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

Gut. 2014 Feb;63(2):272-80. doi: 10.1136/gutjnl-2012-303557. Epub 2013 Feb 1.


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.

Keywords: Bacterial Translocation; Crohn'S Disease; Ibd - Genetics; Immune Response; Infliximab.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adalimumab
  • Adult
  • Antibodies, Monoclonal / blood
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized / blood
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Autophagy-Related Proteins
  • Bacterial Translocation / physiology*
  • Biological Therapy / methods*
  • Carrier Proteins / genetics*
  • Crohn Disease / drug therapy*
  • Crohn Disease / 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


  • 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