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：
9762057
负责人：
Mingyang Song
金额：
$ 18.18万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
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 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762057
关键词：
Adult Alkaline Phosphatase Anti-inflammatory Area Award Bacteria Bifidobacterium Bioinformatics Biological Biological Markers CD8-Positive T-Lymphocytes Cell Maturation Cells Clinic Colon Colorectal Adenoma Colorectal Cancer Cues Data Data Aggregation Dendritic Cells Development Diet Dietary Component Dietary Fats Dietary Intervention Docosahexaenoic Acids Eicosapentaenoic Acid Environment Epidemiologist Epidemiology Excision Fatty Acids Feces Fish Oils Foundations Fusobacterium nucleatum Future Gene Expression Gene Expression Profiling Genes Grant Homeostasis Human Hydroxyl Radical Immune Immune response Immunity Immunosuppressive Agents Inflammatory Intestines Lactobacillus Link Lipopolysaccharides Malignant Neoplasms Marines Mediating Mediator of activation protein Metabolic Methods Microbe Mucous Membrane Mus Natural Products Omega-3 Fatty Acids Pathway interactions Patients Phase Prevention therapy Production Property Randomized Controlled Trials Research Research Personnel Role Shapes Source Structure System T cell response Testing Tissues Training Translating Tumor Escape Tumor Immunity Tumor Tissue Tumor-infiltrating immune cells Volatile Fatty Acids adenoma anti-cancer base cancer immunotherapy cancer initiation cancer prevention cancer therapy carcinogenesis career career development colorectal cancer prevention colorectal cancer risk design docosapentaenoic acid fatty acid supplementation gut bacteria gut microbes gut microbiome gut microbiota host microbiota immunoregulation improved innovation insight lipid mediator metabolome metabolomics microbial microbial community microbiome research microbiota multiple omics novel novel marker nutrition preservation pressure programs tumor tumor progression

项目摘要

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 F. nucleatum abundance and immune infiltrates in tumor tissue, 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 perform 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) acquired training in the K99 phase on the gut microbiome, bioinformatics, and design and conduct of biomarker-based RCT; and 3) the unparalleled research environment to support my career development. Through this study, I will expand my expertise and develop a transdisciplinary research program as an independent investigator in the area of nutritional intervention, gut microbiome, and cancer prevention. 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.

鱼油是海洋 omega-3 多不饱和脂肪酸 (MO3PUFA) 的丰富来源，是最受欢迎的美国成年人使用的天然产品。大量数据支持 MO3PUFA 对结直肠的有益作用癌症（CRC）的预防和治疗。然而，MO3PUFAs 的具体机制 CRC 的影响尚不清楚。越来越多的证据支持肠道微生物在将饮食线索与宿主免疫相结合，并可能介导 MO3PUFA 的抗癌作用。膳食脂肪成分是肠道微生物群落结构的主要驱动力。老鼠喂食高 MO3PUFA 饮食证明支持宿主免疫保护的肠道细菌丰度增加系统并提高癌症免疫治疗的功效，例如双歧杆菌和乳酸杆菌属，并减少抑制抗肿瘤免疫力的微生物（例如梭杆菌）的丰度 nucleatum，已被证明可以通过产生肿瘤允许的微环境来促进结直肠癌。结合我最近的发现，MO3PUFA 的抗 CRC 作用与具核梭菌有关肿瘤组织中的丰度和免疫浸润，这些数据总体支持以下假设： MO3PUFA 调节肠道微生物组成和功能，从而塑造肠道免疫反应和抑制CRC。为了检验这个假设，我将对既往患有此病的患者进行一项随机对照试验 (RCT) 通过研究 MO3PUFA 补充剂对肠道微生物组、代谢组和腺瘤的影响结肠中的基因表达谱。这个创新项目将加深我们对结直肠癌中 MO3PUFA、肠道微生物群和宿主免疫之间的相互作用。我非常适合执行此操作研究基于 1) 我在营养、流行病学、定量方法和生物标志物研究方面的专业知识； 2) 接受了 K99 阶段关于肠道微生物组、生物信息学以及设计和实施的培训基于生物标志物的随机对照试验； 3）无与伦比的研究环境支持我的职业发展。通过这项研究，我将扩展我的专业知识并开发一个跨学科研究计划作为营养干预、肠道微生物组和癌症预防领域的独立研究者。这我的研究结果将揭示饮食与致癌作用相关的新生物机制，并确定可有效转化为临床以改善癌症的新型生物标志物或靶点预防。