Novel xylan-controlled delivery of therapeutic proteins to inflamed colon by the human anaerobic commensal bacterium

• Published in: Annals of the Royal College of Surgeons of England 2013-05, Vol.95 (4), p.235-240
• Main Author: Hamady, Z Z R
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - pharmacology; Bacteria; Bacteroides; Bacteroides Infections - drug therapy; Cloning; Colitis - chemically induced; Colitis - drug therapy; Colon; Cytokines; Deoxyribonucleic acid; Dextran Sulfate; DNA; Drug Delivery Systems; Fibroblast Growth Factor 10 - administration & dosage; Fibroblast Growth Factor 10 - pharmacology; Genetic Engineering; Growth factors; Hunterian Lecture; Hypotheses; Inflammatory bowel disease; Irritants; Male; Mice; Mice, Inbred C57BL; Probiotics; Probiotics - administration & dosage; Proteins; Rodents; Transforming Growth Factor beta - administration & dosage; Transforming Growth Factor beta - pharmacology; Xylans
• ISSN: 0035-8843; 1478-7083
• DOI: 10.1308/003588413X13511609958217

Growth factors such as keratinocyte growth factor-2 (KGF-2) and transforming growth factor-beta (TGF-β) are important immunoregulatory and epithelial growth factors. They are also potential therapeutic proteins for inflammatory bowel disease. However, owing to protein instability in the upper gastrointestinal tract, it is difficult to achieve therapeutic levels of these proteins in the injured colon when given orally. Furthermore, the short half-life necessitates repeated dosage with large amounts of the growth factor, which may have dangerous side effects, hence the importance of temporal and spatial control of growth factor delivery. The human commensal gut bacterium, Bacteroides ovatus, was genetically engineered to produce human KGF-2 or TGF-β1 (BO-KGF or BO-TGF) in a regulated manner in response to the dietary polysaccharide, xylan. The successful application of BO-KGF or BO-TGF in the prevention of dextran sodium sulphate induced murine colitis is presented here. This novel drug delivery system had a significant prophylactic effect, limiting the development of intestinal inflammation both clinically and histopathologically. The ability to regulate heterologous protein production by B ovatus using xylan is both unique and an important safety feature of this drug delivery system. The use of genetically engineered B ovatus for the controlled and localised delivery of epithelial growth promoting and immunomodulatory proteins has potential clinical applications for the treatment of various diseases targeting the colon.