Abstract
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
Highlights
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
FimH, which is expressed by the type of pathogenic E. coli reported to be found in the GI track of patients with CD, has the potential to generate an inflammatory reaction from the intestinal epithelial cells and macrophages residing in non-inflamed mucosa
We showed that TAK-018 aggregates the reference FimH-expressing AIEC E. coli LF82 strain, whereas a FimH negative mutant of E. coli LF82 did not aggregate upon incubation with TAK-018, allowing for the detection of FimHexpressing bacteria with TAK-018 (Fig. 3a)
Summary
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. Even though not reported other mannosylated abundant components like mucus might provide high-capacity substrates for FimH attachment [22], allowing for biofilm formation and bacteria-specific mucosal immune responses [12, 15, 19, 21, 23] Despite their role as sources of proinflammatory cytokines [24], normal healthy intestinal epithelial cells (IECs), as well as intestinal macrophages lack the TLR4-accessory proteins CD14 or MD2, rendering these cell types resistant to lipopolysaccharides (LPS)-induced inflammation [25,26,27,28,29,30,31,32]. The critical role of FimH as a pro-inflammatory mediator in CD stresses the importance of designing therapeutic strategies that can disrupt this pathogenic pathway [35]
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