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Gut 63:272-280 doi:10.1136/gutjnl-2012-303557
  • Inflammatory bowel disease
  • Original article

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

  1. Rubén Francés1,4
  1. 1Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Alicante, Spain
  2. 2Division of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
  3. 3Department of Internal Medicine I, University of Regensburg, Germany
  4. 4CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
  5. 5Department Gastroenterology, University Clinic for Visceral Medicine, Inselspital, Bern, Switzerland
  1. Correspondence to Dr Rubén Francés, CIBERehd, Hospital General Universitario de Alicante, Avda, Pintor Baeza 12, Alicante 03010, Spain; frances_rub{at}gva.es
  • Received 16 August 2012
  • Accepted 7 January 2013
  • Published Online First 1 February 2013

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.