Mediterranean Diet and Weight Loss: Targeting the Bile Acid/Gut Microbiome Axis to Reduce Colorectal Cancer Risk

抽象的。结直肠癌(CRC)与多种危险因素有关，包括肥胖、低纤维饮食、 以及高动物蛋白和饱和脂肪(SFAT)的饮食。非裔美国人(AA)有更高的发病率 这些危险因素都是结直肠癌发病率和相关死亡率最高的。这些多重风险因素 也与更高的循环和粪便胆汁酸(BA)以及BA的氨基酸结合从甘氨酸转移有关 给牛磺酸。这些与BA相关的变化可以改变肠道的组成、结构和代谢活动 微生物区系，培养肠道细菌扩大和代谢牛磺酸偶联基团为遗传毒性的条件 硫化氢(H2S)和促癌剂脱氧胆酸(DCA)；有利于 儿童权利公约的形成。我们已经表明，在中国，产生硫化氢的细菌的丰度显著高于 与非西班牙裔白人相比，AAS的冒号是AA CRC病例中的一个决定性特征，涉及这些 细菌以种族依赖的方式促进结直肠癌的发展。此外，微生物的差异 与AAS中SFAT和动物蛋白的较高摄入量有关，提供了一个关键的干预靶点。我们 假设靶向BA-肠道微生物组轴以抑制细菌的丰度、生长和代谢活动 通过饮食和减肥(WL)产生硫化氢和DCA的细菌可能会降低结直肠癌的风险，特别是在 美国医学会。地中海饮食(MedDiet)，一种主要以植物为基础的饮食模式，与预防和治疗结直肠癌有关 观察性研究中抗癌代谢产物的微生物生产。MedDiet可以改变BA的代谢，因为 在灵长类动物中显示，当与卡路里限制相结合时，显示出更好的依从性和体重控制 人类，考虑到它的可口性。到目前为止，还没有研究在RCT中测试单独使用MedDiet(MedDiet)的效果。 A)，通过生活方式干预(WL-A)或限制热量的MedDiet for WL(WL-Med)在BA-Gut上 微生物群轴及其与腹主动脉结直肠癌预防的相关性。我们的多学科团队将 心理学、营养学、微生物学、分子细胞生物学、计算生物学、医学和 生物统计学，建议进行一项四臂随机对照试验，其中200名肥胖的AA，45-75岁完成其中之一 经过8个月的干预：MED-A，体重稳定；WL-A，热量限制，不改变饮食模式；WL-A 医学；或控制组。我们将使用在基线、研究中期(4个月)和干预后收集的样本和数据 比较干预措施对1)循环和粪便中BAs浓度和组成的影响；2) 肠道微生物区系和代谢功能；3)脱落的肠上皮细胞的基因表达谱。 我们的方法是强有力的，考虑到我们的多学科团队，使用循证生活方式干预，以及 复杂组学分析以检查饮食/WL、肠道微生物组和宿主肠道之间的串扰 生理学。如果成功，这项研究可能会对美国癌症协会和其他疾病的结直肠癌风险产生深远的公共卫生影响 高风险人群，这将转化为及时的传播机会。

ABSTRACT. Colorectal cancer (CRC) is associated with multiple risk factors including, obesity, low fiber diets, and diets high in animal protein and saturated fat (SFat). African Americans (AAs) have a higher prevalence of these risk factors and they have the highest incidence of CRC and related mortality. These multiple risk factors are also linked to higher circulating and fecal bile acids (BA) and a shift in BA amino acid conjugation from glycine to taurine. These BA-related changes can alter the composition, structure, and metabolic activity of the gut microbiota, fostering conditions for gut bacteria to expand and metabolize taurine-conjugated BAs to genotoxic hydrogen sulfide (H2S) and the tumor promoter, deoxycholic acid (DCA); a colonic milieu conducive to the formation of CRC. We have shown that the abundance of H2S-producing bacteria is significantly higher in the colon of AAs compared to non-Hispanic whites and is a defining feature among AA CRC cases implicating these bacteria as contributors to CRC development in a race-dependent manner. Moreover, the microbial difference is associated with higher intake of SFat and animal protein in AAs, providing a pivotal intervention target. We hypothesize that targeting the BA-gut microbiome axis to suppress abundance, growth and metabolic activity of H2S and DCA producing bacteria through diet and weight loss (WL) may reduce CRC risk, especially among AAs. A Mediterranean Diet (MedDiet), a largely plant-based dietary pattern, is relevant to CRC prevention and microbial production of anti-cancer metabolites in observational studies. A MedDiet can shift BA metabolism as shown in primates and when combined with calorie restriction, shows superior adherence and weight control in humans, given its palatability. To date, no studies have tested in an RCT the effects of a MedDiet alone (Med- A), WL through lifestyle intervention (WL-A) or a calorie-restricted MedDiet for WL (WL-Med) on the BA-gut microbiome axis and its relevance to CRC prevention among AAs. Our multidisciplinary team combining expertise in psychology, nutrition, microbiology, molecular cell biology, computational biology, medicine and biostatistics, propose to conduct a four-arm RCT in which 200 obese AAs, 45-75 years old complete one of the following 8-month interventions: Med-A, weight stable; WL-A, calorie restriction with no diet pattern change; WL- Med; or Control. We will use samples and data collected at baseline, mid-study (month-4) and post-intervention to compare the effects of the interventions on 1) Concentration and composition of circulating and fecal BAs; 2) Gut microbiota and metabolic function; and 3) Gene expression profiles of exfoliated intestinal epithelial cells. Our approach is strong given our multidisciplinary team, use of evidence-based lifestyle interventions, and sophisticated –omics analyses to examine crosstalk between diet/WL, gut microbiome, and host intestinal physiology. If successful, this study could have profound public health impact on CRC risk among AAs and other high-risk populations, that would translate into timely dissemination opportunities.