|Whitehead, Terence - Terry|
Submitted to: Gut
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/4/2009
Publication Date: 4/1/2010
Citation: Hamady, Z.Z., Scott, N., Farrar, M.D., Lodge, J.P., Holland, K.T., Whitehead, T.R., Carding, S.R. 2010. Xylan-regulated Delivery of Human Keratinocyte Growth Factor-2 to the Inflamed Colon by the Human Anaerobic Commensal Bacterium Bacteroides ovatus. Gut. 59(4):461-469. Interpretive Summary: Chronic disorders of the human gastrointestinal (GI) tract, for example inflammatory bowel disease (IBD) which includes the disorders Crohn’s disease and ulcerative colitis, affect a significant proportion of the population in developed countries such as the United States. Present therapies are not curative and may cause adverse side effects during treatment. Therefore, there is a need for more targeted and controlled forms of immunotherapy. Previous work has indicated that some bacteria that normally inhabit the GI tract might prove useful for treating certain forms of bowel disease. Therefore, a human isolate of the bacterium Bacteroides ovatus was engineered in NCAUR laboratories as a probiotic for production and secretion of human keratinocyte growth factor-2, important for the treatment of IBD, using a xylan-inducing gene system. In response to feeding xylan, mice treated with the bacterial strain had significant improvements in IBD symptoms. This novel diet-regulated, live bacterial drug delivery system may be applicable to treating various bowel disorders in humans.
Technical Abstract: The use of genetically modified bacteria to deliver biologically active molecules directly to the gut has become an increasingly attractive area of investigation. The challenge of regulation of production of the therapeutic molecule and colonization of the bowel led us to investigate Bacteroides ovatus for the production of these molecules, due to its ability to colonize the colon and xylan utilization properties. The anaerobic nature of B. ovatus provides an inherent biosafety feature. B. ovatus strains expressing human keratinocyte growth factor-2 that plays a central role in intestinal epithelial homeostasis and repair (BO-KGF) were generated by homologous recombination and evaluated using the dextran sodium sulphate (DSS)-induced model of intestinal epithelial injury and colitis. In response to xylan BO-KGF produced biologically active KGF both in vitro and in vivo. In DSS-treated mice administration of xylan and BO-KGF had a significant therapeutic effect in reducing weight loss, improving stool consistency, reducing rectal bleeding, accelerating healing of damaged epithelium, reducing inflammation and neutrophil infiltration, reducing expression of pro-inflammatory cytokines, and accelerating production of goblet cells. BO-KGF and xylan treatment also had a marked prophylactic effect limiting the development of inflammation and disruption of the epithelial barrier. This novel diet-regulated, live bacterial drug delivery system may be applicable to treating various bowel disorders.