Effect of dietary omega 3 fatty acids on colitis and colon cancer development in

描述（由申请人提供）：炎症是结肠癌进展的重要危险因素。建议通过补充omega-3或n-3脂肪酸来调节饮食炎症，以减少炎症和癌症风险。出乎意料的是，我们的实验室最近发现富含n-3脂肪酸二十二碳六烯酸的鱼油（富含DHA的鱼油=DFO）促进了实验诱导的结肠炎症和粘液腺癌的进展。这些肿瘤是在相当于人体剂量的3、5和8克DFO/d（2000千卡）下观察到的。DFO还显著缩短了肿瘤形成的时间。在机制上，n-3脂肪酸被认为通过改变脂肪酸与免疫细胞脂质筏的结合和减少细胞信号传导来影响炎症。在多种情况下，先天免疫反应的减少可能导致负面结果。这对于炎症性肠病非常重要，炎症性肠病被认为是由胃肠道中细菌的先天免疫反应受损引起的。在美国，鱼油补充剂继续快速增长。添加到这些补充剂中的n-3脂肪酸种类差别很大。然而，与疾病结局相关的n-3来源研究较少。这项研究的长期目标是通过饮食策略降低结直肠癌的风险。本提案的短期目标是确定n-3脂肪酸DHA在我们的结肠癌进展模型中的促进作用是否也与其他n-3脂肪酸（EPA）或补充剂中的典型组合一起观察到。该提案以以下具体目的解决这些目标：在实验性结肠炎小鼠模型中建立调节炎症和结肠癌进展的n-3脂肪酸的剂量，来源和红细胞含量。我们假设单独使用EPA或EPA:DHA的低剂量组合不会像使用DHA那样促进结肠炎和加速发育不良。我们将验证这一假设a)利用SMAD3-/-结肠炎小鼠模型，饲养不同n-3来源（DHA和EPA）的饲料，诱导结肠炎并测量炎症/不典型增生，b) SMAD3抗结肠炎的幼崽饲养不同n-3来源（DHA和EPA）的饲料，诱导结肠炎并测量炎症/不典型增生，c)确定与结肠炎严重程度相关的n-3脂肪酸融入红细胞。拟议的项目具有很高的影响力，因为它提供的数据支持了使用与摄入量、炎症和结肠癌进展相关的红细胞指数来确定n-3脂肪酸摄入量的最大可耐受上限的呼吁。这项研究还将有助于基本理解易感模型如何为未来的人体研究提供与膳食补充剂相关的风险和潜在风险/收益。

DESCRIPTION (provided by applicant): 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.