Western-Style Diets Induce Oxidative Stress and Dysregulate Immune Responses in the Colon in a Mouse Model of Sporadic Colon Cancer
Western-Style Diets Induce Oxidative Stress and Dysregulate Immune Responses in the Colon in a Mouse Model of Sporadic Colon Cancer
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DOI：
10.3945/jn.108.104125
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发表时间：
2009-11-01
影响因子：
4.2
通讯作者：
Holt, Peter R.
中科院分区：
文献类型：
--
作者：
Erdelyi, Ildiko;Levenkova, Natasha;Holt, Peter R.
由高脂肪、低钙和维生素D含量定义的西式饮食(WD)与人类结直肠癌风险的增加有关。了解WD改变的分子机制对于制定预防和治疗策略至关重要。以散发性结肠癌模型C57BI/6J小鼠为研究对象，在肿瘤发生前观察WD对小鼠结肠转录组的影响，观察WD是否引起炎性改变，并用半定量形态计量学方法测定其固有层巨噬细胞的数量。转录组的变化被翻译成分子相互作用网络图和途径。与氧化应激反应、脂质、谷胱甘肽和外源新陈代谢相关的通路以及免疫反应都受到WD的干扰。诱导了几个核因子-红系2相关因子2-和芳香烃受体依赖的基因，包括那些编码参与药物代谢和氧化应激反应的第一和第二阶段酶的基因。氧化应激通过测量内源性结肠氧化还原敏感化合物浓度来证实。免疫反应相关途径的紊乱、炎性蛋白的表达以及固有层巨噬细胞数量的增加表明，WD显著改变了局部结肠免疫反应。总而言之，这些数据表明，WD的摄入干扰了涉及结肠脂肪代谢、氧化应激和免疫反应的相关生物反应通路的网络。这些新的发现影响了我们对摄入WD和结肠癌发生之间联系的理解，为开发降低结直肠癌风险的预防方法提供了更多的信息。J.Nutr.139：2072-2078,2009。
A Western-style diet (WD), defined by high-fat, low-calcium, and vitamin D content, is associated with increased risk of human colorectal cancer. Understanding molecular mechanisms altered by the WD is crucial to develop preventive and therapeutic strategies. Effects of a WD on the colonic transcriptome of C57BI/6J mice, a model for sporadic colon cancer, were studied at endpoints before tumors occur, To assess whether a WD induces inflammatory changes, expression profiles of a broad spectrum of inflammatory proteins were performed and numbers of lamina propria macrophages were determined with semiquantitative morphometry. Transcriptome changes were translated into molecular interaction network maps and pathways. Pathways related to oxidative stress response; lipid, glutathione, and xenobiotic metabolism; and the immune response were perturbed by the WD. Several nuclear factor-erythroid 2-related factor 2- and aryl hydrocarbon receptor-dependent genes, including those coding for enzymes involved in phase 1 and 2 drug metabolism and oxidative stress responses, were induced. Oxidative stress was demonstrated by measurements of endogenous colonic redox-sensitive compound concentrations. Perturbations in immune response-related pathways, expression of inflammatory proteins, and increased numbers of lamina propria macrophages showed that the WD significantly alters the local colonic immune response. Collectively, these data suggest that consumption of a WD interferes with networks of related biological response pathways involving colonic lipid metabolism, oxidative stress, and the immune response. These new findings impact our understanding of links between consumption of WD and colon carcinogenesis, providing additional information for developing preventive means for decreasing colorectal cancer risk. J. Nutr. 139: 2072-2078, 2009.