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

地中海饮食和减肥：针对胆汁酸/肠道微生物轴来降低结直肠癌风险

• 批准号: 10328968
• 负责人: Marian L. Fitzgibbon
• 金额: $ 64.08万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328968
• 关键词: Address; Adherence; Adult; Affect; African; African American population; Amino Acids; Animals; Antineoplastic Agents; Bacteria; Bile Acids; Bilophila wadsworthia; Biometry; Body Weight decreased; Butyrates; Caloric Restriction; Calories; Cell Proliferation; Cells; Cellular biology; Clinical Research; Clostridium; Colon; Colorectal Cancer; Computational Biology; Controlled Study; Coupled; DNA Repair; Data; Deoxycholic Acid; Development; Diet; Dietary Factors; Dietary Fiber; Dietary Practices; Epithelial Cells; Exhibits; Fiber; Fostering; Gene Expression; Genes; Genomic Instability; Glycine; Growth; High Prevalence; Human; Hydrogen Sulfide; Incidence; Inflammation; Intake; Intervention; Intestines; Link; Mediating; Medical; Medicine; Mediterranean Diet; Metabolic; Metabolism; Microbiology; Molecular; Mucositis; Not Hispanic or Latino; Obesity; Observational Study; Palate; Pathway interactions; Pattern; Persons; Physiology; Plants; Primates; Production; Proteins; Psychology; Public Health; Race; Randomized; Risk Factors; Risk Reduction; Sampling; Structure; Subgroup; Supervision; Taurine; Testing; Time; Translating; Tumor Promoters; Weight; Weight maintenance regimen; anti-cancer; arm; base; bile acid metabolism; cancer health disparity; carcinogenesis; colon bacteria; colorectal cancer prevention; colorectal cancer risk; dietary restriction; evidence base; genotoxicity; gut bacteria; gut microbes; gut microbiome; gut microbiota; high risk population; innovation; intervention effect; intestinal epithelium; lifestyle intervention; microbial; microbial composition; modifiable risk; mortality; multidisciplinary; nutrition; personalized approach; post intervention; response; saturated fat; tumor

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.

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， 饮食含量高动物蛋白和饱和脂肪（SFAT）。非裔美国人（AAS）的患病率更高 这些危险因素，它们的CRC和相关死亡率最高。这些多重风险因素 还与较高的循环和粪便胆汁酸（BA）以及BA氨基酸偶联的甘氨酸旋转有关 到牛磺酸。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，促进肠道细菌扩展和代谢牛磺酸偶联的碱基的促进条件 硫化氢（H2S）和肿瘤启动子脱氧胆酸（DCA）；一个引导到 CRC的形成。我们已经表明，在 与非西班牙裔白人相比，AA的结肠是AAS的结肠，在AA CRC病例中是一个定义特征 细菌以种族依赖的方式作为CRC发展的贡献者。此外，微生物差异 与AAS中SFAT和动物蛋白的摄入量较高有关，提供了关键的干预靶标。我们 假设针对BA-GUT微生物组轴以抑制抽象，生长和代谢活性 H2S和DCA通过饮食和减肥（WL）产生细菌（WL）可能会降低CRC风险，尤其是在 AAS。地中海饮食（Meddiet）是一种大型植物性饮食模式，与CRC预防和 观察性研究中抗癌代谢物的微生物产生。 Meddiet可以将BA代谢转移为 在Primes中显示并与卡路里限制结合时，显示出较高的依从性和重量控制 鉴于人类的可口性。迄今为止，还没有在RCT中测试过单独的Meddiet的影响（Med- a），通过生活方式干预（WL-A）或BA-GUT上的WL（WL-MED）的卡路里限制的Meddiet，WL 微生物组轴及其与AAS中CRC预防的相关性。我们的多学科团队结合 心理学，营养，微生物学，分子细胞生物学，计算生物学，医学和医学专业知识 生物统计学，提议进行四臂RCT，其中有200名肥胖的AA，45-75岁 遵循8个月的干预措施：MED-A，体重稳定； WL-A，无饮食模式变化的卡路里限制； wl- 医学或控制。我们将使用基线，中期（4个月）和干预后收集的样品和数据 比较干预措施对1）循环和粪便碱的浓度和组成的影响； 2） 肠道菌群和代谢功能； 3）去角质肠上皮细胞的基因表达谱。 我们的方法非常强烈，我们的多学科团队，基于证据的生活方式干预措施以及 软化的 - 组分析以检查饮食/WL，肠道微生物组和宿主肠之间的串扰 生理。如果成功的话，这项研究可能对AAS和其他其他AAS的CRC风险产生深远的影响 高风险的人口将转化为及时的传播机会。