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

项目摘要/摘要 鱼油是海洋omega-3多不饱和脂肪酸(MO3PUFA)的丰富来源，是最受欢迎的天然 美国成年人使用的产品。大量数据支持MO3PUFAs对结直肠癌的有益作用 (CRC)预防和治疗。然而，MO3PUFA影响CRC的具体机制 都没有被很好地理解。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 与宿主免疫有关，并可能介导MO3PUFAs的抗癌作用。膳食脂肪的组成是一种 肠道微生物群落结构的主要驱动力。喂食高MO3PUFA饮食的小鼠表现出 支持宿主免疫保护系统的肠道细菌数量增加，并改善 癌症免疫治疗的疗效，如双歧杆菌和乳杆菌属，并降低 大量抑制抗肿瘤免疫的微生物，如核梭杆菌，它具有 已被证明通过产生一个允许肿瘤的微环境来促进结直肠癌。与我的 最近发现，MO3PUFAs的抗结直肠癌作用与肿瘤免疫微环境有关，这些 数据汇总支持MO3PUFA调节肠道微生物组成和功能的假设 塑造肠道免疫反应，抑制结直肠癌。为了验证这一假设，我将首先利用三个大的 前瞻性队列研究、护士健康研究(NHS)I和II以及卫生专业人员的随访 研究(HPFS)，以表征与长期高摄入MO3PUFAs相关的肠道微生物特征 并评估某些微生物是否介导了MO3PUFAs对CRC发病率和 生死存亡。为了确定因果关系，我将通过随机对照的方法将观察结果与临床联系起来 通过研究MO3PUFA补充剂对肠道的影响对既往腺瘤患者进行试验(RCT) 结肠中的微生物组、代谢组和基因表达谱。这一创新项目将推动我们的 了解结直肠癌中MO3PUFAs、肠道微生物区系和宿主免疫之间的相互作用。我很好 适合根据1)我在营养学、流行病学、定量方法和 生物标记物研究；2)由以下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。穿过 在这项研究中，我将在几个新领域扩展我的专业知识，包括肠道微生物组、生物信息学和 设计和实施基于生物标记物的随机对照试验。拟议的研究和培训将有助于实现我的长期- 任期的职业目标是成为一名独立的调查员，并在 肠道微生物群和人类营养通过整合人群预防癌症 以患者为中心的临床调查的流行病学研究。我的研究成果将会 发现饮食与致癌有关的新生物学机制，并确定新的生物标记物或靶点 这可以有效地转化为临床，以改善癌症的预防和治疗。

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.