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1. Faecalibacterium prausnitzii strain EXL01 boosts efficacy of immune checkpoint inhibitors

Author

Marius Bredon, Camille Danne, Hang Phuong Pham, Pauline Ruffié, Alban Bessede, Nathalie Rolhion, Laura Creusot, Loic Brot, Iria Alonso, Philippe Langella, Lisa Derosa, Alexis B. Cortot, Bertrand Routy, Laurence Zitvogel, Nicola Segata, and Harry Sokol

Subjects
Cancer, gut microbiota, immune checkpoint inhibitor, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Gut microbiota impacts responses to immune checkpoint inhibitors (ICI). A high level of Faecalibacterium prausnitzii have been associated with a positive response to ICI in multiple cancer types. Here, based on fecal shotgun metagenomics data, we show in two independent cohorts of patients with non-small cell lung cancer and advanced melanoma that a high level of F. prausnitzii at baseline is positively associated with a better clinical response to ICI. In MCA205 tumor-bearing mice, administration of F. prausnitzii strain EXL01, already in clinical development for Inflammatory Bowel Disease, restores the anti-tumor response to ICI in the context of antibiotic-induced microbiota perturbation at clinical and tumor transcriptomics level. In vitro, EXL01 strain enhances T cell activation in the presence of ICI. Interestingly, oral administration of EXL01 strain did not induce any change in fecal microbiota diversity or composition, suggesting a direct effect on immune cells in the small intestine. F. prausnitzii strain EXL01 will be evaluated as an adjuvant to ICI in multiple cancers in the near future.

Published
2024
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2. Urbanization associates with restricted gut microbiome diversity and delayed maturation in infants

Author

Francesco Morandini, Kevin Perez, Loic Brot, Sidy Mohammed Seck, Laurence Tibère, Jean-Pierre Grill, Enguerran Macia, and Philippe Seksik

Subjects
Microbiology, Microbiome, Developmental biology, Science
Abstract

Summary: Alterations of the microbiome are linked to increasingly common diseases such as obesity, allergy, and inflammatory bowel disease. Post-industrial lifestyles are thought to contribute to the gut microbiome alterations that cause or aggravate these diseases. Comparing communities across the industrialization spectrum can reveal associations between gut microbiome alterations and lifestyle and health, and help pinpoint which specific aspect of the post-industrial lifestyle is linked to microbiome alterations. Here, we compare the gut microbiomes of 60 mother and infant pairs from rural and urban areas of Senegal over two time points. We find that urban mothers, who were more frequently overweight, had different gut microbiome compositions than rural mothers, showing an expansion of Lachnospiraceae and Enterobacter. Urban infants, on the other hand, showed a delayed gut microbiome maturation and a higher susceptibility to infectious diseases. Thus, we identify new microbiome features associated with industrialization, whose association with disease may be further investigated.

Published
2023
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3. SARS-CoV-2 infection in nonhuman primates alters the composition and functional activity of the gut microbiota

Author

Harry Sokol, Vanessa Contreras, Pauline Maisonnasse, Aurore Desmons, Benoit Delache, Valentin Sencio, Arnaud Machelart, Angela Brisebarre, Lydie Humbert, Lucie Deryuter, Emilie Gauliard, Severine Heumel, Dominique Rainteau, Nathalie Dereuddre-Bosquet, Elisabeth Menu, Raphael Ho Tsong Fang, Antonin Lamaziere, Loic Brot, Celine Wahl, Cyriane Oeuvray, Nathalie Rolhion, Sylvie Van Der Werf, Stéphanie Ferreira, Roger Le Grand, and François Trottein

Subjects
gut microbiota, sars-cov-2, nonhuman primates, gut dysbiosis, metabolic output, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

The current pandemic of coronavirus disease (COVID) 2019 constitutes a global public health issue. Regarding the emerging importance of the gut-lung axis in viral respiratory infections, analysis of the gut microbiota’s composition and functional activity during a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection might be instrumental in understanding and controling COVID 19. We used a nonhuman primate model (the macaque), that recapitulates mild COVID-19 symptoms, to analyze the effects of a SARS-CoV-2 infection on dynamic changes of the gut microbiota. 16S rRNA gene profiling and analysis of β diversity indicated significant changes in the composition of the gut microbiota with a peak at 10–13 days post-infection (dpi). Analysis of bacterial abundance correlation networks confirmed disruption of the bacterial community at 10–13 dpi. Some alterations in microbiota persisted after the resolution of the infection until day 26. Some changes in the relative bacterial taxon abundance associated with infectious parameters. Interestingly, the relative abundance of Acinetobacter (Proteobacteria) and some genera of the Ruminococcaceae family (Firmicutes) was positively correlated with the presence of SARS-CoV-2 in the upper respiratory tract. Targeted quantitative metabolomics indicated a drop in short-chain fatty acids (SCFAs) and changes in several bile acids and tryptophan metabolites in infected animals. The relative abundance of several taxa known to be SCFA producers (mostly from the Ruminococcaceae family) was negatively correlated with systemic inflammatory markers while the opposite correlation was seen with several members of the genus Streptococcus. Collectively, SARS-CoV-2 infection in a nonhuman primate is associated with changes in the gut microbiota’s composition and functional activity.

Published
2021
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4. Inter-kingdom effect on epithelial cells of the N-Acyl homoserine lactone 3-oxo-C12:2, a major quorum-sensing molecule from gut microbiota.

Author

Cécilia Landman, Jean-Pierre Grill, Jean-Maurice Mallet, Philippe Marteau, Lydie Humbert, Eric Le Balc'h, Marie-Anne Maubert, Kevin Perez, Wahiba Chaara, Loic Brot, Laurent Beaugerie, Harry Sokol, Sophie Thenet, Dominique Rainteau, Philippe Seksik, Elodie Quévrain, and Saint Antoine IBD Network

Subjects
Medicine, Science
Abstract

BACKGROUND AND AIMS:N-acyl homoserine lactones (AHLs), which are autoinducer quorum-sensing molecules involved in the bacterial communication network, also interact with eukaryotic cells. Searching for these molecules in the context of inflammatory bowel disease (IBD) is appealing. The aims of our study were to look for AHL molecules in faecal samples from healthy subjects (HS) and IBD patients to correlate AHL profiles with the microbiome and investigate the effect of AHLs of interest on epithelial cells. METHODS:Using mass spectrometry, we characterised AHL profiles in faecal samples from HS (n = 26) and IBD patients in remission (n = 24) and in flare (n = 25) and correlated the presence of AHLs of interest with gut microbiota composition obtained by real-time qPCR and 16S sequencing. We synthesised AHLs of interest to test the inflammatory response after IL1β stimulation and paracellular permeability on Caco-2 cells. RESULTS:We observed 14 different AHLs, among which one was prominent. This AHL corresponded to 3-oxo-C12:2 and was found significantly less frequently in IBD patients in flare (16%) and in remission (37.5%) versus HS (65.4%) (p = 0.001). The presence of 3-oxo-C12:2 was associated with significantly higher counts of Firmicutes, especially Faecalbacterium prausnitzii, and lower counts of Escherichia coli. In vitro, 3-oxo-C12:2 exerted an anti-inflammatory effect on Caco-2 cells. Interestingly, although 3-oxo-C12, the well-known AHL from Pseudomonas aeruginosa, increased paracellular permeability, 3-oxo-C12:2 did not. CONCLUSIONS:We identified AHLs in the human gut microbiota and discovered a new and prominent AHL, 3-oxo-C12:2, which correlates with normobiosis and exerts a protective effect on gut epithelial cells.

Published
2018
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5. Impact of IBD-Associated Dysbiosis on Bacterial Quorum Sensing Mediated by Acyl-Homoserine Lactone in Human Gut Microbiota

Author

Nathan Grellier, Marcelino T. Suzuki, Loic Brot, Alice M. S. Rodrigues, Lydie Humbert, Karine Escoubeyrou, Dominique Rainteau, Jean-Pierre Grill, Raphaël Lami, and Philippe Seksik

Subjects
inflammatory bowel diseases, quorum sensing, acyl-homoserine lactones, gut dysbiosis, metagenomic, in silico, Organic Chemistry, Quorum Sensing, General Medicine, Acyl-Butyrolactones, Inflammatory Bowel Diseases, Catalysis, Computer Science Applications, Inorganic Chemistry, Crohn Disease, Humans, Dysbiosis, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, Ecosystem
Abstract

Intestinal dysbiosis is a key feature in the pathogenesis of inflammatory bowel disease (IBD). Acyl-homoserine lactones (AHL) are bacterial quorum-sensing metabolites that may play a role in the changes in host cells-gut microbiota interaction observed during IBD. The objective of our study was to investigate the presence and expression of AHL synthases and receptor genes in the human gut ecosystem during IBD. We used an in silico approach, applied to the Inflammatory Bowel Disease Multi’omics Database comprising bacterial metagenomic and metatranscriptomic data from stools of patients with Crohn’s disease (CD) (n = 50), ulcerative colitis (UC) (n = 27) and non-IBD controls (n = 26). No known putative AHL synthase gene was identified; however, several putative luxR receptors were observed. Regarding the expression of these receptor genes, the luxR gene from Bacteroides dorei was under-expressed in IBD patients (p = 0.02) compared to non-IBD patients, especially in CD patients (p = 0.02). In the dysbiosis situation, one luxR receptor gene from Bacteroides fragilis appeared to be over-expressed (p = 0.04) compared to that of non-dysbiotic patients. Targeting LuxR receptors of bacterial quorum sensing might represent a new approach to modulate the gut microbiota in IBD.

Published
2022
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6. A Simple Bacterium Links Heart Infection to Inflammatory Liver Disease

Author

Marion Larue, Loic Brot, Julie Bruneau, Jean-Paul Duong Van Huyen, Philippe Seksik, Maxence Rouyer, Pierre Isnard, A. Pitsch, and Sylvain Diamantis

Subjects
Aged, 80 and over, Gastrointestinal tract, Hepatology, biology, business.industry, Endocarditis, Bacterial, Autoimmune hepatitis, medicine.disease, biology.organism_classification, Microbiology, Veillonella, Pathogenesis, Hepatitis, Autoimmune, Liver disease, Echocardiography, Flora (microbiology), Intestinal Microbiome, Humans, Medicine, Endocarditis, Female, Gram-Negative Bacterial Infections, business, Bacteria
Abstract

The alteration of the intestinal microbiome has emerged as a key environmental factor increasingly recognized in the pathogenesis of various diseases. Veillonella species are commensal flora bacteria that have been isolated especially in gastrointestinal tract of humans, yet have rarely been implicated in serious infections such as endocarditis.

Published
2021

7. Diet‐Induced Dysbiosis and Genetic Background Synergize With Cystic Fibrosis Transmembrane Conductance Regulator Deficiency to Promote Cholangiopathy in Mice

Author

Ivan Moszer, Dominique Wendum, Haquima El Mourabit, Dominique Rainteau, Yves Chrétien, Fatiha Merabtene, Harry Sokol, Chantal Housset, Damien Ulveling, Loic Brot, and Dominique Debray

Subjects
0301 basic medicine, medicine.medical_specialty, medicine.drug_class, Gut flora, Cystic fibrosis, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Internal medicine, medicine, lcsh:RC799-869, Intestinal permeability, Hepatology, Bile acid, biology, Fatty liver, Original Articles, medicine.disease, biology.organism_classification, Cystic fibrosis transmembrane conductance regulator, 030104 developmental biology, Endocrinology, biology.protein, 030211 gastroenterology & hepatology, Original Article, lcsh:Diseases of the digestive system. Gastroenterology, Dysbiosis
Abstract

The most typical expression of cystic fibrosis (CF)-related liver disease is a cholangiopathy that can progress to cirrhosis. We aimed to determine the potential impact of environmental and genetic factors on the development of CF-related cholangiopathy in mice. Cystic fibrosis transmembrane conductance regulator (Cftr)-/- mice and Cftr +/+ littermates in a congenic C57BL/6J background were fed a high medium-chain triglyceride (MCT) diet. Liver histopathology, fecal microbiota, intestinal inflammation and barrier function, bile acid homeostasis, and liver transcriptome were analyzed in 3-month-old males. Subsequently, MCT diet was changed for chow with polyethylene glycol (PEG) and the genetic background for a mixed C57BL/6J;129/Ola background (resulting from three backcrosses), to test their effect on phenotype. C57BL/6J Cftr -/- mice on an MCT diet developed cholangiopathy features that were associated with dysbiosis, primarily Escherichia coli enrichment, and low-grade intestinal inflammation. Compared with Cftr +/+ littermates, they displayed increased intestinal permeability and a lack of secondary bile acids together with a low expression of ileal bile acid transporters. Dietary-induced (chow with PEG) changes in gut microbiota composition largely prevented the development of cholangiopathy in Cftr -/- mice. Regardless of Cftr status, mice in a mixed C57BL/6J;129/Ola background developed fatty liver under an MCT diet. The Cftr -/- mice in the mixed background showed no cholangiopathy, which was not explained by a difference in gut microbiota or intestinal permeability, compared with congenic mice. Transcriptomic analysis of the liver revealed differential expression, notably of immune-related genes, in mice of the congenic versus mixed background. In conclusion, our findings suggest that CFTR deficiency causes abnormal intestinal permeability, which, combined with diet-induced dysbiosis and immune-related genetic susceptibility, promotes CF-related cholangiopathy.

Published
2018

8. Prominence of ileal mucosa-associated microbiota to predict postoperative endoscopic recurrence in Crohn’s disease

Author

Philippe Seksik, Xavier Treton, Mathurin Fumery, Claire Auzolle, Nicolas Barnich, Lionel Le Bourhis, Benjamin Pariente, Anthony Buisson, Loic Brot, Stéphane Nancey, Harry Sokol, Carmen Stefanescu, Matthieu Allez, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 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), INSERM, U1160, Département de Gastroentérologie, Université Paris Diderot - Paris 7 (UPD7), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Clermont-Ferrand, CHU Amiens-Picardie, Hôpital Claude Huriez [Lille], CHU Lille, Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Autophagie infection et immunité - Autophagy Infection Immunity (APY), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), INSERM UMR-S 606, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, PRES Sorbonne Paris-Cité, and Université Paris Denis Diderot, This study has been supported by grants from MSD France, Association Francois Aupetit, the Helmsley Charitable Trust and Inserm., Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [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), AgroParisTech, Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de la Recherche Agronomique (INRA), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Centre Hospitalier Universitaire Clermont Ferrand, Centre hospitalier universitaire d'Amiens (CHU Amiens-Picardie), Hôpital Claude Huriez, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Autophagie infections immunité – Autophagy Infection Immunity, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)

Subjects
Adult, Male, medicine.medical_specialty, Firmicutes, Disease, Gut flora, Gastroenterology, digestive system, Endoscopy, Gastrointestinal, Ileal resection, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Crohn Disease, Ileum, Recurrence, Risk Factors, Internal medicine, Proteobacteria, medicine, microbiota, Humans, Postoperative Period, Prospective Studies, Intestinal Mucosa, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Crohn's disease, biology, business.industry, Lachnospiraceae, Healthy subjects, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, mucosa-associated, Middle Aged, biology.organism_classification, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Gastrointestinal Microbiome, Cohort, 030211 gastroenterology & hepatology, Female, business, Ileal mucosa
Abstract

ObjectiveFollowing ileal resection for Crohn’s disease (CD), recurrence is very frequent. Although several clinical risk factors of recurrence have been identified, predicting relapse remains challenging. Performing an ileocolonoscopy within the first year after surgery is currently recommended to assess endoscopic recurrence and to adjust the treatment. We took advantage of a large prospective multicentric cohort to investigate the role of the ileal mucosa-associated microbiota in postoperative endoscopic recurrence.Patients and methodsIleal mucosa-associated microbiota was analysed by 16S sequencing at the time of surgery and/or of endoscopic evaluation in 201 patients (288 samples in total) prospectively recruited in France.ResultsIleal mucosa-associated microbiota exhibits profound changes following surgery in CD. Compared with non-recurrence setting, endoscopic recurrence is associated with strong changes in ileal mucosa-associated microbiota that are highly reminiscent of those observed generally in ileal CD compared with healthy subjects with a reduction in alpha diversity, an increase in several members of the Proteobacteria phylum and a decrease in several members of the Lachnospiraceae and the Ruminococcaceae families within the Firmicutes phylum. At the time of surgery, we identified several bacterial taxa associated with endoscopic recurrence and that can better predict relapse than usual clinical risk factors.ConclusionSurgery has an important impact on ileal mucosa-associated microbiota. Postoperative endoscopic recurrence is associated with changes in microbiota composition and alpha diversity. The gut microbiota has the potential to predict postoperative evolution and recurrence.

Published
2020

9. Palmitic acid damages gut epithelium integrity and initiates inflammatory cytokine production

Author

Philippe Seksik, Sara Ghezzal, Véronique Carrière, Armelle Leturque, Barbara Graziela Postal, Sophie Thenet, Loic Brot, Elodie Quévrain, 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), Laboratoire des biomolécules (LBM UMR 7203), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CCSD, Accord Elsevier, Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), Centre de Recherche Saint-Antoine (CRSA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Male, Cell-cell junction, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Palmitic Acid, Administration, Oral, Palm Oil, Palmitic acid, chemistry.chemical_compound, Feces, Mice, 0302 clinical medicine, Intestinal Mucosa, ComputingMilieux_MISCELLANEOUS, Metabolic Syndrome, biology, Endoplasmic Reticulum Stress, Gut Epithelium, Cell biology, Intestine, [SDV] Life Sciences [q-bio], Cytokine, 030220 oncology & carcinogenesis, Cytokines, medicine.symptom, Inflammation Mediators, Akkermansia muciniphila, Inflammation, Permeability, Tight Junctions, 03 medical and health sciences, medicine, Animals, Humans, Molecular Biology, Gut permeability, Intestinal permeability, Cell Biology, medicine.disease, biology.organism_classification, Fatty acid, Gastrointestinal Microbiome, Oleic acid, Disease Models, Animal, 030104 developmental biology, chemistry, Caco-2 Cells
Abstract

International audience; he mechanisms leading to the low-grade inflammation observed during obesity are not fully understood. Seeking the initiating events, we tested the hypothesis that the intestine could be damaged by repeated lipid supply and therefore participate in inflammation. In mice, 1-5 palm oil gavages increased intestinal permeability via decreased expression and mislocalization of junctional proteins at the cell-cell contacts; altered the intestinal bacterial species by decreasing the abundance of Akkermansia muciniphila, segmented filamentous bacteria, and Clostridium leptum; and increased inflammatory cytokine expression. This was further studied in human intestinal epithelial Caco-2/TC7 cells using the two main components of palm oil, i.e., palmitic and oleic acid. Saturated palmitic acid impaired paracellular permeability and junctional protein localization, and induced inflammatory cytokine expression in the cells, but unsaturated oleic acid did not. Inhibiting de novo ceramide synthesis prevented part of these effects. Altogether, our data show that short exposure to palm oil or palmitic acid induces intestinal dysfunctions targeting barrier integrity and inflammation. Excessive palm oil consumption could be an early player in the gut alterations observed in metabolic diseases.

Published
2020

10. Association Between Microscopic Lesions at Ileal Resection Margin and Recurrence After Surgery in Patients With Crohn’s Disease

Author

Alexandra Traverse-Glehen, Nassim Hammoudi, Olivier Corcos, Philippe Marteau, Julien Loreau, Mariane Maillet, Martine Leconte, Jonathan Catry, Yves Francois, Najim Chafai, Xavier Dray, Marjolaine Ngollo, Philippe Seksik, Pierre Cattan, Benjamin Pariente, Nicolas Munoz-Bongrand, Peggy Falgon, Stéphane Nancey, Nathan Beaupel, Isabelle Nion-Larmurier, Andrée Nisard, Christophe Attencourt, Emmanuel Tiret, Ulrika Chaput, Denis Chatelain, Marion Chauvenet, Dominique Cazals-Hatem, Eddy Cotte, Laurent Beaugerie, Madeleine Bezault, Mircea Chirica, Gilles Boschetti, Sarah Boyer, Loic Brot, Julien Kirchgesner, Hugo Bottois, Anne Dubois, Magali Svrcek, Yoram Bouhnik, Jean-Marc Gornet, Rachid Kaci, Brice Gergaud, Carmen Stefanescu, Helene Corte, Claire Auzolle, Jean-Louis Dupas, Juliette Joubert Zakeyh, Leila Chedouba, Amine Rahili, Elodie Quévrain, Charles Sabbagh, Lionel Le Bourhis, Maria Nachury, Anne Bourrier, Nathalie Guedj, Florence Renaud, Helena Hadjisavvas, Charlotte Gardair, Gilles Bommelaer, Céline Grand, Xavier Treton, Xavier Jouven, Anthony Buisson, Jérémie H. Lefevre, Paul Hofmann, Stéphanie Patouraux, Jérôme Filippi, Xavier Hébuterne, Driffa Moussata, Clotilde Baudry, Nelson Lourenco, Marion Goutte, Harry Sokol, Victor Chardiny, My-Linh Tran-Minh, Bernard Flourié, Pierre Desreumaux, Catherine Godfraind, Coralie Sommeville, Mathurin Fumery, Nicolas Barnich, Joëlle Bonnet, Anne-Laure Charlois, Dilek Coban, Leon Magiorri, Yves Panis, Matthieu Allez, Jean-François Fléjou, Franck Brazier, M. Ferron, Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépato-gastro-entérologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Département de Pathologie [Hôpital Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Laboratoire de pathologie [AP-HP Hôpital Saint-Louis], Hopital Saint-Louis, Assistance Publique – Hôpitaux de Paris (AP-HP), Autophagie infections immunité – Autophagy Infection Immunity, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Service d'Hépato-gastroentérologie, Hôpital Huriez-Université de Lille, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Service de Gastroentérologie [Hôpital Beaujon], Hôpital Beaujon, Service d'Hépato Gastroenterologie [CHU Amiens-Picardie], CHU Amiens-Picardie, Laboratoire des biomolécules (LBM UMR 7203), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Pathologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Autophagie infection et immunité - Autophagy Infection Immunity (APY), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de la Recherche Agronomique (INRA), Hôpital Beaujon [AP-HP], Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, medicine.medical_specialty, Cryptitis, Ileum, REMIND Trial, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, Recurrence, Interquartile range, medicine, Humans, Prospective Studies, Colectomy, Digestive System Surgical Procedures, Outcome, Crohn's disease, Hepatology, medicine.diagnostic_test, business.industry, Prognostic Factor, IBD Surgery, Anastomosis, Surgical, Gastroenterology, Margins of Excision, Histology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Odds ratio, Middle Aged, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Endoscopy, Surgery, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, Complication, business
Abstract

International audience; Background and AimsDifferent types of histologic lesions at the ileal margin, detected by histology, have been associated with increased rates of recurrence after ileocaecal surgery in patients with Crohn’s disease (CD). We aimed to characterize histologic features of the ileal margin and to evaluate their association with disease recurrence.MethodsWe collected histologic data from 211 patients with ileal or ileocolonic CD who underwent ileocolonic resections at hospitals in France from September 2010 through December 2016. Ileal margins were analyzed. Early endoscopic recurrence was defined by a Rutgeerts score of i2 or more, 6 months after surgery. We also collected data from 10 adults with healthy ileum who underwent ileocecal resection for colonic tumors (controls). Clinical relapse was defined by CD-related symptoms confirmed by imaging, endoscopy, therapy intensification, CD-related complication, or subsequent surgery.ResultsSix months after surgery, 49% of patients had endoscopic recurrence; 5 years after surgery, 57% of patients had clinical relapse. Ileal margins were macroscopically affected in 20.9% of patients. CD transmural lesions at the margin (defined by mucosal ulceration or cryptitis, submucosal fibrosis and lymphoplasmacytic infiltrate of the subserosa) were observed in 13.6% of patients. Endoscopic recurrence was observed in 75% of patients with CD transmural lesions vs 46% of patients without (P =.005). In multivariate analysis, CD transmural lesions at the margin were independently associated with early endoscopic recurrence (OR, 3.83; 95% CI, 1.47-11.05; P =.008) and clinical recurrence (OR 2.04; 95% CI, 1.09-3.99; P =.026).ConclusionIn patients with CD, transmural lesions at the ileal margin were associated with an increased risk of post-operative recurrence. Histologic features of the ileal margin should be included in making decisions about post-operative therapy.

Published
2019

11. Anti-Inflammatory Effects of Analogues of N-Acyl Homoserine Lactones on Eukaryotic Cells

Author

Agathe Peyrottes, Loic Brot, Jean-Maurice Mallet, Jean-Pierre Grill, Philippe Seksik, Dominique Rainteau, Garance Coquant, Laboratoire des biomolécules (LBM UMR 7203), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [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), Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Chimie Moléculaire de Paris Centre (FR 2769), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], and Gestionnaire, Hal Sorbonne Université

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Anti-Inflammatory Agents, Stimulation, Acyl-Butyrolactones, Gut flora, 01 natural sciences, lcsh:Chemistry, Mice, lcsh:QH301-705.5, Spectroscopy, chemistry.chemical_classification, biology, Chemistry, food and beverages, General Medicine, Pyrrolidinones, 3. Good health, Computer Science Applications, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Cytokine, lipids (amino acids, peptides, and proteins), Lactone, medicine.drug_class, Article, Catalysis, Anti-inflammatory, Inorganic Chemistry, 03 medical and health sciences, Immune system, inflammatory bowel disease, medicine, Animals, Physical and Theoretical Chemistry, Molecular Biology, Analysis of Variance, Acyl-Homoserine Lactones, gut microbiota, 010405 organic chemistry, Organic Chemistry, Inflammatory Bowel Diseases, biology.organism_classification, Molecular biology, Epithelium, Gastrointestinal Microbiome, 0104 chemical sciences, RAW 264.7 Cells, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, AHL
Abstract

Background: Since acyl-homoserine lactone (AHL) profiling has been described in the gut of healthy subjects and patients with inflammatory bowel disease (IBD), the potential effects of these molecules on host cells have raised interest in the medical community. In particular, natural AHLs such as the 3-oxo-C12-HSL exhibit anti-inflammatory properties. Our study aimed at finding stable 3-oxo-C12-HSL-derived analogues with improved anti-inflammatory effects on epithelial and immune cells. Methods: We first studied the stability and biological properties of the natural 3-oxo-C12-HSL on eukaryotic cells and a bacterial reporter strain. We then constructed and screened a library of 22 AHL-derived molecules. Anti-inflammatory effects were assessed by cytokine release in an epithelial cell model, Caco-2, and a murine macrophage cell line, RAW264.7, (respectively, IL-8 and IL-6) upon exposure to the molecule and after appropriate stimulation (respectively, TNF-&alpha, 50 ng/mL and IFN-&gamma, 50 ng/mL, and LPS 10 ng/mL and IFN-&gamma, 20 U/mL). Results: We found two molecules of interest with amplified anti-inflammatory effects on mammalian cells without bacterial-activating properties in the reporter strain. The molecules furthermore showed improved stability in biological medium compared to the native 3-oxo-C12-HSL. Conclusions: We provide new bio-inspired AHL analogues with strong anti-inflammatory properties that will need further study from a therapeutic perspective.

Published
2020

12. Mo1113 – 3-Oxo-C12:2 N-Acyl Homoserine Lactone, a Quorum Sensing Molecule from the Gut Microbiota: A New Player to Control Gut Inflammation

Author

Sophie Thenet, Céline Osinski, Jean-Maurice Mallet, Cécilia Landman, Elodie Quévrain, Loic Brot, Jean-Pierre Grill, Philippe Seksik, Véronique Carrière, Garance Coquant, Agathe Peyrottes, Doriane Aguanno, and Armelle Leturque

Subjects
Gut inflammation, Quorum sensing, chemistry.chemical_compound, N-Acyl homoserine lactone, Hepatology, biology, chemistry, Biochemistry, Gastroenterology, Gut flora, biology.organism_classification
Published
2019

13. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands

Author

Anne Bourrier, Jane M. Natividad, Soraya Taleb, Loic Brot, Chantal Bridonneau, Philippe Seksik, Laurent Beaugerie, Jacques Cosnes, Harry Sokol, Isabelle Nion-Larmurier, Marie-Laure Michel, Bernhard Ryffel, Jean-Marie Launay, Fatiha Merabtene, Hang-Phuong Pham, Ramnik J. Xavier, Sarah Jegou, Aurélie Couturier-Maillard, Philippe Langella, Bruno Lamas, Grégory Da Costa, Thomas W. Hoffmann, Valentin Leducq, Mathias L. Richard, Université Pierre et Marie Curie - Paris 6 (UPMC), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Rhumatologie [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), McMaster Univ, Farncombe Family Digest Hlth Res Inst, Hamilton, ON L8S 4L8, Canada, Université Paris Diderot - Paris 7 (UPD7), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), CHU Saint-Antoine [AP-HP], Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Technicolor [Cesson Sévigné], Technicolor, Equipe ATIP-Avenir, INSERM-ITMO SP, ECCO grant, Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), CHU Pitié-Salpêtrière [APHP]-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Pitié-Salpêtrière [APHP], Institut de recherche en informatique de Toulouse (IRIT), Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), 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)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Trousseau [APHP], 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 Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], 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, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [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), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Sorbonne Université (SU)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP]

Subjects
Male, 0301 basic medicine, Gut flora, Inflammatory bowel disease, Mice, RNA, Ribosomal, 16S, Lactobacillus, Chromatography, High Pressure Liquid, Mice, Knockout, biology, Reverse Transcriptase Polymerase Chain Reaction, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Dextran Sulfate, Tryptophan, Interleukin, General Medicine, Fecal Microbiota Transplantation, Middle Aged, Colitis, 3. Good health, Cytokines, Female, Adult, Adolescent, Colon, digestive system, General Biochemistry, Genetics and Molecular Biology, Microbiology, Young Adult, 03 medical and health sciences, Immune system, inflammatory bowel disease, mucosal immunology, medicine, Animals, Humans, Gene Expression Profiling, Interleukins, Inflammatory Bowel Diseases, biology.organism_classification, medicine.disease, Aryl hydrocarbon receptor, Gastrointestinal Microbiome, CARD Signaling Adaptor Proteins, 030104 developmental biology, Receptors, Aryl Hydrocarbon, Mucosal immunology, Immunology, biology.protein
Abstract

International audience; Complex interactions between the host and the gut microbiota govern intestinal homeostasis but remain poorly understood. Here we reveal a relationship between gut microbiota and caspase recruitment domain family member 9 (CARD9), a susceptibility gene for inflammatory bowel disease (IBD) that functions in the immune response against microorganisms. CARD9 promotes recovery from colitis by promoting interleukin (IL)-22 production, and Card9-/- mice are more susceptible to colitis. The microbiota is altered in Card9-/- mice, and transfer of the microbiota from Card9-/- to wild-type, germ-free recipients increases their susceptibility to colitis. The microbiota from Card9-/- mice fails to metabolize tryptophan into metabolites that act as aryl hydrocarbon receptor (AHR) ligands. Intestinal inflammation is attenuated after inoculation of mice with three Lactobacillus strains capable of metabolizing tryptophan or by treatment with an AHR agonist. Reduced production of AHR ligands is also observed in the microbiota from individuals with IBD, particularly in those with CARD9 risk alleles associated with IBD. Our findings reveal that host genes affect the composition and function of the gut microbiota, altering the production of microbial metabolites and intestinal inflammation.

Published
2016

14. P780 3-oxo-C12:2-HSL, a new N-acyl-homoserine lactone identified in gut ecosystem exerts an anti-inflammatory effect and does not modify paracellular permeability

Author

Jean-Pierre Grill, Elodie Quévrain, Loic Brot, Sophie Thenet, Cécilia Landman, Dominique Rainteau, E. Le Balc'h, E. Tauziet, and P. Seksik

Subjects
biology, 010405 organic chemistry, medicine.drug_class, business.industry, 010401 analytical chemistry, Gastroenterology, General Medicine, biology.organism_classification, medicine.disease, 01 natural sciences, Anti-inflammatory, 0104 chemical sciences, Quorum sensing, chemistry.chemical_compound, N-Acyl homoserine lactone, Biochemistry, chemistry, Permeability (electromagnetism), Paracellular transport, medicine, Interleukin 8, business, Dysbiosis, Bacteria
Published
2017

15. 3-oxo-C12:2-HSL, quorum sensing molecule from human intestinal microbiota, inhibits pro-inflammatory pathways in immune cells via bitter taste receptors

Author

Garance Coquant, Doriane Aguanno, Loïc Brot, Christine Belloir, Julie Delugeard, Nathalie Roger, Hang-Phuong Pham, Loïc Briand, Marielle Moreau, Luisa de Sordi, Véronique Carrière, Jean-Pierre Grill, Sophie Thenet, and Philippe Seksik

Subjects
Medicine, Science
Abstract

Abstract In the gut ecosystem, microorganisms regulate group behaviour and interplay with the host via a molecular system called quorum sensing (QS). The QS molecule 3-oxo-C12:2-HSL, first identified in human gut microbiota, exerts anti-inflammatory effects and could play a role in inflammatory bowel diseases where dysbiosis has been described. Our aim was to identify which signalling pathways are involved in this effect. We observed that 3-oxo-C12:2-HSL decreases expression of pro-inflammatory cytokines such as Interleukine-1β (− 35%) and Tumor Necrosis Factor-α (TNFα) (− 40%) by stimulated immune RAW264.7 cells and decreased TNF secretion by stimulated PBMC in a dose-dependent manner, between 25 to 100 µM. Transcriptomic analysis of RAW264.7 cells exposed to 3-oxo-C12:2-HSL, in a pro-inflammatory context, highlighted JAK-STAT, NF-κB and TFN signalling pathways and we confirmed that 3-oxo-C12:2-HSL inhibited JAK1 and STAT1 phosphorylation. We also showed through a screening assay that 3-oxo-C12:2-HSL interacted with several human bitter taste receptors. Its anti-inflammatory effect involved TAS2R38 as shown by pharmacologic inhibition and led to an increase in intracellular calcium levels. We thus unravelled the involvement of several cellular pathways in the anti-inflammatory effects exerted by the QS molecule 3-oxo-C12:2-HSL.

Published
2022
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16. P053 Impact of N- acyl-homoserine lactone 3-oxo-C12:2, a major quorum sensing molecule from gut microbiota, on intestinal epithelial barrier function

Author

Sophie Thenet, Cécilia Landman, A Peyrottes, Jean-Maurice Mallet, Loic Brot, P. Seksik, E. Le Balc'h, Jean-Pierre Grill, Elodie Quévrain, A Leturque, and D Aguanno

Subjects
biology, business.industry, Gastroenterology, General Medicine, Gut flora, biology.organism_classification, chemistry.chemical_compound, Quorum sensing, N-Acyl homoserine lactone, chemistry, Biochemistry, Medicine, Epithelial barrier function, Molecule, business
Published
2018

17. Human CD4+CD8α+ Tregs induced by Faecalibacterium prausnitzii protect against intestinal inflammation

Author

Sothea Touch, Emmanuelle Godefroy, Nathalie Rolhion, Camille Danne, Cyriane Oeuvray, Marjolène Straube, Chloé Galbert, Loïc Brot, Iria Alonso Salgueiro, Sead Chadi, Tatiana Ledent, Jean-Marc Chatel, Philippe Langella, Francine Jotereau, Frédéric Altare, and Harry Sokol

Subjects
Gastroenterology, Medicine
Abstract

Abundance of Faecalibacterium prausnitzii, a dominant bacterium of the human microbiota that exhibits antiinflammatory effects, is decreased in patients with inflammatory bowel diseases (IBD). In humans, colonic lamina propria contains IL-10–secreting, Foxp3– Tregs characterized by a double expression of CD4 and CD8α (DP8α) and a specificity for F. prausnitzii. This Treg subset is decreased in IBD. The in vivo effect of DP8α cells has not been evaluated yet to our knowledge. Here, using a humanized model of a NSG immunodeficient mouse strain that expresses the HLA D–related allele HLA-DR*0401 but not murine class II (NSG-Ab° DR4) molecules, we demonstrated a protective effect of a HLA-DR*0401–restricted DP8α Treg clone combined with F. prausnitzii administration in a colitis model. In a cohort of patients with IBD, we showed an independent association between the frequency of circulating DP8α cells and disease activity. Finally, we pointed out a positive correlation between F. prausnitzii–specific DP8α Tregs and the amount of F. prausnitzii in fecal microbiota in healthy individuals and patients with ileal Crohn’s disease.

Published
2022
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18. Mo1815 A Simple Biomarker for IBD Associated Dysbiosis:The Ratio of Iso-LCA/LCA Indicates Alteration of Isomeration of Bile Acids in the Intestinal Lumen

Author

Philippe Seksik, Harry Sokol, Cécilia Landman, Camille Hannotte, Manon Charrier, Dominique Rainteau, Loic Brot, Thomas Bazin, Elodie Quévrain, Valentin Leducq, Marie-Anne Maubert, Laurent Beaugerie, Jacques Cosnes, and Lydie Humbert

Subjects
medicine.medical_specialty, Hepatology, Internal medicine, Gastroenterology, medicine, Biomarker (medicine), Biology, medicine.disease, Dysbiosis
Published
2015

22. 270 Implications of Faecal Microbiota Alterations in Bile Acids Metabolism in Irritable Bowel Syndrome

Author

Harry Sokol, Pauline Jouet, Germain Trugnan, Heloise Delagreverie, Dominique Rainteau, Loic Brot, Jean-Marc Sabate, Dior Marie, Lydie Humbert, Henri Duboc, Benoit Coffin, and Philippe Seksik

Subjects
medicine.medical_specialty, Hepatology, business.industry, Internal medicine, Gastroenterology, medicine, Metabolism, business, medicine.disease, Irritable bowel syndrome
Published
2013

23. Sa1804 Quorum Sensing Driven by N-Acyl-Homoserine Lactone in Inflammatory Bowel Diseases Associated Dysbiosis

Author

Loic Brot, Germain Trugnan, Harry Sokol, Philippe Seksik, Elodie Quévrain, Laurent Beaugerie, Marie-Anne Maubert, Alison Besse, Cécilia Landman, Lydie Humbert, Jacques Cosnes, and Dominique Rainteau

Subjects
chemistry.chemical_compound, Quorum sensing, N-Acyl homoserine lactone, Hepatology, Chemistry, Gastroenterology, medicine, Inflammatory Bowel Diseases, medicine.disease, Dysbiosis, Microbiology
Published
2013

24. Diet‐Induced Dysbiosis and Genetic Background Synergize With Cystic Fibrosis Transmembrane Conductance Regulator Deficiency to Promote Cholangiopathy in Mice

Author

Dominique Debray, Haquima El Mourabit, Fatiha Merabtene, Loïc Brot, Damien Ulveling, Yves Chrétien, Dominique Rainteau, Ivan Moszer, Dominique Wendum, Harry Sokol, and Chantal Housset

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

The most typical expression of cystic fibrosis (CF)–related liver disease is a cholangiopathy that can progress to cirrhosis. We aimed to determine the potential impact of environmental and genetic factors on the development of CF‐related cholangiopathy in mice. Cystic fibrosis transmembrane conductance regulator (Cftr)−/− mice and Cftr+/+ littermates in a congenic C57BL/6J background were fed a high medium‐chain triglyceride (MCT) diet. Liver histopathology, fecal microbiota, intestinal inflammation and barrier function, bile acid homeostasis, and liver transcriptome were analyzed in 3‐month‐old males. Subsequently, MCT diet was changed for chow with polyethylene glycol (PEG) and the genetic background for a mixed C57BL/6J;129/Ola background (resulting from three backcrosses), to test their effect on phenotype. C57BL/6J Cftr−/− mice on an MCT diet developed cholangiopathy features that were associated with dysbiosis, primarily Escherichia coli enrichment, and low‐grade intestinal inflammation. Compared with Cftr+/+ littermates, they displayed increased intestinal permeability and a lack of secondary bile acids together with a low expression of ileal bile acid transporters. Dietary‐induced (chow with PEG) changes in gut microbiota composition largely prevented the development of cholangiopathy in Cftr−/− mice. Regardless of Cftr status, mice in a mixed C57BL/6J;129/Ola background developed fatty liver under an MCT diet. The Cftr−/− mice in the mixed background showed no cholangiopathy, which was not explained by a difference in gut microbiota or intestinal permeability, compared with congenic mice. Transcriptomic analysis of the liver revealed differential expression, notably of immune‐related genes, in mice of the congenic versus mixed background. In conclusion, our findings suggest that CFTR deficiency causes abnormal intestinal permeability, which, combined with diet‐induced dysbiosis and immune‐related genetic susceptibility, promotes CF‐related cholangiopathy.

Published
2018
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