Xylan regulated delivery of human keratinocyte growth factor-2 to the inflamed colon by the human anaerobic commensal bacterium Bacteroides ovatus

Zaed Z R Hamady ¹, Nigel Scott ¹, Mark D Farrar ¹, J Peter A Lodge ¹, Keith T Holland ¹, Terence R Whitehead ² and Simon R Carding ^3*

¹ Univ. Leeds, United Kingdom
² National Cntr Agricult. Res. USDA, United States
³ Univ. Leeds; Institute Food Res. & Univ. East Anglia, United Kingdom

^* To whom correspondence should be addressed. E-mail: simon.carding{at}bbsrc.ac.uk.

Accepted 4 August 2009

Abstract

Background and aim: Human growth factors are potential therapeutic agents for various inflammatory disorders affecting the gastrointestinal tract [1, 2]. However, they are unstable when administered orally and systemic administration requires high doses increasing the risk of unwanted side effects. Live microorganism-based delivery systems can overcome these problems although they suffer from the inability to control heterologous protein production [3]. To overcome these limitations we have developed a new live bacteria drug-delivery system using the human commensal gut bacterium Bacteroides ovatus engineered to secrete human growth factors in response to dietary xylan.

Methods: B. ovatus strains expressing human keratinocyte growth factor-2 that plays a central role in intestinal epithelial homeostasis (BO-KGF) were generated by homologous recombination and evaluated using the dextran sodium sulphate (DSS)-induced model of intestinal epithelial injury and colitis.

Results: In response to xylan BO-KGF produced high levels of 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 prophylactic effect limiting the development of inflammation and disruption of the epithelial barrier.

Conclusion: Treatment with BO-KGF and xylan was effective at both treating and limiting the development of epithelial injury and acute colitis. This novel diet-regulated, live bacterial drug delivery system may be applicable to treating various bowel disorders.