber typology, or mitochondrial function. However, several pertinent glucose metabolism markers, such as ileum gene expression of short fatty acid chain and glucose transporters G protein-coupled receptor 41 and sodium-glucose cotransporter 1 and muscle glycogen level, paralleled the muscle endurance changes observed after treatment with antibiotics for 21 days and reseeding. Because glycogen is a key energetic substrate for prolonged exercise, modulating its muscle availability via gut microbiota represents one potent mechanism that can contribute to the gut microbiota-skeletal muscle axis. Taken together, our results strongly support the hypothesis that gut bacteria are required for host optimal skeletal muscle function.

Published
2019

26. Synergistic convergence of microbiota-specific systemic IgG and secretory IgA

Author

Pascale Ghillani-Dalbin, Lionel Galicier, Claire Fieschi, Hela El Kafsi, Martin Larsen, Karim Dorgham, Patricia Lepage, Jehane Fadlallah, David Boutboul, Makoto Miyara, Christophe Parizot, Guy Gorochov, Christophe Tresallet, Gaëlle Autaa, Marion Malphettes, Hans Yssel, Alexis Mathian, Sébastien André, Karine Clément, Catherine Juste, Zahir Amoura, Delphine Sterlin, Eric Oksenhendler, Florian Marquet, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'immunologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Service d'immunologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris Diderot - Paris 7 (UPD7), CHU Saint Louis [APHP], MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Institut National de la Recherche Agronomique (INRA), Service de nutrition [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [APHP], Service d'Immunologie [CHU Pitié-Salpétrière], 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Gestionnaire, Hal Sorbonne Université, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]

Subjects
0301 basic medicine, Immunology, Inflammation, Gut microbiota, Gut flora, Selective IgA deficiency, Systemic inflammation, anticommensal IgG, 03 medical and health sciences, Feces, 0302 clinical medicine, Western blot, intravenous immunoglobulin, medicine, Immunology and Allergy, Humans, biology, medicine.diagnostic_test, Common variable immunodeficiency, common variable immunodeficiency, biology.organism_classification, medicine.disease, Antibodies, Bacterial, 3. Good health, Gastrointestinal Microbiome, 030104 developmental biology, secretory IgA, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, Immunoglobulin G, Immunoglobulin A, Secretory, biology.protein, IgA deficiency, medicine.symptom, Antibody
Abstract

International audience; BACKGROUND: Commensals induce local IgA responses essential to the induction of tolerance to gut microbiota, but it remains unclear whether antimicrobiota responses remain confined to the gut.OBJECTIVE: The aim of this study was to investigate systemic and intestinal responses against the whole microbiota under homeostatic conditions and in the absence of IgA.METHODS: We analyzed blood and feces from healthy donors, patients with selective IgA deficiency (SIgAd), and patients with common variable immunodeficiency (CVID). Immunoglobulin-coated bacterial repertoires were analyzed by using combined bacterial fluorescence-activated cell sorting and 16S rRNA sequencing. Bacterial lysates were probed by using Western blot analysis with healthy donor sera.RESULTS: Although absent from the healthy gut, serum antimicrobiota IgG are present in healthy subjects and increased in patients with SIgAd. IgG converges with nonoverlapping secretory IgA specificities to target the same bacteria. Each individual subject targets a diverse microbiota repertoire with a proportion that correlates inversely with systemic inflammation. Finally, intravenous immunoglobulin preparations target CVID gut microbiota much less efficiently than healthy microbiota.CONCLUSION: Secretory IgA and systemic IgG converge to target gut microbiota at the cellular level. SIgAd-associated inflammation is inversely correlated with systemic anticommensal IgG responses, which might serve as a second line of defense. We speculate that patients with SIgAd could benefit from oral IgA supplementation. Our data also suggest that intravenous immunoglobulin preparations can be supplemented with IgG from IgA-deficient patient pools to offer better protection against gut bacterial translocations in patients with CVID.

Published
2019

27. Dietary Protein Intake Level Modulates Mucosal Healing and Mucosa-Adherent Microbiota in Mouse Model of Colitis

Author

Marta Grauso, Patricia Lepage, Roselyne Viel, Marion Leclerc, François Blachier, Mireille Andriamihaja, Claire Gaudichon, Sandra Vidal-Lletjós, Annaïg Lan, Anne Blais, Anne-Marie Davila, Physiologie de la Nutrition et du Comportement Alimentaire (PNCA), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de Recherche Agronomique - AgroParisTech, Societe Francaise de Nutrition, Association Francois Aupetit, INRA-Universite Paris-Saclay (ALIAS program), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and AgroParisTech-Institut National de la Recherche Agronomique (INRA)

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, colitis, [SDV]Life Sciences [q-bio], epithelial repair, Inflammation, lcsh:TX341-641, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Inflammation resolution, dietary protein level, mucosa-adherent microbiota, Internal medicine, Animals, Medicine, Intestinal Mucosa, Colitis, Beneficial effects, 2. Zero hunger, 030109 nutrition & dietetics, Nutrition and Dietetics, business.industry, medicine.disease, Animal Feed, Diet, Gastrointestinal Microbiome, 3. Good health, Mice, Inbred C57BL, Disease Models, Animal, Dietary protein, Endocrinology, Mucosal healing, 030211 gastroenterology & hepatology, Dietary Proteins, medicine.symptom, business, lcsh:Nutrition. Foods and food supply, Dietary protein intake, Microbiota composition, Food Science
Abstract

International audience; Mucosal healing after an inflammatory flare is associated with lasting clinical remission. The aim of the present work was to evaluate the impact of the amount of dietary protein on epithelial repair after an acute inflammatory episode. C57BL/6 DSS-treated mice received isocaloric diets with different levels of dietary protein 14% (P14), 30% (P30) and 53% (P53) for 3 (day 10), 6 (day 13) and 21 (day 28) days after the time of colitis maximal intensity. While the P53 diet worsened the DSS- induced inflammation both in intensity and duration, the P30 diet, when compared to the P14 diet, showed a beneficial effect during the epithelial repair process by accelerating inflammation resolution, reducing colonic permeability and increasing epithelial repair together with epithelial hyperproliferation. Dietary protein intake also impacted mucosa-adherent microbiota composition after inflammation since P30 fed mice showed increased colonization of butyrate-producing genera throughout the resolution phase. This study revealed that in our colitis model, the amount of protein in the diet modulated mucosal healing, with beneficial effects of a moderately high-protein diet, while very high-protein diet displayed deleterious effects on this process.

Published
2019

28. Perturbed Microbiota/Immune Homeostasis in Multiple Sclerosis

Author

Catherine Juste, Catherine Lubetzki, Marina Vignes, Gaëlle Autaa, Romain Deschamps, Jennifer Aboab, Caroline Papeix, Christophe Parizot, Patricia Lepage, Karim Dorgham, Jehane Fadlallah, Savine Vicart, Guy Gorochov, Delphine Sterlin, Martin Larsen, Olivier Gout, Elisabeth Maillart, HAL-SU, Gestionnaire, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Fondation Ophtalmologique Adolphe de Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-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 d'Immunologie et de Maladies Infectieuses (CIMI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Adult, Male, Multiple Sclerosis, Adolescent, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Context (language use), Gut flora, digestive system, Article, Flow cytometry, Young Adult, 03 medical and health sciences, Multiple Sclerosis, Relapsing-Remitting, 0302 clinical medicine, Immune system, Immunity, RNA, Ribosomal, 16S, medicine, Homeostasis, Humans, 030304 developmental biology, 0303 health sciences, biology, medicine.diagnostic_test, business.industry, Microbiota, Multiple sclerosis, Patient Acuity, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Middle Aged, medicine.disease, biology.organism_classification, Commensalism, Gastrointestinal Microbiome, Immunoglobulin A, 3. Good health, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Neurology, Immunoglobulin G, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Immunology, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Bacteria
Abstract

ObjectiveBased on animal models and human studies, there is now strong suspicion that host/microbiota mutualism in the context of gut microbial dysbiosis could influence immunity and multiple sclerosis (MS) evolution. Our goal was to seek evidence of deregulated microbiota-induced systemic immune responses in patients with MS.MethodsWe investigated gut and systemic commensal-specific antibody responses in healthy controls (n = 32), patients with relapsing-remitting MS (n = 30), and individuals with clinically isolated syndromes (CISs) (n = 15). Gut microbiota composition and diversity were compared between controls and patients by analysis of 16S ribosomal ribonucleic acid (rRNA) sequencing. Autologous microbiota and cultivable bacterial strains were used in bacterial flow cytometry assays to quantify autologous serum IgG and secretory IgA responses to microbiota. IgG-bound bacteria were sorted by flow cytometry and identified using 16S rRNA sequencing.ResultsWe show that commensal-specific gut IgA responses are drastically reduced in patients with severe MS, disease severity being correlated with the IgA-coated fecal microbiota fraction (r = −0.647, p < 0.0001). At the same time, IgA-unbound bacteria elicit qualitatively broad and quantitatively increased serum IgG responses in patients with MS and CIS compared with controls (4.1% and 2.5% vs 1.9%, respectively, p < 0.001).ConclusionsGut and systemic microbiota/immune homeostasis are perturbed in MS. Our results argue that defective IgA responses in MS are linked to a breakdown of systemic tolerance to gut microbiota leading to an enhanced triggering of systemic IgG immunity against gut commensals occurring early in MS.

Published
2021

29. Nod2Deficiency Leads to a Specific and Transmissible Mucosa-associated Microbial Dysbiosis Which Is Independent of the Mucosal Barrier Defect

Author

Patricia Lepage, Jean-Pierre Hugot, Nicolas Montcuquet, Karine Le Roux, Frédérick Barreau, Ziad Al Nabhani, Dominique Berrebi, Maryline Roy, Monique Dussaillant, and Pascal Mauny

Subjects
0301 basic medicine, Nod2 Signaling Adaptor Protein, Biology, Real-Time Polymerase Chain Reaction, Microbiology, Mice, Peyer's Patches, 03 medical and health sciences, Immune system, Intestinal mucosa, RNA, Ribosomal, 16S, NOD2, medicine, Animals, Intestinal Mucosa, Barrier function, Mice, Knockout, Intestinal permeability, Mucin, Mucins, Gastroenterology, Peyer's patch, General Medicine, medicine.disease, digestive system diseases, Gastrointestinal Microbiome, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Dysbiosis, Female, Antimicrobial Cationic Peptides
Abstract

Background and Aims: Crohn’s disease [CD] is a complex disorder characterised by an inappropriate immune response, impaired barrier function and microbial dysbiosis. Mutations in nucleotide oligomeriation domain 2 [ NOD2 ] are CD risk factors. Increase of intestinal permeability, CD4+ T cell infiltration, and bacterial dysbiosis are also seen in Nod2 -knockout [ Nod2 KO] mice. However, the specificity and relationship between these Nod2 -associated abnormalities remain largely unexplored. Methods: Wild-type [WT], Nod1 -knockout [ Nod1 KO] and Nod2 KO mice were analysed in parallel. Microbial composition was defined by 454-pyrosequencing of bacterial 16S rRNA genes. Mucin and antimicrobial peptide expression was assessed by RT-PCR. Cell populations from Peyer’s patches were determined by flow cytometry. Ussing chambers were used to measure intestinal permeability and bacterial translocation. Finally, to explore the impact of colonisation with mother’s microbiota at birth, analyses were also performed in Nod2 KO and WT mice born from WT surrogate mothers after embryo transfer. Results: Nod2 KO mice exhibited colonic bacterial dysbiosis different from WT and Nod1 KO mice. Altered expression of antimicrobial peptides and mucins in ileum and colon was associated with the microbial composition. Bacterial composition of Nod2 KO and WT mice obtained by embryo transfer was similar to that observed in Nod2 KO mice, arguing for a dominant effect of Nod2 KO-associated dysbiosis. In contrast, increased levels of CD4+ T cells and gut barrier defects across Peyer’s patches were specific to Nod2 deficiency and independent of Microbial dysbiosis. Conclusions: Nod2 deficiency is associated with a specific dominant dysbiosis which does not drive mucosal tissue and immune alterations.

Published
2016

30. Multi-hit early life adversity affects gut microbiota, brain and behavior in a sex-dependent manner

Author

Julien Chevalier, Jean Christophe Helbling, Patricia Lepage, Élodie Lévy, Pierre-Antoine Grohard, Marion Leboyer, Lilian Basso, Marion Rincel, Gérard Eberl, Muriel Darnaudéry, Hélène Boudin, Camille Monchaux de Oliveira, Sophie Layé, Nathalie Vergnolle, Michel Neunlist, Philippe Aubert, Lucile Capuron, Grégoire Chevalier, Nutrition et Neurobiologie intégrée (NutriNeuro), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Microenvironnement et Immunité - Microenvironment and Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Est Créteil, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, University of Bordeaux, INRA, AVIESAN Immunology, Hematology and Pneumology, French Ministry of Research, Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1 (UB)-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique, The Enteric Nervous System in gut and brain disorders [U1235] (TENS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Lipopolysaccharides, Male, MESH: Maternal Deprivation, Physiology, Gut flora, Anxiety, MESH: Animals, Newborn, Marble burying, Behavioral Neuroscience, Mice, 0302 clinical medicine, MESH: Behavior, Animal, MESH: Animals, Mice, Inbred C3H, biology, Behavior, Animal, Maternal Deprivation, Microbiota, Brain, MESH: Stress, Psychological, Compulsive behavior, Female, medicine.symptom, Gut-brain axis, Emotional behavior, MESH: Social Behavior, Elevated plus maze, Offspring, Immunology, Gut–brain axis, Prefrontal Cortex, Intestinal permeability, MESH: Gastrointestinal Microbiome, 03 medical and health sciences, MESH: Brain, Sex Factors, MESH: Sex Factors, medicine, MESH: Microbiota, Animals, Early-life stress, MESH: Mice, Inbred C3H, Social Behavior, MESH: Mice, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, MESH: Anxiety, Endocrine and Autonomic Systems, HPA axis, [SCCO.NEUR]Cognitive science/Neuroscience, Lachnospiraceae, Ultrasonic vocalizations, biology.organism_classification, medicine.disease, Medial prefrontal cortex, MESH: Male, Gastrointestinal Microbiome, 030104 developmental biology, MESH: Dysbiosis, Animals, Newborn, Dysbiosis, MESH: Prefrontal Cortex, MESH: Female, 030217 neurology & neurosurgery, Stress, Psychological
Abstract

International audience; The accumulation of adverse events in utero and during childhood differentially increases the vulnerability to psychiatric diseases in men and women. Gut microbiota is highly sensitive to the early environment and has been recently hypothesized to affect brain development. However, the impact of early-life adversity on gut microbiota, notably with regards to sex differences, remains to be explored. We examined the effects of multifactorial early-life adversity on behavior and microbiota composition in C3H/HeN mice of both sexes exposed to a combination of maternal immune activation (lipopolysaccharide injection on embryonic day 17, 120 μg/kg, i.p.), maternal separation (3hr per day from postnatal day (PND)2 to PND14) and maternal unpredictable chronic mild stress. At adulthood, offspring exposed to multi-hit early adversity showed sex-specific behavioral phenotypes with males exhibiting deficits in social behavior and females showing increased anxiety in the elevated plus maze and increased compulsive behavior in the marble burying test. Early adversity also differentially regulated gene expression in the medial prefrontal cortex (mPFC) according to sex. Interestingly, several genes such as Arc, Btg2, Fosb, Egr4 or Klf2 were oppositely regulated by early adversity in males versus females. Finally, 16S-based microbiota profiling revealed sex-dependent gut dysbiosis. In males, abundance of taxa belonging to Lachnospiraceae and Porphyromonadaceae families or other unclassified Firmicutes, but also Bacteroides, Lactobacillus and Alloprevotella genera was regulated by early adversity. In females, the effects of early adversity were limited and mainly restricted to Lactobacillus and Mucispirillum genera. Our work reveals marked sex differences in a multifactorial model of early-life adversity, both on emotional behaviors and gut microbiota, suggesting that sex should systematically be considered in preclinical studies both in neurogastroenterology and psychiatric research.

Published
2018

31. The gut microbiota drives the impact of bile acids and fat source in diet on mouse metabolism

Author

Patricia Lepage, Valentin Bieth, Katrin Wegner, Eva Rath, Dirk Haller, Geneviève Héry-Arnaud, Josef Ecker, Sarah Just, Thomas Hofmann, Sinah Schmidt, Theresa Streidl, Andreas Dunkel, Till Robin Lesker, Laura Gau, Till Strowig, Stanislas Mondot, Philippe Gérard, Thomas Clavel, Sascha Rohn, Gerhard Liebisch, ZIEL–Institute for Food and Health, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris-Saclay, Nutritional Physiology, Institute of Food Chemistry, Hamburg School of Food Science, University of Hamburg, Nutrition and Immunology, Institute of Medical Microbiology, Functional Microbiome Research Group, University Hospital RWTH Aachen, Food Chemistry and Molecular and Sensory Science, Research Group Microbial Immune Regulation, Helmholtz Centre for Infection Research (HZI), Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Jena, ANR CoriFunc, German Research Foundation (joint DFG/ANR initiative) [CL481/1-1, RO3477/9-1], French National Research Agency [ANR-13-ISV3-0008-04], Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany., Technical University of Munich (TUM), Lepage, Patricia, and Clavel, Thomas

Subjects
Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Enteroendocrine cell, Palm Oil, Gut flora, Mice, Cecum, RNA, Ribosomal, 16S, Amino Acids, 16S rRNA gene amplicon sequencing, Phylogeny, Metatranscriptomics, 2. Zero hunger, Diet-induced obesity, Fatty liver, ddc, 3. Good health, medicine.anatomical_structure, lcsh:QR100-130, DNA, Bacterial, Microbiology (medical), medicine.medical_specialty, Metabolic diseases, Gut microbiota, Germ-free mice, Bile acids, Dietary fat, Lard, Lipidomics, 030106 microbiology, Biology, Diet, High-Fat, DNA, Ribosomal, digestive system, Microbiology, lcsh:Microbial ecology, Bile Acids and Salts, 03 medical and health sciences, Internal medicine, medicine, Animals, Obesity, Bacteria, Gene Expression Profiling, Research, Lachnospiraceae, Metabolism, Lipid Metabolism, medicine.disease, biology.organism_classification, Dietary Fats, Gastrointestinal Microbiome, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology
Abstract

Background As the gut microbiota contributes to metabolic health, it is important to determine specific diet-microbiota interactions that influence host metabolism. Bile acids and dietary fat source can alter phenotypes of diet-induced obesity, but the interplay with intestinal microorganisms is unclear. Here, we investigated metabolic consequences of diets enriched in primary bile acids with or without addition of lard or palm oil, and studied gut microbiota structure and functions in mice. Results In combination with bile acids, dietary lard fed to male C57BL/6N mice for a period of 8 weeks enhanced fat mass accumulation in colonized, but not in germ-free mice when compared to palm oil. This was associated with impaired glucose tolerance, lower fasting insulin levels, lower counts of enteroendocrine cells, fatty liver, and elevated amounts of hepatic triglycerides, cholesteryl esters, and monounsaturated fatty acids. Lard- and bile acid-fed mice were characterized by shifts in dominant gut bacterial communities, including decreased relative abundances of Lachnospiraceae and increased occurrence of Desulfovibrionaceae and the species Clostridium lactatifermentans and Flintibacter butyricus. Metatranscriptomic analysis revealed shifts in microbial functions, including lipid and amino acid metabolism. Conclusions Caution is required when interpreting data from diet-induced obesity models due to varying effects of dietary fat source. Detrimental metabolic consequences of a diet enriched with lard and primary bile acids were dependent on microbial colonization of the host and were linked to hepatic lipid rearrangements and to alterations of dominant bacterial communities in the cecum. Electronic supplementary material The online version of this article (10.1186/s40168-018-0510-8) contains supplementary material, which is available to authorized users.

Published
2018

32. Microbial ecology perturbation in human IgA deficiency

Author

Lionel Galicier, Makoto Miyara, S. Dusko Ehrlich, Sean Kennedy, Zahir Amoura, Patricia Lepage, Martin Larsen, Jean-Paul Pais de Barros, Guy Gorochov, Doriane Gouas, Catherine Juste, Marion Malphettes, Delphine Sterlin, Jehane Fadlallah, Claire Fieschi, Alexis Mathian, Mathieu Almeida, David Boutboul, Nathalie Galleron, Florence Levenez, Joël Doré, Eric Oksenhendler, Nicolas Pons, Karim Dorgham, Gaëlle Autaa, Hela El Kafsi, Christophe Parizot, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Service d'immunologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), US 1367 MetaGénoPolis, Institut National de la Recherche Agronomique (INRA)-Département Microbiologie et Chaîne Alimentaire (MICA), Institut National de la Recherche Agronomique (INRA)-MetaGénoPolis (MGP), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Immunopathologie [Hôpital Saint-Louis, Paris], Université Paris Diderot - Paris 7 (UPD7)-CHU Saint Louis [APHP], Différenciation et progression tumorale des lymphocytes, École pratique des hautes études (EPHE)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine interne [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP], Immunologie clinique [CHU St-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), INRA US1367 MetaGenoPolis, King‘s College London, Service d'Immunologie [CHU Pitié-Salpétrière], 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), University of Maryland [College Park], University of Maryland System, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Universitaire d'Hématologie (IUH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Recherche clinique appliquée à l'hématologie (URP_3518), Université de Paris (UP), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Université Paris Cité (UPCité), université de Bourgogne, LNC, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Immunoglobulin A, Colonization, Lipopolysaccharide, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Human gut microbiome, Systemic inflammation, medicine.disease_cause, Autoimmunity, 03 medical and health sciences, chemistry.chemical_compound, Immune system, Microbial ecology, medicine, Humans, Homeostasis, Innate, Immunoglobulin-a, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, biology, Bacteria, Microbiota, T-cells, IgA Deficiency, General Medicine, 3. Good health, 030104 developmental biology, chemistry, Immunoglobulin M, Immunology, biology.protein, Memory b-cells, Antibody, medicine.symptom, Secretory antibodies
Abstract

International audience; Paradoxically, loss of immunoglobulin A (IgA), one of the most abundant antibodies, does not irrevocably lead to severe infections in humans but rather is associated with relatively mild respiratory infections, atopy, and autoimmunity. IgA might therefore also play covert roles, not uniquely associated with control of pathogens. We show that human IgA deficiency is not associated with massive quantitative perturbations of gut microbial ecology. Metagenomic analysis highlights an expected pathobiont expansion but a less expected depletion in some typically beneficial symbionts. Gut colonization by species usually present in the oropharynx is also reminiscent of spatial microbiota disorganization. IgM only partially rescues IgA deficiency because not all typical IgA targets are efficiently bound by IgM in the intestinal lumen. Together, IgA appears to play a nonredundant role at the forefront of the immune/microbial interface, away from the intestinal barrier, ranging from pathobiont control and regulation of systemic inflammation to preservation of commensal diversity and community networks.

Published
2018

33. Modulation of the microbiota by oral antibiotics treats immunoglobulin A nephropathy in humanized mice

Author

Jonathan M. Chemouny, Erwan Boedec, Karine Le Roux, Gabriella Lauriero, Céline Monot, Marion Leclerc, Julie Bex-Coudrat, Laureline Berthelot, Loreto Gesualdo, Patricia Lepage, Maxime Bredel, Patrick J. Gleeson, Sanae Ben Mkaddem, François Vrtovsnik, Aurélie Sannier, Renato C. Monteiro, Eric Daugas, Lilia Abbad, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), UMR 1599, Centre National de la Recherche Scientifique (CNRS), Service de Néphrologie [Bichat - Claude Bernard], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), CeRTA, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), LABEX Inflamex [ANR-11-IDEX-000502], Agence Nationale pour la Recherche Jeune Chercheur TRAIN, Departement hospitalo-universitaire FIRE projet Emergence et Association pour l'Information et la Recherche sur les maladies Renales Genetiques-FranceFrench National Research Agency (ANR), HUPNVS of Assistance Publique Hopitaux de Paris, Equipe Fondation pour la Recherche Medicale, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Immunoglobulin A, Male, medicine.drug_class, Gut-associated lymphoid tissue, Antibiotics, 030232 urology & nephrology, gut microbiome, Administration, Oral, 030204 cardiovascular system & hematology, Gut flora, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Immunoglobulin G, antibiotics, 03 medical and health sciences, Mice, 0302 clinical medicine, medicine, GALT, Animals, ComputingMilieux_MISCELLANEOUS, Transplantation, Proteinuria, biology, business.industry, Glomerulonephritis, Glomerulonephritis, IGA, IgA nephropathy, medicine.disease, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Anti-Bacterial Agents, Gastrointestinal Microbiome, Disease Models, Animal, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Nephrology, Humanized mouse, Immunology, biology.protein, Female, medicine.symptom, business, IgA
Abstract

Background Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgA is mainly produced by the gut-associated lymphoid tissue (GALT). Both experimental and clinical data suggest a role of the gut microbiota in this disease. We aimed to determine if an intervention targeting the gut microbiota could impact the development of disease in a humanized mouse model of IgAN, the α1KI-CD89Tg mice. Methods Four- and 12-week old mice were divided into two groups to receive either antibiotics or vehicle control. Faecal bacterial load and proteinuria were quantified both at the beginning and at the end of the experiment, when blood, kidneys and intestinal tissue were collected. Serum mouse immunoglobulin G (mIgG) and human immunoglobulin A1 (hIgA1)-containing complexes were quantified. Renal and intestinal tissue were analysed by optical microscopy after haematoxylin and eosin colouration and immunohistochemistry with anti-hIgA and anti-mouse CD11b antibodies. Results Antibiotic treatment efficiently depleted the faecal microbiota, impaired GALT architecture and impacted mouse IgA production. However, while hIgA1 and mIgG serum levels were unchanged, the antibiotic treatment markedly prevented hIgA1 mesangial deposition, glomerular inflammation and the development of proteinuria. This was associated with a significant decrease in circulating hIgA1–mIgG complexes. Notably, final faecal bacterial load strongly correlated with critical clinical and pathophysiological features of IgAN such as proteinuria and hIgA1–mIgG complexes. In addition, treatment with broad-spectrum antibiotics reverted established disease. Conclusions These data support an essential role of the gut microbiota in the generation of mucosa-derived nephrotoxic IgA1 and in IgAN development, opening new avenues for therapeutic approaches in this disease.

Published
2018

34. Enteric delivery of regenerating family member 3 alpha alters the intestinal microbiota and controls inflammation in mice with colitis

Author

Marion, Darnaud, Alexandre, Dos Santos, Patrick, Gonzalez, Sandrine, Augui, Claire, Lacoste, Christophe, Desterke, Gert, De Hertogh, Emma, Valentino, Emilie, Braun, Jinzi, Zheng, Raphael, Boisgard, Christel, Neut, Laurent, Dubuquoy, Franck, Chiappini, Didier, Samuel, Patricia, Lepage, Francesca, Guerrieri, Joel, Doré, Christian, Bréchot, Nicolas, Moniaux, Jamila, Faivre, Physiopathologie et traitement des maladies du foie, Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université Catholique de Louvain = Catholic University of Louvain (UCL), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Imagerie Moléculaire in Vivo (IMIV - U1023 - ERL9218), Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lille, Lille Inflammation Research International Center - U 995 (LIRIC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris Saclay (COmUE), Istituto Italiano di Tecnologia (IIT), Institut Pasteur [Paris], Fondation ARC pour la Recherche sur le Cancer [PJA 20111203952, PJA 20131200221, PJA 20141202048], Association pour la Recherche sur le Cancer Fellowship [R12036LL], Institut National du Cancer, OSEO-BPI Programme d'Investissements d'Avenir (IMODI consortium) [R14035LB], OSEO-BPI Programme d'Investissements d'Avenir (HECAM consortium) [R15065LH], European Project: 259743,EC:FP7:HEALTH,FP7-HEALTH-2010-two-stage,MODHEP(2011), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), ProdInra, Migration, and Systems biology of liver cancer: an integrative genomic-epigenomic approach - MODHEP - - EC:FP7:HEALTH2011-01-01 - 2016-06-30 - 259743 - VALID

Subjects
Time Factors, LPS, [SDV.IMM] Life Sciences [q-bio]/Immunology, Colon, [SDV]Life Sciences [q-bio], IBD, Mice, Transgenic, Pancreatitis-Associated Proteins, Animals, Humans, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Microbial Viability, Mouse Model, Bacteria, Dextran Sulfate, Fecal Microbiota Transplantation, Colitis, Gastrointestinal Microbiome, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], Disease Models, Animal, Oxidative Stress, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Trinitrobenzenesulfonic Acid, Hepatocytes, [SDV.IMM]Life Sciences [q-bio]/Immunology, Reactive Oxygen Species
Abstract

International audience; BACKGROUND & AIMS: Paneth cell dysfunction causes deficiencies in intestinal C-type lectins and antimicrobial peptides, which leads to dysbiosis of the intestinal microbiota, alters the mucosal barrier, and promotes development of inflammatory bowel diseases. We investigated whether transgenic (TG) expression of the human regenerating family member 3 alpha gene (REG3A) alters the fecal microbiota and affects development of colitis in mice. METHODS: We performed studies with C57BL/6 mice that express human regenerating family member 3 alpha (hREG3A) in hepatocytes, via the albumin gene promoter. In these mice, hREG3A travels via the bile to the intestinal lumen. Some mice were given dextran sodium sulfate (DSS) to induce colitis. Feces were collected from mice and the composition of the microbiota was analyzed by 16S ribosomal RNA sequencing. The fecal microbiome was also analyzed from mice that express only 1 copy of human REG3A transgene but were fed feces from control mice (not expressing hREG3A) as newborns. Mice expressing hREG3A were monitored for DSS-induced colitis after co-housing or feeding feces from control mice. Colitis was induced in another set of control and hREG3A-TG mice by administration of trinitrobenzene sulfonic acid; some mice were given intrarectal injections of the hREG3A protein. Colon tissues were collected from mice and analyzed by histology and immunohistochemistry to detect mucin 2, as well as by 16S ribosomal RNA fluorescence in situ hybridization, transcriptional analyses, and quantitative polymerase chain reaction. We measured levels of reactive oxygen species (ROS) in bacterial cultures and fecal microbiota using 20,70-dichloro-fluorescein diacetate and flow cytometry. RESULTS: The fecal microbiota of mice that express hREG3A had a significant shift in composition, compared with control mice, with enrichment of Clostridiales (Ruminococcaceae, Lachnospiraceae) and depletion of Bacteroidetes (Prevotellaceae); the TG mice developed less-severe colitis following administration of DSS than control mice, associated with preserved gut barrier integrity and reduced bacterial translocation, epithelial inflammation, and oxidative damage. A similar shift in the composition of the fecal microbiota occurred after a few months in TG mice heterozygous for REG3A that harbored a wild-type maternal microbiota at birth; these mice developed less-severe forms of colitis following DSS administration. Cohoused and germ-free mice fed feces from REG3A-TG mice and given DSS developed less-severe forms of colitis and had reduced lipopolysaccharide activation of the toll-like receptor 4 and increased survival times compared with mice not fed feces from REG3A-TG mice. REG3A TG mice developed only mild colonic inflammation after exposure to 2,4,6-trinitrobenzene sulfonic acid, compared with control mice. Control mice given intrarectal hREG3A and exposed to 2,4,6-trinitrobenzene sulfonic acid showed less colon damage and inflammation than mice not given intrarectal hREG3A. Fecal samples from REG3A-TG mice had lower levels of ROS than feces from control mice during DSS administration. Addition of hREG3A to bacterial cultures reduced levels of ROS and increased survival of oxygen-sensitive commensal bacteria (Faecalibacterium prausnitzii and Roseburia intestinalis). CONCLUSIONS: Mice with hepatocytes that express hREG3A, which travels to the intestinal lumen, are less sensitive to colitis than control mice. We found hREG3A to alter the colonic microbiota by decreasing levels of ROS. Fecal microbiota from REG3A-TG mice protect non-TG mice from induction of colitis. These findings indicate a role for reduction of oxidative stress in preserving the gut microbiota and its ability to prevent inflammation.

Published
2018

35. TREM-1 Inhibition Restores Impaired Autophagy Activity and Reduces Colitis in Mice

Author

Silvia D'Alessio, Hélène Busby-Venner, Julie Hablot, Laurent Peyrin-Biroulet, David Moulin, Céline Monot, Silvio Danese, Franck Hansmannel, Tunay Kökten, Benjamin Garnier, Jean-Yves Jouzeau, Sébastien Gibot, Ndeye-Coumba Ndiaye, Sylviane Muller, Patricia Lepage, Jean-Louis Guéant, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Faculté de Médecine [Nancy], Université de Lorraine (UL), Service de Réanimation Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Humanitas Clinical and Research Institute, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Département d’Anatomie et Cytologie Pathologiques [CHRU Nancy], Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Immunologie et chimie thérapeutiques (ICT), Cancéropôle du Grand Est-Centre National de la Recherche Scientifique (CNRS), Service d'Hépato-gastro-entérologie [CHRU Nancy], Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), and MOULIN, David

Subjects
0301 basic medicine, DNA, Bacterial, Male, autophagy, TREM-1, Atg1, ATG5, 03 medical and health sciences, Feces, Mice, inflammatory bowel disease, Medicine, Animals, Colitis, Animal models of IBD, endoscopy, ATG16L1, innovative therapy, Mice, Knockout, business.industry, Autophagy, Dextran Sulfate, Gastroenterology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, General Medicine, dysbiosis, Autophagy-related protein 13, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Triggering Receptor Expressed on Myeloid Cells-1, 3. Good health, Gastrointestinal Microbiome, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, inflammation, peptide-based therapy, Cancer research, Unfolded protein response, Unfolded Protein Response, LR12 peptide, endoplasmic reticulum stress, business, Peptides, Dysbiosis
Abstract

International audience; Background and Aims: Triggering receptor expressed on myeloid cells-1 [TREM-1] is known to amplify inflammation in several diseases. Autophagy and endoplasmic reticulum [ER] stress, which activate the unfolded protein response [UPR], are closely linked and defects in these pathways contribute to the pathogenesis of inflammatory bowel disease [IBD]. Both autophagy and UPR are deeply involved in host-microbiota interactions for the clearance of intracellular pathogens, thus contributing to dysbiosis. We investigated whether inhibition of TREM-1 would prevent aberrant inflammation by modulating autophagy and ER stress and preventing dysbiosis.Methods: An experimental mouse model of colitis was established by dextran sulphate sodium treatment. TREM-1 was inhibited, either pharmacologically by LR12 peptide or genetically with Trem-1 knock-out [KO] mice. Colon tissues and faecal pellets of control and colitic mice were used. Levels of macroautophagy, chaperone-mediated autophagy [CMA], and UPR proteins were evaluated by western blotting. The composition of the intestinal microbiota was assessed by MiSeq sequencing in both LR12-treated and KO animals.Results: We confirmed that inhibition of TREM-1 attenuates the severity of colitis clinically, endoscopically and histologically. We observed an increase in macroautophagy [ATG1/ULK-1, ATG13, ATG5, ATG16L1, and MAP1LC3-I/II] and in CMA [HSPA8 and HSP90AA1], whereas there was a decrease in the UPR [PERK, IRE-1α, and ATF-6α] protein expression levels in TREM-1 inhibited colitic mice. TREM-1 inhibition prevented dysbiosis.Conclusions: TREM-1 may represent a novel drug target for the treatment of IBD, by modulating autophagy activity and ER stress.

Published
2018

36. Baseline gut microbiota in metastatic melanoma patients treated with ipilimumab: Relation with clinical response and colitis

Author

Christine Mateus, Franck Carbonnel, V. Asvatourian, Clélia Coutzac, Nathalie Chaput, Emilie Soularue, Patricia Lepage, Emilie Lanoy, C. Robert, Institut Gustave Roussy (IGR), Département d'hématologie [Gustave Roussy], MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Equipe Mobile d’Accompagnement et de Soins Palliatifs (EMASP), Gustave Roussy Cancer Campus, Fondation Gustave Roussy, Direction Generale de l'Offre de Soins (DGOS) [GOLD TRANSLA 12-174], Institut National du Cancer (INCa) [2012-1-RT-14-IGR-01], SIRIC SOCRATE [INCa DGOS INSERM 6043], MMO program [ANR-10IBHU-0001], and European Society Medical Oncology. CHE.

Subjects
Oncology, medicine.medical_specialty, biology, Metastatic melanoma, business.industry, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Ipilimumab, Hematology, Gut flora, biology.organism_classification, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, Colitis, business, ComputingMilieux_MISCELLANEOUS, medicine.drug
Abstract

International audience

Published
2017

37. Microbiota Is Involved in Post-resection Adaptation in Humans with Short Bowel Syndrome

Author

Isabelle Pingenot, Véronique Robert, Muriel Thomas, Francisca Joly, Camille Mayeur, Patricia Lepage, André Bado, Laura Gillard, Johanne Le Beyec, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Service de Gastroentérologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Recherche Agronomique (INRA), Biocodex through Societe Nationale Francaise de Gastro-enterologie, French Ministry of Education and Research, Service de Biochimie Endocrinienne et Oncologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Thomas, Muriel, Joly, Francisca, HAL UPMC, Gestionnaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Hôpital Beaujon, Service de Biochimie Endocrinienne et Oncologique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)

Subjects
0301 basic medicine, Physiology, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Glucagon-like peptide, Encephalopathy, microbiome, Microbiology, entero-endocrine hormones, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Lactobacillus, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], resection, dysbiosis, lactate, short chain fatty acids, Feces, Original Research, biology, Clostridium leptum, biology.organism_classification, Short bowel syndrome, medicine.disease, Small intestine, 030104 developmental biology, medicine.anatomical_structure, 030211 gastroenterology & hepatology, Anaerobic exercise, Dysbiosis
Abstract

International audience; Short bowel syndrome (SBS) is characterized by severe intestinal malabsorption following restrictive surgery. The objective of this study was to determine the functional contribution of SBS-microbiota after resection. It is well-known that SBS-microbiota displayed specific features with a prevalence of Lactobacillus, a low amount of some anaerobic microbes (Clostridium leptum) and an accumulation of fecal lactate in some patients. Patients with jejuno-colonic anastomosis were stratified according to the presence of lactate in their feces and, we observe that the lactate-producing bacteria were predominant in the sub-group of patients accumulating fecal lactate. One case of D-encephalopathy crisis occurred when the D-lactate isoform accumulated in the feces and plasma bicarbonate levels decreased. The fecal sample at the time of the encephalopathy was transferred to germ free rats (SBS-H rats). The SBS-H microbiota conserved some characteristics of the SBS donnor, predominated by lactate-producing bacteria (mainly Lactobacillus), a low level of lactate-consuming bacteria and undetectable C. leptum. However, lactate did not accumulate in feces of recipient rats and the D-encephalopathy was not reproduced in SBS-H rats. This suggests that the intact small bowel of the recipient rats protected them from lactate accumulation and that D-lactate encephalopathy can occur only in the absence of small intestine. After fecal transfer, we also show that gnotobiotic rats exhibited high levels of circulating GLP-1 and ghrelin, two hormones that are known to be induced in SBS patients. Therefore, the microbiota of SBS is a reservoir of biological signals involved in post-resection adaptation.

Published
2017

38. Rapid analysis of bile acids in different biological matrices using LC-ESI-MS/MS for the investigation of bile acid transformation by mammalian gut bacteria

Author

Patricia Lepage, Laura Gau, Sarah Just, Katrin Wegner, Sascha Rohn, Henrike Mueller, Philippe Gérard, Thomas Clavel, Hamburg School of Food Science - Institute of Food Chemistry, University of Hamburg, Junior Research Group Intestinal Microbiome - ZIEL Institute for Food Health, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Hamburg School of Food Science, Institute of Food Chemistry, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, and Technical University of Munich (TUM)

Subjects
0301 basic medicine, Spectrometry, Mass, Electrospray Ionization, Analyte, Taurine, medicine.drug_class, Method validation, [SDV]Life Sciences [q-bio], Liquid-Liquid Extraction, Eggerthella lenta, Targeted metabolite profiling, Gut microbiota, Gut flora, 01 natural sciences, Biochemistry, Analytical Chemistry, Bile Acids and Salts, Mice, 03 medical and health sciences, chemistry.chemical_compound, Collinsella aerofaciens, Tandem Mass Spectrometry, HPLC-ESI-QqQ-MS/MS, medicine, Animals, Coriobacteriaceae, Chromatography, Bacteria, biology, Bile acid, Cholesterol, Solid Phase Extraction, 010401 analytical chemistry, Reproducibility of Results, biology.organism_classification, Bile acids, 0104 chemical sciences, Intestines, 030104 developmental biology, chemistry, Calibration, Fermentation, Glycine, Chromatography, Liquid
Abstract

Bile acids are important signaling molecules that regulate cholesterol, glucose, and energy homoeostasis and have thus been implicated in the development of metabolic disorders. Their bioavailability is strongly modulated by the gut microbiota, which contributes to generation of complex individual-specific bile acid profiles. Hence, it is important to have accurate methods at hand for precise measurement of these important metabolites. Here, a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous identification and quantitation of primary and secondary bile acids as well as their taurine and glycine conjugates was developed and validated. Applicability of the method was demonstrated for mammalian tissues, biofluids, and cell culture media. The analytical approach mainly consists of a simple and rapid liquid-liquid extraction procedure in presence of deuterium-labeled internal standards. Baseline separation of all isobaric bile acid species was achieved and a linear correlation over a broad concentration range was observed. The method showed acceptable accuracy and precision on intra-day (1.42-11.07 %) and inter-day (2.11-12.71 %) analyses and achieved good recovery rates for representative analytes (83.7-107.1 %). As a proof of concept, the analytical method was applied to mouse tissues and biofluids, but especially to samples from in vitro fermentations with gut bacteria of the family Coriobacteriaceae. The developed method revealed that the species Eggerthella lenta and Collinsella aerofaciens possess bile salt hydrolase activity, and for the first time that the species Enterorhabdus mucosicola is able to deconjugate and dehydrogenate primary bile acids in vitro.

Published
2017

39. Colon Immune-Related Adverse Events: Anti-CTLA-4 and Anti-PD-1 Blockade Induce Distinct Immunopathological Entities

Author

Emilie Soularue, Melinda Charrier, Antoine Racine, Christine Mateus, Clélia Coutzac, Lydie Cassard, Nyam Kamsu-Kom, Karim Fizazi, Patricia Lepage, Nathalie Chaput, L. Boselli, Charlotte Mussini, Michael Collins, Yohann Loriot, Caroline Robert, Jean-Yves Scoazec, Julien Adam, Franck Carbonnel, Vincent Ribrag, David Planchard, Institut Gustave Roussy (IGR), Department of Gastroenterology, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Faculté de médecine, Université Paris-Sud - Paris 11 (UP11), Service de dermatologie, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Univ Paris Sud, Fac Med, F-94276 Le Kremlin Bicetre, France, Partenaires INRAE, Dept Canc Med, Gustave Roussy Canc Campus, F-94805 Villejuif, France, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Gustave Roussy Cancer Campus, Fondation Gustave Roussy, Institut national de la sante et de la recherche medicale [INSERM], Direction Generale de l'Offre de Soins [GOLD TRANSLA 12-174], Institut National du Cancer [GOLD 2012-062, Canceropole: 2012-1-RT-14-IGR-01], SIRIC SOCRATE [INCa DGOS INSERM 6043], MMO programme [ANR-10IBHU-0001], and Fondation pour la Recherche Medicale [FRM]

Subjects
Adult, CD4-Positive T-Lymphocytes, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Colon, colitis, Biopsy, T cell, [SDV]Life Sciences [q-bio], Programmed Cell Death 1 Receptor, chemical and pharmacologic phenomena, CD8-Positive T-Lymphocytes, Anti-CTLA-4, Inflammatory bowel disease, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Humans, CTLA-4 Antigen, Intestinal Mucosa, Colitis, Aged, Aged, 80 and over, Lamina propria, business.industry, Gastroenterology, hemic and immune systems, General Medicine, Middle Aged, immune checkpoint blockade, Flow Cytometry, medicine.disease, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, Intraepithelial lymphocyte, anti-PD-1, immune-related adverse events, Tumor necrosis factor alpha, business, CD8
Abstract

International audience; Background and Aim: Immune checkpoint inhibitors targeting CTLA-4 and PD-1 improve survival in cancer patients but may induce immune-related adverse events, including colitis. The immunological characteristics of anti-CTLA-4 [alpha CTLA-4]- and anti-PD-1 [alpha PD-1]-related colitis have been poorly described. The aim of the present study was to compare the immunological and histological characteristics of alpha CTLA-4-induced colitis and alpha PD-1-induced colitis. Methods: Colonic biopsies from patients with alpha CTLA-4-induced colitis, alpha PD-1-induced colitis, and inflammatory bowel disease [IBD] were analysed by immunohistochemistry and flow cytometry. Tumour necrosis factor alpha [TNF alpha] concentration was assessed in biopsy supernatants. Results: CD8(+) T cells were found in the lamina propria and epithelium in alpha PD-1-induced colitis, whereas CD4(+) T cells were found in the lamina propria in alpha CTLA-4-induced colitis. No or low intraepithelial lymphocytes were observed in alpha CTLA-4-induced colitis. No difference in numbers of mucosal regulatory T cells was observed between alpha CTLA-4- or alpha PD-1-induced colitis and IBD patients. Higher numbers of activated ICOS+ conventional CD4(+) T cells were observed in alpha CTLA-4- induced colitis compared with patients with IBD. Among ICOS+ CD4(+) T cells, conventional CD4(+) T cells were the main T cell population in patents with alpha CTLA-4-induced colitis, whereas Treg cells were predominant in IBD or alpha PD-1-induced colitis. High mucosal TNF alpha concentrations were observed in alpha CTLA-4-induced colitis. Low mucosal TNF alpha concentrations were associated with steroid sensitivity. Conclusions: These observations show that alpha CTLA-4- and alpha PD-1-induced colitis have distinct immunological characteristics. Mucosal TNF alpha concentration might detect patients at risk of developing corticosteroid resistance after CTLA-4 blockade.

Published
2017

40. Enhancing the clinical coverage and anticancer efficacy of immune checkpoint blockade through manipulation of the gut microbiota

Author

Mathias Chamaillard, Marie Vétizou, Patricia Lepage, Ivo G. Boneca, Laurence Zitvogel, Jonathan M. Pitt, Institut Gustave Roussy (IGR), Université Paris-Sud 11 - Faculté de médecine (UP11 UFR Médecine), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, Equipe Avenir, Institut National de la Santé et de la Recherche Médicale (INSERM), Biology and genetics of the bacterial cell wall Unit, Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Réseau International des Instituts Pasteur (RIIP), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunité et cancer (U932), Institut Curie-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy ( IGR ), Université Paris-Sud 11 - Faculté de médecine ( UP11 UFR Médecine ), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), MICrobiologie de l'ALImentation au Service de la Santé humaine ( MICALIS ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 ( CIIL ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR142-Université de Lille-Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire de Lille ( CHRU de Lille ), Réseau International des Instituts Pasteur ( RIIP ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Curie, Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, T cell, [SDV]Life Sciences [q-bio], Immunology, microbiome, Ipilimumab, chemical and pharmacologic phenomena, Gut flora, Anti-CTLA-4, 03 medical and health sciences, 0302 clinical medicine, medicine, microbiota, Immunology and Allergy, Bacteroides, cancer, Microbiome, ipilimumab, Adverse effect, Author's View, biology, [ SDV ] Life Sciences [q-bio], biology.organism_classification, Immune checkpoint, 3. Good health, Blockade, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, medicine.drug
Abstract

Although anticancer therapy with immune checkpoint blockers has seen unprecedented success, it fails to control neoplasia in most patients and often causes immune-related adverse events (irAEs). Our recent research shows the immunostimulatory and antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species of the gut microbiota, signifying novel approaches to improve such immunotherapies.

Published
2017

41. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab

Author

K. Le Roux, L. Marthey, Franck Carbonnel, Emilie Lanoy, Michael Collins, Emilie Routier, Lydie Cassard, Christine Mateus, T. Vaysse, Patricia Lepage, C. Monot, Nathalie Chaput, Caroline Robert, V. Asvatourian, Alexander M.M. Eggermont, L. Boselli, Emilie Soularue, Clélia Coutzac, Laboratoire d’Immunomonitoring en Oncologie (LIO), 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), Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Pharmacie [Châtenay-Malabry], Université Paris-Sud 11 - Faculté de médecine (UP11 UFR Médecine)-Université Paris-Saclay, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris-Saclay, Faculté de Médecine, Université de Ngozi, Faculté de Pharmacie, Université Paris-Sud - Paris 11 (UP11)-Université Paris-Saclay, Département de Gastroentérologie, Hôpital Européen [Fondation Ambroise Paré - Marseille], Service de dermatologie, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôpital Bicêtre, Assistance Publique - Hôpitaux de Paris (AP-HP), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre de recherche en épidémiologie et santé des populations (CESP), Hôpital Paul Brousse-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Paris-Sud - Paris 11 (UP11), Université Paris-Saclay-Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11)-Université Paris-Sud - Paris 11 (UP11), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11)-Université Paris-Sud - Paris 11 (UP11)-Université Paris-Saclay, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11)

Subjects
0301 basic medicine, Male, colitis, [SDV]Life Sciences [q-bio], Faecalibacterium prausnitzii, Ipilimumab, Gut flora, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Agents, Immunological, RNA, Ribosomal, 16S, medicine, microbiota, melanoma, Humans, IL-2 receptor, Microbiome, Prospective Studies, Colitis, Neoplasm Metastasis, ipilimumab, 030304 developmental biology, Aged, Enterocolitis, 0303 health sciences, biology, business.industry, Melanoma, Hematology, biology.organism_classification, medicine.disease, 3. Good health, Intestines, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Immunology, Female, medicine.symptom, business, medicine.drug
Abstract

Background Ipilimumab, an immune checkpoint inhibitor targeting CTLA-4, prolongs survival in a subset of patients with metastatic melanoma (MM) but can induce immune-related adverse events, including enterocolitis. We hypothesized that baseline gut microbiota could predict ipilimumab anti-tumor response and/or intestinal toxicity. Patients and methods Twenty-six patients with MM treated with ipilimumab were prospectively enrolled. Fecal microbiota composition was assessed using 16S rRNA gene sequencing at baseline and before each ipilimumab infusion. Patients were further clustered based on microbiota patterns. Peripheral blood lymphocytes immunophenotypes were studied in parallel. Results A distinct baseline gut microbiota composition was associated with both clinical response and colitis. Compared with patients whose baseline microbiota was driven by Bacteroides (cluster B,n = 10), patients whose baseline microbiota was enriched with Faecalibacterium genus and other Firmicutes (cluster A,n = 12) had longer progression-free survival (P = 0.0039) and overall survival (P = 0.051). Most of the baseline colitis-associated phylotypes were related to Firmicutes (e.g. relatives of Faecalibacterium prausnitzii and Gemmiger formicilis), whereas no colitis-related phylotypes were assigned to Bacteroidetes. A low proportion of peripheral blood regulatory T cells was associated with cluster A, long-term clinical benefit and colitis. Ipilimumab led to a higher inducible T-cell COStimulator induction on CD4+ T cells and to a higher increase in serum CD25 in patients who belonged to Faecalibacterium-driven cluster A. Conclusion Baseline gut microbiota enriched with Faecalibacterium and other Firmicutes is associated with beneficial clinical response to ipilimumab and more frequent occurrence of ipilimumab-induced colitis.

Published
2017

42. Association of germ-free mice with a simplified human intestinal microbiota results in a shortened intestine

Author

Gunnar Loh, Joël Doré, Sylvie Rabot, Kathleen Slezak, Florence Levenez, Michael Blaut, Zuzana Krupova, Patricia Lepage, Sylvain Bellier, and Amandine Descamps

Subjects
Male, Microbiology (medical), Spermine, Butyrate, Gut flora, Microbiology, Andrology, Mice, chemistry.chemical_compound, Polyamines, Animals, Humans, Intestinal Mucosa, chemistry.chemical_classification, biology, digestive, oral, and skin physiology, Gastroenterology, Maternal effect, biology.organism_classification, Intestines, Spermidine, Butyrates, Infectious Diseases, chemistry, Biochemistry, Propionate, Putrescine, Female, Propionates, Polyamine, Research Paper
Abstract

Genetic, nutritional, and gut microbiota-derived factors have been proposed to play a role in the development of the whole intestine that is around 40% longer in PRM/Alf mice compared with other mouse strains. The PRM/Alf genotype explains 60% of this length difference. The remaining 40% are due to a maternal effect that could depend on the gut microbiota transmitted by the mother to their pups. Germ-free PRM/Alf mice and C3H/He mice were associated with a simplified human microbiota (SIHUMI) to study its impact on gut length. The small intestines of the SIHUMI-associated mice were 16.4% (PRM/Alf) and 9.7% (C3H/He) shorter than those of the corresponding germ-free counterparts. Temporal temperature gradient gel electrophoresis and quantitative real-time PCR revealed differences in microbiota composition between both SIHUMI-associated mouse strains. Anaerostipes caccae was one log lower in PRM/Alf mice than in C3H/He mice. Since polyamines and short-chain fatty acids (SCFAs) are important intestinal growth factors, their concentrations were explored. Cecal concentrations of putrescine, spermine, spermidine, and N-acetylspermine were 1.5-fold, 3.7-fold, 2.2-fold, and 1.4-fold higher, respectively, in the SIHUMI-C3H/He mice compared with the SIHUMI-PRM/Alf mice. In addition, cecal acetate, propionate, and butyrate concentrations in SIHUMI-C3H/He mice were 1.4-fold, 1.1-fold, and 2.1-fold higher, respectively, than in SIHUMI-PRM/Alf mice. These results indicate that polyamines and SCFAs did not promote gut lengthening in any of the two mouse strains. This suggests that as yet unknown factors provided by the SIHUMI prevented gut lengthening in the SIHUMI-associated mice compared with the germfree mice.

Published
2014

43. Lentinula edodes (Shiitake) Modulates Chemically Induced Mutagenesis by Enhancing Pitting

Author

Lízia C. Vilela, Marina Mariko Sugui, Angela I.M. Petrício, Lúcia Regina Ribeiro, Daisy Maria Favero Salvadori, Ramon Kaneno, Patricia Lepage Alves de Lima, Priscila Raquel Martins, Daniel Araki Ribeiro, and Andréa Vanessa Ferreira da Silva Pinto

Subjects
Male, Alkylating Agents, Reticulocytes, Phagocytosis, Shiitake Mushrooms, Medicine (miscellaneous), Bone Marrow Cells, Spleen, Pharmacology, Biology, Mice, Reticulocyte, In vivo, Vegetables, medicine, Animals, Nutrition and Dietetics, Macrophages, Cell Cycle, Antimutagenic Agents, biology.organism_classification, medicine.anatomical_structure, Lentinula, Mutagenesis, Immunology, Micronucleus test, Bone marrow, Micronucleus, Mutagens
Abstract

This study was undertaken to understand how Lentinula edodes modulates in vivo mutagenesis induced by alkylating agents in bone marrow and peripheral blood as described in our previous article. Male Swiss mice were pretreated for 15 consecutive days with aqueous extracts prepared from L. edodes, after which, the number of circulating blood cells, normal erythroid bone marrow cell cycling, and phagocytosis of micronucleated reticulocyte (MNRET) and activation of spleen macrophages were assessed. The results indicate that the antimutagenicity seen in bone marrow and peripheral blood is exerted by distinct compounds with different actions. The antimutagenic effect in bone marrow is exerted by compounds subject to degradation at deep-freeze storage temperature of -20°C. On the other hand, compounds responsible for antimutagenicity in peripheral blood are not subject to degradation at -20°C. The results also indicate that the antimutagenic action in peripheral blood leading to the reduction of circulating MNRET occurs in the spleen primarily through a phagocytic activity due to higher macrophage numbers and probably not due to the enhanced activation state of individual cells.

Published
2013

44. Mining gut microbiome oligopeptides by functional metaproteome display

Author

Stefan Dübel, Jonas Zantow, Michael Hust, Sarah Just, Sigrid Kisling, Thomas Clavel, Ilias Lagkouvardos, Patricia Lepage, Clavel, Thomas, Hust, Michael, Technical University Braunschweig, ZIEL – Institute for Food and Health, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), and Institut National de la Recherche Agronomique (INRA)-AgroParisTech

Subjects
0301 basic medicine, Phage display, Proteome, [SDV]Life Sciences [q-bio], 030106 microbiology, Mice, Transgenic, Computational biology, Bioinformatics, Article, Mice, 03 medical and health sciences, Immune system, Antigen, Peptide Library, Animals, Peptide library, Multidisciplinary, biology, Gastrointestinal Microbiome, Ileitis, ddc, 3. Good health, 030104 developmental biology, Metagenomics, Chronic Disease, biology.protein, Metagenome, Antibody, Oligopeptides
Abstract

Pathogen infections, autoimmune diseases and chronic inflammatory disorders are associated with systemic antibody responses from the host immune system. Disease-specific antibodies can be important serum biomarkers, but the identification of antigens associated with specific immune reactions is challenging, in particular if complex communities of microorganisms are involved in the disease progression. Despite promising new diagnostic opportunities, the discovery of these serological markers becomes more difficult with increasing complexity of microbial communities. In the present work, we used a metagenomic M13 phage display approach to select immunogenic oligopeptides from the gut microbiome of transgenic mice suffering from chronic ileitis. We constructed three individual metaproteome phage display libraries with a library size of approximately 107 clones each. Using serum antibodies, we selected and validated three oligopeptides that induced specific antibody responses in the mouse model. This proof-of-concept study provides the first successful application of functional metaproteome display for the study of protein-protein interactions and the discovery of potential disease biomarkers.

Published
2016

45. Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and -extrinsic factors

Author

Marie Vétizou, Laurence Zitvogel, Maria Paula Roberti, Bertrand Routy, Patricia Lepage, Ivo G. Boneca, Jonathan M. Pitt, Guido Kroemer, Takahiro Yamazaki, Mathias Chamaillard, Romain Daillère, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Institut Pasteur [Paris], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Apoptose, cancer et immunité (U848), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), 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)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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), Karolinska Institutet [Stockholm], Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Association pour la Recherche sur le Cancer (ARC), Ligue contre le Cancer, Ligue Nationale contre le Cancer (Equipes labellisees), Agence Nationale pour la Recherche (ANR AUTOPH), Agence Nationale pour la Recherche (ANR Emergence), European Commission (ArtForce), European Research Council Advanced Investigator Grant, Fondation pour la Recherche Medicale (FRM), Institut National du Cancer, Fondation de France, Canceropole Ile-de-France, Fondation Bettencourt-Schueller, Swiss Bridge Foundation, LabEx Immuno-Oncology, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination, SIRIC Cancer Research and Personalized Medicine, Paris Alliance of Cancer Research Institutes, ARC [PGA120140200851], FRM, Fondation ARC pour la Recherche sur le Cancer, ProdInra, Migration, Institut Pasteur [Paris] (IP), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and École Pratique des Hautes Études (EPHE)

Subjects
0301 basic medicine, medicine.medical_treatment, antitumor immunity, [SDV]Life Sciences [q-bio], Immunology, regulatory t-cells, Biology, ctla-4 blockade, 03 medical and health sciences, Immune system, Costimulatory and Inhibitory T-Cell Receptors, Neoplasms, Tumor Microenvironment, medicine, Animals, Humans, Immunology and Allergy, exome analysis reveals, Molecular Targeted Therapy, Microbiome, dendritic cells, breast-cancer, Tumor microenvironment, human gut microbiome, colorectal-cancer, Antibodies, Monoclonal, Immunotherapy, Immune checkpoint, 3. Good health, Blockade, [SDV] Life Sciences [q-bio], 030104 developmental biology, Infectious Diseases, Tumor Escape, Drug Resistance, Neoplasm, CTLA-4, Cancer research, pd-1 blockade, metastatic melanoma
Abstract

International audience; Inhibition of immune regulatory checkpoints, such as CTLA-4 and the PD-1-PD-L1 axis, is at the forefront of immunotherapy for cancers of various histological types. However, such immunotherapies fail to control neoplasia in a significant proportion of patients. Here, we review how a range of cancer-cell-autonomous cues, tumor-microenvironmental factors, and host-related influences might account for the heterogeneous responses and failures often encountered during therapies using immune-checkpoint blockade. Furthermore, we describe the emerging evidence of how the strong interrelationship between the immune system and the host microbiota can determine responses to cancer therapies, and we introduce a concept by which prior or concomitant modulation of the gut microbiome could optimize therapeutic outcomes upon immune-checkpoint blockade.

Published
2016

46. Statement of Retraction. Replication of Obesity and Associated Signaling Pathways Through Transfer of Microbiota From Obese-Prone Rats. Diabetes 2014;63:1624-1636. DOI: 10.2337/db13-1526

Author

Yassine Sakar, Fabienne Devime, Mihai Covasa, Frank A. Duca, Patricia Lepage, Bénédicte Langelier, and Joël Doré

Subjects
0301 basic medicine, medicine.medical_specialty, business.industry, Endocrinology, Diabetes and Metabolism, 030106 microbiology, medicine.disease, Obesity, 03 medical and health sciences, Endocrinology, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Signal transduction, business
Published
2016

47. Phylogenetic network analysis applied to pig gut microbiota identifies an ecosystem structure linked with growth traits

Author

Claire Rogel-Gaillard, Jean-Jacques Leplat, Mustapha Berri, Yvon Billon, Florence Levenez, Yuliaxis Ramayo-Caldas, Núria Mach, Jordi Estellé, Joël Doré, Patricia Lepage, Gaetan Lemonnier, Catherine Denis, Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), DSV-IRCM-LREG, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Génétique, Expérimentation et Système Innovants (GenESI), Institut National de la Recherche Agronomique (INRA), Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), European Project: 267196,EC:FP7:PEOPLE,FP7-PEOPLE-2010-COFUND,AGREENSKILLS(2012), and Institut National de la Recherche Agronomique (INRA)-Université de Tours

Subjects
0301 basic medicine, Operational taxonomic unit, Swine, Short Communication, Gut flora, Microbiology, digestive system, 03 medical and health sciences, Feces, Microbial ecology, Phylogenetics, RNA, Ribosomal, 16S, Prevotella, Animals, Cluster Analysis, Humans, Ecology, Evolution, Behavior and Systematics, Phylogeny, 2. Zero hunger, biology, Bacteria, Ecology, Ruminococcus, [SDV.BA]Life Sciences [q-bio]/Animal biology, biology.organism_classification, Biota, Gastrointestinal Microbiome, 030104 developmental biology, Environmental biotechnology, Evolutionary biology, Enterotype
Abstract

International audience; The ecological interactions within the gut microbial communities are complex and far from being fully understood. Here we report the first study that aims at defining the interaction network of the gut microbiota in pigs and comparing it with the enterotype-like clustering analysis. Fecal microbiota of 518 healthy piglets was characterized by 16S ribosomal RNA gene sequencing. Two networks were constructed at the genus and operational taxonomic unit levels. Within-network interactions mirrored the human gut microbiota relationships, with a strong co-exclusion between Prevotella and Ruminococcus genera, and were consistent with the two enterotype-like clusters identified in the pig microbiota. Remarkably, the cluster classification of the individuals was significantly associated with the body weight at 60 days of age (P=0.005) and average daily gain (P=0.027). To the best of our knowledge, this is the first study to provide an integrated overview of the porcine gut microbiota that suggests a conservation of the ecological community interactions and functional architecture between humans and pig. Moreover, we show that the microbial ecosystems and porcine growth traits are linked, which allows us to foresee that the enterotype concept may have an important role in the animal production industry.The ISME Journal advance online publication, 13 May 2016; doi:10.1038/ismej.2016.77.

Published
2016

48. Structural robustness of the gut mucosal microbiota is associated with Crohn's disease remission after surgery

Author

Marion Leclerc, Yoram Bouhnik, Joël Doré, Matthieu Allez, P Pochart, Philippe Marteau, J-F Colombel, P. Seksik, Patricia Lepage, Stanislas Mondot, Xavier Treton, MICrobiologie de l'ALImentation au Service de la Santé humaine ( MICALIS ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Institut Curie, Université Pierre et Marie Curie - Paris 6 ( UPMC ), Alloimmunité-Autoimmunité-Transplantation ( A2T ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Gastroentérologie [Hôpital Beaujon], Hôpital Beaujon, Icahn School of Medicine at Mount Sinai [New York], Laboratoire de Biologie, Conservatoire National des Arts et Métiers [CNAM] ( CNAM ), Université Paris Descartes - Paris 5 ( UPD5 ), Service de Gastroentérologie [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Pierre et Marie Curie - Paris 6 (UPMC), Alloimmunité-Autoimmunité-Transplantation (A2T), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Université Paris Descartes - Paris 5 (UPD5), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière, Institut Curie [Paris], Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), and HAL-UPMC, Gestionnaire

Subjects
0301 basic medicine, medicine.medical_specialty, Colon, Biopsy, IBD, Faecalibacterium prausnitzii, Biology, Inflammatory bowel disease, 03 medical and health sciences, Intestinal mucosa, Crohn Disease, Double-Blind Method, Ruminococcus gnavus, INFLAMMATORY BOWEL DISEASES, Ileum, Recurrence, medicine, Humans, COHORT, Intestinal Mucosa, Lactobacillus johnsonii, Crohn's disease, Lachnospiraceae, Remission Induction, Gastroenterology, RIBOSOMAL-RNA, COLITIS, RECURRENCE, BACTERIA, PATHWAYS, HEALTH, TRACT, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, biology.organism_classification, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Surgery, Gastrointestinal Microbiome, 030104 developmental biology, Immunology, Dysbiosis, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Follow-Up Studies
Abstract

the GETAID : Groupe d'Etude des Traitements des Affections Inflammatoires Digestives, Paris, France; International audience; Objectives: Preventing postoperative recurrence after ileocolonic resection (ICR) for Crohn's disease (CD) is challenging. Defining the disturbances of the microbial composition and community structure after ICR and their link with early disease recurrence is crucial.Design: Microbiota composition (fingerprinting and 16S rDNA sequencing) and community structure (correlation networks of bacterial species) were assessed from ileal mucosa sampled in 20 patients undergoing ICR and 6 months later during endoscopy from above (neoterminal ileum) and below (subanastomotic colon) the surgical anastomosis.Results: ICR had a dramatic effect on gut microbial ecosystem. At surgery, CD mucosa harboured a dysbiotic microbiota with high proportions of α/β Proteobacteria and Bacilli. Six months later, half of the patients had recurrent lesions at ileocolonoscopy and presented higher numbers of Lachnospiraceae. Recurrence of endoscopic lesions was associated with enrichment in Enterococcus durans while patients in remission had increased proportions of Dorea longicatena and Bacteroides plebeius. Structural differences were striking between recurrence and remission microbiota; while the microbiota of patients with CD recurrence exhibited a loose community structure, the microbiota of patients in remission displayed communities that were robustly correlated to each other. Microbiota colonising the neoterminal ileum and subanastomotic colon 6 months after ICR only differed in patients with recurrence.Conclusions: ICR modifies the gut microbiome. Remission after 6 months was associated with homogenous bacterial distribution around the anastomosis. Community structure and bacterial networks highlight target species, including Faecalibacterium prausnitzii and Ruminococcus gnavus, which may allow precise modulations of the overall microbial ecosystem towards remission pattern.

Published
2016

49. Gender specific behavioral alterations are associated with gut dysbiosis in mice exposed to multifactorial early-life adversity

Author

Hélène Boudin, P.-A. Grohard, Lucile Capuron, Grégoire Chevalier, C. Monchaux, Muriel Darnaudéry, De Oliveira, Sophie Layé, Marion Leboyer, Julien Chevalier, Patricia Lepage, Marion Rincel, Philippe Aubert, Michel Neunlist, Gérard Eberl, E. Lévy, Nathalie Vergnolle, Lilian Basso, Nutrition et Neurobiologie intégrée (NutriNeuro), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1 (UB)-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microenvironnement et Immunité - Microenvironment and Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Albert Chenevier, MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA)-Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Ecole nationale supérieure de chimie, biologie et physique, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Pharmacology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, [SDV]Life Sciences [q-bio], Early life, 030227 psychiatry, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, 03 medical and health sciences, Psychiatry and Mental health, 0302 clinical medicine, Neurology, Immunology, Medicine, Pharmacology (medical), Neurology (clinical), Gut dysbiosis, business, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery, Biological Psychiatry
Abstract

International audience

Published
2017

50. Transcriptional activity of the dominant gut mucosal microbiota in chronic inflammatory bowel disease patients

Author

Stefan Schreiber, Andreas Nolte, Stephan Hellmig, Ateequr Rehman, Patricia Lepage, and Stephan J. Ott

Subjects
Adult, Microbiology (medical), Transcription, Genetic, Firmicutes, Microbiology, Inflammatory bowel disease, Pathogenesis, Intestinal mucosa, RNA, Ribosomal, 16S, medicine, Humans, Aged, Gene Library, Crohn's disease, Bacteria, biology, Gene Expression Regulation, Bacterial, General Medicine, Middle Aged, Ribosomal RNA, Inflammatory Bowel Diseases, medicine.disease, biology.organism_classification, Ulcerative colitis, Chronic Disease, Immunology, Dysbiosis
Abstract

Dysbiosis of the gut mucosa-associated microbiota (MAM) plays a pivotal role in the pathogenesis of chronic inflammatory bowel diseases (IBD). To date, dysbiosis only describes the altered composition of the different bacterial populations, but little is known about transcriptional activity, metabolism and the ‘live’ status of the MAM. In this study we investigated the transcriptional activity of the dominant intestinal bacterial populations in patients with IBD. Colonic mucosal biopsies from patients with active Crohn's disease (CD; n=10), active ulcerative colitis (UC; n=10) and healthy individuals (HI; n=10) were compared by 16S rRNA gene and rRNA profiles using clone libraries with more than 1700 sequenced clones. Bacterial richness was significantly lower in clone libraries based on rRNA compared to those based on the rRNA genes in the CD group (3.01 vs 3.91) and the UC group (3.61 vs 4.15), but showed no difference in HI (3.81 vs 3.85). The qualitative composition of rRNA and rRNA gene clone libraries was significantly different, with the phylum Bacteroidetes being the most active (PActinobacteria and Firmicutes were inactive in the CD group, while Escherichia sp. were both abundant and active in the CD and UC groups. Most of the phylotypes showing the highest activity index ratios represented less than 1 % of the microbiota. Our findings indicate that specific bacterial populations are activated in IBD patients, while other groups are in an inactive or ‘dormant’ state. The transcriptional activity points to a more functional role of the intestinal mucosal microbiota and may lead to the identification of therapeutic targets in the active modulation of microbial factors.

Published
2010

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