Nutritional and Pharmacological Targeting of the Calcium-Sensing Receptor Influences Chemically Induced Colitis in Mice

Nutrients. 2019 Dec 16;11(12):3072. doi: 10.3390/nu11123072.


The calcium-sensing receptor (CaSR) is the main regulator of extracellular Ca2+ homeostasis. It has diverse functions in different tissues, including the intestines. Intestine-specific knockout of the CaSR renders mice more susceptible to dextran sulphate sodium (DSS)-induced colitis. To test our hypothesis that the CaSR reduces intestinal inflammation, we assessed the effects of nutritional and pharmacological agonists of the CaSR in a colitis model. We treated female Balb/C mice with dietary calcium and protein (nutritional agonists of the CaSR) or pharmacological CaSR modulators (the agonists cinacalcet and GSK3004774, and the antagonist NPS-2143; 10 mg/kg), then induced colitis with DSS. The high-protein diet had a strong pro-inflammatory effect-it shortened the colons (5.3 ± 0.1 cm vs. 6.1 ± 0.2 cm normal diet, p < 0.05), lowered mucin expression and upregulated pro-inflammatory cytokines, such as interferon-γ, (4.2-fold, p < 0.05) compared with the normal diet. Cinacalcet reduced mucin expression, which coincided with an increase in tumor necrosis factor-α (4.4-fold, p < 0.05) and IL-6 (4.9-fold, p < 0.05) in the plasma, compared with vehicle. The CaSR antagonist, NPS-2143, significantly reduced the cumulative inflammation score compared with the vehicle control (35.3 ± 19.1 vs. 21.9 ± 14.3 area under the curve, p < 0.05) and reduced infiltration of inflammatory cells. While dietary modulation of the CaSR had no beneficial effects, pharmacological inhibition of the CaSR may have the potential of a novel add-on therapy in the treatment of inflammatory bowel diseases.

Keywords: IBD; calcium; colitis; inflammation; mucin.

MeSH terms

  • Animals
  • Calcium, Dietary / pharmacology*
  • Colitis / chemically induced
  • Colitis / metabolism*
  • Colon / metabolism
  • Cytokines / metabolism
  • Dextran Sulfate
  • Diet, High-Protein / adverse effects*
  • Dietary Proteins / pharmacology*
  • Female
  • Inflammation
  • Intestinal Mucosa / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Naphthalenes / administration & dosage
  • Receptors, Calcium-Sensing / agonists*


  • CASR protein, mouse
  • Calcium, Dietary
  • Cytokines
  • Dietary Proteins
  • N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine
  • Naphthalenes
  • Receptors, Calcium-Sensing
  • Dextran Sulfate