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

Abstract

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.

• Authors: Ana Gutiérrez, Michael Scharl, Laura Sempere, Ernst Holler, Pedro Zapater, Isabel Almenta, José M González-Navajas, José Such, Reiner Wiest, Gerhard Rogler, Rubén Francés
• Journal: Gut (Gut) Vol. 63 Issue 2 Pg. 272-80 (Feb 2014) ISSN: 1468-3288 [Electronic] England
• PMID: 23376290 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATG16L1 protein, human
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Autophagy-Related Proteins
• Carrier Proteins
• DNA, Bacterial
• Interleukin-12 Subunit p40
• Nod2 Signaling Adaptor Protein
• Peptide Fragments
• Tumor Necrosis Factor-alpha
• interferon gamma (1-39)
• Interferon-gamma
• Infliximab
• Adalimumab

Topics

• Adalimumab
• Adult
• Antibodies, Monoclonal (blood, therapeutic use)
• Antibodies, Monoclonal, Humanized (blood, therapeutic use)
• Autophagy-Related Proteins
• Bacterial Translocation (physiology)
• Biological Therapy (methods)
• Carrier Proteins (genetics)
• Crohn Disease (drug therapy, microbiology)
• DNA, Bacterial (genetics)
• Female
• Genetic Predisposition to Disease
• Genotype
• Humans
• Infliximab
• Interferon-gamma (blood)
• Interleukin-12 Subunit p40 (blood)
• Male
• Middle Aged
• Nod2 Signaling Adaptor Protein (genetics)
• Peptide Fragments (blood)
• Recurrence
• Treatment Outcome
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)