Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation?

Abstract

Background and aim: A genetically impaired intestinal barrier function has long been suspected to be a predisposing factor for Crohn's disease (CD). Recently, mutations of the capsase recruitment domain family, member 15 (CARD15) gene have been identified and associated with CD. We hypothesise that a CARD15 mutation may be associated with an impaired intestinal barrier. Methods: We studied 128 patients with quiescent CD, 129 first degree relatives (CD-R), 66 non-related household members (CD-NR), and 96 healthy controls. The three most common CARD15 polymorphisms (R702W, G908R, and 3020insC) were analysed and intestinal permeability was determined by the lactulose/mannitol ratio. Results: Intestinal permeability was significantly increased in CD and CD-R groups compared with CD-NR and controls. Values above the normal range were seen in 44% of CD and 26% of CD-R but only in 6% of CD-NR, and in none of the controls. A household community with CD patients, representing a common environment, was not associated with increased intestinal permeability in family members. However, 40% of CD first degree relatives carrying a CARD15 3020insC mutation and 75% (3/4) of those CD-R with combined 3020insC and R702W mutations had increased intestinal permeability compared with only 15% of wild-types, indicating a genetic influence on barrier function. R702W and G908R mutations were not associated with high permeability. Conclusions: In healthy first degree relatives, high mucosal permeability is associated with the presence of a CARD15 3020insC mutation. This indicates that genetic factors may be involved in impairment of intestinal barrier function in families with IBD.

NOD2 polymorphisms predict severe acute graft-versus-host and treatment-related mortality in T-cell-depleted haematopoietic stem cell transplantation

“…8 The pathogenesis is not fully understood but there are several hypotheses involving the loss of antimicrobial activity and a deregulated immune response. Reduced antimicrobial activity results from decreased production of antimicrobial peptides, 9,10 decreased autocrine cytokine release 11 and increased gut permeability, 12 leading to bacterial translocation that elicits an immune response through toll-like receptor (TLR) signalling. This response is deregulated with increased production of Th1 and probably Th17 cytokines due to reduced inhibition of TLR-mediated cytokine release ('loss of tolerance') [13][14][15][16] or decreased production of IL-10.…”

Yersinia pseudotuberculosis induces transcytosis of nanoparticles across human intestinal villus epithelium via invasin-dependent macropinocytosis

“…For example, individuals with NOD2 alterations show increased intestinal permeability, 18 and alterations in secretion of the antimicrobial peptides, a-defensins 19 and DMBT1. 20 Moreover, CD-related E. coli strains can enhance the expression of CEACAM-6, which increases invasion of E. coli into ileal mucosa mediated by type-1 pili-dependent adhesion.…”

Bin1: A New Player in IBD Barrier Dysfunction

“…However, NOD2 penetrance of the most at-risk genotypes is low [8], and it is likely that cooperation with other genetic factors, such as TJ defects, is required for disease development. Interestingly, Buhner et al detected increased permeability in IBD patients and family members with NOD2 mutations [9]. Altogether, these findings support the speculation that altered permeability constitutes one of several genetically determined variables that enhances the risk for developing IBD.…”