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.

项目摘要 /摘要 饮食是结构直肠癌（CRC）的既定病因学因素，估计占40％以上 CRC病例和死亡。尽管建议有几个健康的饮食指数为CRC预防 与CRC风险的关联仍然适中。饮食指数指导饮食调制，以进行有效的CRC 到目前为止，仍然缺乏预防。一个重要的原因是所有这些饮食指标都是基于开发的 关于他们与心脏代谢风险或某些一般生物学途径的关联，而不是机制 越来越多的证据表明肠道微生物代谢物在 介导对CRC风险的饮食影响。在代谢物中，次生胆汁酸（SBA）建议 广泛的证据以引发结肠中多种肿瘤作用，指向肠道微生物组轴 作为CRC预防的新兴结肠特异性途径。高脂摄入量增加了SBA的生产，但 SBA刺激特性取决于脂肪类型。另外，碳氢化物，蛋白质和其他一些营养/食物 也影响SBA，但仍然被理解。这些数据支持饮食指数特别的假设 靶向肠道微生物组SBA轴可改善当前弱的CRC饮食预防。测试这个 假设，我们将通过利用血液代谢组并反复进行AIM 1进行观察性研究 在大约四个大型队列中的大致/种族多样化的人群中，测量了30年以上的饮食和CRC诊断： 护士健康研究I和II，卫生专业人员的后续研究和南方社区队列研究。 在AIM 2中，我们将对最近经历的40名患者进行一臂干预研究 切除结直肠腺瘤并消耗习惯西方饮食来评估饮食的影响 干预4周在SBA生产的4周内，以植物性和较少动物为基础的食物，肠道微生物群， 和结肠基因通过详细的食物日记和重复的粪便，血液和结肠组织收集。我们 还将指导患者食用更多食物（如果有的话），这些食物会大大减少SBA 1。我非常适合基于1）我在流行病学，定量方法和 生物标志物研究； 2）卓越的多学科指导团队在各自的领导人完成 字段； 3）无与伦比的研究环境，以支持我的职业发展。一支杰出的团队 科学家将指导我帮助我实现这一目标：安德鲁·陈（Andrew Chan）博士，临床干预的领导者和 结直肠癌的预防；肠道微生物组和生物信息学领导者柯蒂斯·赫特霍尔（Curtis Huttenhower）博士；博士 Mingyang Song，临床流行病学和营养干预的领导者；和爱德华·乔瓦努奇（Edward Giovannucci）博士 饮食对癌症的影响的领导者。通过这项研究，我将在包括 预防癌症的营养策略，肠道微生物组和生物信息学以及临床试验。提议 研究和培训将有助于实现我的长期职业目标，成为一名独立研究者， 制定人类营养的跨学科研究计划和预防癌症的肠道微生物组。

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