Dietary prevention for colorectal cancer: targeting the bile acid/gut microbiome axis

结直肠癌的饮食预防：针对胆汁酸/肠道微生物组轴

• 批准号: 10723195
• 负责人: Kai Wang
• 金额: $ 12.41万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-13 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723195
• 关键词: Adherence; Alcohols; Alkaline Phosphatase; American; Animals; Apoptosis; Area; Bifidobacterium; Bile Acid Biosynthesis Pathway; Bile Acids; Bioinformatics; Biological; Biological Markers; Biological Sciences; Blood; CD3 Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; Calories; Carbohydrates; Cell Maturation; Cells; Cessation of life; Clinical; Clinical Trials; Coffee; Cohort Studies; Colon; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Communities; Consumption; Data; Dendritic Cells; Deoxycholic Acid; Development; Diet; Diet Records; Dietary Fiber; Dietary Intervention; Dietary Practices; Environment; Epidemiology; Escherichia coli; Etiology; Excision; FOXP3 gene; Fatty acid glycerol esters; Feces; Follow-Up Studies; Food; Foundations; Fusobacterium nucleatum; Future; Gene Expression; Genes; Goals; Health Professional; Human; Immune; Inflammation; Intake; Intervention; Intervention Studies; Intestines; Life; Link; Lithocholic Acid; Liver; Malignant Neoplasms; Measures; Mediating; Mediator; Mentors; Mentorship; Metabolic; Methods; Microbe; Nurses' Health Study; Nutrient; Nutritional; Nuts; Observational Study; Olive oil preparation; PTPRC gene; Pathway interactions; Patients; Plants; Play; Population Heterogeneity; Potato; Prevention; Preventive; Processed Meats; Production; Property; Prospective cohort; Proteins; Reducing diet; Reporting; Research; Research Personnel; Resistance; Risk; Risk Factors; Role; Scientist; Secondary to; Sulfoxide; T cell response; Tea; Testing; Time; Tissue Banks; Tomatoes; Training; arm; bacterial community; bile acid metabolism; cancer diagnosis; cancer prevention; cancer subtypes; cardiometabolic risk; career; career development; clinical epidemiology; cohort; colorectal cancer prevention; colorectal cancer risk; cruciferous vegetable; design; diet and cancer; dietary; epidemiology study; ethnic diversity; food consumption; good diet; gut microbes; gut microbiome; gut microbiota; improved; indexing; innovation; mecysteine; metabolomics; microbial; multidisciplinary; nutrition; nutritional epidemiology; oxidative DNA damage; programmed cell death protein 1; programs; prospective; racial diversity; response; treatment arm; tumor; tumorigenic; western diet

PROJECT SUMMARY / ABSTRACT Diet is an established etiologic factor for colorectal cancer (CRC) and is estimated to account for more than 40% of CRC cases and deaths. Despite several healthy dietary indices were suggested to be CRC-preventive, their associations with CRC risk remain moderate. A dietary index guiding dietary modulation for an efficacious CRC prevention remains lacking so far. One important reason is that all those dietary indices were developed based on their associations with cardiometabolic risk or certain general biological pathways, rather than mechanisms specifically targeting the colon. Growing evidence indicates an important role of gut microbial metabolites in mediating dietary effects on CRC risk. Among the metabolites, secondary bile acids (SBA) are suggested by extensive evidence to trigger a plethora of tumorigenic effects in colon, pointing to the gut microbiome-SBA axis as an emerging colon-specific pathway for CRC prevention. High-fat intake increases SBA production, but its SBA-stimulating property depends on fat type. Also, carbohydrates, proteins, and some other nutrients/foods also influence SBA but remain understudied. These data support the hypothesis that a dietary index specifically targeting the gut microbiome-SBA axis improves the currently weak CRC dietary prevention. To test this hypothesis, we will conduct an observational study in Aim 1 by leveraging the blood metabolomics and repeatedly measured diet and CRC diagnosis over 30 years in a racially/ethnically diverse population from four large cohorts: the Nurses’ Health Study I and II, Health Professionals Follow-up Study, and Southern Community Cohort Study. In Aim 2, we will conduct a single-arm intervention study among 40 patients who have recently undergone resection of colorectal adenoma and consume a habitual Western diet to assess the effect of a dietary intervention for more plant-based and less animal-based food over 4 weeks on SBA production, gut microbiota, and colonic gene expression via detailed food diary and repeated stool, blood, and colonic tissue collection. We will also guide patients to consume more foods, if there is any, that are found to substantially reduce SBA in Aim 1. I am well suited to perform this research based on 1) my expertise in epidemiology, quantitative methods, and biomarker research; 2) the exceptional multidisciplinary mentoring team comprised of leaders in their respective fields; and 3) the unparalleled research environment to support my career development. A team of outstanding scientists will mentor me to help me achieve this goal: Dr. Andrew Chan, a leader in clinical intervention and colorectal cancer prevention; Dr. Curtis Huttenhower, a leader in gut microbiome and bioinformatics; Dr. Mingyang Song, a leader in clinical epidemiology and nutritional intervention; and Dr. Edward Giovannucci, a leader in dietary effects on cancer. Through this study, I will expand my expertise in several new areas, including nutritional strategy for cancer prevention, the gut microbiome and bioinformatics, and clinical trial. The proposed research and training will help achieve my long-term career goal to become an independent investigator and develop a transdisciplinary research program in human nutrition and the gut microbiome for cancer prevention.

项目总结/摘要 饮食是结直肠癌（CRC）的既定病因因素，估计占40%以上。 CRC病例和死亡。尽管一些健康的饮食指数被认为是CRC预防， 与CRC风险的相关性仍为中度。指导有效CRC饮食调节的饮食指数 迄今为止，预防工作仍然不足。一个重要的原因是，所有这些饮食指数都是根据 它们与心脏代谢风险或某些一般生物学途径的关系，而不是机制 专门针对结肠越来越多的证据表明，肠道微生物代谢产物的重要作用， 调节饮食对CRC风险的影响。在代谢产物中，次级胆汁酸（SBA）被认为是 广泛的证据表明，在结肠中引发了过多的致瘤作用，指向肠道微生物组-SBA轴 作为一种新兴的结肠特异性途径预防CRC。高脂肪摄入会增加SBA的产生，但其 SBA刺激特性取决于脂肪类型。此外，碳水化合物，蛋白质和其他一些营养素/食物 也影响SBA，但仍未得到充分研究。这些数据支持这样一种假设，即饮食指数 靶向肠道微生物组-SBA轴改善了目前薄弱的CRC饮食预防。为了验证这一 假设，我们将通过利用血液代谢组学并重复进行Aim 1中的观察性研究 在来自四个大队列的种族/民族多样化人群中，测量30年的饮食和CRC诊断： 护士健康研究I和II，卫生专业人员随访研究和南方社区队列研究。 在目标2中，我们将在40名最近接受过 切除结直肠腺瘤，并习惯性进食西方饮食，以评估饮食的影响。 在4周内干预更多的植物性食物和更少的动物性食物对SBA产生，肠道微生物群， 以及通过详细的食物日记和重复的粪便、血液和结肠组织收集的结肠基因表达。我们 还将指导患者食用更多的食物，如果有的话，这些食物被发现可以大大减少Aim中的SBA 1.我很适合进行这项研究的基础上，1）我的专业知识，流行病学，定量方法， 生物标志物研究; 2）由各自领域的领导者组成的卓越的多学科指导团队 3）无与伦比的研究环境，以支持我的职业发展。优秀的团队 科学家们将指导我，帮助我实现这一目标：安德鲁陈博士，临床干预的领导者， 结肠直肠癌的预防;柯蒂斯Huttenhower博士，肠道微生物组和生物信息学的领导者; Mingyang Song，临床流行病学和营养干预的领导者; Edward Giovannucci博士， 饮食对癌症影响的领导者。通过这项研究，我将扩大我的专业知识在几个新的领域，包括 癌症预防的营养策略，肠道微生物组和生物信息学以及临床试验。拟议 研究和培训将有助于实现我的长期职业目标，成为一名独立的调查员， 在人类营养和肠道微生物组预防癌症方面制定跨学科研究计划。

项目成果

Development and validation of a risk prediction model for post-polypectomy colorectal cancer in the USA: a prospective cohort study.

• DOI: 10.1016/j.eclinm.2023.102139
• 发表时间: 2023-08
• 期刊: ECLINICALMEDICINE
• 影响因子: 15.1
• 作者: Knudsen, Markus Dines;Wang, Kai;Wang, Liang;Polychronidis, Georgios;Berstad, Paula;Wu, Kana;He, Xiaosheng;Hang, Dong;Fang, Zhe;Ogino, Shuji;Chan, Andrew T.;Giovannucci, Edward;Wang, Molin;Song, Mingyang
• 通讯作者: Song, Mingyang