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Xylan regulated delivery of human keratinocyte growth factor-2 to the inflamed colon by the human anaerobic commensal bacterium Bacteroides ovatus
  1. Zaed Z R Hamady (zaed.hamady{at}doctors.org.uk)
  1. Univ. Leeds, United Kingdom
    1. Nigel Scott (nigel.scott{at}doctors.org.uk)
    1. Univ. Leeds, United Kingdom
      1. Mark D Farrar (m.d.farrar{at}leeds.ac.uk)
      1. Univ. Leeds, United Kingdom
        1. J Peter A Lodge (peter.lodge{at}leedsth.nhs.uk)
        1. Univ. Leeds, United Kingdom
          1. Keith T Holland (mickth{at}bmb.leeds.ac.uk)
          1. Univ. Leeds, United Kingdom
            1. Terence R Whitehead (terry.whitehead{at}ars.usda.gov)
            1. National Cntr Agricult. Res. USDA, United States
              1. Simon R Carding (simon.carding{at}bbsrc.ac.uk)
              1. Univ. Leeds; Institute Food Res. & Univ. East Anglia, United Kingdom

                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.

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