Salmonella-mediated gene therapy in experimental colitis in mice

Abstract

Bacterial gene therapy - bactofection is a simple and effective method to deliver plasmid DNA into target tissue. We hypothesize that oral in vivo bactofection can be an interesting approach to influence the course of inflammatory bowel diseases. The aim of this study was to prove the effects of antioxidative and anti-inflammatory bactofection in dextran sulfate sodium (DSS)-treated mice. Attenuated bacteria Salmonella Typhimurium SL7207 carrying plasmids with genes encoding Cu-Zn superoxide dismutase and an N-terminal deletion mutant of monocyte chemoattractant protein-1 were prepared. Male Balb/c mice had ad libitum access to 1% DSS solution in drinking water during 10 days (mild model of colitis). The animals were daily fed with 200 Mio bacteria via gastric gavage during the experiment. Fecal consistency, clinical status, food and water intake were monitored. After 10 days samples were taken and markers of oxidative stress and inflammatory cytokine levels were measured. Colonic tissue was scored histologically by a blinded investigator. DSS treatment significantly increased the levels of inflammatory cytokines and malondialdehyde as a marker of lipoperoxidation in the colon. Anti-inflammatory gene therapy improved the total antioxidative capacity. In comparison with the untreated group, bacterial gene therapy lowered the histological colitis score. Salmonella-mediated antioxidative and anti-inflammatory gene therapy alleviated colitis in mice. The effect seems to be mediated by increased antioxidative status. Further studies will show whether recombinant probiotics expressing therapeutic gene might be used for the therapy of inflammatory bowel diseases.

The role of innate immune-stimulated epithelial apoptosis during gastrointestinal inflammatory diseases

“…This line of thinking has lead to the emergence of probiotics for both the prophylactic prevention and treatment of gastrointestinal inflammatory diseases. In an extremely exciting line of investigation, evidence suggests that transgenic probiotic bacteria may serve as a method of reducing manipulating apoptosis and inflammation [124,125]. While this a promising therapeutic approach, there may be some apprehension towards the delivery of transgenic bacteria to compromised individuals.…”

Manipulation of Microbiome, a Promising Therapy for Inflammatory Bowel Diseases

“…The pioneering work of Steidler and colleagues introduced genetically engineered Lactococcus lactis that produces IL-10 to DSS-treated mice, reducing the incidence of colitis by 50% [167]. Another study using weakened Salmonella Typhimurium SL7207 carrying superoxide dismutase and anti-inflammatory peptides showed some benefits in a murine colitis model [168]. Along with this line, Hamady and colleagues constructed a stain of Bacteriodes ovatus, an anaerobe that adheres to the mucus layer, to secrete KGF2 [169].…”

In vivo reprogramming in inflammatory bowel disease

“…67,68 In the last few decades, bacteria-mediated gene therapy has attracted the interest of researchers due to its wide applications. Palffy et al 69,70 used an approach called bactofection in their study. They analyzed the effects of salmonella-mediated gene therapy using attenuated bacteria Salmonella typhimurium SL7207 carrying plasmids with genes for SOD1 and 7ND genes in DSS-induced colitis.…”

“…Results showed that the salmonella-mediated antioxidative and anti-inflammatory gene therapy is able to ameliorate colitis in both mice and rats. 69,70 Also under active investigation is stem cell therapy and its use in IBD. It has been proved in several experimental studies in rodents.…”