Zusammenfassung
Background: Recent insights into the pathogenesis of Crohn's disease (CD) point to an important role of the mucosal barrier and intestinal microflora that may induce a chronic inflammation after crossing the intestinal barrier. The first detected susceptibility gene for CD, NOD2, is a pattern recognition receptor (PRR) for the recognition of the bacterial cell wall component muramyldipeptide ...
Zusammenfassung
Background: Recent insights into the pathogenesis of Crohn's disease (CD) point to an important role of the mucosal barrier and intestinal microflora that may induce a chronic inflammation after crossing the intestinal barrier. The first detected susceptibility gene for CD, NOD2, is a pattern recognition receptor (PRR) for the recognition of the bacterial cell wall component muramyldipeptide (MDP). Binding of MDP to NOD2 is followed by activation of proinflammatory pathways mainly regulated by nuclear factor kappa B (NF-kappa B). In this study we investigated whether impaired recognition of MDP via NOD2 variants is associated with increased bacterial translocation across the epithelial barrier and whether this is followed by increased or decreased NF-kappa B activation. Methods: NOD2 variants were analyzed in 36 CD patients and 30 controls. Endotoxin was stained by immunohistochemistry in 30 intestinal biopsies from patients carrying NOD2 variants (NOD2-mut) or being NOD2 wildtype (WT). Junctional proteins were visualized by immunofluorescence and quantified by Western blotting. NF-kappa B activation was analyzed by immunohistochemistry in specimens from NOD2-WT and NOD2-mut CD and control patients. Results: We demonstrated the increased presence of endotoxin in the mucosal lamina propria of CD patients carrying NOD2 variants. This was associated with an altered composition of epithelial cell cell contacts. Patients carrying NOD2 variants displayed increased NF-kappa B activation in the mucosa. Conclusions: This study for the first time demonstrates that translocation of luminal bacteria and/or bacterial products into the intestinal mucosa is increased in patients carrying NOD2 variants, leading to higher activation of proinflammatory signaling cascades.
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