Blockage of bacterial FimH prevents mucosal inflammation associated with Crohn’s disease

Autor: Cendrine Nicoletti, Vijay Yajnik, Mobidic Study Investigators, Francesco Strozzi, Christophe Bonny, Arnaud Laveissière, Guillaume Desachy, Marc Maresca, Jonathan Plassais, Kenneth W. Simpson, Harry Sokol, Nicolas Barnich, Eric Di Pasquale, Grégoire Chevalier, Rachel Morra, Margarita Martinez-Medina, Alessandra C. L. Cervino, Adeline Sivignon
Přispěvatelé: Enterome, 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), Institut des Sciences Moléculaires de Marseille (ISM2), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Universitat de Girona (UdG), College of Veterinary Medicine [Cornell University], Cornell University [New York]-State University of New York (SUNY), Takeda Pharmaceuticals U.S.A., 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), 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), Paris Center for Microbiome Medicine (FHU PaCeMM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ANR-11-DPBS-0001,MGP,MetaGenoPolis(2011), Cornell University College of Veterinary Medicine, State University of New York (SUNY), 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), FHU Paris Center for Microbiome Medicine (PaCeMM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris-Sud-Université Sorbonne Paris Cité (COMUE) (USPC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris Descartes-Assistance Publique - Hopitaux de Paris (AP-HP)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Microbiome
Microbiome, 2021, 9 (1), pp.1-16. ⟨10.1186/s40168-021-01135-5⟩
Microbiome, BioMed Central, 2021, 9 (1), pp.1-16. ⟨10.1186/s40168-021-01135-5⟩
Microbiome, Vol 9, Iss 1, Pp 1-16 (2021)
Microbiome, 2021, vol. 9, art.núm. 176
Articles publicats (D-B)
DUGiDocs – Universitat de Girona
instname
ISSN: 2049-2618
DOI: 10.1186/s40168-021-01135-5⟩
Popis: MOBIDIC Study Investigators: Temitayo Adegbamigbe (Carolinas Medical Center, Charlotte, North Carolina, United States), Tariq Ahmad (Department of Gastroenterology, Royal Devon and Exeter Hospital National Health Service Foundation Trust, Exeter, UK), Ian Arnott (Gastrointestinal Unit, Western General Hospital, Edinburgh, UK), Yoram Bouhnik (Beaujon Hospital, University Paris 7 Denis Diderot, Clichy, France), Franck Carbonnel (Department of Gastroenterology, Kremlin-Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France), Jean-Frédéric Colombel (Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States), Glen Doherty (Center for Colorectal Disease, St. Vincent’s University Hospital & School of Medicine, UniversityCollege Dublin, Ireland), J. R. Fraser Cummings (Department of Gastroenterology, University Hospital Southampton National Health Service Foundation Trust, Southampton, UK), Xavier Hébuterne (Nice University Hospital, University of Nice Sophia-Antipolis, Nice, France), Hans Herfarth (Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina, United States), David Kevans (Gastroenterologist at St James’s Hospital, Dublin, Ireland), Guillaume Pineton de Chambrun (Hôpital Saint-Eloi, University Hospital of Montpellier,Montpellier, France), Maria Nachury (Huriez Hospital, Université of Lille, Lille, France), Stéphane Nancey (Hospices Civils de Lyon and University Claude Bernard Lyon 1, Pierre-Benite,France), Xavier Roblin (Saint-Etienne University Hospital, Saint-Etienne, France), and Mark A. W. Tremelling (Department of Gastroenterology, Norfolk and Norwich University Hospital, Colney Lane, Norwich, NR4 7UY, UK) Background: An Escherichia coli (E. coli) pathotype with invasive properties, first reported by Darfeuille-Michaud and termed adherent-invasive E. coli (AIEC), was shown to be prevalent in up to half the individuals with Crohn’s Disease (CD), suggesting that these bacteria could be involved in the pathophysiology of CD. Among the genes related to AIEC pathogenicity, fim has the potential to generate an inflammatory reaction from the intestinal epithelial cells and macrophages, as it interacts with TLR4, inducing the production of inflammatory cytokines independently of LPS. Therefore, targeting the bacterial adhesion of FimH-expressing bacteria seems a promising therapeutic approach, consisting of disarming bacteria without killing them, representing a selective strategy to suppress a potentially critical trigger of intestinal inflammation, without disturbing the intestinal microbiota. Results: We analyzed the metagenomic composition of the gut microbiome of 358 patients with CD from two different cohorts and characterized the presence of FimH-expressing bacteria. To assess the pathogenic role of FimH, we used human intestinal explants and tested a specific FimH blocker to prevent bacterial adhesion and associated inflammation. We observed a significant and disease activity-dependent enrichment of Enterobacteriaceae in the gut microbiome of patients with CD. Bacterial FimH expression was functionally confirmed in ileal biopsies from 65% of the patients with CD. Using human intestinal explants, we further show that FimH is essential for adhesion and to trigger inflammation. Finally, a specific FimH-blocker, TAK-018, inhibits bacterial adhesion to the intestinal epithelium and prevents inflammation, thus preserving mucosal integrity. Conclusions: We propose that TAK-018, which is safe and well tolerated in humans, is a promising candidate for the treatment of CD and in particular in preventing its recurrence
Databáze: OpenAIRE
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