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 饮食是结直肠癌(CRC)的既定病因，估计占40%以上。 结直肠癌病例和死亡人数。尽管有几项健康饮食指标被认为是预防结直肠癌的，但他们的 与结直肠癌风险的关联仍然是适度的。指导有效结直肠癌患者膳食调整的膳食指标 到目前为止，仍然缺乏预防措施。一个重要的原因是，所有这些饮食指数都是基于 关于它们与心脏代谢风险或某些一般生物途径的关系，而不是机制 特别是针对结肠。越来越多的证据表明，肠道微生物代谢物在 饮食对结直肠癌风险的调节作用。在代谢产物中，次级胆汁酸(SBA)是由 大量证据表明肠道微生物组-SBA轴在结肠中引发过多的致癌效应 作为预防结直肠癌的一种新的结肠特异性途径。高脂肪摄入增加了SBA的产生，但其 SBA的刺激作用取决于脂肪类型。还有碳水化合物、蛋白质和其他一些营养素/食物 也影响了SBA，但仍未得到充分研究。这些数据支持这样一种假设，即一种饮食指数 以肠道微生物组-SBA轴为靶点改善了目前薄弱的结直肠癌饮食预防。为了测试这一点 假设，我们将利用血液代谢组学在目标1进行一项观察性研究，并重复 在来自四个大队列的种族/民族多样化人群中，测量了30年来的饮食和结直肠癌诊断： 护士健康研究I和II，卫生专业人员跟踪研究，以及南方社区队列研究。 在目标2中，我们将在40名最近接受治疗的患者中进行单臂干预研究。 结直肠腺瘤切除和习惯的西方饮食以评估饮食的效果 干预更多植物性食物和较少动物性食物4周对SBA生产、肠道微生物区系、 通过详细的食物日记和反复采集大便、血液和结肠组织来表达结肠基因。我们 还将引导患者摄入更多被发现显著降低AIM SBA的食物(如果有的话) 1.我非常适合根据我在流行病学、定量方法和 生物标记物研究；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，支持我的职业发展。一支优秀的团队 科学家将指导我实现这一目标：安德鲁·陈博士，临床干预和治疗的领导者 肠道微生物组和生物信息学的领导者柯蒂斯·哈滕豪威尔博士； 宋明阳，临床流行病学和营养干预领域的领导者；爱德华·乔万努奇博士， 饮食对癌症影响的领先者。通过这项研究，我将在几个新领域扩大我的专业知识，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。建议数 研究和培训将有助于实现我的长期职业目标，成为一名独立调查员和 制定人类营养和肠道微生物群的跨学科研究计划，以预防癌症。

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