Vitamin D3, Calcium and Inflammation, Immunomodulation and Colonic Permeability

说明(申请人提供)：补钙可减少零星的结直肠腺瘤复发，较高的血清维生素D水平与降低结直肠癌的风险有关，结直肠癌是美国癌症死亡的第二大原因。尽管有很强的生物学可信度和支持性的观察数据，但钙和维生素D在人类中的独立抗肿瘤作用，特别是协同作用尚不清楚。已提出的机制包括保护结肠上皮免受胆汁酸的影响，直接影响细胞周期，以及调节生长因子信号、炎症和免疫功能。根据基础科学和有限的人类证据，我们假设补充钙和维生素D可以降低人类血液中炎症和结肠通透性的生物标志物的水平。我们将在一项正在进行的多中心、随机、双盲、安慰剂对照、2×2因素化学预防临床试验(n=2,259)的辅助研究中对这一点进行调查。该临床试验是补充钙(每天1,200毫克元素钙作为碳酸钙)和维生素D3(每天1,000国际单位)的补充，持续3-5年，与安慰剂相比(“父母研究”)。这项辅助研究选择了一组参与者(n=460)，他们在治疗结束时对外观正常的直肠粘膜进行了3年或5年的结肠镜检查。本研究的目的是：1)检测补充钙和维生素D对460例散发性结直肠腺瘤患者(n=460)不同类型炎症反应的单独和联合作用；2)获得关于单独或联合补充钙和维生素D对结肠通透性生物标记物(脂多糖和鞭毛蛋白的特异性Ig G和Ig A)(n=120)的影响的初步数据；以及3)获得关于生物标记物水平的变化是否与减少散发性结直肠腺瘤复发有关的初步数据。拟议的工作范围仅限于使用生物样本和“家长研究”的问卷数据进行的实验室和统计分析。这项辅助研究在一项正在进行的大型人体试验中提供了一个独特的、具有成本效益的机会，以1)证实钙和维生素D对人类的抗炎作用；2)探索钙和维生素D有益地调节结肠通透性的新假设；3)阐明钙和维生素D对炎症生物标志物的联合作用；以及4)作为次要目标，获得关于调节这些生物标志物是否能预测是否可以预防散发性结直肠腺瘤复发的初步数据。阐明维生素D和钙的抗炎作用具有重要意义 这不仅对结直肠癌的化学预防，而且对预防其他炎症介导的慢性疾病都具有重要意义。

DESCRIPTION (provided by applicant): Calcium supplementation reduces sporadic colorectal adenoma recurrence, and higher serum vitamin D levels are associated with reduced risk for colorectal cancer, the second leading cause of cancer deaths in the US. Despite strong biological plausibility and supportive observational data, the independent and, especially, synergistic anti-neoplastic effects of calcium and vitamin D in humans are not clear. Proposed mechanisms have included protection of the colonic epithelium against bile acids, direct effects on the cell cycle, and modulation of growth factor signaling, inflammation, and immune function. Based on basic science and limited human evidence, we hypothesize that calcium and vitamin D supplementation decrease blood levels of biomarkers of inflammation and colonic permeability in humans. We will investigate this in an adjunct study to an ongoing multi-center, randomized, double-blind, placebo-controlled, 2 x 2 factorial chemoprevention clinical trial (n = 2,259) of supplemental calcium (1,200 mg elemental calcium daily as calcium carbonate) and vitamin D3 (1,000 IU daily), alone and in combination vs. placebo over 3 - 5 years (the 'parent study'). A sub-set of participants (n = 460) with end-of-treatment biopsies of normal-appearing rectal mucosa taken at 3- or 5-year follow-up colonoscopies is selected for this adjunct study. The aims of the proposed study are to 1) test the separate and joint effects of calcium and vitamin D supplementation on a custom panel of biomarkers of inflammation/immunomodulation (GM-CSF, IFN?, TNF¿, IL-6, IL-1¿, IL-4, IL-8, IL-10, IL-12p40, and IL-17) representing different classes of inflammatory responses in patients with previous sporadic colorectal adenomas (n = 460); 2) obtain preliminary data on the effects of supplementation with calcium and vitamin D alone or in combination on biomarkers of colonic permeability (specific IgG and IgA to lipopolysaccharide [LPS] and flagellin) (n = 120); and 3) obtain preliminary data on whether changes in the biomarker levels are associated with decreased sporadic colorectal adenoma recurrence. The proposed scope of work is limited to laboratory and statistical analyses using biological samples and questionnaire data from the 'parent study'. This adjunct study offers a unique, cost-effective opportunity in a large, ongoing trial in humans to 1) confirm anti-inflammatory effects of calcium and vitamin D in humans; 2) explore a novel hypothesis that calcium and vitamin D beneficially modulate colonic permeability; 3) elucidate the combined effects of calcium and vitamin D on biomarkers of inflammation; and 4) as a secondary objective, obtain preliminary data on whether modulation of these biomarkers predicts preventing sporadic colorectal adenoma recurrence. Elucidation of vitamin D and calcium anti-inflammatory effects is of great importance, not only to colorectal cancer chemoprevention, but also to the prevention of other inflammation-mediated chronic diseases.