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.

项目概要/摘要 饮食是结直肠癌 (CRC) 的既定病因，估计占 40% 以上 尽管有几种健康饮食指数被认为可以预防结直肠癌，但它们的 与 CRC 风险的关联仍然中等。指导饮食调节以实现有效 CRC 的饮食指数。 迄今为止，预防措施仍然缺乏，一个重要原因是所有这些饮食指标都是基于这一点而制定的。 与心脏代谢风险或某些一般生物途径的关联，而不是机制 越来越多的证据表明肠道微生物代谢物在其中发挥着重要作用。 介导饮食对 CRC 风险的影响的代谢物中，次级胆汁酸 (SBA) 被认为是介导的。 大量证据表明肠道微生物组-SBA 轴会引发结肠中的多种致瘤效应 作为预防 CRC 的新兴结肠特异性途径，高脂肪摄入会增加 SBA 的产生，但其效果并不理想。 SBA 刺激特性还取决于脂肪类型、碳水化合物、蛋白质和一些其他营养素/食物。 也影响 SBA，但尚未得到充分研究。这些数据支持饮食指数专门的假设。 针对肠道微生物群-SBA 轴可改善目前薄弱的 CRC 饮食预防。 假设，我们将利用血液代谢组学在目标 1 中进行观察性研究，并反复进行 30 年来对来自四个大群体的种族/族裔不同人群的饮食和 CRC 诊断进行了测量： 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，我们将对 40 名最近接受过治疗的患者进行单臂干预研究。 切除结直肠腺瘤并采用西方习惯饮食来评估饮食的效果 在 4 周内对 SBA 生产、肠道微生物群、多吃植物性食物和少吃动物性食物进行干预 我们通过详细的食物日记和重复的粪便、血液和结肠组织采集来评估结肠基因的表达。 还将指导患者食用更多被发现可显着降低 Aim 中 SBA 的食物（如果有的话） 1. 我非常适合开展这项研究，因为 1) 我在流行病学、定量方法和方面的专业知识 2) 杰出的多学科指导团队，由各自领域的领导者组成 领域；3）无与伦比的研究环境支持我的职业发展。 科学家们将指导我实现这一目标：Andrew Chan 博士，临床干预和治疗领域的领导者 结肠直肠癌预防；Curtis Huttenhower 博士，肠道微生物组和生物信息学领域的领导者； Mingyang Song，临床流行病学和营养干预领域的领军人物；Edward Giovannucci 博士， 通过这项研究，我将扩展我在几个新领域的专业知识，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。 研究和培训将有助于实现我成为一名独立调查员的长期职业目标 制定人类营养和肠道微生物组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.

美国息肉切除术后结直肠癌风险预测模型的开发和验证：一项前瞻性队列研究。

• 发表时间: 2023-08
• 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

Ultra-processed food consumption and mortality among patients with stages I-III colorectal cancer: a prospective cohort study.

I-III 期结直肠癌患者的超加工食品消费和死亡率：一项前瞻性队列研究。

• 发表时间: 2024-05
• 影响因子: 15.1
• 作者: Hang, Dong;Du, Mengxi;Wang, Lu;Wang, Kai;Fang, Zhe;Khandpur, Neha;Rossato, Sinara Laurini;Steele, Eurídice Martínez;Chan, Andrew T;Hu, Frank B;Meyerhardt, Jeffrey A;Mozaffarian, Dariush;Ogino, Shuji;Sun, Qi;Wong, John B;Zhang, Fang Fang;So
• 通讯作者: So