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

摘要。结直肠癌（CRC）与多种风险因素相关，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（AAs）的患病率较高， 这些风险因素，他们有最高的发病率CRC和相关死亡率。这些多重风险因素 也与较高的循环和粪便胆汁酸（BA）以及BA氨基酸结合从甘氨酸的转移有关 牛磺酸这些与BA相关的变化可以改变肠道的组成、结构和代谢活性 微生物群，促进肠道细菌扩增和代谢牛磺酸结合的BA的条件，以遗传毒性 硫化氢（H2S）和肿瘤促进剂脱氧胆酸（DCA）;结肠环境有助于 CRC的形成。我们已经表明，在海洋中，产生H2S的细菌的丰度明显较高， 与非西班牙裔白人相比，AA的结肠是AA CRC病例的定义特征， 细菌作为CRC发展的贡献者，以种族依赖的方式。此外，微生物的差异 与AAs中较高的SFat和动物蛋白摄入量相关，提供了关键的干预目标。我们 假设靶向BA-肠道微生物组轴以抑制微生物的丰度、生长和代谢活性， 通过饮食和减肥（WL）产生H2S和DCA的细菌可能会降低CRC风险，尤其是在 原子吸收法地中海饮食（MedDiet）是一种主要以植物为基础的饮食模式，与CRC预防相关， 在观察性研究中，微生物产生抗癌代谢物。MedDiet可以改变BA代谢， 在灵长类动物中显示，并且当与卡路里限制结合时，在以下方面显示出优越的上级依从性和体重控制： 人类，因为它的美味。到目前为止，没有研究在RCT中测试单独的MedDiet（Med-Diet）的效果。 A），WL通过生活方式干预（WL-A）或热量限制的MedDiet用于WL（WL-Med）对BA-肠道 微生物组轴及其与AA中CRC预防的相关性。我们的多学科团队 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45-75岁的肥胖AA完成其中一项 8个月干预后：Med-A，体重稳定; WL-A，热量限制，无饮食模式改变; WL- Med;或Control。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BA的浓度和组成; 2） 肠道微生物群和代谢功能;和3）脱落的肠上皮细胞的基因表达谱。 我们的方法是强大的，因为我们的多学科团队，使用基于证据的生活方式干预， 复杂的组学分析，以检查饮食/WL，肠道微生物组和宿主肠道之间的串扰 physiology.如果成功，这项研究可能对AA和其他癌症患者的CRC风险产生深远的公共卫生影响。 高风险人群，这将转化为及时传播的机会。

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.