Discovering the mechanism of action of nutritional therapy and evolving an innovative formula for the treatment of Crohn's disease

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Embargoed until 2017-06-30
Copyright: Alhag Amhmad, Moftah
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Abstract
Exclusive Enteral Nutrition (EEN), utilizing a nutritionally complete polymeric formula (PF), can suppress gut inflammation and induce remission in active Crohn disease (CD). However, PF’s used for EEN therapy were developed for nutritional support and not for therapeutic roles. The aim of this thesis was to identify and describe components of PF that actively suppress inflammation and to investigate if these components can be manipulated to enhance the anti-inflammatory properties of PF. Utilising an in vitro model of intestinal inflammation, a number of components of PF were identified that could considerably attenuate IL-8 production from TNF stimulated colonic epithelial cells. Two of these components attenuated IL-8 production in a dose-dependent response. These components where shown to interfere with Iκκ and IκB phosphorylation and thereby block IκB degradation and P65 nuclear migration. These components were also shown to inhibit P38 signalling by phosphorylation blockade. The anti-inflammatory activity of PF could be enhanced through manipulation of the concentrations of these two components. The anti-inflammatory properties of PF could be further enhanced by including an additional nutrient component, which had previously been described with anti-inflammatory properties similar to the two PF identified components. The combination of these three components resulted in the complete suppression of the Iκκ complex activity and the complete suppression of IL-8 production from TNF stimulated colonic epithelial cells. A novel formula consisting of standard PF with the addition of enhanced concentrations of the three anti-inflammatory components was tested in a mouse model of colitis. The novel formula prevented colitis induced weight loss, suppressed colonic expression of the major inflammatory mediators and ameliorated local tissue injury. In summary, several key active ingredients of polymeric formula that supress inflammation, were identified. These components had an anti-inflammatory effect by limiting the NF-κB and P38 MAPK signalling transduction pathways. Further, a novel PF was constructed by manipulating concentrations of these components. This novel PF displayed superior efficacy in attenuating intestinal inflammation in an in vitro model and a murine model of colitis. This novel PF may have utility in the treatment of CD and further clinical studies are now required.
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Author(s)
Alhag Amhmad, Moftah
Supervisor(s)
Leach, Steven
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Publication Year
2015
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
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