高脂及肠道微生态代谢异常影响大肠癌发病风险的机制研究

Colorectal cancer is a common malignancy, and the changes of dietary structure, the increase in the proportion of high-fat foods is related to the incidence of colorectal cancer, although the mechanism is not yet clear. On the basis of our previous research of colorectal characteristic metabolic, miRNA related regulation network and probiotic intervention in colorectal cancer (CRC), we hypothesized that dietary changes in the structure may affect the gut microflora and metabolism, causing changes in the miRNA regulatory network in the colonic epithelial cells, and then lead to the development of colorectal carcinoma through the downstream signaling pathways. To test this hypothesis, we take the lead in screening different intestinal symbiotic microflora spectrum, the metabolism of food spectrum and its regular change in between the people of two communities with different diet and finding carcinogenic bacterium using high-throughput sequencing technology and metabolomics approach, explore the pathway of diet- intestinal flora- metabolites-miRNA regulatory network-tumor, to study the the influence of high fat - intestinal microecology - miRNA related signaling pathways on the occurrence and development of CRC in cell, animal and human specimens levels; and further to elucidate the effect of the optimization of dietary structure and the maintence of intestinal microecological balance on the CRC risk in the two communities mentioned above. This research will provide important theoretical foundation and practice basis for clearifing the intestinal flora and the metabolism model of high risk population, and exploring the reduction of CRC incidence through adjusting diet structure and reducing the abundance of carcinogenic bacterium.

大肠癌(colorectal cancer)是常见的恶性肿瘤之一，膳食结构的变化、高脂食物比重增加与大肠癌发病率增高密切相关，但其中机制尚不明确。我们基于前期对大肠癌特征性代谢模式、大肠癌相关miRNA调控网络及益生菌对肠癌干预效果的研究为基础，提出膳食结构的改变可能通过影响肠道微生态及代谢模式，引起结肠上皮细胞内miRNA调控网络的变化，进而通过下游相关信号通路导致大肠癌的发生发展。为此，我们率先利用高通量测序技术及代谢组学方法筛选二个社区人群肠道中共生菌群谱的差异、找出特征性致癌菌；同时分析高脂饮食及其代谢产物、肠道菌群严重失衡与肠癌发生的关联性；通过细胞及动物模型实验进一步阐明miRNA及相关信号通路在其中发挥的重要作用。同时，在上述地区观察优化肠道微生态平衡对大肠癌发病风险的影响，为添加微生态制剂以调整肠道菌群、降低致癌性菌株的丰度，从而降低肠癌发病提供理论基础和实践依据。

大肠癌（colorectal cancer, CRC）是人类常见的恶性肿瘤之一，膳食结构的变化及肠道菌群紊乱与CRC发病率增高密切相关，但其中机制尚不明确。为此，项目组开展以下一系列研究工作：1.通过16S rRNA基因焦磷酸测序分析了CRC患者和健康人粪便的微生物组成，筛选出了CRC患者特征性"核心菌群"，分别为：梭杆菌属、假单胞菌和拟杆菌。构建相应肠道“核心菌群”诊断模型发现其对腺瘤和CRC患者诊断效率和粪便免疫化学检测（Fecal Immunochemical Test，FIT）诊断的结果相似，但是其检测腺瘤与CRC合并的肠道病变效果优于FIT。基于以上CRC患者存在的菌群紊乱，通过16S rRNA基因焦磷酸测序确定益生菌改变微生物群的程度，发现应用益生菌治疗增加了结肠粘膜微生物的丰度和多样性，并改变了粘膜相关的微生物群，同时接受益生菌治疗的CRC患者术后排气功能和腹泻等并发症发生情况明显改善。2. 基于前期发现大肠癌特征性致病菌-具核梭杆菌（fusobacterium nucleatum, Fn），开展针对Fn促癌分子机理的研究：首先临床样本验证发现Fn丰度与CRC患者的miR-21表达、T分期、淋巴浸润及Ki-67指数相关，预后分析提示Fn 高表达的患者总体生存期（Overall survival，OS）显著降低，当联合Fn和miR-21对患者生存期进行分析，发现Fn高丰度且miR-21高表达的患者其OS显著降低。在III/IV期CRC患者中，Fn为患者独立不良预后因素且与术后化疗效果显著相关。体内体外实验证明Fn通过经典TLR-4/MyD88/NF-κB通路影响miR-21表达，最终促进肠癌细胞的增殖和转移。3.对CRC患者及癌前病变患者粪便样本进行真菌鉴定，发现癌前病变和CRC中的真菌紊乱，包括癌前病变患者的多样性减少、子囊菌门/担子菌门比例增加、机会性真菌毛孢子菌属和马拉色霉菌属比例增加，推测这些改变可能利于CRC的进展。4.自主研发微生态制剂MIMP并构建DSS诱导肠炎小鼠模型，发现其具有保护肠屏障、改善菌群紊乱及抑制炎症反应的作用。综上，这些研究结果进一步揭示肠道菌群在CRC发生发展中的关键作用，为通过微生态干预防治CRC提供重要理论基础。

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