Effects of bacteria-mediated reprogramming and antibiotic pretreatment on the course of colitis in mice

Abstract

Since the original study by Takahashi and Yamanaka in 2006, there have been significant advances in the field of induced pluripotent stem cells. However, to the best of our knowledge, all of the studies published to date are based on ex vivo gene delivery and subsequent reimplantation of the cells. By contrast, in vivo reprogramming allows the direct administration of DNA encoding the reprogramming factors into the target tissue. In our previous study we demonstrated the beneficial effects of Salmonella-mediated oral delivery of genes into colonic mucosa as a therapy for colitis. In the present study, the effect of the bacterial vector Salmonella typhimurium SL7207, carrying a plasmid encoding the reprogramming factors Sox2, Oct3/4 and Klf4, on colitis in mice was investigated. Therapeutic intervention, consisting of repeated gavaging following the induction of colitis, did not exhibit beneficial effects. However, preventive oral administration of the therapeutic bacterial strain resulted in improvements in weight loss, colon length and stool consistency. Recently it has been shown that antibiotic pretreatment may alleviate chemically induced colitis in mice. Therefore, in the present study it was investigated whether antibiotic pretreatment of mice was able to enhance colonization of the administered bacterial strain in the colon, and therefore improve therapeutic outcome. C57BL/6 mice were administered streptomycin and metronidazole for four days, prior to multiple oral administrations of therapeutic bacteria every other day. Following three gavages, mice were administered dextran sulfate sodium in their drinking water to induce colitis. Disease activity parameters, including stool consistency, weight loss and colon length, were improved in the group receiving antibiotics and bacterial vectors. These results indicate that antibiotic pretreatment may enhance bacterial gene delivery into the colon. Furthermore,the anticipated in vivo reprogramming of colon cells appears to have a beneficial effect on the severity of colitis. These effects, however, still require further analyses.