1887

Abstract

Inflammatory bowel diseases (IBDs) affect the gastrointestinal tract and are characterized by recurrent inflammation that requires lifelong therapies. Probiotics such as lactic acid bacteria (LAB) have been proposed to complement current treatment protocols for these patients; however, their characteristics are strain dependent. In this regard, certain novel characteristics are only possible through the genetic modification of these beneficial micro-organisms. Different delivery systems, such as protein delivery of anti-oxidant enzymes and anti-inflammatory cytokines, have been shown to be effective in preventing and treating IBD in animal models. In this study, the safety of the recombinant LAB (recLAB) CRL807 : CAT, CRL807 : SOD, NCDO2118 pXILCYT :  IL-10, MG1363 pValac : IL-10 and MG1363 pGroESL : IL-10 with proven beneficial effects was compared to their progenitor strains CRL807, NCDO2118 or MG1363. The prolonged administration of these genetically modified strains showed that they were just as safe as the native strains from which they derive, as demonstrated by normal animal growth and relative organ weights, absence of microbial translocation from the gastrointestinal tract, normal blood parameters and intestinal histology. The results show the potential use of these recLAB in future therapeutic formulations; however, the use of modern bio-containment systems is required for the future acceptance of these recLAB by the medical community and patients with IBD.

Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.000323
2016-09-01
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/jmm/65/9/1038.html?itemId=/content/journal/jmm/10.1099/jmm.0.000323&mimeType=html&fmt=ahah

References

  1. Basso P. J., Fonseca M. T., Bonfá G., Alves V. B., Sales-Campos H., Nardini V., Cardoso C. R. 2014; Association among genetic predisposition, gut microbiota, and host immune response in the etiopathogenesis of inflammatory bowel disease. Braz J Med Biol Res 47:727–737 [View Article][PubMed]
    [Google Scholar]
  2. Braat H., Rottiers P., Hommes D. W., Huyghebaert N., Remaut E., Remon J. P., van Deventer S. J., Neirynck S., Peppelenbosch M. P., Steidler L. 2006; A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease. Clin Gastroenterol Hepatol 4:754–759 [View Article][PubMed]
    [Google Scholar]
  3. De Greef E., Vandenplas Y., Hauser B., Devreker T., Veereman G. 2014; The use of probiotics in IBD and IBS. Minerva Pediatr 66:491–500[PubMed]
    [Google Scholar]
  4. de Moreno de LeBlanc A., LeBlanc J. G., Perdigón G., Miyoshi A., Langella P., Azevedo V., Sesma F. 2008; Oral administration of a catalase-producing Lactococcus lactis can prevent a chemically induced colon cancer in mice. J Med Microbiol 57:100–105 [View Article][PubMed]
    [Google Scholar]
  5. de Moreno de LeBlanc A., Chaves S., Perdigon G. 2009; Effect of yoghhurt on the cytokine profile using a murine model of intestinal inflammation. Eur J Inflam 7:97–109
    [Google Scholar]
  6. de Moreno de LeBlanc A., LeBlanc J. G. 2014; Effect of probiotic administration on the intestinal microbiota, current knowledge and potential applications. World J Gastroenterol 20:16518–161528 [View Article][PubMed]
    [Google Scholar]
  7. de Moreno de LeBlanc A., del Carmen S., Chatel J. M., Miyoshi A., Azevedo V., Langella P., Bermúdez-Humarán L. G., LeBlanc J. G. 2015; Current review of genetically modified lactic acid bacteria for the prevention and treatment of colitis using murine models. Gastroenterol Res Pract 2015:10.1155/2015/146972 [View Article][PubMed]
    [Google Scholar]
  8. del Carmen S., de Moreno de LeBlanc A., Perdigon G., Bastos Pereira V., Miyoshi A., Azevedo V., LeBlanc J. G. 2012; Evaluation of the anti-inflammatory effect of milk fermented by a strain of IL-10-producing Lactococcus lactis using a murine model of Crohn’s disease. J Mol Microbiol Biotechnol 21:138–146 [View Article]
    [Google Scholar]
  9. del Carmen S., Leblanc J. G., de Moreno de Leblanc A. 2013a; Use of probiotics in the treatment of Crohn's disease. In Crohn’s Disease: Etiology, Diagnosis and Treatment Options Edited by Leblanc J. G., de Moreno de Leblanc A. Hauppauge, NY: Nova Science Publishers, Inc;
    [Google Scholar]
  10. del Carmen S., Zurita-Turk M., Alvarenga Lima F., Coelho Dos Santos J. S., Leclercq S. Y., Chatel J.-M., Azevedo V., de Moreno de Leblanc A., Miyoqhi A., Leblanc J. G. 2013b; A novel interleukin-10 DNA mucosal delivery system attenuates intestinal inflammation in a mouse model. Eur J Inflamm 11:641–655
    [Google Scholar]
  11. del Carmen S., de Moreno de LeBlanc A., Martin R., Chain F., Langella P., Bermúdez-Humarán L. G., LeBlanc J. G. 2014a; Genetically engineered immunomodulatory Streptococcus thermophilus strains producing antioxidant enzymes exhibit enhanced anti-inflammatory activities. Appl Environ Microbiol 80:869–877 [View Article][PubMed]
    [Google Scholar]
  12. del Carmen S., Martín Rosique R., Saraiva T., Zurita-Turk M., Miyoshi A., Azevedo V., de Moreno de LeBlanc A., Langella P., Bermúdez-Humarán L. G., LeBlanc J. G. 2014b; Protective effects of lactococci strains delivering either IL-10 protein or cDNA in a TNBS-induced chronic colitis model. J Clin Gastroenterol 48:S12–S17 [View Article][PubMed]
    [Google Scholar]
  13. del Carmen S., Miyoshi A., Azevedo V., de Moreno de LeBlanc A., LeBlanc J. G. 2015; Evaluation of a Streptococcus thermophilus strain with innate anti-inflammatory properties as a vehicle for IL-10 cDNA delivery in an acute colitis model. Cytokine 73:177–183 [View Article][PubMed]
    [Google Scholar]
  14. FAO/WHO 2001; Evaluation of health and nutritional properties of powder milk and live lactic acid bacteria. Food and Agriculture Organization of the United Nations and World Health Organization Expert Consultation Report. Available from ftp://ftp.fao.org/docrep/fao/009/a0512e/a0512e00.pdf
  15. Gasson M. J. 1983; Plasmid complements of Streptococcus lactis NCDO 712 and other lactic streptococci after protoplast-induced curing. J Bacteriol 154:1–9[PubMed]
    [Google Scholar]
  16. Laiño J. E., Zelaya H., Juárez del Valle M., Savoy de Giori G., LeBlanc J. G. 2015; Milk fermented with selected strains of lactic acid bacteria is able to improve folate status of deficient rodents and also prevent folate deficiency. J Func Foods 17:22–32 [View Article]
    [Google Scholar]
  17. LeBlanc J. G., Garro M. S., Giori G. S., Valdez G. F., Savoy De Giori G., Font De Valdez G. 2004; A novel functional soy-based food fermented by lactic acid bacteria: effect of heat treatment. J Food Sci 69:M246–M250 [View Article]
    [Google Scholar]
  18. LeBlanc J. G., Van Sinderen D., Hugenholtz J., Piard J. C., Sesma F., de Giori G. S. 2010; Risk assessment of genetically modified lactic acid bacteria using the concept of substantial equivalence. Curr Microbiol 61:590–595 [View Article][PubMed]
    [Google Scholar]
  19. LeBlanc J. G., Aubry C., Cortes-Perez N. G., de Moreno de LeBlanc A., Vergnolle N., Langella P., Azevedo V., Chatel J. M., Miyoshi A., Bermúdez-Humarán L. G. 2013a; Mucosal targeting of therapeutic molecules using genetically modified lactic acid bacteria: an update. FEMS Microbiol Lett 344:1–9 [View Article][PubMed]
    [Google Scholar]
  20. LeBlanc J., Carmen S., Turk M., Lima F., Pontes D., Miyoshi A., Azevedo V., de LeBlanc A. 2013b; Mechanisms involved in the anti-inflammatory properties of native and genetically engineered lactic acid bacteria. Anti-Infective Agents 11:59–69 [View Article]
    [Google Scholar]
  21. Limaye S. A., Haddad R., Cilli F., Sonis S. T., Colevas A. D., Brennan M. T., Hu K. S., Murphy B. A. 2013; Phase 1b, multicenter, single blinded, placebo-controlled, sequential dose escalation study to assess the safety and tolerability of topically applied AG013 in subjects with locally advanced head and neck cancer receiving induction chemotherapy. Cancer 119:4268–4276 [View Article][PubMed]
    [Google Scholar]
  22. Luerce T. D., Gomes-Santos A. C., Rocha C. S., Moreira T. G., Cruz D. N., Lemos L., Sousa A. L., Pereira V. B., de Azevedo M. et al. 2014; Anti-inflammatory effects of Lactococcus lactis NCDO 2118 during the remission period of chemically induced colitis. Gut Pathog 6:1–11 [View Article][PubMed]
    [Google Scholar]
  23. Mandell D. J., Lajoie M. J., Mee M. T., Takeuchi R., Kuznetsov G., Norville J. E., Gregg C. J., Stoddard B. L., Church G. M. 2015; Biocontainment of genetically modified organisms by synthetic protein design. Nature 518:55–60 [View Article][PubMed]
    [Google Scholar]
  24. Martín R., Chain F., Miquel S., Natividad J. M., Sokol H., Verdu E. F., Langella P., Bermúdez-Humarán L. G. 2014; Effects in the use of a genetically engineered strain of Lactococcus lactis delivering in situ IL-10 as a therapy to treat low-grade colon inflammation. Hum Vaccin Immunother 10:1611–1621 [View Article][PubMed]
    [Google Scholar]
  25. Pontes D., Innocentin S., del Carmen S., Almeida J. F., Leblanc J. G., de Moreno de Leblanc A., Blugeon S., Cherbuy C., Lefèvre F. et al. 2012; Production of fibronectin binding protein A at the surface of Lactococcus lactis increases plasmid transfer in vitro and in vivo. PLoS One 7:e44892 [View Article][PubMed]
    [Google Scholar]
  26. Rovner A. J., Haimovich A. D., Katz S. R., Li Z., Grome M. W., Gassaway B. M., Amiram M., Patel J. R., Gallagher R. R. et al. 2015; Recoded organisms engineered to depend on synthetic amino acids. Nature 518:89–93 [View Article][PubMed]
    [Google Scholar]
  27. Steidler L., Neirynck S., Huyghebaert N., Snoeck V., Vermeire A., Goddeeris B., Cox E., Remon J. P., Remaut E. 2003; Biological containment of genetically modified Lactococcus lactis for intestinal delivery of human interleukin 10. Nat Biotechnol 21:785–789 [View Article][PubMed]
    [Google Scholar]
  28. Sybesma W., Hugenholtz J., De Vos W. M., Smid E. J. 2006; Safe use of genetically modified lactic acid bacteria in food. Bridging the gap between consumers, green groups, and industry. Elect J Biotechnol 9:424–448
    [Google Scholar]
  29. Zurita-Turk M., del Carmen S., Santos A. C., Pereira V. B., Cara D. C., Leclercq S. Y., de LeBlanc A., Azevedo V., Chatel J. M. et al. 2014; Lactococcus lactis carrying the pValac DNA expression vector coding for IL-10 reduces inflammation in a murine model of experimental colitis. BMC Biotechnol 14:73 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.000323
Loading
/content/journal/jmm/10.1099/jmm.0.000323
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error