Mechanisms of intestinal calcium absorption

Calcium is absorbed in the mammalian small intestine by two general mechanisms: a transcellular active transport process, located largely in the duodenum and upper jejunum; and a paracellular, passive process that functions throughout the length of the intestine. The transcellular process involves three major steps: entry across the brush border, mediated by a molecular structure termed CaT1, intracellular diffusion, mediated largely by the cytosolic calcium-binding protein (calbindinD(9k) or CaBP); and extrusion, mediated largely by the CaATPase. Chyme travels down the intestinal lumen in approximately 3 h, spending only minutes in the duodenum, but over 2 h in the distal half of the small intestine. When calcium intake is low, transcellular calcium transport accounts for a substantial fraction of the absorbed calcium. When calcium intake is high, transcellular transport accounts for only a minor portion of the absorbed calcium, because of the short sojourn time and because CaT1 and CaBP, both rate-limiting, are downregulated when calcium intake is high. Biosynthesis of CaBP is fully and CaT1 function is approximately 90% vitamin D-dependent. At high calcium intakes CaT1 and CaBP are downregulated because 1,25(OH)(2)D(3), the active vitamin D metabolite, is downregulated.     

In-situ intestinal loop study of the carbohydrate and phosphate modulation of calcium absorption]

Absorption of 45Ca from a 10 or 20 mM CaCl2 solution given into rat by injection in jejunal or ileal loops in situ is lowered by sodium phosphate and enhanced by L-xylose. Curves relative to the magnitude of absorption depending of doses of phosphate (5 to 50 mM) or carbohydrate (10 to 150 mM) are similar to those which account for the effect of activators or inhibitors upon the activity of enzymes.     

Mechanisms and functional aspects of intestinal calcium absorption

Calcium absorption, in terms of mechanisms and function, is well adapted to meet the calcium needs of mammals. When calcium levels in the food are low, the active, mediated transcellular calcium transport assumes primary importance. This process is vitamin D-dependent, largely localized in the duodenum, and involves three steps: entry across the brush border, mediated by a molecular structure, CaT1, with two components; a facilitated transport that saturates at low luminal calcium concentration; and a channel component through which most calcium enters the cell at the higher luminal concentrations. Intracellular diffusion is assured by a small, cytosolic calcium binding molecule, calbindinD(9k), which carries more than 90% of the calcium that traverses the duodenal cell, thus also serving as a buffer. Extrusion is by the CaATPase and is not a limiting step. Calcium entry is reduced by more than 90% in the absence of vitamin D, with biosynthesis of calbindinD(9k) totally vitamin D-dependent. Active transport is upregulated on low calcium intake and downregulated at high calcium intake, when paracellular calcium transport through the tight junctions of the intestine becomes the dominant process. The amount of calcium absorbed paracellularly is a function of the calcium gradient between lumen and plasma and of the time the chyme spends at a given intestinal site. The coexistence of mediated and nonmediated transport processes assures the organism of an adequate calcium supply, yet prevents excessive calcium absorption.     

Enhancement of rat intestinal calcium absorption by vanadate.

Vanadate alters intestinal transport and may have a role in regulating cell function. To determine whether it influences calcium absorption, we tested the effects of acute and chronic vanadate administration on calcium absorption using single-pass perfusion of jejunal and ileal segments of the in vivo rat intestine. Acute vanadate administration increased the lumen-to-mucosa and net fluxes of calcium in both the jejunum and ileum. The increase was largely due to an enhancement of the saturable fluxes of calcium and was observed at 10(-4) M concentration of vanadate, but not at higher or lower concentrations of the oxyanion, except at the highest concentration used, 10(-2) M, where calcium absorption was inhibited. Chronic vanadate administration caused, on the other hand, no changes in calcium absorption. We have demonstrated previously that rat intestinal (Na+ + K+)-ATPase is inhibited by vanadate, an effect that could raise cell sodium and increase the efflux of sodium across the brush border membrane. The results suggest that the vanadate enhancement of calcium absorption may be related to an increased entry of calcium into the mucosa, possibly as a result of an augmented exchange through the Na+/Ca+ antiport system. Alternatively, vanadate may influence access to a calcium channel in the mucosal membrane of the intestinal epithelium, leading to the observed increase in absorption.     

Effects of calcium and sugars on intestinal manganese absorption

An in vivo luminal perfusion technique was used to investigate the influence of Ca, Mg, lactose, and glucose on Mn absorption in different segments of the rat intestine. Mn absorption was determined by measuring disappearance of⁵⁴Mn activity from the perfusion solution containing 0.1 or 0.01 mmol/L Mn. Na and water absorption were also determined. Mn absorption decreased during the first 30 min of perfusion to reach a steady state thereafter. Ca (1 mmol/L) inhibited Mn absorption in the proximal jejunum and in the colon, whereas Mn absorption was increased by Ca in the distal jejunum. Mg (1 mmol/L), lactose, and glucose (25 mmol/L each) had no effect on Mn absorption in the jejunum. These results can be explained by a direct interaction of Mn and Ca during transcellular Ca transport in the proximal jejunum and colon. The reason for the stimulatory effect of Ca in the distal jejunum is unknown.     

Control of calcium absorption and intestinal calcium-binding protein synthesis

A current hypothesis suggests that the degree of Ca absorption is hormonally controlled via the feed-back regulation of 1,25-dihydroxycholecalciferol (1,25-(OH)₂D₃) production from 25-hydroxycholecalciferol (25-OHD₃) by kidney 1-hydroxylase. To test this hypothesis, dihydrotachysterol₃ (DHT₃), a steroid not requiring 1-hydroxylation for biological activity, was given to chicks as the only source of vitamin D-activity. As expected, DHT₃-treated chicks did not adapt to a calcium-deficient diet. However, both the efficiency of Ca absorption and net synthesis of CaBP were stimulated in DHT₃-treated chicks by a low phosphorus intake, providing evidence for an alternate pathway of control.     

Effect of dietary phosphate on intestinal calcium and phosphate absorption

Intestinal Ca and P absorption was investigated on rachitic chicks raised on diets with a 1% Ca and 0.3% or 1% P contents. 45Ca and 32P absorption was determined by the technique of the isolated gut sac in vivo. In addition, 32P transport was also measured by the everted gut sac procedure in vitro. Treatment with vit. D3 during 7 days increased the 45Ca absorption in animals fed diets containing 0.3% or 1% P. 32P absorption showed an increase after 2 days of treatment and a decrease afterwards. The reduction of 32P absorption was larger in animals fed diet with 1% P. Study of 32P transport with the everted gut sac technique showed an increase after vit. D3 and a loss of intracellular P, regardless the duration of treatment.     

Ion microscopic imaging of calcium during 1,25-dihydroxyvitamin D-mediated intestinal absorption

A combination of ion microscopic and conventional radionuclide techniques was employed to investigate the temporal-spatial dynamics of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃]-stimulated intestinal calcium (Ca) absorption. At varying times following the administration of a single intravenous dose of 1,25(OH)₂D₃, to vitamin D-deficient chicks, transepithelial transport and tissue retention of Ca were quantitated in vivo, using the ligated duodenal loop technique and⁴⁷Ca as the tracer. The localization of Ca in the intestinal tissue during absorption was monitored by ion microscopy, using the stable Ca isotope,⁴⁴Ca, as the absorbed species. There was little transepithelial absorption of Ca in the vitamin D-deficient animals despite a substantial tissue accumulation of luminally derived Ca, the latter localizing predominantly in the brush border region of the enterocyte, as shown by the⁴⁴Ca-ion microscopic images. The early (30 min-1 h) response to 1,25(OH)₂D₃ was an increased tissue uptake of luminal⁴⁷Ca, which also primarily associated with the brush border region, again as shown by ion microscopy. At 2–4 h after the 1,25(OH)₂)D₃ dose, there was a progressive redistribution of Ca from the brush border region throughout the cytoplasm and into the lamina propria. At 8–16 h,⁴⁷Ca absorption was maximal and⁴⁴Ca was sparsely distributed in the intestinal tissue.⁴⁷Ca absorption gradually declined and reached pre-dose levels by 72 h. At this time, tissue⁴⁴Ca was again largely limited to the brush border region. These results provide support for the multiple actions of 1,25(OH)₂D₃ on the intestinal Ca absorption     

Regulation of goby intestinal ion absorption by the calcium messenger system

The role of the calcium messenger system in the regulation of ion absorption across the teleost intestine was studied using pharmacological intervention. Radiochloride transport was independent of external Ca2+ over the range 10 microM to 2.5 mM. Treatment with the Ca2+ ionophore A23187 (to hyperpolarization of the apical membrane potential of intestinal epithelial cells. The Ca2+-calmodulin antagonists trifluoperazine (TFP) and calmidazolium (R24571) produced opposite effects, i.e., stimulation of Cl- absorption and cellular depolarization. Treatment with TFP or R24571 will block or override the inhibitory action of A23187. These data suggest a regulatory role for Ca2+ in the control of intestinal NaCl absorption and mediation via calmodulin.     

Effects of different metabolites of vitamin D3 and of calcium concentration on the intestinal absorption of strontium]

The effect of calcium concentration and vitamin B3 25 OHD3 and 1.25 diOHD3 upon intestinal strontium transport was studied in vitamin D deficient rats with duodenal perfusion in situ. When the calcium concentration was increased, the strontium passive absorption was decreased. The vitamin D3 and its derivatives increased intestinal strontium transport significantly and this increment was not modified by calcium. In our experiment, calcium is competitive with strontium only in passive absorption.     

Effect of dietary calcium and phosphorus on intestinal calcium absorption and vitamin D metabolism.

To understand better dietary regulation of intestinal calcium absorption, a quantitative assessment of the metabolites in plasma and duodenum of rats given daily doses of radioactive vitamin D₃ and diets differing in calcium and phosphorus content was made. All known vitamin D metabolites were ultimately identified by high-pressure liquid chromatography. In addition to the known metabolites (25-hydroxyvitamin D₃, 24,25-dihydroxyvitamin D₃, 1,25-dihydroxyvitamin D₃, 25,26-dihydroxyvitamin D₃, and 1,24,25-trihydroxyvitamin D₃), several new and unidentified metabolites were found. In addition to 1,25-dihydroxyvitamin D₃ and 1,24,25-trihydroxyvitamin D₃, the levels of some of the unknown metabolites could be correlated with intestinal calcium transport. However, whether or not any of these metabolites plays a role in the stimulation of intestinal calcium absorption by low dietary calcium or low dietary phosphorus remains unknown.     

Maltobionic acid enhances intestinal absorption of calcium and magnesium in rats

ABSTRACT

In Experiment 1, the effects of calcium maltobionate (MBCa) on calcium and magnesium absorption were examined using male rats. Four diets were designed in which 25%, 50%, and 100% of calcium carbonate (CaCO₃, Control) were substituted with MBCa and were designated as MBCa-25, MBCa-50, and MBCa-100, respectively. The cecal concentration of short-chain fatty acids was significantly higher in groups MBCa-50 and MBCa-100; however, pH of cecal contents did not significantly differ among the groups. Retention rates of calcium and magnesium were significantly higher in all MBCa groups as compared to the Control. In Experiment 2, the efficiency of calcium absorption was compared using everted sacs of jejunum and ileum with CaCO₃ and MBCa as calcium sources. More calcium from MBCa was absorbed as the concentration of calcium increased in comparison to CaCO₃. It was concluded that MBCa is a better calcium source than CaCO₃ in terms of both calcium retention and absorption.

Abbreviations: ANOVA: analysis of variance; Ca: Calcium; CaCO_3: calcium carbonate; ICP-OES: Inductivity coupled plasma optical emission spectrometer; Mg: magnesium; MBCa: calcium maltobionate; OCPC: o-cresolphthalein complexone; SCFAs: short-chain fatty acids; SE: standard error; TRPM6: transient receptor potential melastatin 6.     

Simple test of intestinal calcium absorption measured by stable strontium.

A clinical test of intestinal calcium absorption has been developed using non-radioactive stable strontium as a calcium tracer. In nine elderly subjects there was a close correlation between the fractional absorption of strontium and radioactive calcium (45Ca) during a five hour period after the simultaneous oral administration of the two tracers. Comparable precision was achieved with each tracer in six subjects in whom the test was repeated after two weeks. The effect of food on strontium absorption was examined in a further 33 normal subjects (age 21-60 years), and the administration of the strontium with a standard breakfast was shown to reduce the variance at individual time points. A simplified test in which serum strontium concentration was measured four hours after the oral dose given with a standard breakfast was adopted as the routine procedure. The normal range (mean (2 SD], established over 97 tests in 53 patients, was 7.0-18.0% of the dose in the extracellular fluid. A further 30 patients with possible disorders of calcium absorption (10 with primary hyperparathyroidism and 20 with coeliac disease) were studied by this standard test. In both groups of patients the mean four hour strontium values were significantly different from normal. This standard strontium absorption test allows assessment of calcium absorption with sufficient sensitivity and precision to have a wide application in clinical practice.