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

富含海洋omega-3多不饱和脂肪酸(MO3PUFAs)的鱼油是最受欢迎的 美国成年人使用的天然产品。大量数据支持MO3PUFAs对结直肠的有益作用 癌症(CRC)预防和治疗。然而，MO3PUFA通过的具体机制 对《儿童权利公约》的影响还没有很好的理解。越来越多的证据支持肠道微生物在 将饮食信号与宿主免疫相结合，并潜在地介导MO3PUFAs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。小鼠喂食高剂量的- MO3PUFA饮食显示支持宿主免疫保护的肠道细菌数量增加 系统和提高癌症免疫治疗的效果，如双歧杆菌和乳杆菌 属，并减少抑制抗肿瘤免疫的微生物的丰度，如梭杆菌 核素，已被证明通过产生肿瘤允许的微环境来促进结直肠癌。 综合考虑我最近的发现，MO3PUFAs的抗结直肠癌作用与核藻有关。 在肿瘤组织中的丰度和免疫渗透，这些数据聚集在一起支持了这样的假设 MO3PUFA调节肠道微生物的组成和功能，以形成肠道免疫反应和 抑制CRC。为了验证这一假设，我将在先证者中进行随机对照试验 通过研究MO3PUFA补充剂对肠道微生物组、代谢组和 结肠中的基因表达谱。这个创新的项目将增进我们对 结直肠癌中MO3PUFA、肠道微生物区系和宿主免疫之间的相互作用。我非常适合做这件事 研究基于1)我在营养学、流行病学、定量方法和生物标记物研究方面的专业知识； 2)在K99阶段获得关于肠道微生物组、生物信息学以及设计和实施 基于生物标记物的随机对照试验；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，并开发一个跨学科的研究计划，作为 在营养干预、肠道微生物群和癌症预防领域的独立研究员。这个 我的研究成果将揭示饮食与致癌有关的新的生物学机制， 并确定可有效转化到临床以改善癌症的新生物标记物或靶点 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.