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Although vitamin D is critical for the function of the intestine, most studies have focused on the duodenum. We show that transgenic expression of the vitamin D receptor (VDR) only in the distal intestine of VDR null mice (KO/TG mice) results in the normalization of serum calcium and rescue of rickets. Although it had been suggested that calcium transport in the distal intestine involves a paracellular process, we found that the 1,25(OH)2D3 activated genes in the proximal intestine associated with active calcium transport (Trpv6, S100g, Atp2b1) are also induced by 1,25(OH)2D3 in the distal intestine of KO/TG mice. In addition, Slc30a10, a manganese efflux transporter, was one of the genes most induced by 1,25(OH)2D3 in both proximal and distal intestine. Both villus and crypt were found to express Vdr and VDR target genes. RNA-seq analysis of human enteroids indicated that the effects of 1,25(OH)2D3 observed in mice are conserved in humans. Using Slc30a10 -/- mice, a loss of cortical bone and a marked decrease in S100g and Trpv6 in the intestine was observed. Our findings suggest an interrelationship between vitamin D and intestinal Mn efflux and indicate the importance of distal intestinal segments to vitamin D action.

The central role of vitamin D in calcium homeostasis is to increase calcium absorption from the intestine. This article describes the early work that served as the foundation for the initial model of vitamin D mediated calcium absorption. In addition, other research related to the role of vitamin D in the intestine, including those which have challenged the traditional model and the crucial role of specific calcium transport proteins, are reviewed. More recent work identifying novel targets of 1,25(OH) 2 D 3 action in the intestine and highlighting the importance of 1,25(OH) 2 D 3 action across the proximal/distal and crypt/villus axes in the intestine is summarized.

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