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Marine Omega-3 Polyunsaturated Fatty Acid, Gut Microbiome, and Colorectal Cancer Prevention

海洋 Omega-3 多不饱和脂肪酸、肠道微生物组和结直肠癌预防

基本信息

批准号：
9452588
负责人：
Mingyang Song
金额：
$ 17.91万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-19 至 2018-07-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9452588
关键词：
Adult Alkaline Phosphatase Anti-inflammatory Area Award Bacteria Bifidobacterium Bioinformatics Biological Biological Markers CD8-Positive T-Lymphocytes Cancer and Nutrition Cell Maturation Cells Clinic Cohort Studies Colon Colorectal Adenoma Colorectal Cancer Complement Cues Data Data Aggregation Dendritic Cells Development Diet Dietary Component Dietary Fats Docosahexaenoic Acids Dose Eicosapentaenoic Acid Environment Epidemiologist Epidemiology Etiology Excision Fatty Acids Feces Fish Oils Follow-Up Studies Foundations Fusobacterium nucleatum Future Gene Expression Gene Expression Profiling Genes Goals Health Professional Homeostasis Human Hydroxyl Radical Immune Immune response Immunity Immunosuppression Immunosuppressive Agents Incidence Inflammation Inflammatory Intake Intestines Lactobacillus Life Style Link Lipopolysaccharides Malignant Neoplasms Marines Mediating Mediator of activation protein Mentors Mentorship Metabolic Methods Microbe Mucous Membrane Mus Natural Products Nurses&apos Health Study Omega-3 Fatty Acids Outcome Participant Pathway interactions Patients Phase Prevention therapy Property Prospective cohort Prospective cohort study Randomized Controlled Trials Research Research Personnel Research Training Role Shapes Source Specimen Structure System T cell response Testing Time Tissues Training Translating Tumor Escape Tumor Immunity Tumor Tissue Volatile Fatty Acids adenoma anti-cancer base cancer diagnosis cancer immunotherapy cancer initiation cancer prevention cancer survival cancer therapy carcinogenesis career career development clinical investigation colorectal cancer prevention colorectal cancer risk design docosapentaenoic acid epidemiology study fatty acid supplementation gut bacteria gut microbes gut microbiome gut microbiota host microbiota immunoregulation improved innovation insight metabolome microbial microbiome research multidisciplinary multiple omics novel novel marker novel strategies nutrition patient oriented population based programs protective effect response stool sample tumor tumor progression

项目摘要

PROJECT SUMMARY / ABSTRACT Fish oil, a rich source of marine omega-3 polyunsaturated fatty acids (MO3PUFAs), is the most popular natural product used by U.S. adults. Substantial data support the beneficial effect of MO3PUFAs on colorectal cancer (CRC) prevention and treatment. However, the specific mechanisms through which MO3PUFAs influence CRC are not well understood. Increasing evidence supports a pivotal role of gut microbes in integrating dietary cues with host immunity and potentially mediating the anticancer effect of MO3PUFAs. Dietary fat composition is a major driver of the gut microbial community structure. Mice fed with a high-MO3PUFA diet demonstrate increased abundance of the gut bacteria that support the host immunoprotective system and improve the efficacy of cancer immunotherapy, such as Bifidobacterium and Lactobacillus genera, and decreased abundance of the microbes that dampen antitumor immunity, such as Fusobacterium nucleatum, which has been shown to promote CRC by generating a tumor-permissive microenvironment. Taken together with my recent findings that the anti-CRC effect of MO3PUFAs is related to the tumor immune microenvironment, these data aggregately support the hypothesis that MO3PUFAs modulate the gut microbial composition and function to shape the gut immune response and suppress CRC. To test this hypothesis, I will first leverage three large prospective cohort studies, the Nurses' Health Study (NHS) I and II and the Health Professionals Follow-up Study (HPFS), to characterize the gut microbial signature associated with long-term high intake of MO3PUFAs and assess whether certain microbes mediate the protective effect of MO3PUFAs on CRC incidence and survival. To establish causality, I will then bridge the observations to the clinic through a randomized controlled trial (RCT) in patients with prior adenoma by investigating the effect of MO3PUFA supplements on the gut microbiome, metabolome, and gene expression profiling in the colon. This innovative project will advance our understanding about the interplay between MO3PUFAs, gut microbiota, and host immunity in CRC. I am well suited to perform this research based on 1) my expertise in nutrition, 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. Through this study, I will expand my expertise in several new areas, including the gut microbiome, bioinformatics, and design and conduct of biomarker-based RCT. 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 the gut microbiome and human nutrition for cancer prevention through integration of population-based epidemiologic study with patient-oriented clinical investigation. The findings yielded from my research will uncover new biological mechanisms relating diet to carcinogenesis, and identify novel biomarkers or targets that can be effectively translated into the clinic to improve cancer prevention and treatment.

项目总结/摘要鱼油是海洋欧米伽-3多不饱和脂肪酸（MO 3 PUFAs）的丰富来源，是最受欢迎的天然美国成年人使用的产品。大量数据支持MO 3 PUFAs对结直肠癌的有益作用 (CRC)预防和治疗。然而，MO 3 PUFAs影响CRC的具体机制并没有得到很好的理解。越来越多的证据支持肠道微生物在整合饮食线索中的关键作用具有宿主免疫力，并可能介导MO 3 PUFA的抗癌作用。膳食脂肪组成是一种肠道微生物群落结构的主要驱动力。用高MO 3 PUFA饮食喂养的小鼠证明，增加支持宿主免疫保护系统和改善免疫系统的肠道细菌的丰度。癌症免疫疗法的功效，如双歧杆菌属和乳杆菌属，并减少大量抑制抗肿瘤免疫力的微生物，例如具核梭杆菌，它具有已被证明通过产生肿瘤容许微环境来促进CRC。加上我的最近的研究发现MO 3 PUFAs的抗CRC作用与肿瘤免疫微环境有关，数据综合支持MO 3 PUFAs调节肠道微生物组成和功能的假设以塑造肠道免疫反应并抑制CRC。为了验证这一假设，我将首先利用三个大型前瞻性队列研究，护士健康研究（NHS）I和II以及卫生专业人员随访研究（HPFS），以表征与长期大量摄入MO 3 PUFA相关的肠道微生物特征并评估某些微生物是否介导MO 3 PUFAs对CRC发病率的保护作用，生存为了建立因果关系，我将通过随机对照试验将观察结果与临床联系起来。通过研究MO 3 PUFA补充剂对肠道的影响，在既往腺瘤患者中进行了一项随机对照试验（RCT）微生物组、代谢组和结肠中的基因表达谱。这一创新项目将推动我们的了解MO 3 PUFAs，肠道微生物群和CRC中宿主免疫力之间的相互作用。我很适合进行这项研究的基础上，1）我在营养学，流行病学，定量方法，生物标志物研究; 2）由他们的领导者组成的特殊的多学科指导团队 3）无与伦比的研究环境，以支持我的职业发展。通过这项研究，我将扩大我的专业知识在几个新的领域，包括肠道微生物组，生物信息学，设计和实施基于生物标志物的RCT。这项研究和培训将有助于实现我的长期目标- 长期的职业目标是成为一名独立的调查员，并制定一个跨学科的研究计划，肠道微生物组和人类营养，通过整合基于人群的流行病学研究和以病人为中心的临床调查。我的研究成果将发现饮食与致癌作用相关的新生物学机制，并确定新的生物标志物或靶点可以有效地转化为临床，以改善癌症预防和治疗。