肠道微生物调节昼夜节律诱导结直肠癌发生、发展的机制研究

In recent years, colorectal cancer incidence keeps increasing along with rapid living pace, change of diet habit and irregular work routine. Studies reported that intestinal microbes were involved in colorectal carcinoma initiation and development; circadian rhythm disorder aggravated colorectal carcinoma course, decreased therapeutic effects. bacteria and their metabolites orchestrated intestinal transcription; Our previous works indicate that bacterial inhabiting on intestinal mucosa showed a time and location heterogeneity；small molecular compound-decreased inhibitions of colorectal cancer cell proliferation were related to circadian rhythm; further, Escherichia coli insulting depressed expressions of circadian clock proteins PER1 and PER2 in mouse colon tissue. Therefore, we hypothesized that circadian rhythm disorder-induced intestinal microbiota dysbiosis boosts colorectal carcinogenesis and development. Our next works will focus on the connection of circadian rhythm disorder-induced intestinal microbiota dysbiosis with survival of colorectal cancer patients, and related mechanism. Our foci are expected to clear the circadian mutual action between intestinal microbes and host, provide basic supports for colorectal carcinoma therapeutic via combining intestinal microbes and circadian rhythm.

近年来，随着社会生活节奏加快、饮食结构变化和生活作息不规律，结直肠癌发病率逐年升高。研究表明多种肠道微生物参与结直肠癌的发生、发展；昼夜节律紊乱促进结直肠癌病程进展，降低了治疗效果；结直肠组织的昼夜节律受到肠道微生物及其代谢产物调节。我们的前期工作证明肠道粘膜定植微生物具有时间和空间异质性；小分子化合物对结直肠癌细胞增殖的抑制作用呈现昼夜节律规律；而且，体内试验还验证了大肠杆菌抑制结肠组织昼夜节律钟蛋白PER1和PER2的表达。因此，我们认为肠道菌群失调引起的昼夜节律紊乱可能参与结直肠癌的发生、发展。我们拟研究肠道菌群失调和昼夜节律紊乱与结直肠癌患者生存率之间的关联，以及相关分子机制。研究工作将有助于阐明结直肠癌患者肠道微生物与宿主昼夜节律互作机制，为肠道微生态联合昼夜节律治疗结直肠癌提供理论基础。

近年来，伴随饮食和作息不规律，结直肠癌发病率逐年升高。其中，昼夜节律紊乱促进结直肠癌病程进展，降低了治疗效果；肠道微生物参与结直肠癌的发生、发展；同时，肠道微生物与宿主昼夜节律之间存在相互调节作用。本项目研究证实：（1）病原性大肠杆菌不仅促进分子钟基因分子钟基因CLOCK表达，同时抑制负反馈基因PER1表达水平，双荧光素酶报告实验也证明大肠杆菌对结直肠癌细胞分子钟基因表达的直接调控作用。2）相较于癌旁组织，癌组织分子钟核心基因表达上调，负反馈基因被显著抑制，而且负反馈基因与患者生存率呈现显著相关性；在结直肠癌细胞过表达上述负反馈基因会引起细胞凋亡、坏死，降低细胞增殖活性。3）小鼠模型实验也验证病肠道菌群紊乱造成结直肠细胞分子钟基因表达失衡，引起结直肠肿瘤生长速度加快。项目研究工作揭示了肠道菌群失调和昼夜节律紊乱与结直肠癌患者生存率之间的关联，以及相关分子机制，相关数据阐明结直肠癌患者肠道微生物与宿主昼夜节律互作机制，为肠道微生态联合昼夜节律治疗结直肠癌提供理论基础。