维生素D信号通路在肠道微生态与结直肠癌关系中的作用及其机制研究

Colorectal cancer is a gut microbiota associated disease. Recent studies suggest that colorectal cancer arises from a series of events that are initiated through the combined effects of diminished gut mucosal integrity, which is caused by some genetic mutations of epithelial cells, and gut microbiota dysbiosis. The result from our study supported that vitamin D is a protective factor of colorectal cancer. It remains unclear whether vitamin D signaling plays an important role in the relationship between gut microbiota and risk for colorectal cancer. After reviewing a lot of related studies, we proposed a hypothesis that vitamin D signaling reduces the risk for colorectal cancer by modulating the composition, structure and function of the microbial community, maintaining normal gut barrier, and depressing inflammation responses. In order to validate the hypothesis, we will conduct a two-stage epidemiological study (a case-control study firstly, and a nested case-control study secondly) to explore the relationship between vitamin D signaling, gut microbiota, and risk for colorectal cancer, and thus to understand the role of vitamin D signaling in the relationship between gut microbiota and risk for colorectal cancer. In addition, we will also study the mechanisms of the effect of vitamin D signaling on the relationship between gut microbiota and risk for colorectal cancer by exploring the effect of vitamin D on gut microbiota, mucosal barrier, and chronic inflammation, respectively. Our result will provide the scientific evidence for the prevention and control of colorectal cancer.

结直肠癌是肠道微生态相关性疾病。肠道黏膜上皮细胞基因突变致肠黏膜屏障破坏和肠道微生态失衡共同作用是结直肠癌发生的关键环节。我们的研究证实，维生素D是结直肠癌的保护因素。目前尚不清楚维生素D及其信号通路在肠道微生态与结直肠癌关系中的作用。根据文献，我们推测：维生素D信号通路可能通过调节肠道菌群结构和功能、维持正常肠黏膜屏障、抑制炎症反应等机制降低结直肠癌的发病风险。为验证上述假设，本项目拟在前期已建立的研究队列的基础上，采用两阶段流行病学研究设计（第一阶段病例对照研究、第二阶段巢式病例对照研究），通过探讨维生素D信号通路、肠道菌群结构和功能与结直肠癌发病关系，明确维生素D信号通路在肠道微生态与结直肠癌关系中的作用；通过探讨维生素D对肠道微生态影响，及其与肠黏膜屏障、慢性炎症反应的关系，初步阐明维生素D信号通路在肠道微生态与结直肠癌关系中的作用机制。研究结果可望为结直肠癌预防控制提供理论依据。

目前研究认为，结直肠癌是肠道微生态相关性疾病；肠道黏膜上皮细胞基因突变致肠黏膜屏障破坏和肠道微生态失衡共同作用是结直肠癌发生的关键环节；维生素D是结直肠癌的保护因素。故推测维生素D及其信号通路可能通过调节肠道菌群结构和功能、维持正常肠黏膜屏障、抑制炎症反应等机制降低结直肠癌的发病风险。为验证上述研究假设，本项目采用病例对照研究方法，比较结直肠癌病例和健康人群对照血浆中维生素D水平、肠道菌群结构差异；采用病例-病例-对照研究方法，探讨维生素D受体表达、肠道菌群结构与结直肠癌发病关系。综合上述分析结果，探讨维生素D、维生素D受体表达、肠道菌群与结直肠癌发病关系，明确维生素D信号通路在肠道菌群与结直肠癌关系中的作用。同时，在两组人群的组内，分别对高血浆维生素D人群、低血浆维生素D人群的肠道菌群结构、血浆内毒素浓度、血浆C反应蛋白、IL-6、sTNFR-2浓度进行比较，以探讨维生素D对肠道微生态影响，及其与肠黏膜屏障、慢性炎症反应的关系，初步阐明维生素D信号通路在肠道微生态与结直肠癌关系中的作用机制。本项目共纳入年龄和性别匹配的结直肠癌病例130例、健康对照130例。研究发现：（1）两组肠道菌群结构存在明显差异；（2）肠道菌群结构与结直肠癌发病关系密切，维生素D信号通路对肠道菌群与结直肠癌关系具有重要的影响；（3）高血浆维生素D浓度人群和低血浆维生素D浓度人群的肠道菌群结构存在明显差异；（4）血浆维生素D水平与血浆内毒素水平无统计学联系；（5）血浆维生素D水平与C反应蛋白、IL-6浓度水平无统计学联系，与sTNFR-2浓度呈明显负相关关系；（6）维生素D可能通过影响肠道菌群结构、降低sTNFR2浓度，抑制炎症反应，从而降低结直肠癌的发病风险。研究结果进一步阐明了维生素D、肠道微生态与结直肠癌发病关系，从而为结直肠癌相关防制策略和措施的制定提供了科学依据。