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

Grégoire Chevalier 1, * Arnaud Laveissière 1 Guillaume Desachy 1 Nicolas Barnich 2 Adeline Sivignon 2 Marc Maresca 3 Cendrine Nicoletti 3 Eric Di Pasquale 4 Margarita Martinez-Medina 5 Kenneth Simpson 6 Vijay Yajnik 7 Harry Sokol 8, 9, 10 Jonathan Plassais 1 Francesco Strozzi 1 Alessandra Cervino 1 Rachel Morra 1 Christophe Bonny 1 Mobidic Study Investigators
* Corresponding author
10 PaCeMM - FHU Paris Center for Microbiome Medicine
CEA - Commissariat à l'énergie atomique et aux énergies alternatives, INSERM - Institut National de la Santé et de la Recherche Médicale, SU - Sorbonne Université, Université Paris-Sud, USPC - Université Sorbonne Paris Cité (COMUE), INRAE - Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement, Université Paris Descartes, AP-HP - Assistance Publique - Hopitaux de Paris
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.
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Submitted on : Thursday, September 23, 2021 - 3:49:22 PM
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Grégoire Chevalier, Arnaud Laveissière, Guillaume Desachy, Nicolas Barnich, Adeline Sivignon, et al.. Blockage of bacterial FimH prevents mucosal inflammation associated with Crohn’s disease. Microbiome, BioMed Central, 2021, 9 (1), pp.1-16. ⟨10.1186/s40168-021-01135-5⟩. ⟨hal-03352896⟩

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