Vitamin D3, Calcium and Biomarkers of Gut Barrier Function

维生素 D3、钙和肠道屏障功能的生物标志物

• 批准号: 8755182
• 负责人: Veronika Fedirko
• 金额: $ 21.61万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8755182
• 关键词: Apoptosis; Bacteria; Basic Science; Bile Acids; Biological; Biological Assay; Biological Markers; Biopsy; Biopsy Specimen; Blood; CD14 Antigen; Calcium; Calcium Carbonate; Cancer Etiology; Cancerous; Cell Adhesion; Cell Cycle; Cell Proliferation; Cessation of life; Chemoprevention; Chemopreventive Agent; Cholecalciferol; Cholesterol; Cleaved cell; Clinical Trials; Colon; Colonic Polyps; Colorectal; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Complex; Consumption; Controlled Clinical Trials; Cytoprotection; Data; Diet; Dietary Intervention; Double-Blind Method; E-Cadherin; Epithelium; Flagellin; Future; Gastrointestinal tract structure; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Factor; Heart Diseases; Human; IL8 gene; Immunoglobulin A; Immunoglobulin G; Immunohistochemistry; Inflammation; Inflammatory; Inflammatory disease of the intestine; Intercellular Junctions; Interferon Type II; Interferons; Interleukin-1; Interleukin-10; Interleukin-2; Interleukin-6; Intervention Trial; Joints; Ki-67 Antigen; Laboratories; Lead; Lipopolysaccharides; Malignant Neoplasms; Measures; Mucins; Mucous Membrane; NF-kappa B; Nuclear; Observational Study; Parents; Participant; Patients; Persons; Placebo Control; Placebos; Prevention; Proteins; Protocols documentation; Questionnaires; Randomized; Recurrence; Reducing Agents; Resected; Risk; Role; Sample Size; Sampling; Serum; Sigmoidoscopy; Signal Transduction; Supplementation; Surrogate Endpoint; TLR4 gene; TLR5 gene; Techniques; Testing; Tight Junctions; Time; Tissues; Toll-like receptors; Tumor Necrosis Factor-alpha; Vitamin D; Work; adhesion receptor; base; beta catenin; caspase-3; claudin-1 protein; cost effective; cytokine; disorder risk; efficacy testing; follow-up; immune function; intestinal fatty acid binding protein; lipopolysaccharide-binding protein; neoplastic; novel; occludin; pressure; prevent; public health relevance; receptor; rectal; response; toll-like receptor 4

DESCRIPTION (provided by applicant): Calcium supplementation educes 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 U.S. Despite strong biological plausibility and supportive observational data, the independent and 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, modulation of growth factors signaling, inflammation, and immune function. Based on basic science and limited human evidence, we propose to test a novel hypothesis that calcium and vitamin D supplementation strengthens the gut mucosal barrier as indicated by modulation of cell cycle, cell adhesion, receptors responsive to bacterial components, and markers of intestinal inflammation in humans. We also hypothesize that these changes in the colon will be accompanied by decreases in circulating levels of biomarkers of colonic hyperpermeability and pro-inflammatory cytokines. 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 = 112) with "non-prep" biopsies of normal-appearing rectal mucosa taken at baseline and 1-year follow-up sigmoidoscopies is selected for this adjunct study. The primary aims of the proposed study are to 1) obtain preliminary data on the separate and joint effects of calcium and vitamin D3 supplementation on biomarkers of gut barrier function (Ki-67/MIB-1, caspase-3, TLR4, TLR5, ZO-1, claudin-1, occludin, mucin-17, E-cadherin, and beta-catenin) and inflammation (NFkappaB and TNFalpha) in biopsies of normal-appearing rectal mucosa, and 2) investigate whether the findings for the tissue-specific biomarkers are correlated with circulating biomarkers of gut barrier function (specific IgG and IgA to lipopolysaccharide [LPS] and flagellin, LPS binding protein [LBP], and intestinal fatty acid binding protein [I-FABP]) and inflammation (GM-CSF, IFNgamma, IL-6, IL-1beta, IL-2, IL-8, IL- 10, IL-12p70, and TNFalpha). 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 explore a novel hypothesis that calcium and vitamin D beneficially modulate gut barrier function, and to elucidate the combined effects of calcium and vitamin D on biomarkers of gut barrier function and inflammation. Understanding the role of vitamin D and calcium in gut barrier function is of great importance, not only to colorectal neoplasm chemoprevention, but also to the prevention of multiple pathological conditions of the gastrointestinal tract.

描述（由申请人提供）：钙补充剂可诱发散发性结直肠腺瘤复发，血清维生素D水平升高与结直肠癌风险降低相关，结直肠癌是美国癌症死亡的第二大原因。尽管生物相容性强，观察数据支持，但钙和维生素D在人体中的独立和协同抗肿瘤作用尚不清楚。提出的机制包括保护结肠上皮免受胆汁酸的影响，对细胞周期的直接影响，生长因子信号传导的调节，炎症和免疫功能。基于基础科学和有限的人类证据，我们建议测试一个新的假设，即钙和维生素D补充剂增强肠道粘膜屏障，如通过调节细胞周期，细胞粘附，对细菌成分有反应的受体和人类肠道炎症标志物所示。我们还假设结肠的这些变化将伴随着结肠通透性过高和促炎细胞因子的生物标志物的循环水平的降低。我们将在一项正在进行的多中心、随机、双盲、安慰剂对照、2 x 2因子化学预防临床试验（n = 2，259）的辅助研究中对此进行研究，该临床试验是补充钙（1，200 mg元素钙，每日碳酸钙）和维生素D3（1，000 IU，每日），单独使用和联合使用，与安慰剂相比，为期3 - 5年（“母研究”）。选择在基线和1年随访乙状结肠镜检查时对外观正常的直肠粘膜进行“非准备”活检的受试者子集（n = 112）用于该辅助研究。本研究的主要目的是：1）获得补充钙和维生素D3对肠道屏障功能生物标志物的单独和联合作用的初步数据（Ki-67/MIB-1、半胱天冬酶-3、TLR 4、TLR 5、ZO-1、claudin-1、occludin、粘蛋白-17、E-钙粘蛋白和β-连环蛋白）和炎症（NF κ B和TNF α），和2）研究组织特异性生物标志物的发现是否与肠屏障功能的循环生物标志物（脂多糖[LPS]和鞭毛蛋白的特异性IgG和伊加，LPS结合蛋白[LBP]和肠脂肪酸 结合蛋白[I-FABP]）和炎症（GM-CSF、IFN γ、IL-6、IL-1 β、IL-2、IL-8、IL- 10、IL-12 p70和TNF α）。拟定的工作范围仅限于使用“母研究”的生物样本和问卷调查数据进行实验室和统计分析。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，以探索钙和维生素D有益于调节肠道屏障功能的新假设，并阐明钙和维生素D对肠道屏障功能和炎症生物标志物的联合作用。了解维生素D和钙在肠道屏障功能中的作用不仅对结直肠肿瘤的化学预防，而且对预防胃肠道的多种病理状况具有重要意义。