Xylan-regulated delivery of human keratinocyte growth factor-2 to the inflamed colon by the human anaerobic commensal bacterium Bacteroides ovatus
Xylan-regulated delivery of human keratinocyte growth factor-2 to the inflamed colon by the human anaerobic commensal bacterium Bacteroides ovatus
BACKGROUND: Human growth factors are potential therapeutic agents for various inflammatory disorders affecting the gastrointestinal tract. 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 and there are concerns regarding biosafety and environmental contamination.
METHODS: 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. The anaerobic nature of B ovatus provides an inherent biosafety feature. B ovatus strains expressing human keratinocyte growth factor-2, which plays a central role in intestinal epithelial homeostasis and repair (BO-KGF), were generated by homologous recombination and evaluated using the dextran sodium sulfate (DSS)-induced model of intestinal epithelial injury and colitis.
RESULTS: 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.
CONCLUSION: This novel, diet-regulated, live bacterial drug delivery system may be applicable to treating various bowel disorders.
Animals, Bacteroides/drug effects, Biological Assay/methods, Cell Proliferation/drug effects, Colitis/chemically induced, Dextran Sulfate, Disease Models, Animal, Drug Delivery Systems/methods, Endo-1,4-beta Xylanases/genetics, Fibroblast Growth Factor 10/administration & dosage, Genetic Engineering/methods, Intestinal Mucosa/drug effects, Male, Mice, Mice, Inbred C57BL, Mucins/biosynthesis, Promoter Regions, Genetic, Xylans/pharmacology
461-469
Hamady, Zaed Z R
545a1c81-276e-4341-a420-aa10aa5d8ca8
Scott, Nigel
d9f917a3-afb5-47e2-81da-5149c0420c82
Farrar, Mark D
5b6b2aad-3bb6-400f-9ae3-cb8f9be8cd57
Lodge, J Peter A
c97dd104-0cb2-4f05-a008-9b9af01e4820
Holland, Keith T
59cafad5-1008-4848-aef6-bc9b0a249839
Whitehead, Terence
6d7a75b8-215f-4602-afba-07c97be26ba4
Carding, Simon R
1104c711-b95b-4ed5-9cc6-6d09f1f268ea
23 March 2010
Hamady, Zaed Z R
545a1c81-276e-4341-a420-aa10aa5d8ca8
Scott, Nigel
d9f917a3-afb5-47e2-81da-5149c0420c82
Farrar, Mark D
5b6b2aad-3bb6-400f-9ae3-cb8f9be8cd57
Lodge, J Peter A
c97dd104-0cb2-4f05-a008-9b9af01e4820
Holland, Keith T
59cafad5-1008-4848-aef6-bc9b0a249839
Whitehead, Terence
6d7a75b8-215f-4602-afba-07c97be26ba4
Carding, Simon R
1104c711-b95b-4ed5-9cc6-6d09f1f268ea
Hamady, Zaed Z R, Scott, Nigel, Farrar, Mark D, Lodge, J Peter A, Holland, Keith T, Whitehead, Terence and Carding, Simon 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), .
(doi:10.1136/gut.2008.176131).
Abstract
BACKGROUND: Human growth factors are potential therapeutic agents for various inflammatory disorders affecting the gastrointestinal tract. 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 and there are concerns regarding biosafety and environmental contamination.
METHODS: 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. The anaerobic nature of B ovatus provides an inherent biosafety feature. B ovatus strains expressing human keratinocyte growth factor-2, which plays a central role in intestinal epithelial homeostasis and repair (BO-KGF), were generated by homologous recombination and evaluated using the dextran sodium sulfate (DSS)-induced model of intestinal epithelial injury and colitis.
RESULTS: 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.
CONCLUSION: This novel, diet-regulated, live bacterial drug delivery system may be applicable to treating various bowel disorders.
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More information
e-pub ahead of print date: 7 September 2009
Published date: 23 March 2010
Additional Information:
© 2009, Published by the BMJ Publishing Group Limited
Keywords:
Animals, Bacteroides/drug effects, Biological Assay/methods, Cell Proliferation/drug effects, Colitis/chemically induced, Dextran Sulfate, Disease Models, Animal, Drug Delivery Systems/methods, Endo-1,4-beta Xylanases/genetics, Fibroblast Growth Factor 10/administration & dosage, Genetic Engineering/methods, Intestinal Mucosa/drug effects, Male, Mice, Mice, Inbred C57BL, Mucins/biosynthesis, Promoter Regions, Genetic, Xylans/pharmacology
Identifiers
Local EPrints ID: 457902
URI: http://eprints.soton.ac.uk/id/eprint/457902
ISSN: 1468-3288
PURE UUID: 3d3802ee-910f-418c-80ca-3abab7c48212
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Date deposited: 21 Jun 2022 18:17
Last modified: 17 Mar 2024 04:12
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Contributors
Author:
Zaed Z R Hamady
Author:
Nigel Scott
Author:
Mark D Farrar
Author:
J Peter A Lodge
Author:
Keith T Holland
Author:
Terence Whitehead
Author:
Simon R Carding
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