Increased Intestinal Permeability and NOD2 Variants in Familial and Sporadic Crohn's Disease

R. D'incà; V. Annese; V. Di Leo; A. Latiano; V. Quaino; C. Abazia; M. G. Vettorato; G. C. Sturniolo

Disclosures

Aliment Pharmacol Ther. 2006;23(10):1455-1461. 

In This Article

Summary and Introduction

Summary

Background: Abnormal barrier function may be genetically determined in Crohn's disease.
Aim: To examine the role of abnormal intestinal permeability in genetic predisposition in multiplex vs. sporadic Crohn's disease families.
Methods:Intestinal permeability was measured in patients, relatives and partners by means of lactulose/mannitol test. Healthy subjects from the hospital staff served as controls. CARD15 mutations were investigated in sporadic and familial Crohn's disease patients and in a group of blood donors.
Results: The median lactulose/mannitol ratio was increased significantly in Crohn's disease patients vs. their relatives [0.03 (0.01–0.24) vs. 0.01 (0.003–0.19), P = 0.005]. The percentage of abnormal tests was significantly higher in familial vs. sporadic first-degree relatives of Crohn's disease patients (29% vs. 11%, P = 0.0281). Abnormal permeability occurred significantly more frequent in patients with familial Crohn's disease carrying the frameshift mutation. The frameshift mutation 3020insC was associated with increased permeability in 75% in the multiplex and in 61% of the sporadic CD patients. One partner had abnormal lactulose/mannitol ratio.
Conclusion:Intestinal permeability is raised in Crohn's disease patients and relatives, with higher rates in familial vs. sporadic healthy relatives. CARD15 mutations are associated with abnormal permeability in ileal Crohn's disease.

Introduction

The increase in intestinal permeability has been reported in several aspects of Crohn's disease (CD), including genetic predisposition,[1] disease activity,[2,3] susceptibility to relapse[4,5] and response to therapy.[6,7] The hypothesis of a leaky gut as a pathogenetic factor in CD has been suggested by several studies that showed fundamental changes of tight junctions even in unaffected bowel segments of CD patients[8] and increased permeability through apparently normal small bowel.[9] Moreover, functional and morphological changes[2] and increased epithelial uptake of protein antigens has been demonstrated in macroscopically normal segments of distal ileum of CD patients.[10] The genetic component has been regarded as one of the mayor predisposing factors because approximately 20% of healthy relatives of CD patients have increased intestinal permeability, measured with different methodology.[1,11,12,13] These studies hypothesized the role of abnormal barrier function for causing CD.

Evidence for the role of genetic factors include the 15- to 30-fold increased risk of contracting the disease in first-degree relatives and high degree of concordance of disease in monozygotic twins as opposed to dizygotic ones.[14] Family studies have also documented the higher risk of inflammatory bowel disease (IBD) in children when both parents have IBD.[15]

Crohn's disease is a polygenic disorder and several susceptibility genes may have implications for the permeability defect. Genetic variants in the NOD2/CARD15 gene are strongly associated with susceptibility to CD[16,17,18] and recently a genetic basis for increased intestinal permeability has been suggested.[19]The study reports increased permeability in CD as associated with the presence of variants of CARD15, regarded as pathogenic for CD. The 3020insC variant could be the genetic defect causing subclinical inflammation and subsequently permeability alterations. The association with high mucosal permeability and the presence of a CARD15 mutation have been confirmed in CD patients and in their first-degree relatives but not in non-related household members.

The question arises whether there is an increased risk of abnormal permeability when CD occurs in families. We therefore investigated the permeability patterns in familial and sporadic CD cases and in their first-degree relatives. As the genotype of our CD patients was available, we also investigated the possible correlation between NOD2/CARD15 gene mutations and intestinal permeability in familial and sporadic cases of CD.

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