Diet and Gastrointestinal Cancer Risk in African Americans and Rural Africans

描述(申请人提供)：癌症发病率的地理差异一般可归因于环境原因，特别是饮食原因。我们担心，美国非裔美国人结肠癌的发病率(占总人口的70,000)和死亡率最高的原因是饮食因素，因为非洲原住民的饮食非常不同，他们几乎不会患上结肠癌(1：100,000)。我们在这两个社区进行的研究，得到了大量实验证据的支持，表明原因可能在于AAs在饮食中大量摄入红肉，这增加了硫磺还原细菌(SRB)的微生物群，这些微生物群产生细胞毒性和遗传毒性的硫化氢作为最终产物。实验证明，这种铅会导致慢性粘膜炎症和过度增殖，这种状态会增加癌症风险。相比之下，非洲人受到大量产甲烷菌的保护，这些产甲烷菌在高碳水化合物、无肉的条件下茁壮成长，并产生无毒的终端产品甲烷。我们的研究还表明，AAS中产生次级胆盐的细菌数量较多，这些细菌受到高动物脂肪饮食的刺激，产生致癌的次级胆盐。相比之下，高抵抗力的淀粉饮食刺激粘膜保护乳杆菌确实在非洲人中更常见。这些观察结果导致了我们的假设，即患结肠癌的风险是由饮食和驻留的微生物群之间的相互作用决定的，这会影响结肠粘膜中的慢性炎症和上皮细胞增殖水平，从而影响癌症风险。在目前的提案中，我们计划通过研究匹兹堡地区AA人群中的20名健康中年受试者来证实这一假设，并将他们与相同数量的非洲人在改变饮食之前和之后2周进行比较。具体地说，我们将把AA饮食改变为高抗淀粉、低肉类饮食，将非洲饮食改变为高红肉、低碳水化合物的西化饮食。如果我们的假设得到支持，我们将有望在AA组观察到甲烷生成增加，结肠SRBS和硫化氢产生减少，从而减少粘膜炎症和结肠上皮增殖，这是我们癌症风险的主要生物标志物。相比之下，我们预计会在抑制产甲烷的非洲人中发现SRB种群增长增加。对粘膜基因表达的微阵列分析，以及随后的RT-PCR确认，将被用来识别可能解释饮食、细菌代谢、炎症和过度增殖的机制的新途径。我们的发现将为深入了解如何操纵饮食来修改微生物区系以促进粘膜健康，从而降低结肠癌风险，减少与诊断和治疗相关的医疗成本，并降低非裔美国人目前不可接受的高发病率和死亡率。公共卫生相关性：结肠癌是美国癌症死亡的第二大原因，与美国其他种族相比，非裔美国人的发病率(每10万人中有70人)和死亡率最高。这些统计数据与当地非洲人的报告形成了鲜明对比，当地非洲人的发病率为每10万人中就有1人。我们之前的研究表明，这种差异可以归因于非裔美国人相对较高的肉类和动物脂肪摄入量，以及非洲人较高的抗性淀粉摄入量。

DESCRIPTION (provided by applicant): Geographical variations in cancer incidence can be attributed to environmental causes in general, and to diet, in particular. We are concerned that the reason why African Americans (AAs) have the highest incidence (c1:70,000 of the population) and death rate from colon cancer in the USA is due to dietary factors as native Africans, who consume a very different diet, hardly ever get the disease (<1: 100,000). Studies of ours in the 2 communities, supported by a wealth of experimental evidence, have suggested that the explanation may lie in the high dietary intake of red meat by AAs which increases microbiota populations of sulfur-reducing bacteria (SRBs), which produce cytotoxic and genotoxic hydrogen sulfide as a terminal product. This leads has been shown experimentally to lead to chronic mucosal inflammation and hyperproliferation, a state that increases cancer risk. In contrast, Africans are protected by high populations of methanogens which thrive in high carbohydrate, meat-free conditions and produce the non-toxic terminal product, methane. Our studies have also showed higher populations of secondary bile salt producing bacteria in AAs which are stimulated by high animal fat diets to produce carcinogenic secondary bile salts. In contrast, a high resistant starch diet stimulates mucosal-protective Lactobacillus species were, indeed, found to be more common in Africans. These observations have lead to our hypothesis that the risk of developing cancer of the colon is determined by the interaction between diet and resident microbiota, which influences the level of chronic inflammation and epithelial proliferation - and therefore cancer risk - in the colonic mucosa. In the present proposal, we plan to substantiate this hypothesis by studying 20 healthy middle aged subjects from the population of AAs in the Pittsburgh area and compare them to the same number of Africans before and 2 weeks after dietary switch. Specifically, we will change the AA diet to a high resistant starch, low meat diet and the African diet to a high red meat, low carbohydrate "westernized" diet. If our hypothesis is supported, we will expect to observe in the AA group an increase in methanogenesis and a reduction in colonic SRBs and hydrogen sulfide production, resulting in a reduction in mucosal inflammation and colonic epithelial proliferation, our primary biomarker of cancer risk. In contrast, we will expect to find increased SRB population growth in Africans with suppression of methanogenesis. Microarray analysis of mucosal gene expression, followed up by RT- PCR confirmation will be employed to identify novel pathways that may explain the mechanisms that link diet, bacterial metabolism, inflammation, and hyper-proliferation. Our findings will provide insight into how the diet can be manipulated to modify microbiota to promote mucosal health, and therefore reduce colon cancer risk, diminish health care costs related to diagnosis and treatment, and decrease the unacceptably high present morbidity and mortality from this disease in African Americans. PUBLIC HEALTH RELEVANCE: Colon cancer is the second leading cause of cancer death in the USA, and compared to other U.S. racial groups African-Americans have the highest incidence (70 per 100,000 of the population) and mortality. These statistics contrast sharply from those reported in native Africans where incidence rates are <1 per 100,000. Our previous studies have suggested the difference can be attributed to the relatively higher meat and animal fat intake by African Americans and the higher resistant starch intake by Africans.