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.

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.提出的机制包括保护结肠上皮对胆汁酸的保护，对细胞周期的直接影响，生长因子信号传导，炎症和免疫功能的调节。基于基础科学和有限的人类证据，我们建议测试一种新的假设，即补充钙和维生素D的补充可以增强肠粘膜屏障的增强，如细胞周期的调节，细胞粘附，对细菌成分有效的受体以及人类肠炎的标记。我们还假设结肠中的这些变化将伴随着结肠高度过度性和促炎性细胞因子的生物标志物的循环水平降低。我们将在一项辅助研究中对正在进行的多中心，随机，双盲，安慰剂对照，2 x 2 forsorial化学预防临床试验（n = 2,259）补充钙（每天为1,200 mg元素钙作为钙含量为1,200 mg元素钙）和'每日的维生素d3（1,000 IU），''''''''''为这项辅助研究选择了参与者（n = 112），该参与者的“非prep”活检的正常直肠粘膜和1年的随访sigmoidoscopies。 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 结合蛋白[I-FABP]）和炎症（GM-CSF，Ifngamma，IL-6，IL-1Beta，IL-2，IL-2，IL-8，IL-8，IL-10，IL-12P70和TNFALPHA）。拟议的工作范围仅限于实验室和统计分析，并使用“家长研究”中的生物样品和问卷数据进行了统计分析。这项辅助研究在人类正在进行的大型试验中提供了独特的，具有成本效益的机会，以探讨一种新的假设，即钙和维生素D有益地调节肠屏障功能，并阐明钙和维生素D对肠屏障功能和炎症的生物标志物的综合作用。了解维生素D和钙在肠道屏障功能中的作用至关重要，这不仅在结直肠肿瘤化学预防上，而且对预防胃肠道多种病理条件的预防。