CpG Motifs of Bacterial DNA Essentially Contribute to the Perpetuation of Chronic Intestinal Inflammation

Background & Aims: Recently, we demonstrated a proinflammatory effect of cytosin-guanosin dinucleotide (CpG)-oligodeoxynucleotide (ODN) treatment in established dextran sulphate sodium (DSS)-induced colitis. Here, we investigated whether DNA derived from luminal bacteria plays a role in the perpetuation of chronic intestinal inflammation. Methods: Toll-like receptor (TLR9)-deficient and wild-type (wt) control mice were used for the induction of chronic DSS colitis. Moreover, mice with established chronic colitis using different experimental models were treated with adenoviral ODN (AV-ODN) known to block CpG effects. Colonic inflammation was scored and cytokine production was quantified both in colonic tissue and draining mesenteral lymph node cells (MLC). Results: Eight weeks after induction of chronic DSS colitis in TLR9-deficient mice, intestinal inflammation was significantly lower (−68%), and proinflammatory cytokine production was drastically reduced. Treatment of wt mice with chronic DSS-induced colitis with AV-ODN resulted in a significant amelioration of disease with a reduced histologic score (−43%) and reduced cytokine production of MLC (interleukin [IL]-6: −68%; interferon [IFN]-γ: −48%) and RNA expression of the T helper (Th)1-specific transcription factor T-bet (−62%) in colonic tissue. Qualitatively, the same results were obtained in the severe combined immunodeficiency disease (SCID) transfer model of colitis and in spontaneous colitis in IL-10–deficient mice. Conclusions: Bacterial DNA derived from luminal bacteria contributes significantly to the perpetuation of chronic intestinal inflammation. Inhibition of the immune-stimulating properties of bacterial DNA using AV-ODN may offer a novel and specific tool for the treatment of inflammatory bowel disease.

Abbreviations used in this paper:  AV-ODN, oligodeoxynucleotide containing inhibitory adenoviral motifs , CpG, cytosin-guanosin dinucleotide , CpG-ODN, CpG containing oligodeoxynucleotide , DSS, dextran sulphate sodium , MLC, mesenteral lymph node cells , ODN, oligodeoxynucleotide , TLR9, toll-like receptor 9