Inflammation is an important risk factor for progression of colon carcinogenesis. Dietary modulation of inflammation via supplementation by omega-3 or n-3 fatty acids is proposed to reduce inflammation and cancer risk. Unexpectedly, our laboratory recently showed that fish oil enriched with the n-3 fatty acid docosahexaenoic acid (fish oil enriched with DHA=DFO) promoted experimentally induced colon inflammation and progression to mucinous adenocarcinoma. These tumors were observed at human equivalent doses of 3, 5 and 8 grams of DFO/d (2000 kcal). DFO also significantly reduced the time to tumor formation. Mechanistically, the n-3 fatty acids are proposed to influence inflammation by altering the incorporation of fatty acids into the lipid raft of immune cells and reducing cell signaling. There are multiple situations where reduced innate immune responses may result in negative outcomes. This is highly significant to inflammatory bowel diseases that are proposed to result from impaired innate immune responses to bacteria in the gastrointestinal tract. Fish oil supplementation continues to rapidly increase in the US. The type of n-3 fatty acid added to these supplements varies widely. However, the source of n-3 associated with disease outcome is less widely studied. The long-term goal of this research is to reduce colorectal cancer risk using dietary strategies. The short-term goal of this proposal is to determine if the promotional effect of the n-3 fatty acid DHA in our model of colon cancer progression is also observed with other n-3 fatty acids (EPA) or a combination, typical in supplements. The proposal addresses these goals with the following specific aim: establish dose, source and red blood cell content of n-3 fatty acids that modulate inflammation and colon cancer progression in a mouse model of experimental colitis. We hypothesize that EPA alone or lower combinations of EPA:DHA will not promote colitis and accelerate dysplastic development in a manner similar to that observed with DHA. We will test this hypothesis a) utilizing the SMAD3-/- mouse model of colitis fed diets varying the source of n-3 (DHA and EPA), induce colitis and measure inflammation/dysplasia, b) SMAD3 colitis resistant litter mates fed diets varying the source of n-3 (DHA and EPA), induce colitis and measure inflammation/dysplasia and c) determine the n-3 fatty acid incorporation into the RBC that correlates with colitis severity. The proposed project has high impact by providing data supporting a call for a maximum tolerable upper limit for n-3 fatty acid intake using a red blood cell index correlated with intake, inflammation and colon cancer progression. This research will also contribute to the basic understanding of how susceptible models can inform the risks associated with dietary supplementation and potential risk/benefit for future human studies.

Public Health Relevance

Fish oil supplementation continues to rapidly increase in the US. Unexpectedly, our laboratory recently showed that fish oil enriched with the omega-3 fatty acid docosahexaenoic acid promoted experimentally induced colon inflammation and progression to tumors. Research understanding the differential effects of the source and dose of dietary omega-3 fatty acids on carcinogenesis is extremely timely and crucial for making future dietary recommendations regarding omega-3 intake.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
5R03CA162427-02
Application #
8324204
Study Section
Special Emphasis Panel (ZCA1-SRLB-F (M1))
Program Officer
Emenaker, Nancy J
Project Start
2011-09-01
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$76,750
Indirect Cost
$26,750
Name
Michigan State University
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Gurzell, Eric A; Wiesinger, Jason A; Morkam, Christina et al. (2014) Is the omega-3 index a valid marker of intestinal membrane phospholipid EPA+DHA content? Prostaglandins Leukot Essent Fatty Acids 91:87-96
Teague, Heather; Harris, Mitchel; Fenton, Jenifer et al. (2014) Eicosapentaenoic and docosahexaenoic acid ethyl esters differentially enhance B-cell activity in murine obesity. J Lipid Res 55:1420-1433
Fenton, Jenifer I; Hord, Norman G; Ghosh, Sanjoy et al. (2013) Immunomodulation by dietary long chain omega-3 fatty acids and the potential for adverse health outcomes. Prostaglandins Leukot Essent Fatty Acids 89:379-90
Gurzell, Eric A; Teague, Heather; Harris, Mitchel et al. (2013) DHA-enriched fish oil targets B cell lipid microdomains and enhances ex vivo and in vivo B cell function. J Leukoc Biol 93:463-70