维生素D与维生素C联合应用防治溃疡性结肠炎的研究

Ulcerative colitis (UC) is a chronic intestinal diseases, which is nonspecific and autoimmune illness. Its etiology is unknown. The incidence increases year by year, and has an increased risk of cancer. At present, anti-infection treatment, hormones and immunosuppressive drugs were applied to cure the disease. However, its side effect, expensive price and high recurrence rate had to be taken into account. UC was losely associated with dietary factors including nutrients. Using nutrients to prevent and cure UC have become an international research focus in the field. Vitamin D has the function of immune regulation is becoming a consensus, especially in rats or mice. But but complement trial did not find the corresponding function in the crowd. We speculate that because the body cannot synthesize vitamin C, which can effectively promote the activation of vitamin D. The project is based on the above assumptions, through the clinical research to observe the effect of vitamin C and vitamin D in the prevention and treatment of UC, further through animal experiments, analyze whether its role from oxidation, regulating cell factors and exert its functions such as immune regulation. It is of great significance to practice and perfect the theory of prevention and treatment of UC with Combining use of vitamin C and vitamin D.

溃疡性结肠炎（Ulcerative colitis ,UC）是病因不明的慢性非特异性自身免疫性疾病，病程迁延不愈，发病率逐年升高，并增加癌症发生的风险。目前治疗临床治疗药物副作用大，复发率高。该病与膳食营养因素关系密切，应用膳食营养防治UC已成为国际该领域的研究热点。维生素D具有调节免疫的功能，在给大鼠或小鼠补充未活化的维生素D的试验中均能有效地防治UC的发生和发展，然而在人群补充试验中未发现相应功能。研究发现UC患者普遍存在维生素C缺乏，维生素C作为羟化酶的辅助因子，可能影响维生素D的活化，即不能充分合成1,25-(OH)2D3。本项目基于上述假设，通过人群补充试验来观察两种维生素在防治UC方面的作用，进一步通过动物实验分析其发挥作用的机制。其结果为丰富维生素D防治UC的理论，以及对用维生素D防治UC的临床应用均具有十分重要的意义。

溃疡性结肠炎(UC)是病因不明的慢性非特异性自身免疫性疾病，该病与膳食营养因素关系密切。流调显示，UC患者血清维生素D(VD)普遍较低，但多数人群补充试验未发现其可改善UC，且患者存在维生素C(VC)缺乏，VC参与体内代谢，推测可能影响VD的活化。基于上述假设，拟通过人群联合补充VD和VC研究其对UC是否有所改善；通过动物与细胞实验探讨其机制。研究内容：建立UC患者VC、25(OH)D3、1,25-(OH)2D3、CRP、VDR、IL-6、TNF-α等基线数据，收集部分患者粪便用于肠道菌群研究；探讨VD联合VC对UC疾病活动指数、血清中VC和VD、氧化因子、炎性因子及肠道菌群影响；建立豚鼠UC模型，从大体形态、组织学、生化、分子生物学角度研究VD联合VC对实验动物UC的防治作用；探讨VC可否通过促进VD3羟化防治UC，机制是否涉及对氧化损伤、免疫调节及肠道菌群的影响；二者联合干预SW480细胞，研究其通过Notch信号通路对UC肠道通透性的影响。重要结果：患者血清VC水平与25(OH)D3和1,25-(OH)2D3水平有关，VC和VD干预后，免疫因子和氧化因子均有改善；VD和VC干预水平对健康豚鼠的血清1,25(OH)2D3和肾脏CYP24A1 mRNA的影响存在交互作用，而对UC豚鼠的肝脏CYP27A1和肾脏CYP24A1 mRNA的影响存在交互作用；VC在适宜范围内可促进VD3羟化为1,25-(OH)2D3，VC联合VD3对UC豚鼠具有一定防治作用；1,25-(OH)2D3可能通过Notch信号通路介导的抗氧化作用对UC肠粘膜屏障有一定保护作用。关键数据：VC联合VD干预前后 1,25-(OH)2D3、IL-6和MPO分别为(12.10±2.25vs18.11±5.75)、(12.41±4.88vs10.41±1.74)和(8.11±2.26vs 6.18±2.63)，有统计学差异。豚鼠UC造模5ug /(kg·d)VD3剂量组，高VC较低VC剂量组肝脏CYP27A1 mRNA表达增加(2.28±0.43 vs 1.06±0.18)，肾脏CYP24A1mRNA表达降低(0.88±0.55vs2.90±1.13)。科学意义：综上所述，证实VC联合VD干预对UC症状缓解、相关细胞因子改善均具有一定意义，在VD羟化中VC和VD具有交互作用，为营养素防治UC提供理论依据