Preventive and therapeutic effects of nitrite supplementation in experimental inflammatory bowel disease

Abstract

BackgroundInorganic nitrate and nitrite have emerged as alternative substrates for nitric oxide (NO) generation in the gastrointestinal tract, and have shown to be protective against drug-induced gastric injury. The aim of this study was to investigate the preventive and therapeutic effects of nitrate and nitrite in a model of experimental colitis.MethodsColitis was induced in mice by administrating dextran sulfate sodium (DSS) with concurrent administration of nitrite (1 mM) or nitrate (10 mM) in the drinking water for 7 days. A therapeutic approach was also investigated by initiating nitrite treatment 3 days after DSS-induced colitis. Clinical and inflammatory markers were assessed and the colonic mucus thickness was measured in vivo. The effect of nitrite on wound healing was evaluated using colon epithelial cells.ResultsConcurrent administration of DSS and nitrite (1 mM) alleviated inflammation as determined by reduced disease activity index score (DAI) and increased colon length, while nitrate (10 mM) only reduced the DAI-score. Nitrite also displayed therapeutic effects by ameliorating established colonic inflammation with reduced colonic expression of iNOS and improving histopathology. DSS-induced decrease in colonic mucus thickness was completely prevented by nitrite administration. In addition, goblet cell abundance was lower by DSS treatment, but was increased by addition of nitrite. Further studies using colon epithelial cells revealed an NO-dependent improvement in wound healing with nitrite administration.ConclusionNitrite exerts both preventive and therapeutic effects in colonic inflammation. The protective effects involve preservation of an intact adherent mucus layer and regulation of epithelial cell restitution.

Overview of cytokines and nitric oxide involvement in immuno-pathogenesis of inflammatory bowel diseases

“…While several studies conducted using animal models indicate the deleterious effect of NO, recent studies have shown that NO may also exert a protective effect against colitis [29][30][31][32] . One study conducted using a DSSinduced colitis model found that nitrite administration exerts both preventive and therapeutic effects in colonic inflammation [33] . More recently, iNOS deficiency enhanced the inflammation aggravation in an animal model of colitis through enhancing a Th17 differentiated subset [34] .…”

Cytokines and Nitric Oxide in Immunopathogenesis of IBD and Potential Therapeutic Approaches

“…While several studies conducted on animal models report the deleterious effect of NO, some recent studies have shown that NO may also exert protective effect against colitis [29][30][31][32]. Indeed, because of its strong bactericidal and cytostatic properties, high NO generation by iNOS may represent a protective mechanism [28].…”

“…Indeed, because of its strong bactericidal and cytostatic properties, high NO generation by iNOS may represent a protective mechanism [28]. Recent study conducted on DSS-induced colitis model has shown that nitrite administration exerts both preventive and therapeutic effects in colonic inflammation [30]. More recently, iNOS deficiency was shown to aggravate inflammation in animal model of colitis through enhancing TH17 differentiation [31].…”

Analysing the effect of I1 imidazoline receptor ligands on DSS-induced acute colitis in mice

“…Colitis was induced by adding DSS (2.5 %, molecular weight: 35000-55 000 Da; TdB Consultancy, Uppsala, Sweden) (Jädert et al 2014) to the drinking water (tap water) for 3, 5 or 7 days (see Section 2.3). The DSS-containing drinking water was made up fresh every second day to avoid bacterial contamination, and the consumption of water and food was monitored in all groups.…”

“…At day 7 7-10 after colitis induction mice were sacrificed by decapitation and their whole colons were removed. The reduction of colon length was used as another parameter to assess colonic inflammation (Jädert et al 2014). Care was taken not to stretch the colon.…”