Vitamin D: A Critical Regulator of Intestinal Physiology

Calcium is required for the functioning of numerous biological processes and is essential for skeletal health. The major source of new calcium is from the diet. The central role of vitamin D in the maintenance of calcium homeostasis is to increase the absorption of ingested calcium from the intestine. The critical importance of vitamin D in this process is noted in the causal link between vitamin D deficiency and rickets, as well as in studies using genetically modified mice including mice deficient in the vitamin D receptor (Vdr null mice) or in the cytochrome P-450 enzyme, 25-hydroxyvitamin D₃-1α- hydroxylase (CYP27B1) that converts 25-hydroxyvitamin D₃ to the hormonally active form of vitamin D, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] (Cyp27b1 null mice). When these mice are fed diets with high calcium and lactose, rickets is prevented. The studies using mouse models provide supporting evidence indicating that the major physiological function of 1,25(OH)₂D₃/VDR is intestinal calcium absorption. This review summarizes what is known about mechanisms involved in vitamin D-regulated intestinal calcium absorption. Recent studies suggest that vitamin D does not affect a single entity, but that a complex network of calcium-regulating components is involved in the process of 1,25(OH)₂D₃-mediated active intestinal calcium absorption. In addition, numerous 1,25(OH)₂D₃ actions in the intestine have been described independent of calcium absorption. Although the translatability to humans requires further definition, an overview is presented that provides compelling evidence from the laboratory of 1,25(OH)₂D₃ intestinal effects, which include the regulation of adhesion molecules to enhance barrier function, the regulation of intestinal stem cell function, cellular homeostasis of other divalent cations, the regulation of drug metabolizing enzymes, and anti-inflammatory effects. © 2021 The Author. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.