TY - JOUR
T1 - Calcium and 1,25-dihydroxyvitamin D3 modulate genes of immune and inflammatory pathways in the human colon
T2 - A human crossover trial
AU - Protiva, Petr
AU - Pendyala, Swaroop
AU - Nelson, Celeste
AU - Augenlicht, Leonard H.
AU - Lipkin, Martin
AU - Holt, Peter R.
N1 - Funding Information:
Supported in part by the Rockefeller University Center for Clinical and Translational Science grant UL1 TR000043 and by the Center for Basic and Translational Research on Disorders of the Digestive System and National Cancer Institute grants U54, CA100926, and CA29502-24.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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 calciumcarbonate/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).
AB - 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 calciumcarbonate/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).
KW - 125-dihydroxyvitamin D
KW - Calcium
KW - Colon
KW - Gene expression
KW - Western diet
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UR - http://www.scopus.com/inward/citedby.url?scp=84969567806&partnerID=8YFLogxK
U2 - 10.3945/ajcn.114.105304
DO - 10.3945/ajcn.114.105304
M3 - Article
C2 - 27009752
AN - SCOPUS:84969567806
SN - 0002-9165
VL - 103
SP - 1224
EP - 1231
JO - American Journal of Clinical Nutrition
JF - American Journal of Clinical Nutrition
IS - 5
ER -
