title: Calcium and 1,25-dihydroxyvitamin D3 modulate genes of immune and inflammatory pathways in the human colon: a human crossover trial.
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.
  
  
  METHODS
  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).
authors.affiliation: Yale University and Veterans Affairs Connecticut Healthcare System, New Haven, CT; The Rockefeller University, New York, NY;
authors.forename: Petr
authors.initials: P
authors.lastname: Protiva
authors.affiliation: The Rockefeller University, New York, NY;
authors.forename: Swaroop
authors.initials: S
authors.lastname: Pendyala
authors.affiliation: The Rockefeller University, New York, NY;
authors.forename: Celeste
authors.initials: C
authors.lastname: Nelson
authors.affiliation: Albert Einstein College of Medicine, Bronx, NY; and.
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Augenlicht
authors.affiliation: Weill Cornell Medical College, New York, NY.
authors.forename: Martin
authors.initials: M
authors.lastname: Lipkin
authors.affiliation: The Rockefeller University, New York, NY; petr.protiva@yale.edu.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Holt
mesh_terms: D000368:Aged; D002117:Calcitriol / Q000008:administration & dosage*; D002118:Calcium / Q000097:blood / Q000652:urine; D002136:Calcium, Dietary / Q000008:administration & dosage*; D003106:Colon / Q000187:drug effects* / Q000276:immunology; D018592:Cross-Over Studies; D066273:Diet, Western; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D010758:Phosphorus / Q000097:blood; D015854:Up-Regulation
chemical_list: D002136:Calcium, Dietary; D010758:Phosphorus; D002117:Calcitriol; D002118:Calcium
keywords: 1,25-dihydroxyvitamin D3; Western diet; calcium; colon; gene expression