Antimicrobial peptide response to blood translocation of bacterial DNA in Crohn's disease is affected by NOD2/CARD15 genotype

Blood translocation of bacterial-DNA has been described in patients with Crohn's disease (CD). The host's immune cell types cooperate to respond against bacterial insults. Some antimicrobial peptides are inducible after culture with bacterial products and a linkage has been established between them and NOD2/CARD15. The aim was to test whether defensins and cathelicidin (LL-37) expression and NOD2/CARD15 mutations in blood neutrophils are related to molecular bacterial translocation events in CD patients.

Genetic susceptibility to increased bacterial translocation influences the response to biological therapy in patients with Crohn's disease

OBJECTIVE: The aetiology of Crohn's disease (CD) has been related to nucleotide-binding oligomerisation domain containing 2 (NOD2) and ATG16L1 gene variants. The observation of bacterial DNA translocation in patients with CD led us to hypothesise that this process may be facilitated in patients with NOD2/ATG16L1-variant genotypes, affecting the efficacy of anti-tumour necrosis factor (TNF) therapies. DESIGN: 179 patients with Crohn's disease were included. CD-related NOD2 and ATG16L1 variants were genotyped. Phagocytic and bactericidal activities were evaluated in blood neutrophils. Bacterial DNA, TNFα, IFNγ, IL-12p40, free serum infliximab/adalimumab levels and antidrug antibodies were measured. RESULTS: Bacterial DNA was found in 44% of patients with active disease versus 23% of patients with remitting disease (p=0.01). A NOD2-variant or ATG16L1-variant genotype was associated with bacterial DNA presence (OR 4.8; 95% CI 1.1 to 13.2; p=0.001; and OR 2.4; 95% CI 1.4 to 4.7; p=0.01, respectively). This OR was 12.6 (95% CI 4.2 to 37.8; p=0.001) for patients with a double-variant genotype. Bacterial DNA was associated with disease activity (OR 2.6; 95% CI 1.3 to 5.4; p=0.005). Single and double-gene variants were not associated with disease activity (p=0.19). Patients with a NOD2-variant genotype showed decreased phagocytic and bactericidal activities in blood neutrophils, increased TNFα levels in response to bacterial DNA and decreased trough levels of free anti-TNFα. The proportion of patients on an intensified biological therapy was significantly higher in the NOD2-variant groups. CONCLUSIONS: Our results characterise a subgroup of patients with CD who may require a more aggressive therapy to reduce the extent of inflammation and the risk of relapse