The Vat-AIEC protease promotes crossing of the intestinal mucus layer by Crohn's disease-associatedEscherichia coli

Abstract

The aetiology of Crohn's disease (CD) involves disorders in host genetic factors and intestinal microbiota. Adherent-invasive Escherichia coli (AIEC) are receiving increased attention because in studies of mucosa-associated microbiota, they are more prevalent in CD patients than in healthy subjects. AIEC are associated both with ileal and colonic disease phenotypes. In this study, we reported a protease called Vat-AIEC from AIEC that favours the mucosa colonization. The deletion of the Vat-AIEC-encoding gene resulted in an adhesion-impaired phenotype in vitro and affected the colonization of bacteria in contact with intestinal epithelial cells in a murine intestinal loop model, and also their gut colonization in vivo. Furthermore, unlike LF82Δvat-AIEC, wild-type AIEC reference strain LF82 was able to penetrate a mucus column extensively and promoted the degradation of mucins and a decrease in mucus viscosity. Vat-AIEC transcription was stimulated by several chemical conditions found in the ileum environment. Finally, the screening of E. coli strains isolated from CD patients revealed a preferential vat-AIEC association with AIEC strains belonging to the B2 phylogroup. Overall, this study revealed a new component of AIEC virulence that might favour their implantation in the gut of CD patients.

Roles for Intestinal Bacteria, Viruses, and Fungi in Pathogenesis of Inflammatory Bowel Diseases and Therapeutic Approaches

“…Mechanisms by which AIEC adhere to, invade, and persist within cells have been characterized 107, 108 . Unique AIEC gene products determine epithelial attachment via long polar fimbria and mutated FimH to human epithelial CEACAM 6, biofilm formation, mucus penetration, epithelial cell invasion and persistence within epithelial cells and macrophages 109–113 . Variants in genes associated with risk for Crohn’s disease that regulate autophagy promote AIEC intracellular persistence; AIEC modulate autophagic clearance 114, 115 .…”

Adherent-invasive Escherichia coli in inflammatory bowel disease

“…A recently described protease secreted by AIEC (VAT-AIEC) has been reported to contribute to gut colonisation in a murine model by enhancing the spread of bacteria through the mucous layer and adhesion to IEC (figure 1). 88 The secretion of host defence antimicrobial peptides can also be altered by some isolates of AIEC by the presence of two genes in a plasmid-encoded genomic island (called PI-6), arlA , which encodes a Mig-14 family protein implicated in defensin resistance, and arlC , an OmpT family outer membrane protease 89…”

Mechanisms of Intestinal Epithelial Barrier Dysfunction by Adherent-Invasive Escherichia coli

“…However, there may be some genetic signatures that differ between the B2 AIEC phylotype compared with other AIEC phylotypes 12 . One potential AIEC candidate gene is the novel AIEC serine protease Vat-AIEC, which promotes expansion and adherence of AIEC to intestinal epithelial cells (IECs) 15 . Expression of this gene was approximately 3-fold higher in CD-AIEC isolates compared with non-AIEC isolates from CD patients or healthy subjects 15 .…”

“…One potential AIEC candidate gene is the novel AIEC serine protease Vat-AIEC, which promotes expansion and adherence of AIEC to intestinal epithelial cells (IECs) 15 . Expression of this gene was approximately 3-fold higher in CD-AIEC isolates compared with non-AIEC isolates from CD patients or healthy subjects 15 . It therefore could be considered a selective rather than an exclusive genetic marker for AIEC.…”