Randomized Controlled Trial of Resistant Starch to Reduce Colon Cancer Risk in Alaska Native People

阿拉斯加原住民(An)，一个服务不足的美国少数民族，报告的发病率最高 (91：100,000)和死亡率(~35：100,000)。有压倒性的 实验和人类证据表明，无论遗传背景如何，饮食都会导致癌症风险。世界 癌症研究基金会发现令人信服的证据表明肉类会增加癌症风险，而这种纤维 抑制它[2，3]。因此，AN的高风险可能归因于他们非常低的纤维(8g/d) 以及高肉类消耗量。我们假设他们的极端风险是由纤维的综合作用造成的 缺乏，导致结肠微生物群产生的抗癌丁酸盐减少，加上高暴露 从肉类、脂肪、烟熏食品和烟草中提取的致癌物质。为了探索这一假设，我们将进行一项 多达100名健康、中年、随机、随机、双盲、为期4周的临床试验 接受结肠镜筛查，目标是获得60个完整的介入治疗。这个 干预措施包括大剂量“无法消化”的抗性淀粉纤维补充剂(42g/d) 一种饮料，这将使他们的每日摄入量增加到&gt；50g/d，或者是一种对照的“可消化”的淀粉饮料。衡量 对癌症发展的潜在疗效我们将使用可以测量的增殖生物标记物 乙状结肠镜活检(主要终点)。同时，我们 将通过测量结肠微生物区系来研究导致这些预期变化的机制 微生物16S-rRNA基因的下一代测序及其代谢物的组成和活性 核磁共振、UPLC-M和GC-M光谱，用先进的数学模型进行解释。我们有信心 我们将达到我们的终点，因为我们使用的光纤剂量比 以前的临床试验是每天50g，这一水平被证明与非洲农村人的最低风险有关。 第二，我们预期AN的鱼油消耗量持续高企，将会加强它们对 纤维补充剂。进行这种分子概念验证研究是在进行 大剂量纤维补充剂预防大肠息肉和结肠炎的临床研究 癌症。虽然长期目标将是增加富含纤维的食物的消费，但低成本具有抵抗力 淀粉补充剂可能会提供一种直接的策略来拯救阿拉斯加原住民的生命，也可以在高海拔地区 冒着非洲裔美国人和全球不断增长的人口食用低纤维西方饮食的风险。 好了！

Alaska Native people (AN), an underserved minority US population, have the highest reported incidence (91:100,000) and death (~35:100,000) rate from colon cancer in the world. There is overwhelming experimental and human evidence that diet drives cancer risk, irrespective of genetic background. The World Cancer Research Foundation found convincing evidence that meat increases cancer risk, and that fiber suppresses it [2, 3]. Consequently, the high risk in AN may be attributed to their remarkably low fiber (8g/d) and high meat consumption. We hypothesize that their extreme risk results from the combined effects of fiber deficiency, resulting in decreased colonic microbiota production of anti-cancer butyrate, plus the high exposure to carcinogens derived from meat, fat, smoked foods and tobacco. To explore this hypothesis, we will conduct a randomized double-blinded 4-week clinical trial in up to 100 randomizable healthy, middle-aged AN undergoing screening colonoscopy, with the objective of obtaining 60 completed interventions. The interventions will consist of either a high-dose `indigestible' resistant starch fiber supplement (42g/d) given as a drink, which will increase their daily intake to >50g/d, or a control `digestible' starch drink. To gauge potential efficacy against cancer development we will use proliferative biomarkers which can be measured sequentially in colonic mucosa obtained by sigmoidoscopy biopsy (primary endpoint). At the same time, we will investigate the mechanisms responsible for these anticipated changes by measuring the colonic microbiota composition and activity by next generation sequencing of microbial 16S-rRNA genes, and its metabolome by NMR, UPLC-M, and GC-M spectrometry, interpreted with advanced mathematical modeling. We are confident that we will achieve our endpoint because we are using a much higher dose of fiber than has been used in previous clinical trials at >50g/d, which is the level shown to be associated with minimal risk in rural Africans. Secondly, we expect that the continued high fish oil consumption by AN will enhance their responsiveness to fiber supplementation. The conduct of this molecular proof-of-concept study is essential before the conduct of a large-scale definitive clinical trial of high dose fiber supplementation in the prevention of colonic polyps and cancer. While the long-term goal will be to increase the consumption of fiber-rich foods, low cost resistant starch supplementation may offer an immediate strategy to save lives in Alaska Native people, and also in high risk African Americans and the growing populations across the globe consuming low fiber Western diets. !