Beneficial effects of live and dead Salmonella-based vector strain on the course of colitis in mice.

Dysbiosis of intestinal microbiota and hyperactive immune responses seem to be crucial for the uncontrolled inflammation in inflammatory bowel diseases (IBD). Modulation of the microbiome and immune stimulation of the intestinal epithelium were suggested as therapeutic approaches. In this study, live attenuated and dead bacterial cells of Salmonella Typhimurium SL7207 - a widely used bacterial vector for gene therapy were administered in DSS-induced colitis in mice. C57BL/6 mice were divided into four groups. The first group received pure water (CTRL). The other three groups received 2% dextran sulphate sodium (DSS) to induce colitis. Two DSS groups were treated with live attenuated (DSS live) or inactivated (DSS dead) Salmonella by gastric gavage. Intake of 2% DSS caused weight loss in all DSS groups compared to control mice with some improvement in DSS live group on the last day of the experiment. Significantly longer colon and improved stool consistency were reported in DSS live group, but not DSS dead group, when compared with DSS. Significant enlargement of spleens was observed only in DSS and DSS dead groups compared to control. Significant differences in stool consistency, colon length and spleen enlargement were observed between DSS live and DSS dead groups with beneficial effects of live bacteria. Interestingly, significant decrease in myeloperoxidase activity was detected in both, DSS live and DSS dead groups compared to the DSS group. On the basis of these results, progression of colitis seems to be beneficially influenced not only by live attenuated but to some extent also by inactivated Salmonella Typhimurium SL7207. Our results provide evidence that Salmonella-based gene therapy vectors are able to positively alter gut homeostasis during DSS-induced colitis. SIGNIFICANCE AND IMPACT OF THE STUDY: Restoration of gut homeostasis has a great importance in IBD. Here, we tested the nonspecific effect of the strain Salmonella Typhimurium SL7207 on the course of colitis to find out whether the potential effect would be mediated by activity of live bacterial cells or by bacterial structures that are also present in dead bacteria. Live bacterial therapy of colitis showed a beneficial effect on clinical signs as well as on macroscopic and inflammatory markers of colitis. On the other hand, therapy with dead bacteria showed inconsistent effects, negative in most clinical outcomes, positive especially in myeloperoxidase activity. Our data indicate that the beneficial effect of bacterial gene therapy vectors carrying therapeutic genes might be, at least partially, caused by the bacterial vector instead of the therapeutic gene.

In vivo reprogramming in inflammatory bowel disease.

The direct reprogramming of somatic cells has immense implications in various areas of medicine. Although remarkable progress has been made in developing novel reprogramming methods, the efficiency and fidelity of reprogramming still need to be improved. Inflammatory bowel disease (IBD) involves chronic inflammatory diseases of the gastrointestinal tract with a complex etiology caused by various genetic, immunological and environmental factors. Recently, the role of stem cells has been proposed in pathogenesis and therapy of IBD. However, the efficiency and the safety of the stem cell treatments depend on the origin of the stem cell and the administration method. We hypothesize that the reprogramming of the intestinal cells into a pluripotent state is of huge importance for IBD therapy and prevention. The vectors carrying reprogramming genes encoding pluripotency factors can be transferred to the damaged tissue, in this case the intestine, by means of invasive bacterial vectors able to colonize colon mucosa. Reconstruction of tissues in vivo might avoid problems encountered in tissue rebuilding in vitro because of lack of appropriate scaffolds and microenvironments. Herein we present a review of recent literature and a perspective of in vivo reprogramming in IBD using bacterial vectors and analyze the rationale for such approach.