An overview of current information on the mechanisms by which intestinal calcium absorption occurs is described in this article. Both paracellular and transcellular pathways are analyzed. Special emphasis focuses on molecules participating in the latter pathway, such as TRPV5 and TRPV6 channels, located in the apical region of the enterocytes, CB9k and CB28k, presumably involved in the cation movement from the apical to the basolateral pole of the cell, and PMCA1b and Na+/Ca2+ exchanger, proteins that extrude Ca2+ from the cells. Current concepts on the relative importance of paracellular and transcellular calcium transport and the vitamin D dependence of each pathway are referred and analyzed showing the contrasting views on this issue. More detailed information is given regarding the stimulatory effect of vitamin D on intestinal Ca2+ absorption either in animal models or in the human intestine. The possible mechanisms triggered by hormones such as PTH, calcitonin, estrogen, thyroid hormone, glucocorticoids and different nutritional factors on intestinal calcium absorption are also reviewed. Finally, the influence of physiological conditions such as growth, pregnancy, lactation and aging on intestinal calcium absorption are discussed.

Intestinal calcium (Ca2+) absorption is an important process involved in the maintenance of Ca2+ homeostasis. It occurs by two main mechanisms: a transcellular, metabolically driven transport, and a passive non-saturable route, called the paracellular pathway [1]. These mechanisms are regulated by hormones, nutrients and other factors, which have been studied for many years due to their enormous relevance in the prevention of osteoporosis and other abnormalities related to the Ca2+ metabolism. The transcellular pathway is mainly regulated by vitamin D, precisely by its hormonal metabolite 1,25(OH)2D3, via transcriptional activation of genes through binding of the ligand to the classical nuclear vitamin D receptor (VDR) [2]. Some polymorphisms of VDR such as the Fok I polymorphic site seem also to affect intestinal Ca2+ absorption [3] by a not well-understood mechanism.

Under physiological conditions, Ca2+ ions are absorbed mainly in the small intestine, responsible for about 90% of overall Ca2+ absorption [4]. In rat small intestine, Marcus and Lengemann [5] found that 88% of Ca2+ absorption occurs in the ileum, 4% in the jejunum, and 8% in the duodenum. In dogs, Cramer [6] found 80, 16 and 4% in ileum, jejunum and duodenum, respectively. The longer residence time of Ca2+ in the ileum as compared to the other intestinal segments favors Ca2+ absorption in that segment. The transit half-time in rat ileum is around 100–120 min, whereas in the duodenum it is around 2–6 min [5, 6]. Minor amounts of Ca2+ ions are absorbed from the stomach and large intestine; the colon accounts for less than 10% of the total Ca2+ absorbed [4]. The major contributors to the amount of Ca2+ absorbed are the residence time and the rate of absorption in the particular segment. The order of absorption rate is: duodenum > jejunum > ileum [7]. Colonic Ca2+ absorption is also vitamin D-responsive and it is quite possible that it becomes important in conditions such as short bowel syndrome [8].

The bioavailability of dietary Ca2+ affects the efficiency of intestinal Ca2+ absorption. Low Ca2+ diets increase the intestinal Ca2+ absorption ratio, at least in part, by altering the vitamin D endocrine system [9, 10] and the lipid composition and fluidity of intestinal membranes [11].

Variability of intestinal Ca2+ absorption is also related to the physiological Ca2+ needs, but in general when the requirements increase and/or the intake is low, the efficiency of Ca2+ absorption improves [11]. Growth, pregnancy and lactation stimulate intestinal Ca2+ absorption, whereas aging is accompanied by a decrease in the absorption of the cation.

The intestinal epithelium is a continuous layer of individual cells with very narrow spaces between them that allow the diffusion of small molecules and ions [12]. The paracellular pathway must be regulated by the epithelium in order to maintain the selective permeability. Tight junctions constitute a barrier to the movement of molecules and ions through this pathway. These junctions are specialized membrane domains located in the apical region of enterocytes. They are intercellular structures where the plasma membranes of adjacent cells come into very close contact [12]. The proteins that form these structures are synthesized in the adjacent cells and they include occludin and another protein member of the claudin family [13]. Movement of Ca2+ through the tight junctions is a passive process that depends on the concentration and the electric gradients across the epithelium. It is a passive non-saturable process that prevails in the jejunum and ileum, mainly when Ca2+ intake is adequate or high [14]. It depends on the solubility of Ca2+ in the distal small intestine, the length of sojourn of the chyme in a particular intestinal segment and the rate of diffusion from the lumen to lymph or blood [14]. When Ca2+ intake is high, the paracellular pathway becomes important because the sojourn time in the intestine is short and the proteins involved in the transcellular route are downregulated [15].

Epithelial Ca2+ Channels

The molecules involved in the apical Ca2+ entry step in the intestine remained unknown until the discovery of the epithelial Ca2+ channels TRPV5 (previously named ECaC1 or CaT2) and TRPV6 (previously named ECaC2 or CaT1) [16]. Both channels are homologous members of the transient receptor potential (TRP) superfamily, belonging precisely to the vanilloid subfamily (TRPV) to be differentiated from the canonical (TRPC) and melastatin subfamilies (TRPM). The pattern of expression of these proteins is quite variable, which can be due to differences between species or expressions below detection levels [17]. TRPV5 is the major isoform in the kidney, while TRPV6 is highly expressed in the intestine. However, TRPV5 and TRPV6 are coexpressed in human kidney and intestine, and also in other organs such as pancreas, prostate, mammary, sweat and salivary glands [16]. TRPV5 and TRPV6 have 75% homology and their main differences are located in the N and C terminal tails. Both channels permeate Ca2+ ions, but they also permeate other divalent cations and monovalent cations in the absence of divalent ones. These channels have three unique properties: (1) they have a constitutively activated Ca2+ permeability; (2) the selectivity for Ca2+ over Na+ is much larger than in other members of the TRP family (PCa/PNa >100), and (3) the current-voltage relationship of both channels shows inward rectification instead of outward rectification as shown by other TRPV channels. The structure of these channels is similar to that of other members of the TRP family, including 6 transmembrane domains, a short hydrophobic stretch between segments 5 and 6 which would be involved in the Ca2+ pore and large intracellular N and C terminal tails [17]. The intracellular segments contain regulatory sites involved in the regulation of channel activity and trafficking. Among them, there are phosphorylation sites, postsynaptic density protein (zona occludens) motifs, and ankyrin repeat domains. All of them participate in the maintenance of the activity of the channels, in the interaction with other proteins, and in the targeting of those channels to specific membrane regions [17].

Hoenderop et al. [18] demonstrated that channels TRPV5 and TRPV6 have a tetrameric structure and they can combine each other to form heterotetrameric channel complexes with novel properties. The tetrameric architecture of TRPV5/6 implies that 4 aspartic residues form a ring that is negatively charged and functions as a selective filter for Ca2+.

Although both channels originate from two genes juxtaposed on human chromosome 7q35, the proteins share several properties and have some differences. At the transcriptional level, they are regulated by 1,25(OH)2D3, estrogen and dietary Ca2+. Regarding the activity, both are inactivated by intracellular Ca2+, but the inactivation of TRPV6 shows two phases, whereas that of TRPV5 shows only a slow inactivation phase. The affinity of TRPV5 for the inhibitor ruthenium red is 100 times higher than that of TRPV6 [19].

TRPV5 and TRPV6 are located in the brush border membrane of enterocytes and it is quite possible that they are the rate-limiting entry step of active intestinal Ca2+ absorption [20]. To determine the in vivo function of TRPV6, Bianco et al. [21] generated mice with targeted disruption of the TRPV6 gene. They have demonstrated that TRPV6 knockout (KO) mice were viable but showed a 60% decrease in intestinal Ca2+ absorption, deficient weight gain, decreased bone mineral density (BMD), and lower fertility. Their data indicate that the TRPV6 channel not only plays a role in the tissues directly involved in Ca2+ homeostasis, but also in other tissues.

Walters et al. [22] characterized TRPV6 transcript expression in normal human intestinal biopsies. TRPV6 transcripts were detected in the duodenum but not in the ileum. Duodenal expression of TRPV6 was vitamin D-dependent in men; however, in elderly women TRPV6 and VDR expressions were reduced and were not vitamin D-dependent, which can explain, at least in part, the lower intestinal Ca2+ absorption in elderly postmenopausal women.


There are two calbindins (CBs) thought to be responsible for removing Ca2+ from the apical side of the enterocytes and carrying the Ca2+ transcellular movement to the basal region of the cell. In the duodenum, CB D28k (CB28k) is present in the avian species, while CB D9k (CB9k) is present in mammals [23]. Both proteins are encoded by separate genes. It has been proposed that CBs not only carry Ca2+ ions from the entry side to the basolateral membrane (BLM) of the enterocyte, but also buffer Ca2+ ions providing protection against toxic Ca2+ levels during high Ca2+ influx. In addition, CBs may function as Ca2+ sensors due to their biochemical properties related to their EF-hand motifs. CB28k has 6 EF-hand motifs that bind Ca2+ in a cooperative fashion. Nuclear magnetic resonance analyses indicated that Ca2+ binding to CB28k produce conformational changes in the protein [24]. Lambers et al. [25] have shown that renal CB28k acts as a dynamic Ca2+ buffer, regulating the Ca2+ concentration in the vicinity to the TRPV5 pore by a direct association with the channel. Similar mechanisms could occur in the intestine and other tissues where CBs are abundant and where cells tolerate important fluctuations in intracellular Ca2+ concentration.

Genetic studies give controversial data regarding the role of CBs on Ca2+ homeostasis. Ablation of CB28k gene in mice does not produce calcemic abnormalities [26]. VDR KO mice show hypocalcemia, secondary hyperparathyroidism, rickets and a 90% reduction in renal CB9k expression with no change in CB28k. VDR/CB28k double KO mice develop more severe secondary hyperparathyroidism and rachitic skeletal phenotype, and the rescue diet with high calcium and lactose does not completely correct the skeletal alterations. The authors think that CB28k plays an important role in Ca2+ homeostasis and suggest that its calcemic role might be compensated by CB9k[27]. However, recent data from CB9k KO mice indicate that those mice are not different from wild-type mice in phenotype and Ca2+ serum level [28]. In addition, the CB9k null mutant mice are able to absorb Ca2+ from the intestine in response to 1,25(OH)2D3, which would mean that CB9k is not required for vitamin D-dependent intestinal Ca2+ absorption.

Ca2+ Pump and Na+/Ca2+ Exchanger

The exit of Ca2+ ions from enterocytes to the lamina propria is performed by two molecules: the plasma membrane Ca-ATPase or Ca2+ pump (PMCA) and the Na+/Ca2+ exchanger (NCX1). The Ca2+ pump has a Mr of 130 kDa and Km for Ca2+ of 0.2 µM in the presence of calmodulin [29]. It is located in small invaginations in the plasma membrane, called caveolae, which can exist in open and closed forms that control Ca2+ efflux from the cell [30]. It presents several isoforms but, apparently, PMCA1b is the predominant form in the intestine. The expression and activity of PMCA1b is higher in enterocytes from the villus tip as compared to those from the villus crypt, which supports the idea that mature enterocytes have the greatest capacity for transcellular Ca2+ movement [10]. Vitamin D deficiency decreases the expression and activity of PMCA1b in chick intestine, which is partially reversed by a single large dose of cholecalciferol [31].

The intestinal Na+/Ca2+ exchanger, which has received little attention, is responsible for about 20% of Ca2+ extrusion and its activity depends on the gradient created by Na+/K+-ATPase [32]. There are several isoforms that result from three different genes [33]. The Na+/Ca+ exchanger is present in the intestine. It has a Mr of 90 kDa and it is constituted by 11 transmembrane domains and an intracellular loop between segments 5 and 6. In this loop there is an inhibitory region involved in the inactivation of the exchanger, named exchange inhibitory peptide domain and a regulatory site with high affinity for Ca2+. The stoichiometry of exchange of this protein is 3 Na+:1 Ca2+[34]. In the intestine, the Na+/Ca2+ exchanger has been detected in rats [32], mice [35] and chicks [10], but not in rabbits [36]. This transporter can operate in either a forward mode (Ca2+ exit) or in a reversed mode (Ca2+ entry), which depends on the Na+ and Ca2+ gradients and the potential across the plasma membrane [37]. The expression and activity of the Na+/Ca2+ exchanger is quite similar between mature and immature enterocytes, being slightly higher in the villus tip cells [10].

Calcitriol or 1,25(OH)2D3 induces changes in the structure and function of intestinal epithelial cells, which results in an increased intestinal Ca2+ absorption. As previously mentioned, calcitriol primarily stimulates the transcellular Ca2+ movement. Calcitriol enhances intestinal Ca2+ absorption through binding to VDR, nuclear receptor and transcription factor. This binding promotes heterodimerization with the retinoid X receptor (RXR). The 1,25(OH)2D3-VDR-RXR complex translocates to the nucleus to bind the vitamin D-responsive element(s) (VDRE) that is (are) usually located on the DNA upstream of the transcription site. Thus, the VDR complex can regulate gene transcription [38]. The four proteins or their transcripts considered to be essential for transcellular Ca2+ absorption (TRPV6, CB, calcium pump and Na+/Ca2+ exchanger) are known to be enhanced by calcitriol in mouse and chick intestine [10, 31, 39, 40, 41]. However, recent data obtained in CB9k null mutant mice indicate that CB9k is not required by calcitriol-mediated Ca2+ absorption in the small intestine [42].

The sensitivity of the genes related to the intestinal Ca2+ absorption to the VDR levels remains unclear. VDR KO mice have a phenotype of vitamin D-resistance rickets and reduced calcium absorption [43]. Song and Fleet [2] tested the role of VDR levels in the intestinal response to calcitriol in wild-type mice and mice lacking one VDR allele (heterozygous) that have only half the intestinal VDR content. They found that a reduced intestinal VDR level causes vitamin D resistance and impairs intestinal Ca2+ absorption in mice. The resistance is not uniform in the vitamin D-dependent genes involved in the intestinal Ca2+ absorption, because apparently the effects of VDR levels have been only detected in the translation of CB9k. Meyer et al. [44], by using a chromatin immunoprecipitation scanning method, have identified multiple VDREs in the distal promoter region of the TRPV6 gene. It is quite possible that the number of VDREs in each promoter, the location or the local DNA environment of each VDRE or the affinity of each VDRE for VDR could account for the differential sensitivity of each gene involved in the intestinal Ca2+ absorption to VDR level [2]. In addition, differences in the promoters of the genes for intestinal Ca2+ absorption proteins or for VDR could also explain the interspecies differences in responsiveness to calcitriol between humans and experimental animals [45].

The well-known rapid effects (minutes to an hour) of calcitriol on Ca2+ uptake by epithelial cells or other responses brought up the question about the possibility of a second VDR located in the plasma membrane. It now appears that the classic VDR could also be associated with caveolae present in the plasma membrane [46].

Regarding the vitamin D dependency of the paracellular pathway, the picture is less clear as compared to the transcellular pathway. However, some data indicate that vitamin D increases tight-junction conductance and paracellular Ca2+ transport in Caco-2 cell lines [47]. It has been reported that 1,25(OH)2D3 activates protein kinase C, which apparently increases paracellular permeability by affecting cytoskeleton activity [48].

Figure 1 is a schematic representation of the possible mechanisms involved in the intestinal Ca2+ absorption triggered by calcitriol as has been described above.

Fig. 1

Schematic representation of possible mechanisms involved in the intestinal Ca2+ absorption. The epithelial Ca2+ transport occurs by paracellular and transcellular pathways. The paracellular Ca2+ transport is carried out through tight junctions (TJ) by an electrochemical gradient (long arrow between cells). The transcellular Ca2+ transport consists of three steps: (1) apical entry of Ca2+ through epithelial Ca2+ channels TRPV5 and TRPV6 (the last one is the most abundant in intestine); (2) cytosolic diffusion bound to calbindins, and (3) extrusion across the basolateral membranes by the plasma membrane Ca2+-ATPase (PMCA1b) and the Na+/Ca2+ exchanger (NCX1). Calcitriol (1,25(OH)2D3) stimulates the individual steps of transcellular Ca2+ transport. Calcitriol molecules bind to their nuclear receptors (VDR), and the complex 1,25(OH)2D3-VDR interacts with specific DNA sequences inducing transcription and increasing the expression levels of TRPV 5/6, calbindins and the extrusion systems.

Fig. 1

Schematic representation of possible mechanisms involved in the intestinal Ca2+ absorption. The epithelial Ca2+ transport occurs by paracellular and transcellular pathways. The paracellular Ca2+ transport is carried out through tight junctions (TJ) by an electrochemical gradient (long arrow between cells). The transcellular Ca2+ transport consists of three steps: (1) apical entry of Ca2+ through epithelial Ca2+ channels TRPV5 and TRPV6 (the last one is the most abundant in intestine); (2) cytosolic diffusion bound to calbindins, and (3) extrusion across the basolateral membranes by the plasma membrane Ca2+-ATPase (PMCA1b) and the Na+/Ca2+ exchanger (NCX1). Calcitriol (1,25(OH)2D3) stimulates the individual steps of transcellular Ca2+ transport. Calcitriol molecules bind to their nuclear receptors (VDR), and the complex 1,25(OH)2D3-VDR interacts with specific DNA sequences inducing transcription and increasing the expression levels of TRPV 5/6, calbindins and the extrusion systems.

Close modal

It is still debated whether intestinal Ca2+ absorption takes place predominantly through a passive or an active process and whether vitamin D constitutes a major regulator of the passive paracellular pathway. Interesting analyses and opinions regarding this issue have been reported by McCormick [49], Bronner et al. [50] and Wasserman [4]. Basically, McCormick [49] refers to evidence indicating that the contribution of passive diffusion is about 8–23% in normal adults, while in children this process is of little practical significance. The author cited two different studies on children lacking a VDR system [51, 52] that did not show improvement in their calcium status by oral calcium supplementation, but instead presented beneficial effects of calcium infusion as early as 2 weeks later. Besides, through analysis of data from Bronner et al. [53] and Pansu et al. [54], he suggested that, early in development and for several weeks after birth, intestinal Ca2+ absorption depends on passive diffusion and not on vitamin D-dependent processes. This would change with the age, becoming more important the saturable process that requires vitamin D in the adulthood. In addition, McCormick suggested that species differences could also complicate the interpretation of the relative importance of both pathways.

On the contrary, Bronner et al. [50] reported that the estimation of passive transport from the data of Ireland and Fordtran [55] must be calculated using a value of diffusible plasma calcium of 1.1–1.2 mmol/l instead of 1.5 mmol/l. This would almost double the slope of passive diffusion, and with the new approach that they suggested, the active transport accounted for only 27%. Bronner et al. [50] also cite the data of Sheikh et al. [56], who reported that when healthy young subjects increased their Ca2+ intake from 502 to 1,071 mg/day, their total absorption doubled, the increase being due to the vitamin D-independent passive transport. Although Bronner et al. [50] point out that vitamin D administration increases intestinal Ca2+ absorption, they consider that increasing Ca2+ intake is more effective and involves less risk for normal adults.

Contrary to the aforementioned views, Wasserman [4] presented evidence that both paracellular and transcellular pathways are positively affected by vitamin D in the ileum, the site where most of the dietary Ca2+ is absorbed. The author mentions several papers [57, 58] demonstrating that the ileum can absorb Ca2+ by an active process which is stimulated by vitamin D. Wasserman [4] suggests that the slower rate of absorption in the ileum as compared to the duodenum might be the absence of an entry Ca2+ channel in the rat ileum (but present in the human and mouse ileum) and the lower CB and Ca2+ pump concentrations compared with the duodenum, but the long transit time of the cation in the ileum would have a considerable effect on overall Ca2+ absorption. Wasserman [4] also suggests that calcitriol might control the paracellular permeability as was previously demonstrated in other systems by different hormones.

Parathyroid Hormone

It is well known that parathyroid hormone (PTH) plays an important role in the maintenance of the extracellular Ca2+ concentration, sensing minute by minute changes in the blood Ca2+. When the extracellular Ca2+ is low, the parathyroid glands secrete PTH to the circulation and then PTH binds to the PTH/PTH receptor protein (PTHrP) receptor, mainly in the bone and kidney stimulating bone resorption and Ca2+ reabsorption, respectively. At the intestinal level, PTH seems to act indirectly on intestinal Ca2+ absorption by stimulation of renal 1α-hydroxylase and, thereby, increasing 1,25(OH)2D3-dependent absorption of Ca2+ from the intestine. However, direct effects of PTH on Ca2+ uptake by enterocytes from rat duodenum have been demonstrated. PTH stimulates enterocyte Ca2+ influx, which could be blocked by the Ca2+ channel antagonists verapamil and nitrendipine [59], and modulates intracellular Ca2+ concentration [60]. Furthermore, PTH/PTHrP receptors have been localized by immunocytochemistry in intestinal epithelial cells along the villus [61]. Aside from its rapid signal transduction mechanism, PTH also promotes nuclear effects such as regulation of gene transcription and cell proliferation [61, 62]. Studies that demonstrated the direct effect of PTH on the global process of intestinal Ca2+ absorption have not been reported yet.


Although calcitonin is considered one of the three major regulating hormones of plasma calcium, little information is available about its effect on intestinal calcium absorption. Jaeger et al. [63] have studied the effect of chronic calcitonin infusion in thyroparathyroidectomized animals. Calcitonin increased plasma calcium levels in animals on a regular diet by 50%, which was most likely due to an enhancement of intestinal calcium absorption since removal of calcium from the diet markedly blunted this effect. The authors concluded that calcitonin stimulates intestinal calcium absorption through an increase in 1,25(OH)2D3 circulating levels. Afterwards, Yoshida et al. [64] demonstrated that calcitonin stimulates the 25-hydroxyvitamin D3 1α-hydroxylase mRNA level in LLC-PK1 cells via the protein kinase C pathway. So far, there have been no reports of pathologies caused by either calcitonin deficiency or excess [65].

Thyroid Hormone

Thyrotoxicosis is quite often accompanied by hypercalcemia in either humans or animals [66, 67]. However, this issue has received little attention. Cross et al. [68, 69] reported that thyroid hormone and vitamin D have a cooperative effect not only on intestinal calcium transport but also on intestinal phosphate movement. The authors also demonstrated that thyroid hormones increase the genomic action of calcitriol in the intestine. Recently, it has been shown that hyperthyroid rats show higher Ca2+ uptake by brush border membrane vesicles and Ca2+ efflux from the BLMs of enterocytes than hypothyroid rats. Ca2+-ATPase activity was not changed by the thyroid hormones, while the Na+/Ca2+ exchanger activity was highly increased possibly via the cAMP-mediated pathway [67].


Several studies have reported that the global Ca2+ absorption in normal postmenopausal women is decreased, an effect that is more pronounced in postmenopausal osteoporotic women [70]. Estrogen therapy corrects the decline in Ca2+ absorption efficiency at the onset of menopause as indicated by cell culture studies [71]. However, the mechanisms that underlie this effect are not clear. Some studies indicate that estrogen acts independently of 1,25 (OH)2D3 in the intestine [72], whereas others suggest that estrogen modifies intestinal Ca2+ absorption through the vitamin D endocrine system [71]. Most of the estrogen studies were performed in ovariectomized animals. This ablation significantly reduces endogenous estrogen production, but not completely due to the fact that adrenal androgens can be aromatized to estrogen [70]. Because of that, KO animals for estrogen receptor-α (ERα) and ERβ were obtained to totally abolish the genomic actions of estrogen mediated by their receptors. ERαKO mice showed a decrease in the duodenal ECaC2 mRNA expression, while CB9k, PMCA1b and VDR levels were unchanged. ERβKO mice did not change the genes for intestinal calcium transporter. Apparently, in mice the genomic effects of estrogen are mainly mediated by the ERα. This concept must not be extrapolated to humans because it has been demonstrated that in normal colon and cancer colon cells the subtype β is the predominant form of the ER [73].

Van Abel et al. [74] supplemented ovariectomized rats with estradiol and found increased duodenal gene expression of TRPV5, TRPV6, CB9k and PMCA1b. In addition, they used 25-hydroxyvitamin D3 1α-hydroxylase KO mice to study the 1,25(OH)2D3 dependency of the stimulatory effects of estradiol on intestinal Ca2+ absorption. Under this condition of undetectable levels of 1,25(OH)2D3, the estradiol treatment increased mRNA levels of duodenal TRPV6. During pregnancy or lactation, estrogen or hormonal changes produce vitamin D-independent effects at the genomic level on duodenal calcium absorption. Estrogen seems to upregulate the calcium influx channel CaT1, which apparently is only mediated by ERα [75]. Cotter and Cashman [76] have investigated the effect of two dietary phytoestrogens (coumestrol and apigenin) as well as ipriflavone, a synthetic phytoestrogen, on Ca absorption in the human Caco-2 cell line. The authors did not find a direct effect of these compounds on intestinal Ca absorption. These equivocal results evidence that further studies are needed to clarify the mechanism(s) triggered by estrogen in intestine.


Glucocorticoids (GCs) are extensively used as anti-inflammatory drugs. Osteoporosis is one of the most important side effects after long-term GC treatments. Reduced intestinal Ca2+ absorption seems to be part of the pathogenesis of GC-induced osteoporosis [77]. However, the mechanisms triggered by GCs on the intestine are not clear. Some data have shown that short-term GC excess in young animals affects bone metabolism but not the expression of genes involved in intestinal Ca2+ absorption such as TRPV6, CB9k and PMCA1b[78]. In contrast, sustained dexamethasone suppresses mouse duodenal CB9k expression via the GC receptor pathway [79]. Recently, it has been reported that 10 mg/kg body weight prednisolone for 10 days decreases rat intestinal Ca2+ absorption through diminished expression of the active calcium transporters such as the channel TRPV6 and CB9k, independently of 1,25(OH)2D3[80]. A similar finding was also reported by Scholz-Ahrens et al. [81]. These authors used adult Göttingen miniature pigs treated orally with prednisolone at a dose of 1 mg·kg body weight–1· day–1 for 8 weeks (short-term) and thereafter at 0.5 mg·kg body weight–1·day–1 (long-term). These animals are omnivore and thus have more similarities with humans than other animals. By looking at the parallel decline in calcium balance and BMD and the parallel lower bone ash content, the authors concluded that GC-induced osteoporosis was the consequence of reduced intestinal mineral absorption. Scholz-Ahrens et al. [81] think that GCs may directly alter the vitamin D-independent transmucosal absorption of calcium because they did not find large effects on plasma vitamin D metabolites or on PTH. Their conclusion is that alterations in vitamin D metabolites associated with the GC-induced osteoporosis might be the consequence of preexistent disorders.

Dietary Ca2+

About 70% of dietary Ca2+ is provided by milk and dairy products, 16% by green vegetables and fruits, and 6–7% by drinking water including mineral water [82]. Milk provides large amounts of calcium and phosphorus and other components such as lactose and casein phosphopeptides that may increase calcium absorption and mineral retention. This must be emphasized because intestinal absorption does not completely reflect the bioavailability of calcium. The bioavailability of calcium has been defined as the fraction of dietary Ca2+ that is potentially absorbable by the intestine and can be used for physiological functions, mainly bone mineralization, or to limit bone loss [82]. In brief, the bioavailability of Ca2+ depends on absorbability, urinary excretion and fecal loss of endogenous Ca2+. The effect of several factors affecting the bioavailability of Ca2+ has been extensively examined in several reviews [82, 83, 84, 85].

The amount of dietary Ca2+ influences the process of intestinal absorption of the cation. Low Ca2+ diets enhance the efficiency of intestinal Ca2+ absorption [39]. This is an adaptation process performed as a compensation mechanism in order to cover the cation needs of the organism. When dietary Ca2+ is low, serum levels of 1,25(OH)2D3 are enhanced by stimulation of renal 1α- hydroxylase activity in chicks [9]. Consequently, intestinal CB28k and its mRNA are increased, in addition to the protein expression and activity of PMCA1b and the Na+/Ca2+ exchanger [10, 39]. Low Ca2+ diets also provoke alteration in lipid composition and increment in the fluidity of intestinal BLM [11]. It appears, then, that the Ca2+ exit through BLM from enterocytes of animals adapted to a low Ca2+ diet is greater than that of control animals because of the increment in PMCA1b and Na+/Ca2+ exchanger activities and changes in lipid composition and fluidity of BLM, which might alter the microdomains of cation transporters and, hence, increase their activities [86]. The gene expression of the epithelial Ca2+channels CaT1 and CaT2 has also been shown to increase by dietary Ca2+ deficiency either in young or adult animals [87]. In other words, the activities of all genes involved in the transcellular pathway (Ca2+ channels, CBs, PMCA1b and Na+/Ca2+ exchanger) are enhanced by the low Ca2+ diet, probably by activation of the vitamin D endocrine system.

Other Nutritional Factors

In general, carbohydrates increase intestinal Ca2+ absorption, but lactose contained mainly in dairy food seem to be the most efficient one [85]. However, studies done in lactose-tolerant healthy adults did not show an effect of lactose on intestinal Ca absorption by using a stable strontium test under controlled metabolic conditions [88]. Lately, the use of lactosucrose in humans and animals seems to be very important in order to increase intestinal Ca2+ absorption due to the fact that it promotes a decrease in intestinal pH increasing the solubility of Ca2+ salts [89, 90]. Data regarding protein intake and intestinal Ca2+ absorption indicate that dietary protein does not alter the intestinal Ca2+ absorption and, hence, intestinal calcium absorption does not explain hypercalciuria induced by high protein intake [91]. For many years, steatorrhea has been associated with decreased intestinal Ca2+ absorption [92]. However, the data related to the effects of dietary lipids on intestinal Ca2+ absorption are not clear [85]. Human intestinal Caco-2 cells were exposed to conjugated linoleic acid (CLA) and medium chain fatty acids to measure transepithelial and transcellular transport of 45Ca, fluorescein transport (a marker of paracellular Ca transport) and transepithelial electrical resistance (an indicator of permeability). Overall Ca transport and transepithelial electrical resistance in Caco-2 cells were unaffected by exposure to any of the fatty acids for 24 h or 22 days, whereas paracellular (but not total transepithelial and transcellular) Ca2+ transport across Caco-2 cells was significantly increased after 22 days [93]. Later, the same authors reported that both isomers of CLA increased overall transepithelial Ca2+ transport as well as transcellular and paracellular Ca2+ transport in monolayers of Caco-2 cells, an effect that could be related to changes in the zona occludens-1 (a tight junction protein) [94]. Recently, Murphy et al. [95] investigated the molecular mechanisms underlying CLA-induced stimulation of Ca transport using microarray data together with quantitative reverse transcriptase-PCR analysis. They found that zona occludens-1, occludin, and claudin-4 were all upregulated and claudin-1 downregulated by trans-10, cis-12 CLA, which might explain the increase in the paracellular route [95]. However, since they did not find alterations in the genes involved in the transcellular pathway, the mechanism/s involved in this route remain unknown.

The effect of probiotics on stimulation of intestinal Ca2+ absorption has been proposed to be produced by the increased production of short-chain fatty acids by bacteria. In a recent review, it was suggested that prebiotics are the most promising and also the best investigated substances with respect to bone health-promoting potential, as compared to probiotics and synbiotics [96].

Other components of the diet such as phytates, oxalates and tannins can form insoluble complexes with Ca2+, which reduce the cation absorption, this effect being very important when the diets are unbalanced, for example diets lacking dairy products and enriched in fibers [82].

Intestinal Ca2+ absorption varies according to the age and physiological conditions of individuals. In general, when the needs are high and/or dietary Ca2+ is low, intestinal Ca2+ absorption is found to be more efficient. Growth, gender, pregnancy and lactation and high physical activity increase the Ca2+ demands and, therefore, promote Ca2+ absorption from the intestine. Ca2+ absorption is high during pregnancy. This increment is evident in early to mid pregnancy and precedes the increased Ca2+ demand from the fetus for skeletal growth. This alteration in Ca2+ absorption during pregnancy may be due to an increase in serum calcitriol with little alteration in PTH and calcitonin concentrations [97]. Kent et al. [98], in contrast, demonstrated that the efficiency of intestinal Ca2+ absorption is increased in late pregnancy but not during lactation. Zhu et al. [99] found in rats that at 21 days of gestation both Ca2+ pump and CB mRNA levels increased 2- to 3-fold. They also demonstrated that the Ca2+ pump and CB mRNA remained elevated at 7 days of lactation. Intestinal Ca2+ absorption in pregnant adolescents has also been reported to be significantly higher in the third trimester of pregnancy than in the early postpartum period [100]. In colon biopsies from dairy goats and sheep, it was found that VDR immunohistochemistry revealed a lower staining in early lactation as compared to late lactation, which would mean that VDR seems to be involved in the metabolic changes related to intestinal Ca2+ absorption during the lactation period [101]. Yamagishi et al. [102] found in rats that vitamin D deficiency during pregnancy produces severe hypocalcemia due to reduced intestinal Ca2+ absorption and elevated fetal demand for the cation.

Braun et al. [103] recently presented data showing that Ca2+ retention in boys is higher than in girls at different Ca2+ intakes, and this difference is attributed to a higher intestinal Ca2+ absorption and lower urinary excretion in boys as compared to girls. To optimize Ca2+ intake it is crucial in adolescents to maximize calcium retention, acquire a good peak of bone mass and prevent osteoporosis later in life. A Spanish study in boys aged 11–14 years on their usual diets revealed that the adolescents absorbed 31% of dietary intake, retained 20% of the total intake, but dietary Ca2+ intake failed to meet the recommended values [104]. It has also been demonstrated in adolescents that polymorphisms of the Fok I site in the VDR gene are significantly associated with Ca2+ absorption and BMD; individuals carrying the genotype ff have deficit in whole Ca2+ accretion compared to those with the genotype FF [3].

Advancing age has been associated with lower intestinal Ca2+ absorption [105]. This decrease occurs, at least in part, because of a declination in the serum calcitriol levels, but in addition, a resistance to the actions of calcitriol in the intestine has been reported [22]. Although the mechanisms are poorly known, in women the lack of estrogen during menopause could partially explain this age-associated intestinal resistance to calcitriol. It has also been reported that duodenal TRPV6 expression is not vitamin D-dependent in postmenopausal women [22]. Recent data have shown that in mice, heterozygotes for the VDR gene KO, low levels of VDR produce resistance to intestinal Ca2+ absorption of 1,25(OH)2D3. This resistance appears to be generated by the low translation of CB9k that is mediated by binding of VDR to the ligand [2].

Table 1 summarizes the effects of hormones, factors and physiological conditions that participate in the regulation of uptake, transport and extrusion of Ca2+ in the intestine from different species.

Table 1

Hormones, factors and physiological conditions affecting intestinal Ca2+ absorption in different species

Hormones, factors and physiological conditions affecting intestinal Ca2+ absorption in different species
Hormones, factors and physiological conditions affecting intestinal Ca2+ absorption in different species

The intestine is the gate of Ca2+ entry to the entire body. Due to the enormous participation of the cation in different important physiological processes such as muscle contraction, neuronal activity, strength of the skeleton, etc., the mechanisms of intestinal Ca2+ absorption have been studied for many years. The transcellular pathway seems to be highly regulated mainly by calcitriol, which acts through activation of intestinal channels TRPV6 and TRPV5, CBs and PMCA1b and the Na+/Ca2+ exchanger. PTH, estrogen, GC, thyroid hormone and other hormones also regulate these proteins or their genes by mechanisms under investigation. Dietary Ca2+ and many nutritional factors have been studied in order to elucidate their role in cation absorption. Growth, pregnancy and lactation promote intestinal Ca2+ absorption, while aging and many pathological conditions occur with deterioration in the Ca2+ absorption. Although many findings have been achieved during the last decade on the regulation of intestinal Ca2+ absorption, there are many open questions that need further investigation, for instance: (1) is the Ca2+ pump the main molecule to extrude Ca2+ from the intestinal cell in humans? (2) how is the intestinal Na+/Ca2+ exchanger regulated by calcitriol and other hormones that stimulate intestinal Ca2+ absorption? (3) does PTH stimulate intestinal Ca2+ absorption or simply trigger rapid responses in enterocytes that finally do not promote the global process of Ca absorption? (4) what are the mechanisms by which Ca2+ diffuses between enterocytes? The responses to these and other basic questions on the regulation of intestinal Ca absorption could give some clues to improve cation absorption in the elderly and in some pathologies, and also to develop nutritional or medical strategies to stimulate the efficiency of intestinal Ca2+ absorption.

Additional Information

N.G.T. de T., G.P. and A.R.C. are Career Investigators of the National Council of Scientific Investigation (CONICET, Argentina). M.E.P.L. is a fellow from the Secretary of Science and Technology, National University of Córdoba, SECYT (UNC), Argentina.

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