Genetic susceptibility to increased bacterial translocation influences the response to biological therapy in patients with Crohn's disease
- Ana Gutiérrez1,
- Michael Scharl2,
- Laura Sempere1,
- Ernst Holler3,
- Pedro Zapater1,4,
- Isabel Almenta1,
- José M González-Navajas1,4,
- José Such1,4,
- Reiner Wiest5,
- Gerhard Rogler2,
- Rubén Francés1,4
- 1Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Alicante, Spain
- 2Division of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
- 3Department of Internal Medicine I, University of Regensburg, Germany
- 4CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
- 5Department Gastroenterology, University Clinic for Visceral Medicine, Inselspital, Bern, Switzerland
- Correspondence to Dr Rubén Francés, CIBERehd, Hospital General Universitario de Alicante, Avda, Pintor Baeza 12, Alicante 03010, Spain;
- Received 16 August 2012
- Accepted 7 January 2013
- Published Online First 1 February 2013
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.