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

Microbiome

Cendrine Nicoletti¹  Marc Maresca¹  Eric Di Pasquale²  Kenneth William Simpson³  Rachel Morra⁴  Francesco Strozzi⁴  Arnaud Laveissière⁴  Alessandra Cervino⁴  Christophe Bonny⁴  Jonathan Plassais⁴  Grégoire Chevalier⁴  Guillaume Desachy⁴  Vijay Yajnik⁵  Harry Sokol⁶  Margarita Martinez-Medina⁷  Nicolas Barnich⁸  Adeline Sivignon⁸ 

[1] Aix Marseille Université, CNRS, Centrale Marseille, iSm2, Marseille, France;Aix-Marseille Université, CNRS, INP, Institut de Neurophysiopathologie, Marseille, France;College of Veterinary Medicine, Cornell University, 14853, Ithaca, NY, USA;Enterome, 94-96 Avenue Ledru-Rollin, 75011, Paris, France;GI Therapeutic Area Unit, Takeda Pharmaceuticals, 02139, Cambridge, MA, USA;Gastroenterology Department, Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, 75012, Paris, France;INRA, UMR1319 Micalis & AgroParisTech, Jouy en Josas, France;Paris Center for Microbiome Medicine (PaCeMM) FHU, AP-HP, Paris, France;Microbiology of Intestinal Diseases, Biology Department, Universitat de Girona, Girona, Spain;Université Clermont Auvergne, Inserm U1071, M2iSH, USC-INRA 2018, F-63000, Clermont-Ferrand, France;

关键词: Crohn’s disease;    Inflammation;    FimH;    Enterobacteriaceae;   

DOI  :  10.1186/s40168-021-01135-5

来源: Springer

【 摘 要 】

BackgroundAn 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.ResultsWe 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.ConclusionsWe 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.Dv5gxXFC6aaMrbE5qenQmhVideo abstract

【 授权许可】

CC BY