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

鱼油是海洋欧米伽-3多不饱和脂肪酸（MO 3 PUFAs）的丰富来源， 美国成年人使用的天然产品。大量数据支持MO 3 PUFAs对结直肠癌的有益作用 癌症（CRC）的预防和治疗。然而，MO 3 PUFAs的具体机制 影响CRC还没有被很好地理解。越来越多的证据支持肠道微生物在 整合饮食线索与宿主免疫力，并可能介导MO 3 PUFAs的抗癌作用。 膳食脂肪组成是肠道微生物群落结构的主要驱动力。喂高浓度- MO 3 PUFA饮食显示支持宿主免疫保护的肠道细菌丰度增加 系统和提高癌症免疫治疗的疗效，如双歧杆菌和乳酸杆菌 属，并减少了抑制抗肿瘤免疫的微生物的丰度，如梭杆菌属， nucleatum，其已被证明通过产生肿瘤容许微环境来促进CRC。 结合我最近的发现，MO 3 PUFAs的抗CRC作用与F.具核 肿瘤组织中的丰度和免疫浸润，这些数据总体上支持以下假设， MO 3 PUFAs调节肠道微生物组成和功能以形成肠道免疫应答， 抑制CRC。为了验证这一假设，我将在既往有 通过研究MO 3 PUFA补充剂对肠道微生物组、代谢组和 结肠中的基因表达谱这一创新项目将促进我们对 CRC中MO 3 PUFAs、肠道微生物群和宿主免疫之间的相互作用。我很适合做这个 研究基于1）我在营养学，流行病学，定量方法和生物标志物研究方面的专业知识; 2)在K99阶段获得了关于肠道微生物组，生物信息学以及 基于生物标志物的RCT; 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，并制定一个跨学科的研究计划， 营养干预、肠道微生物组和癌症预防领域的独立研究者。的 我的研究成果将揭示饮食与致癌作用的新生物学机制， 并确定新的生物标志物或目标，可以有效地转化为临床，以改善癌症 预防

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.