The effects of dietary eicosapentaenoic acid and arachidonic acid on gene expression changes in a mouse model of human inflammatory bowel diseases : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Nutritional Science at Massey University, Palmerston North, New Zealand
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Date
2010
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Massey University
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Abstract
Nutrigenomics studies the genome-wide influence of nutrients to understand the
association between nutrition and human health. Studies in animal models and humans
have demonstrated that dietary n-3 polyunsaturated fatty acids (PUFA) from fish oil
may be beneficial in inflammatory bowel diseases (IBD).
This thesis aimed to test the hypothesis that dietary n-3 PUFA eicosapentaenoic acid
(EPA) reduced and n-6 PUFA arachidonic acid (AA) increased colitis in the interleukin-
10 gene-deficient (Il10–/–) mouse model of IBD, and that these PUFA altered the
intestinal bacteria community during colitis development using genome-wide
expression and bacterial profiling.
Using a combined transcriptomic and proteomic approach, the time-course study
defined the onset and progression of colitis in Il10–/– mice. Histopathology, transcript
and protein changes before and after colitis onset involved in innate and adaptive
immune responses suggested delayed remodelling processes in colitic Il10–/– mice and
11 weeks of age as suitable time point to study the effects of dietary PUFA on colitis
development. Comparing the transcriptome and proteome profiles associated with colon
inflammation of mice fed with the AIN-76A or oleic acid (OA) diet showed that OA
was an appropriate control for unsaturated fatty acids in multi-omic studies. The PUFA
intervention study indicated that dietary EPA-induced lipid oxidation might have a
potential anti-inflammatory effect on inflamed colon tissue partially mediated through
activation of peroxisome proliferator-activated receptor alpha (PPARα). Unexpectedly,
dietary AA decreased the expression of inflammatory and stress colonic genes in Il10–/–
mice. Altered intestinal bacteria community observed in Il10–/– mice before and after
colitis onset was associated with the lack of IL10 protein led to changes in intestinal
metabolic and signalling processes. Interestingly, dietary EPA and AA seemed to
change intestinal bacteria profiles during colitis development. The role of PPARα in the
colon was further examined in a concluding study which identified vanin1 as a likely
new PPARα-target gene which may also be involved in lipid metabolism.
These findings using a state-of-the-art approach combining transcriptomics, proteomics
and physiology provide a basis for future research on molecular mechanisms underlying
the effects of dietary PUFA, and might contribute to the development of fortified foods
that improve intestinal health and wellness.
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Keywords
Nutrigenomics, Polyunsaturated fatty acids, Colitis