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.

摘要：结直肠癌 (CRC) 与多种危险因素相关，包括肥胖、低纤维饮食、 富含动物蛋白和饱和脂肪 (SFat) 的饮食中，非洲裔美国人 (AA) 的患病率较高。 这些危险因素导致他们的 CRC 发病率和相关死亡率最高。 还与较高的循环胆汁酸和粪便胆汁酸 (BA) 以及 BA 氨基酸缀合从甘氨酸的转变有关 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。 微生物群，为肠道细菌扩增和代谢牛磺酸结合的 BA 产生基因毒性提供条件 硫化氢 (H2S) 和肿瘤促进剂脱氧胆酸 (DCA)； 我们已经表明，产生 H2S 的细菌的丰度明显更高。 与非西班牙裔白人相比，AA 结肠癌是 AA CRC 病例的一个决定性特征，涉及这些病例 细菌对结直肠癌的发展具有种族依赖性。此外，微生物之间存在差异。 与 AA 中 SFat 和动物蛋白的摄入量较高有关，提供了一个关键的干预目标。 随后针对 BA-肠道微生物组轴来抑制细菌的丰度、生长和代谢活动 通过饮食和减肥 (WL) 产生 H2S 和 DCA 的细菌可能会降低 CRC 风险，尤其是在人群中 地中海饮食 (MedDiet) 是一种主要以植物为基础的饮食模式，与 CRC 预防和治疗相关。 观察研究中微生物产生的抗癌代谢物可以改变 BA 代谢。 在灵长类动物中显示，当与热量限制相结合时，在 鉴于其适口性，迄今为止，还没有研究在随机对照试验中测试过单独使用 MedDiet 的效果（Med- A)、通过生活方式干预 (WL-A) 或 BA-gut 进行热量限制的 WL 饮食 (WL-Med) 来实现 WL 微生物组轴及其与 AA 中 CRC 预防的相关性。 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，提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，热量限制，饮食模式无变化； 我们将使用基线、研究中期（第 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 的浓度和组成的影响； 肠道微生物群和代谢功能；3) 脱落肠上皮细胞的基因表达谱。 我们的方法是基于我们的多学科团队、基于证据的生活方式干预措施的使用，以及 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 如果成功，这项研究可能会对 AA 和其他人群的 CRC 风险产生深远的公共卫生影响。 高危人群，这将转化为及时传播的机会。