Blockage of bacterial FimH prevents mucosal inflammation associated with Crohn’s disease
dc.contributor.author
dc.date.accessioned
2021-10-15T07:35:36Z
dc.date.available
2021-10-15T07:35:36Z
dc.date.issued
2021-08-23
dc.identifier.uri
dc.description
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)
dc.description.abstract
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
dc.format.mimetype
application/pdf
dc.language.iso
eng
dc.publisher
Springer Nature
dc.relation.isformatof
Reproducció digital del document publicat a: https://doi.org/10.1186/s40168-021-01135-5
dc.relation.ispartof
Microbiome, 2021, vol. 9, art.núm. 176
dc.relation.ispartofseries
Articles publicats (D-B)
dc.rights
Attribution 4.0 International
dc.rights.uri
dc.subject
dc.title
Blockage of bacterial FimH prevents mucosal inflammation associated with Crohn’s disease
dc.type
info:eu-repo/semantics/article
dc.rights.accessRights
info:eu-repo/semantics/openAccess
dc.type.version
info:eu-repo/semantics/publishedVersion
dc.identifier.doi
dc.type.peerreviewed
peer-reviewed
dc.identifier.eissn
2049-2618