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人口，报告的发病率最高 (91：100，000）和结肠癌死亡率（~35：100，000）。有压倒性 实验和人类证据表明，饮食驱动癌症风险，无论遗传背景如何。世界 癌症研究基金会发现令人信服的证据表明，肉类增加癌症风险， 将其删除[2，3]。因此，AN的高风险可能归因于其显著的低纤维（8g/d） 高肉类消费。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，我们将进行一次 在多达100例可随机化的健康中年AN中进行的随机双盲4周临床试验 接受结肠镜检查筛查，目标是获得60个完整的干预措施。的 干预措施将包括高剂量的"难消化"抗性淀粉纤维补充剂（42 g/d）， 饮料，这将增加他们的每日摄入量> 50克/天，或对照"可消化"淀粉饮料。衡量 针对癌症发展的潜在功效，我们将使用可以测量的增殖生物标志物 在通过乙状结肠镜活检获得的结肠粘膜中依次进行（主要终点）。同时我们 将通过测量结肠微生物群来研究这些预期变化的机制 通过下一代微生物16S-rRNA基因测序分析其组成和活性， NMR、UPLC-M和GC-M光谱分析，采用先进的数学建模进行解释。我们相信 我们将达到我们的终点，因为我们使用的纤维剂量比过去使用的高得多。 在以前的临床试验中，> 50 g/d，这是非洲农村地区风险最小的水平。 其次，我们预计，AN持续的高鱼油消费量将提高他们对以下问题的反应能力： 纤维补充剂在进行以下研究之前，进行这项分子概念验证研究至关重要： 一项关于高剂量纤维补充剂预防结肠息肉的大规模确定性临床试验， 癌虽然长期目标将是增加富含纤维的食物的消费， 补充淀粉可能为拯救阿拉斯加原住民的生命提供一种直接的策略， 非裔美国人和地球仪上不断增长的人口消费低纤维西方饮食的风险。 !

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. !