钙和1,25 - 二羟基维生素D3调节人类结肠中免疫和炎症通路的基因：一项人体交叉试验。
Calcium and 1,25-dihydroxyvitamin D3 modulate genes of immune and inflammatory pathways in the human colon: a human crossover trial.
作者信息
Protiva Petr, Pendyala Swaroop, Nelson Celeste, Augenlicht Leonard H, Lipkin Martin, Holt Peter R
机构信息
Yale University and Veterans Affairs Connecticut Healthcare System, New Haven, CT; The Rockefeller University, New York, NY;
The Rockefeller University, New York, NY;
出版信息
Am J Clin Nutr. 2016 May;103(5):1224-31. doi: 10.3945/ajcn.114.105304. Epub 2016 Mar 23.
BACKGROUND
A high dietary calcium intake with adequate vitamin D status has been linked to lower colorectal cancer risk, but the mechanisms of these effects are poorly understood.
OBJECTIVE
The objective of this study was to elucidate the effects of a Western-style diet (WD) and supplemental calcium and/or 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on the colorectal mucosa.
DESIGN
We conducted 2 crossover trials to define molecular pathways in the human colorectum altered by 1) a 4-wk WD supplemented with and without 2 g calcium carbonate/d and 2) a 4-wk WD supplemented with 1,25(OH)2D3 (0.5 μg/d) with or without 2 g calcium carbonate/d. The primary study endpoint was genome-wide gene expression in biopsy specimens of the rectosigmoid colonic mucosa. Serum and urinary calcium concentrations were also measured.
RESULTS
Changes in urinary calcium accurately reflected calcium consumption. The WD induced modest upregulation of genes involved in inflammatory pathways, including interferon signaling, and calcium supplementation reversed these toward baseline. In contrast, supplementation of the WD with 1,25(OH)2D3 induced striking upregulation of genes involved in inflammation, immune response, extracellular matrix, and cell adhesion. Calcium supplementation largely abrogated these changes.
CONCLUSIONS
Supplementing 1,25(OH)2D3 to a WD markedly upregulated genes in immune response and inflammation pathways, which were largely reversed by calcium supplementation. This study provides clinical trial evidence of global gene expression changes occurring in the human colorectum in response to calcium and 1,25(OH)2D3 intervention. One action of 1,25(OH)2D3 is to upregulate adaptive immunity. Calcium appears to modulate this effect, pointing to its biological interaction in the mucosa. This trial was registered at clinicaltrials.gov as NCT00298545 Trial protocol is available at http://clinicalstudies.rucares.org (protocol numbers PHO475 and PHO554).
背景
高膳食钙摄入量以及充足的维生素D状态与较低的结直肠癌风险相关，但这些作用的机制尚不清楚。
目的
本研究旨在阐明西式饮食（WD）以及补充钙和/或1,25 - 二羟基维生素D3 [1,25(OH)2D3]对结肠直肠黏膜的影响。
设计
我们进行了2项交叉试验，以确定人类结肠直肠中因以下因素改变的分子途径：1）为期4周的西式饮食，分别补充和不补充2克碳酸钙/天；2）为期4周的西式饮食，补充1,25(OH)2D3（0.5微克/天），同时补充和不补充2克碳酸钙/天。主要研究终点是直肠乙状结肠黏膜活检标本中的全基因组基因表达。还测量了血清和尿钙浓度。
结果
尿钙变化准确反映了钙的摄入量。西式饮食导致参与炎症途径（包括干扰素信号传导）的基因适度上调，补充钙可使其恢复至基线水平。相比之下，在西式饮食中补充1,25(OH)2D3会导致参与炎症、免疫反应、细胞外基质和细胞黏附的基因显著上调。补充钙在很大程度上消除了这些变化。
结论
在西式饮食中补充1,25(OH)2D3可显著上调免疫反应和炎症途径中的基因，补充钙可在很大程度上逆转这些变化。本研究提供了临床试验证据，证明人类结肠直肠在钙和1,25(OH)2D3干预下发生的全基因组基因表达变化。1,25(OH)2D3的一个作用是上调适应性免疫。钙似乎可调节这种作用，表明其在黏膜中的生物学相互作用。本试验在clinicaltrials.gov上注册为NCT00298
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