Nutritional and pharmacological targeting of the calcium-sensing receptor influences chemically induced colitis in mice

Elajnaf, Taha, Iamartino, Luca, Mesteri, Ildiko, Mueller, Christian, Bassetto, Marcella, Manhardt, Teresa, Baumgartner-Parzer, Sabina, Kallay, Enikoe and Schepelmann, Martin 2019. Nutritional and pharmacological targeting of the calcium-sensing receptor influences chemically induced colitis in mice. Nutrients 11 (12) , 3072. 10.3390/nu11123072

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Abstract

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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Pharmacy
Date of First Compliant Deposit:	28 February 2023
Date of Acceptance:	13 December 2019
Last Modified:	03 May 2023 08:53
URI:	https://orca.cardiff.ac.uk/id/eprint/157362

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