A Transgenic Probiotic Secreting a Parasite Immunomodulator for Site-Directed Treatment of Gut Inflammation
| Autor: | Dorothee Günzel, Karsten Nöckler, Friederike Ebner, Nina A. Hering, Jan F. Richter, Lothar H. Wieler, Anja A. Kühl, Jörg-Dieter Schulzke, Ahmed Keles, Pawel Janczyk, Susanne Hartmann, Rose A. K. Whelan, Sebastian Rausch |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Transgene Biology Inflammatory bowel disease Microbiology law.invention Probiotic law Drug Discovery medicine Genetics Macrophage Animals Immunologic Factors Molecular Biology Acute colitis Pharmacology Probiotics FOXP3 Interleukin medicine.disease Genetically modified organism Gastroenteritis Immunology Molecular Medicine Original Article |
| Zdroj: | Molecular Therapy. 22(10):1730-1740 |
| ISSN: | 1525-0016 |
| DOI: | 10.1038/mt.2014.125 |
| Popis: | New treatment strategies for inflammatory bowel disease are needed and parasitic nematode infections or application of helminth components improve clinical and experimental gut inflammation. We genetically modified the probiotic bacterium Escherichia coli Nissle 1917 to secrete the powerful nematode immunomodulator cystatin in the gut. This treatment was tested in a murine colitis model and on post-weaning intestinal inflammation in pigs, an outbred model with a gastrointestinal system similar to humans. Application of the transgenic probiotic significantly decreased intestinal inflammation in murine acute colitis, associated with increased frequencies of Foxp3+ Tregs, suppressed local interleukin (IL)-6 and IL-17A production, decreased macrophage inflammatory protein-1α/β, monocyte chemoattractant protein -1/3, and regulated upon activation, normal T-cell expressed, and secreted expression and fewer inflammatory macrophages in the colon. High dosages of the transgenic probiotic were well tolerated by post-weaning piglets. Despite being recognized by T cells, secreted cystatin did not lead to changes in cytokine expression or macrophage activation in the colon. However, colon transepithelial resistance and barrier function were significantly improved in pigs receiving the transgenic probotic and post-weaning colon inflammation was reduced. Thus, the anti-inflammatory efficiency of a probiotic can be improved by a nematode-derived immunoregulatory transgene. This treatment regimen should be further investigated as a potential therapeutic option for inflammatory bowel disease. |
| Databáze: | OpenAIRE |
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