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Calcium and 1,25-dihydroxyvitamin D3 modulate genes of immune and inflammatory pathways in the human colon: a human crossover trial.
Protiva, P, Pendyala, S, Nelson, C, Augenlicht, LH, Lipkin, M, Holt, PR
The American journal of clinical nutrition. 2016;(5):1224-31
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Abstract
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).
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Vitamin D and calcium: a systematic review of health outcomes.
Chung, M, Balk, EM, Brendel, M, Ip, S, Lau, J, Lee, J, Lichtenstein, A, Patel, K, Raman, G, Tatsioni, A, et al
Evidence report/technology assessment. 2009;(183):1-420
Abstract
BACKGROUND Since the 1997 Dietary Reference Intake (DRI) values for vitamin D and calcium were established new data have become available on their relationship, both individually and combined, to a wide range of health outcomes. The Institute of Medicine/Food and Nutrition Board has constituted a DRI committee to undertake a review of the evidence and potential revision of the current DRI values for these nutrients. To support this review, several US and Canadian federal government agencies commissioned a systematic review of the scientific literature for use during the deliberations by the committee. The intent of providing a systematic review to the committee is to support transparency of the literature review process and provide a foundation for subsequent reviews of the nutrients. PURPOSE To systematically summarize the evidence on the relationship between vitamin D, calcium, and a combination of both nutrients on a wide range of health outcomes as identified by the IOM, AHRQ and technical expert panel convened to support the project. DATA SOURCES MEDLINE; Cochrane Central; Cochrane Database of Systematic Reviews; and the Health Technology Assessments; search limited to English-language articles in humans. STUDY SELECTION Primary interventional or observational studies that reported outcomes of interest in human subjects in relation to vitamin D and/or calcium, as well as systematic reviews that met the inclusion and exclusion criteria. Cross sectional and retrospective case-control studies were excluded. DATA EXTRACTION A standardized protocol with predefined criteria was used to extract details on study design, interventions, outcomes, and study quality. DATA SYNTHESIS We summarized 165 primary articles and 11 systematic reviews that incorporated over 200 additional primary articles. Available evidence focused mainly on bone health, cardiovascular diseases or cancer outcomes. For many outcomes, it was difficult to draw firm conclusions on the basis of the available literature concerning the association of either serum 25(OH)D concentration or calcium intake, or the combination of both nutrients. Findings were inconsistent across studies for colorectal and prostate cancer, and pregnancy-related outcomes including preeclampsia. There were few studies for pancreatic cancer and immune function. Among trials of hypertensive adults, calcium supplementation lowered systolic, but not diastolic, blood pressure by 2-4 mm Hg. For body weight, the trials were consistent in finding no significant effect of increased calcium intake on weight. For growth rates, a meta-analysis did not find a significant effect on weight or height gain attributable to calcium supplement in children. For bone health, one systematic review found that vitamin D plus calcium supplementation resulted in small increases in BMD of the spine and other areas in postmenopausal women. For breast cancer, calcium intakes in premenopausal women were associated with a decreased risk. For prostate cancer, some studies reported that high calcium intakes were associated with an increased risk. LIMITATIONS Studies on vitamin D and calcium were not specifically targeted at life stages (except for pregnant and postmenopausal women) specified for the determination of DRI. There is large variation on the methodological quality of studies examined. Use of existing systematic reviews limits analyses that could be performed on this source of information. CONCLUSIONS The majority of the findings concerning vitamin D, calcium, or a combination of both nutrients on the different health outcomes were inconsistent. Synthesizing a dose-response relation between intake of either vitamin D, calcium, or both nutrients and health outcomes in this heterogeneous body of literature proved challenging.