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The Journal of Physiological Sciences (2019) 69:683–696 https://doi.org/10.1007/s12576-019-00688-3

REVIEW

Factors inhibiting intestinal absorption: hormones and luminal factors that prevent excessive calcium uptake

Kannikar Wongdee1,2 · Mayuree Rodrat2,3 · Jarinthorn Teerapornpuntakit2,4 · Nateetip Krishnamra2,3 · Narattaphol Charoenphandhu2,3,5,6

Received: 4 March 2019 / Accepted: 9 June 2019 / Published online: 20 June 2019 © The Physiological Society of Japan and Springer Japan KK, part of Springer Nature 2019

Abstract

Besides the two canonical calciotropic hormones, namely and 1,25-dihydroxyvitamin D [1,25(OH)2D3], there are several other endocrine and paracrine factors, such as prolactin, estrogen, and -like growth factor that have been known to directly stimulate intestinal calcium absorption. Generally, to maintain an optimal plasma calcium level, these positive regulators enhance calcium absorption, which is indirectly counterbalanced by a long-loop mechanism, i.e., through calcium-sensing receptor in the parathyroid chief cells. However, several lines of recent evidence have revealed the presence of calcium absorption inhibitors present in the intestinal lumen and extracellular fuid in close vicinity to , which could also directly compromise calcium absorption. For example, luminal iron, circulating fbroblast growth factor (FGF)-23, and stanniocalcin can decrease calcium absorption, thereby preventing excessive calcium uptake under certain conditions. Interestingly, the intestinal epithelial cells themselves could lower their rate of calcium uptake after exposure to high luminal calcium concentration, suggesting a presence of an ultra-short negative feedback loop independent of systemic hormones. The existence of neural regulation is also plausible but this requires more supporting evidence. In the present review, we elaborate on the physiological signifcance of these negative feedback regulators of calcium absorption, and provide evidence to show how our body can efciently restrict a food of calcium infux in order to maintain calcium .

Keywords Calcium absorption · Calcium-sensing receptor (CaSR) · Fibroblast growth factor (FGF)-23 · Iron transport · Parathyroid hormone (PTH) ·

Introduction

Besides being the major inorganic component in , cal- cium is an essential element that has roles in several func- * Narattaphol Charoenphandhu tions, e.g., neurotransmitter release, , [email protected] blood , and intracellular signal transduction. Ninety-nine percent of body calcium is stored in bone in 1 Faculty of Allied Health Sciences, Burapha University, the form of crystal ­[Ca (PO ) (OH) ], while Chonburi, Thailand 10 4 6 2 the remaining 1% is distributed in the plasma, interstitium, 2 Center of Calcium and Bone Research (COCAB), Faculty intracellular fuid, and within the cells in mitochondria and of Science, Mahidol University, Bangkok, Thailand . The intracellular calcium is main- 3 Department of , Faculty of Science, Mahidol tained at concentration as low as 0.1 µM, which is lower than University, Rama VI Road, Bangkok 10400, Thailand the extracellular calcium concentration (free ionized cal- 4 Department of Physiology, Faculty of Medical Science, cium of 1.1–1.3 mM) by ~ 1000-fold. An excess of calcium Naresuan University, Phitsanulok, Thailand in either the intracellular or extracellular fuid is extremely 5 Institute of Molecular Biosciences, Mahidol University, dangerous. Because free ionized calcium is toxic to the cell, Nakhon Pathom, Thailand a prolonged rise in the intracellular calcium can lead to cell 6 The Academy of Science, The Royal Society of Thailand, death by activating various enzymes, such as protein kinase Dusit, Bangkok, Thailand

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C, caspases, phospholipases, proteases, and endonucleases in the ingested foods, e.g., iron, phytate, oxalate, and as well as apoptotic process [59]. Therefore, the intestine, tannin (Fig. 1), can inhibit calcium absorption, the which is the only site for calcium entry into the body, must physiological significance of these substances is not have mechanisms to regulate calcium uptake. Besides, the fully understood. The present article thus focuses on intestinal epithelial cells themselves also need to tightly the regulatory roles of these intestine- and nutrient- control their intracellular calcium concentration to prevent derived factors and their feedback mechanisms in the superfuous calcium uptake, which may damage themselves suppression of intestinal calcium absorption. It is gen- as well as other cells in the body [57, 59, 106]. erally accepted that both stimulatory and inhibitory Since the intestine is the only route for calcium regulators of calcium absorption are humoral factors uptake, it is subjected to local and systemic regulation, with autocrine, paracrine, and endocrine functions, which helps protect against inadequate as well as exces- as depicted in Fig. 1. Apparently, the possible role of sive absorption of calcium. Both stimuli and inhibitors neural regulation may also exist and may be analogous of calcium absorption have been described, with the to the splanchnic nerve regulation of calcium uptake plasma calcium-PTH-vitamin D feedback loop as the across the gallbladder mucosa [73]. The overview of most prominent feedback regulation. Although local factors controlling intestinal calcium transport is sum- hormones, secretory factors, and some components marized in Table 1.

Fig. 1 Intrinsic (humoral and neural) and extrinsic (luminal) regulators of intestinal calcium absorption (please see text for details)

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Table 1 Summary of possible factors afecting calcium absorption across the intestinal Factors Transcellular Paracellular Net ­Ca2+ absorption References

Extrinsic/luminal Ca2+ (long-term low luminal Increase expression of TRPV5/6, N/A ↑ [4, 8, 10] 2+ ­Ca or low calcium diet) CaBP-D9k, NCX1, ­PMCA1b, Increase activity of ­PMCA1b and NCX1 Ca2+ (prolong exposure to high Possibly by increase FGF-23 N/A ↓ [84] luminal Ca2+) expression ­(Ca2+ > 30 mM) and inhibit transcellular transport by unknown mechanism Iron N/A N/A ↓ [58]

Glucose/galactose (SGLT1 Decrease ­Cav1.3 activity Increase solvent drag-induced ↑ [52, 91] substrates) paracellular calcium fow Amino acids N/A Increase NHE activity ↑ [96] Increase nutrient-induced paracel- lular calcium fow Fructose Decrease expression of TRPV6 and N/A ↓ [27, 28] CaBP-D9k Intrinsic Hormone

1,25(OH)2D3 Increase expression of TRPV5/6, Stimulate nongenomic signaling ↑ [32, 40] CaBP-D9k, NCX1, ­PMCA1b pathways involving PI3K, PKC, and MEK to enhance calcium transport Increase expression of claudin-2, 12 PTH Increase calcium uptake N/A ↑ [71] (Unknown mechanism)

FGF-23 Decrease 1,25(OH)2D3-enhanced Decrease 1,25(OH)2D3-enhanced ↓ [53, 54] expressions of TRPV5/6, CaBP- paracellular calcium transport D9k and calcium permeability Paracrine FGF-23 Increase CaSR activity N/A ↓ [84] Stanniocalcin-1 Decrease expression of TRPV5/6, N/A ↓ [107] CaBP-D9k No change in the expression of NCX1, ­PMCA1b Neural (ENS) VIP N/A N/A ↑ [73] (Indirect evidence)

CaBP-D9k -D9k, CaSR calcium-sensing receptor, Cav1.3 L-type voltage-gated calcium channel, FGF-23 fbroblast growth factor 23, ENS enteric nervous system, N/A not available, NCX1 calcium exchanger 1, TJ tight junction, VIP vasoactive intestinal peptide

Mechanisms of intestinal calcium absorption humans and rodents, the vitamin D-dependent transcellu- in mammals lar calcium transport is predominant in the proximal small intestine, particularly the , and is of importance In mammals, calcium is absorbed through the intestinal in low-calcium intake conditions [3, 7, 103]. A regular diet epithelial cells via two major pathways, i.e., transcellular without dairy products is generally considered as a low-nor- and paracellular pathways [24]. The relative contribution of mal calcium diet, which requires an active calcium transport transcellular and paracellular calcium absorption depends mechanism. on several factors including the amount of calcium intake, The uphill transcellular is composed of solubility and chyme alkalinity, bioavailability, and segment three steps, i.e., (1) apical vitamin D-dependent calcium transit time [52]. Although both calcium transport mecha- entry via the transient receptor potential cation channel, nisms are found along the entire length of the intestine in subfamily V, member 6 (TRPV6), and to a lesser extent

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TRPV5, (2) cytoplasmic calcium translocation (bound to luminal calcium > 5 mM), calcium prefers to difuse into calbindin-D9k), and (3) basolateral calcium extrusion via the body. On the other hand, an extremely low calcium con- 2+ + plasma membrane ­Ca -ATPase 1b ­(PMCA1b) and ­Na / centration in the lumen may aggravate calcium secretion, Ca2+-exchanger 1 (NCX1) [13, 24]. Regarding calcium which probably results in net calcium loss during claudin-2 entry into the enterocytes, besides TRPV5/6 channels, the overexpression. However, further experiment is required to apical voltage-dependent L-type calcium channel subtype confrm the latter hypothesis. 1.3 ­(Cav1.3) is also involved in calcium uptake, particularly in the presence of depolarizing nutrients in the lumen, such as glucose, galactose, and some amino acids [52, 68, 96]. Possible feedback loops for intestinal Once calcium enters the cells, it is bufered by the cyto- calcium absorption plasmic calcium-binding protein, calbindin-D9k [24, 86]. Other calcium-binding proteins such as may also To maintain calcium homeostasis, the amount of calcium contribute, albeit to a lesser extent, to the intracellular cal- absorbed by the intestine is fne-tuned to match the body cium translocation [24]. Finally, calcium is extruded across calcium requirement by several factors, including hor- the basolateral membrane through several transporters, e.g., mones and luminal nutrients [57]. Since calcium absorp- + + + 2+ PMCA­ 1b, NCX1 coupled to ­Na /K -ATPase, and ­Na /Ca / tion is relatively low under normal conditions (~ 25–35% K+-exchanger (NCKX), the latter of which extrudes one ­K+ of total calcium intake) as compared with other minerals and one ­Ca2+ with infux of four sodium ions to maintain (such as magnesium and ), most regulatory low intracellular calcium concentration [52, 57, 88]. factors are stimulators for enhancing calcium absorption. The second major route is the paracellular pathway, which However, little is known regarding how calcium absorption allows calcium to traverse the lateral intercellular (paracel- is regulated when faced with excessive calcium intake and lular) space. Calcium transport via this route can be both a potential risk of calcium toxicity. Normally, the level of cellular energy-dependent active or gradient-dependent pas- plasma calcium is considered as a component of the nega- sive transport. The paracellular active transport is generally tive feedback regulation to suppress parathyroid hormone mediated by solvent drag, which is induced by sodium efux (PTH) release and production of 1,25-dihydroxycholecal- + + by ­Na /K -ATPase that creates hyperosmotic environment ciferol [1,25(OH)2D3], thereby slowing down the intestinal in the paracellular space. This subsequently induces water calcium absorption as discussed below. difusion in a lumen-to-plasma direction, dragging along with it small permeable molecules, including calcium [6, Roles of hormones 24, 52]. Regarding the paracellular passive calcium transport The classical hormones involved in the positive regu- driven by the concentration gradient of calcium between the lation of intestinal calcium absorption are PTH and lumen and plasma, it occurs more readily in the condition of 1,25(OH)2D3, the latter of which is synthesized in the high-calcium intake—generally considered signifcant when by the renal proximal tubule and which directly luminal calcium > 5 mM—and can occur throughout the enhances the intestinal calcium absorption through active entire length of the intestine [24, 30]. Paracellular transport transcellular and passive paracellular pathways in both is also determined notably by the size- and charge-selective genomic and non-genomic fashion (for review, please properties of the tight junction, which creates specifc bar- see Ref. [57]). For the active transcellular pathway, riers for ions, such as calcium, sodium, and chloride [112]. 1,25(OH)2D3 exerts genomic actions by binding to vita- Claudins is the major family of the tight junction-associated min D receptor (VDR), thus increasing the expression proteins responsible for the paracellular size- and charge- of calcium transport machinery, i.e., TRPV6, calbindin- selective properties. Claudin-2, -12, and -15 in particular D9k, ­PMCA1b, and NCX1 [11, 20, 24, 104]. In addition, have been shown to have signifcant roles in the regulation 1,25(OH)2D3 probably exerts a non-genomic action of paracellular calcium transport across the intestinal epi- to rapidly enhance calcium transport by binding to the thelia [14, 24, 32]. Claudin-2 has negatively charged amino plasma membrane receptor 1,25(OH)2D3-MARRS (mem- acids (e.g., aspartate) in the extracellular domains, which brane-associated, rapid response steroid-binding) pro- protrude into the paracellular space to form a tight junction tein [72]. In brief, the non-genomic action occurs when pore. With these negative charges, claudin-2 is permeable to 1,25(OH)2D3 binds to the membrane-bound 1,25(OH)2D3- cations [21, 110]. In the presence of upregulated claudin-2 MARRS instead of the intracellular/nuclear VDR, which expression, the luminal calcium is expected to easily difuse is a transcription factor [29]. This membrane-bound across the paracellular space in both lumen-to-plasma and receptor can activate certain second messengers, includ- plasma-to-lumen directions. When the luminal concentra- ing phospholipase A2 (PLA2) and protein kinase C tion is greater than the plasma ionized calcium level (e.g., (PKC) [26, 87]. Regarding the paracellular absorption,

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1,25(OH)2D3 enhances calcium transport through both Roles of calcium‑sensing receptor (CaSR) passive diffusion and solvent drag mechanisms, in part by modifying the charge- and size-selective properties Parathyroid chief cells, renal tubular cells, and of the tight junction proteins, particularly claudin-2 and are known to express CaSR for sensing pericellular calcium. -12 [32]. Normally, CaSR also senses other positively charged ions PTH is widely known as a hypercalcemic and (e.g., ­Mg2+, ­Cd2+, ­Ba2+, ­La3+ and ­Gd3+), cationic molecules hypophosphatemic hormone upstream to 1,25(OH)2D3. It (e.g., γ-glutathione), and amino acids and polyamines (e.g., elevates the plasma calcium levels by enhancing osteo- tryptophan, l-phenylalanine, spermidine, and spermine) [12, clastic bone resorption, renal calcium reabsorption, and 22]. Thus, an increase in plasma calcium level is detect- increasing intestinal calcium uptake [37]. However, the able by parathyroid chief cells, resulting in an inhibition of role of PTH on intestinal calcium absorption is normally PTH release and decrease in calcium absorption (Fig. 2a). indirect through renal 1,25(OH)2D3 production. Specif- However, up until now, the role of CaSR in the intestinal cally, PTH stimulates the transcription of the CYP27B1 epithelial cells has been elusive, and whether it can directly gene for renal enzyme 1α-hydroxylase, and suppresses modulate intestinal calcium absorption independent of PTH CYP24A1 for renal 24-hydroxylase, an enzyme respon- is largely unknown. Indeed, CaSR may potentially play a sible for 1,25(OH)2D3 degradation [111], thus elevating role in local regulation of intestinal calcium absorption the plasma level of 1,25(OH)2D3. For the direct action of since it is abundantly expressed in both apical and baso- PTH on the intestinal calcium absorption, it was reported lateral membranes of the enterocytes [17]. However, most that N-terminal fragment 1–34 of PTH could stimulate studies on the intestinal CaSR have been performed in the calcium transport in perfused duodenal loops from nor- large intestine rather than the small intestine where calcium mal chicks transcaltachia (rapid, non-genomic)—a rapid absorption is most active [5, 18, 41]. Direct activation of hormonal stimulation of intestinal calcium absorption [71, this receptor in the apical membrane can increase calcium 75]. Moreover, the presence of PTH receptor 1 (PTH1R) in absorption in the large intestine [18, 50], while reducing the basolateral membrane of rat intestinal epithelial cells calcium uptake in the small intestinal-like Caco-2 monolayer suggests possible direct action of PTH in the intestine. (Fig. 2b). Rodrat et al. have reported that CaSR probably However, this study did not demonstrate the regulation of sensed high apical calcium which in turn increased FGF-23 PTH on intestinal calcium absorption [36]. Indeed, direct expression to suppress calcium transport [84]. The roles of exposure to PTH not only increases calcium absorption intestinal CaSR were also studied in Casr intestinal-specifc but also promotes transport of other ions, e.g., potassium, knockout mice. Although Casr-defcient mice manifested an chloride, and bicarbonate, across the intestinal epithelium. impaired intestinal integrity, altered composition of the gut There was evidence that PTH regulation of bicarbonate microbiota and infammation [19, 77], the function related secretion is not an adaptive mechanism but is more like to the regulation of calcium transport was not determined. transcaltachia (rapid, non-genomic). These studies used Similarly, the renal tubular epithelia also use local CaSR Caco-2 cells, which may refect a colonic phenotype unless to modulate calcium reabsorption. Activation of CaSR on the results are confrmed in small intestine [16, 61]. Up till the luminal side of renal proximal tubular cells is capable of now, the physiological signifcance of the PTH-regulated stimulating ­Na+/H+-exchanger 3 (NHE3), thereby enhanc- ion transport in the gut is not clearly known. ing the paracellular calcium transport via a solvent drag- Another hormone that was recently shown to have a mediated mechanism (Fig. 2c) [101]. On the other hand, the calcium-regulating function is the bone-derived fbroblast basolateral CaSR plays a role in the inhibition of the para- growth factor (FGF)-23 [53, 54, 79]. FGF-23 was gener- cellular calcium reabsorption in the thick ascending limb of ally recognized as a phosphaturic hormone produced and Henle’s loop independent of PTH action [98]. secreted from osteocytes and osteoblasts. Its secretion is enhanced by high serum , 1,25(OH)2D3, and perhaps calcium [64, 79, 100]. The systemic actions of Stimulation of intestinal calcium absorption FGF-23 are to increase urinary phosphate excretion and by luminal nutrients suppress 1,25(OH)2D3 production. FGF-23 suppresses CYP27B1 gene expression and stimulates CYP24A1 gene It has also been reported that a number of nutrients, includ- expression, leading to a decreased circulating 1,25(OH)2D3 ing amino acids, oligosaccharides, disaccharides, and mono- [78, 89]. Furthermore, FGF-23 has recently been shown to saccharides (glucose and galactose), can stimulate calcium act directly on the intestine to abolish the 1,25(OH)2D3- absorption [91, 92, 96, 109], however, it remains largely stimulated intestinal calcium absorption [53, 54]. The cel- unknown how this process is counterbalanced. Generally, lular mechanism of FGF-23 as a local inhibitor of calcium there are at least three possible mechanisms to explain how absorption is elaborated in “intrinsic inhibitory factors”. the enterocytes enhance calcium transport in response to

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Fig. 2 Responses of calcium- A sensing receptor (CaSR) to extracellular calcium in a para- chief cells, b intestinal epithelial cells, and c renal tubular epithelial cells (please see text for details)

B

C

luminal nutrients, i.e., nutrient-induced paracellular calcium Therefore, this calcium transport is referred to as the sol- fow, ­Cav1.3 activation, and NHE3 activation. vent drag-induced calcium absorption [52, 91]. In addi- tion, the fermented dairy products and incomplete digested Solvent drag and nutrient‑induced paracellular carbohydrate, e.g., short-chain fatty acid, oligosaccharides, calcium fow and polysaccharides, can also enhance calcium absorption in the small and large intestine in rats by increasing tight Glucose and/or galactose enter the intestinal cells via api- junction permeability to calcium [80, 108]. Although the cal sodium-dependent glucose transporter-1 (SGLT1), solvent drag was not directly determined in most studies, after which sodium is pumped out into the paracellular the solvent drag-induced paracellular calcium transport space by ­Na+/K+-ATPase especially those at the lateral should contribute to the process since the uptake of these membrane. As explained earlier, the increase in the para- small organic molecules is often sodium-dependent. How- cellular osmolality together with relative permeability ever, the direct efect of microbiota-derived organic mol- of tight junction to water drives paracellular water fow ecules on the transcellular calcium transporters cannot be from luminal to the blood side, bringing calcium with it. ruled out and requires future investigation.

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Cav1.3 activation Counterregulatory and inhibitory factors for intestinal calcium absorption Under normal conditions, the resting membrane potential of the intestinal epithelial cells is approximately − 47 mV. Although the body has a calcium-lowering hormone, calci- Infux of sodium together with glucose can depolarize the tonin, and the kidney to prevent hypercalcemia through sup- apical membrane, thereby activating ­Cav1.3 for transcellular pression of bone resorption and enhancement of urinary cal- calcium uptake particularly when the transmembrane poten- cium excretion, respectively. These mechanisms take place tial reaches the ­Cav1.3 threshold of approximately − 20 mV only after calcium has already been taken up into the body [52]. Lactose—the major disaccharide in milk—also stimu- and raise its plasma concentration. It is tempting to postulate lates intestinal calcium absorption [1], but the mechanism that the intestine as a front line to encounter calcium has a remains unclear. It is possible that the efect of lactose is monitoring mechanism to prevent fooding of calcium into due to the elevated concentrations of glucose and galactose the enterocytes. Several lines of evidence have suggested following lactose digestion by lactase in the intestinal lumen. the presence of counterregulatory or inhibitory factors for Both glucose and galactose are substrates of SGLT1, which limiting calcium absorption, e.g., hormones, luminal ions, can induce sodium entry, thereby depolarizing the apical or byproduct of nutrient digestion [9, 60]. In this review, plasma membrane and activating apical calcium channel, we subdivide these counterregulatory factors into two major ­Cav1.3, for calcium to difuse down its concentration gradi- groups, i.e., factors in the lumen (extrinsic) and those in the ent into the cell [52]. plasma (intrinsic), as shown in Fig. 1.

NHE3 activation Extrinsic inhibitory factors

Although some amino acids are transported by sodium- The extrinsic or luminal factors are defned as luminal con- dependent amino acid transporter (e.g., B­ 0AT1) similar to tent-derived factors that may be either nutrient or non-nutri- monosaccharide absorption by SGLT1 [47], oligopeptides ent substances with inhibitory efect on calcium absorption, are taken up into the enterocytes by H­ +-coupled peptide e.g., high luminal calcium concentration, iron, sugars, and transporter (PepT1) [102]. It is possible that ­H+ is extruded byproducts of nutrient digestion (e.g., phytate, oxalate, and from the cell back into the lumen via NHE3, allowing only tannin), as follows. sodium to enter the cell down its concentration gradient and to exit the cell by the basolateral ­Na+/K+-ATPase into the Prolonged exposure to high luminal calcium paracellular space, thus generating solvent drag along the paracellular space. Previously, calcium has been known to exert indirect nega- The exact mechanism by which NHE3 modulates cal- tive feedback on calcium absorption. Briefy, CaSR has been cium absorption is largely unknown, but the NHE3 inhibi- reported in the apical and basolateral plasma membrane [17, tor, tenapanor, was found to completely abolish intestinal 18]. It is postulated that CaSR exerts its signaling through calcium transport [96]. Interestingly, NHE3 not only acts as activation of phosphodiesterases (PDE) which in turn a carrier for sodium uptake but also plays an important role enhances cyclic nucleotide degradation [35, 94]. Although in the regulation of intestinal pH. Apical NHE3 transports information on specifc PDE in the intestinal epithelial cells ­H+ into the lumen in exchange with Na­ +, thus preventing is scant, PDE might be an important mediator in the nega- intracellular acidifcation, and at the same time making the tive regulatory process because of the existence of PDE1–5 lumen more acid, which is known as acid microclimate [97]. isoforms in human colonic cancer cells [76, 94]. A slight luminal acidifcation promotes the generation of Interestingly, Rodrat et al. [84] recently demonstrated ionized calcium, which might subsequently increase calcium that transepithelial calcium transport across Caco-2 mon- absorption [31]. NHE3 knockout animals were found to have olayer was diminished after direct exposure to high-dose impaired absorption of calcium, sodium, and water, as well 1,25(OH)2D3 (10 nM) or high concentration of apical ion- as acid/base imbalance [74, 81]. This fnding could be par- ized calcium (30 mM CaCl­ 2). Since CaSR inhibitors (calhex tially explained by the fact that NHE3 normally transports 231 and NPS2143) could prevent the high luminal calcium- ­H+ to the lumen while uptaking Na­ + into the cytoplasm. A induced suppression of calcium transport, it is likely that reduction in the transcellular calcium absorption in NHE3 apical CaSR acts as a component of an anticipatory or feed- null mice was mainly due to a decrease in calcium fux in back mechanism to prevent excessive calcium infux into mucosal-to-serosal direction, consistent with the downregu- the cell, while CaSR in the basolateral membrane probably lation of TRPV6 expression [81]. helps detect the amount of absorbed calcium ions that accu- mulate in the immediate vicinity of the basal membrane or

1 3 690 The Journal of Physiological Sciences (2019) 69:683–696 paracellular space. In other words, the intestinal epithelial Nigerian children fed phytase-treated or untreated meal cells are able to closely monitor ionized calcium levels at showed no diference in their fractional calcium absorption both entry and exit points by using CaSR which in turn acti- [95]. Nevertheless, a correlation analysis on calcium and vates secondary negative regulators, e.g., FGF-23, to slow inhibitory factors, including oxalate, tannin, phytate, and down calcium absorption, thus preventing excessive calcium dietary fber revealed that oxalate had the greatest negative uptake into the body [53, 54, 84]. Detail of the inhibitory efect on calcium bioavailability [2]. efect of FGF23 is further described in the following section. Besides nutrient and non-nutrient substances, other lumi- nal compounds can inhibit calcium absorption, for instance, Iron lithocholic acid (LCA), deoxycholic acid or its salt, sodium deoxycholate (NaDOC). LCA and NaDOC are secondary It has long been known that high oral calcium intake inter- bile acids that are formed by enzymes of the intestinal fora. feres with heme and nonheme iron absorption [63, 76], A high concentration of NaDOC not only damages liver but whether high iron intake causes a reduction in calcium tissue and promotes colon cancer [92], but also impairs absorption is still uncertain. A recent investigation in iron intestinal calcium absorption [46, 66, 83]. Determination hyperabsorptive β-thalassemic mice showed that duodenal of calcium absorption in chick duodenum revealed that calcium absorption had an inverse correlation with tran- NaDOC suppressed calcium absorption by downregulating sepithelial iron transport [58]. Interestingly, after injection transcellular calcium transport machinery, i.e., PMCA­ 1b, of —a liver-derived inhibitory factor of intestinal calbindin-D28k, and NCX1. Such negative efects might be iron absorption [38]—the thalassemia-induced impair- a consequence of oxidative stress as suggested by concurrent ment of calcium absorption was alleviated [58]. However, increases reactive oxygen species (ROS) production, glu- the exact cellular and molecular mechanisms of iron-asso- tathione reduction, and mitochondrial swelling. Indeed, ROS ciated impairment of calcium absorption require further has been shown to inhibit calcium absorption [83]. More investigation. studies are required to show if NaDOC-induced impaired intestinal calcium absorption would be of clinical concern Sugars on bone health.

Although some monosaccharides, particularly SGLT1 sub- Intrinsic inhibitory factors strates (e.g., glucose and galactose) stimulate intestinal cal- cium absorption, a ketonic monosaccharide fructose found Intestinal calcium absorption can be afected by humoral in fruits, vegetables, and grains can produce an inhibitory agents acting from the serosal side. Although is efect [28, 85]. Both in vitro and in vivo studies revealed known as a hypocalcemic hormone, it does not have any that fructose diminished intestinal calcium absorption, in direct action on the intestinal epithelial cells. It induces part by reducing circulating 1,25(OH)2D3 levels, TRPV6 mainly by inhibiting -mediated and calbindin-D9K expression, and thus transcellular calcium bone resorption and enhancing renal calcium excretion [57]. transport [28]. Furthermore, high fructose intake was found So the importance of calcitonin in the day-to-day calcium to diminish calcium absorption in growing and lactating rats homeostasis is negligible. Recently, bone-derived FGF-23 through disrupting 1,25(OH)2D3 , i.e., enhanc- was proposed as a novel inhibitory regulator of intestinal ing 1,25(OH)2D3 catabolism and impairing 1,25(OH)2D3 calcium absorption [53, 54, 105]. synthesis [27, 28]. FGF‑23 Natural substances and byproducts of nutrient digestion In general, calcium in the plasma is the major factor mod- A number of naturally occurring substances in many green erate the intestinal calcium absorption through the long leafy vegetables (e.g., spinach, beet greens, and tea), for loop negative feedback by inhibiting PTH production and example, oxalate, phytate, and tannin, can block the intesti- release. Specifcally, a slight increase in the plasma-free ion- nal calcium absorption by binding to calcium, thereby ren- ized calcium leads to activation of CaSR in the parathyroid dering calcium insoluble and unavailable for absorption [2, chief cells [82], thereby reducing PTH release. A reduc- 69]. However, their physiological signifcance and the fnal tion in serum PTH results in decreases in the circulating efect on calcium absorption remain controversial. For exam- 1,25(OH)2D3 level and fnally the intestinal calcium absorp- ple, calcium bioavailability of green leafy vegetables such tion. However, some factors can also reduce the plasma cal- as centella, quinoa, and roselle, all of which contain high cium by acting at the absorption site. amounts of inhibitory factors, was not changed by cook- As mentioned earlier, FGF-23 is primarily known as a ing process or phytase digestion [2, 69]. On the other hand, bone-derived phosphaturic hormone that mainly enhances

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renal phosphate excretion and 1,25(OH)2D3 catabolism [39, remains elusive, several signaling proteins, such as MAPK/ 51]. Besides being produced by bone cells, it is also abun- ERK, p38 MAPK, and PKC might be involved in the process dantly expressed in other cells, such as kidney, brain, lung, [53, 54]. liver, spleen, and intestinal enterocytes [53, 56]. Normally, FGF-23 production is not only stimulated by an increase in serum phosphate stimulates the secretion of 1,25(OH)2D3, it is also enhanced by other calciotropic hor- PTH and FGF-23, both of which enhance urinary phosphate mones, such as prolactin [105]. In mammalian, prolactin is excretion to prevent undesirable clinical problems due to known as a milk-producing hormone that acts as a major hyperphosphatemic spikes, such as ectopic calcifcation [43, calcium-regulating hormone during pregnancy and lactation, 49]. FGF-23 enhances phosphate excretion directly through the reproductive periods of high calcium demand [15]. Since inactivation of sodium/phosphate cotransporter (NaPi)-2a prolactin markedly stimulates the transcellular and solvent and -2c in the proximal renal tubules and indirectly by sup- drag-induced paracellular calcium absorption across the pressing 1,25(OH)2D3 synthesis and promoting 1,25(OH)2D3 intestinal epithelium [48, 91], the local production of FGF- conversion to inactive 24,25(OH)2D3, thereby reducing the 23 may be a counterregulatory mechanism to restrict exces- circulating 1,25(OH)2D3 levels and also intestinal phosphate sive calcium absorption during these reproductive periods. [51, 56, 90]. These complete the negative feedback loop for phosphorus homeostasis. However, an experiment in VDR knockout mice sug- Stanniocalcin gested that elevation of plasma calcium was a potent stimu- lator of FGF-23 production in a VDR-independent manner Previously recognized as a hypocalcemic hormone from the [90]. Later evidence supported the notion that FGF-23 not corpuscles of Stannius in osteichthyan fsh, stanniocalcin-1 only controls phosphorus metabolism but also acts as a cal- was also identifed in the kidney of several mammal species, cium-regulating hormone that directly controls the intestinal including rodent, cow, and human [44, 45, 99]. Regulation calcium absorption through both systemic and local (parac- of stanniocalcin production and release in mammals remain rine) mechanisms. The systemic efect was demonstrated by elusive, but 1,25(OH)2D3 may be a part of its regulatory complete abolishment of 1,25(OH)2D3-enhanced duodenal loop [44], similar to the negative feedback loop of FGF- calcium transport by intravenous FGF-23 injection [53]. Fur- 23. In opossum kidney proximal tubular cells, 1,25(OH)2D3 thermore, the fnding that FGF-23 in the intestine, ex vivo exposure was found to enhance stanniocalcin expression studies in murine duodenum demonstrated that FGF-23 in a dose-dependent manner [42, 44]. Once released from directly diminished the 1,25(OH)2D3-enhanced transcellular the kidney, the circulating stanniocalcin is thought to acti- and paracellular calcium absorption in ex vivo murine duo- vate its receptor on the basolateral membrane, but not the denum evinced that FGF-23 could exert direct action on the apical membrane, of enterocytes, to enhance the intestinal intestine [53, 54]. Moreover, other studies reported that FGF phosphate absorption, while suppressing calcium absorp- receptors (FGFRs) express in both small and large intestinal tion [45, 65]. In the gut, stanniocalcin has been reported to cells [70, 93, 105]. These fndings confrmed that FGF-23 express in stomach, small intestine, and colon of neonatal may have direct actions on the intestinal cells. Although and mature rats [55]. Functional study by Madsen and col- there were a number of reports in Fgfr1−/−, Fgfr3−/−, and leagues reported the negative efect of stanniocalcin-1 on net Fgfr4−/− mice [33, 34], the intestinal calcium fux in FGFRs calcium absorption across the swine duodenum, consistent knockout animals has never been investigated. with its hypocalcemic action observed in fsh [65]. Interestingly, FGF-23 not only elicits action from the Furthermore, stanniocalcin-1 not only functions as an basolateral side but also exerts a negative feedback regu- endocrine factor but is also produced locally in the intestine lation on calcium transport across the Caco-2 monolayer to control calcium absorption. Xiang et al. [107] demon- from the apical side [84], consistent with the presence of strated in intestinal epithelium-like Caco-2 cells that over- FGF receptors in both apical and basolateral membranes of expression of stanniocalcin-1 could downregulate TRPV5 the duodenal enterocytes [53]. The expression of FGF-23 and TRPV6 protein expression, suggesting that stannioc- protein in the enterocytes is upregulated by 1,25(OH)2D3 alcin-1—as a paracrine/autocrine factor—might directly as well as high apical calcium in a concentration-dependent and locally fine-tune calcium flux across the intestinal manner [84]. As mentioned earlier, CaSR on both apical epithelium. Exposure to recombinant stanniocalcin-1 also and basolateral membrane of the enterocytes have a role directly suppressed TRPV5 and TRPV6 expression in stan- in the monitoring of calcium transport across the entero- niocalcin-1-knockdown Caco-2 cell without having an efect cytes. It was interesting to note that activation of CaSR led on PMCA­ 1b, NCX1, or VDR expression [107]. Although to FGF-23 production and suppression of calcium transport. stanniocalcin-2 with ~ 80% homology to stanniocalcin-1 Although the exact molecular mechanism and signaling has been identifed in mammals, it is unclear whether this pathway by which FGF-23 reduces the calcium transport peptide can locally modulate intestinal calcium absorption.

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Neural regulation of calcium transport responses, including inhibition of calcium absorption [23, 62]. Furthermore, there are certain molecules such Enterocytes are innervated by neurons from myenteric as FGF-23 that is produced by the enterocytes and nega- and submucosal plexuses in the enteric nervous system tively control calcium absorption in a paracrine/autocrine (ENS), which are in turn controlled by the autonomic neu- manner. Specifcally, bone-derived FGF-23 is probably an rons from both sympathetic and parasympathetic systems important part of the negative feedback loop, as depicted [67]. The ENS secretomotor neurons release a number of in Fig. 1, to help prevent excess calcium input or calcium neurotransmitters [67], such as serotonin, galanin, neuro- overload. Nevertheless, our knowledge on the negative peptide Y, , and vasoactive intestinal pep- regulators and their actions in the maintenance of calcium tide (VIP), the last of which was found to modulate cal- homeostasis is far from adequate, especially at organ level. cium absorption. However, there were few investigations For instance, the cellular and molecular mechanism(s) for regarding possible neural control on calcium absorption. local and systemic FGF-23 actions in the feedback regula- An in vitro study in Caco-2 and HT29.19A monolayers tion of calcium absorption are not completely understood, reported that transcellular calcium uptake was increased neither its contribution to body calcium homeostasis. Nev- by carbachol (a cholinomimetic drug) and VIP, whereas ertheless, most investigations are from the large intestine, paracellular calcium transport was decreased by VIP [6]. therefore, more investigations are required for the small In vivo study in rats supported the possibility of this neural intestine in order to confrm its physiological signifcance. control of calcium absorption since blockage of neural Moreover, most reports were from animal study, therefore transmission by a potent voltage-dependent ­Na+ channel its role in human is worth exploring. inhibitor, tetrodotoxin (TTX), diminished the leucine- Besides the humoral factors, luminal factors, particularly induced transcellular calcium transport (Thammayon, and iron and negatively charged molecules, can also hinder calcium Charoenphandhu, unpublished observation). Indeed, the absorption. For example, when iron absorption is upregulated, sympathetic and VIP-ergic neurons may be essential for calcium absorption is suppressed presumably as result of iron- calcium and anion transport in other organs, e.g., the feline induced oxidative stress and inhibition of vesicular calcium gallbladder mucosa. It was evident that noradrenergic transport [25, 58]. Meanwhile, negatively charged molecules, stimulation enhanced net absorption of calcium, bicarbo- e.g., phytate and oxalate, are able to physically trap calcium in nate, and water, whereas VIP induced an opposite response the lumen, thus reducing calcium uptake. Since it is possible to [73]. Therefore, it is possible that neurons could regulate alter the luminal content in the intestine by dietary manipula- intestinal calcium absorption. However, more investigation tion, better understanding of how luminal factors and nutrients is required to demonstrate how ENS controls the intestinal fne-tune or interfere with calcium absorption would provide calcium transport as well as the fnal outcome(s) when a strong foundation for dietary recommendation and further multiple types of neurotransmitters are simultaneously development of safe and efective calcium-fortifed products released from the ENS neurons. for calcium-defcient osteoporotic patients and those with high calcium demand, such as pregnant and lactating mothers.

Perspective and concluding remarks Funding This work was supported by grants from Mahidol University (to NC), the Thailand Research Fund (TRF) through the TRF Senior Research Scholar Grant (RTA6080007 to NC), the Faculty of Science, We have elaborated herein that to maintain appropriate Mahidol University (to NC), TRF International Research Network calcium balance besides being stimulated by the well Program (IRN60W0001 to KW and NC), Research Grant for New established PTH-1,25(OH) D hormonal axis, calcium Scholar from TRF and Ofce of the Higher Education Commission 2 3 (MRG6280198 to JT), and TRF through the Royal Golden Jubilee transport across the intestinal epithelium can be restricted Ph.D. Program (PHD/0105/2557 to MR). by a number of mechanisms. At the molecular level, when calcium concentration reaches a certain threshold level, Compliance with ethical standards binding of calcium ions to calcium-transporting proteins, channels, or tight junction proteins can inactivate these Conflict of interest The authors declare that they have no conficts of transporters and diminish transcellular and paracellular interest. calcium transport [23, 52, 62]. Enterocytes also express Ethical approval This article does not contain any studies with human CaSR, which detects free-ionized calcium on both luminal participants or animals performed by any of the authors. and pericellular vicinity, thereby initiating various cellular

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