Intestinal amino acid transporters are regulated by changes in levels of dietary protein or free amino acid mixtures (63,64), following the principles outlined by Ferraris and Diamond (58). Transport systems that take up solely nonessential amino acids typically are regulated monotonically by dietary levels of their substrates, and increase in activity when dietary protein levels increase. Regulation of systems that transport essential or relatively toxic amino acids is more complex; amino acids can induce their own transporters but also modulate the other transporters (65). A high-protein or a protein-deficient diet can induce a modest increase in uptake of essential amino acids (64). A recent study demonstrated that amino acid absorption at 1 intestinal site can be regulated by the intraluminal concentration of that amino acid at a more proximal or more distal intestinal site, through neural mechanisms (66). Amino acid uptake may also be indirectly modulated by PEPT1 activity. Because many amino acid transport systems function as exchangers, the entry of amino acids in the form of peptides through PEPT1 may be important for the net movement of amino acids (67), and this exchange pathway may allow absorption of certain amino acids that modulate activity of transporters for which they are not substrates.
The human small intestine seems capable of amino acid transport early during ontogenetic development. Changes in electrical activity (transepithelial potential difference) associated with alanine transport have been reported in the intestine of 14- to 16-week-old fetuses (68). Transport typical of systems Bo, X2−AG, bo,+, y+L, and IMINO was detected in intestinal brush border membrane vesicles of 17- to 20-week-old fetuses (69,70). Transport rates decreased along the proximodistal gradient of the fetal intestine, unlike those of adults that were greatest in the ileum (69). In rats, amino acid transport characteristic of systems X−AG and A are described in E17 embryos; intestinal mRNA transcripts for system A appear by E14, a full week before parturition (71,72). In piglets, transport of leucine initially detected in 7-week-old fetuses increased gradually in the last 2 weeks of gestation, along with the appearance of the proximodistal gradient of transport typical of adults (73).
Amino acid uptake normalized to intestinal weight tends to decrease with postnatal age. In piglets, a sharp decrease in uptake rates of various amino acids occurs in the first 24 hours after birth. Uptake rates then return to birth values at day 7 of life and decline further until weaning (73,74). Nevertheless, the total capacity of the piglet intestine to absorb amino acids increased with age due to increased length and mass of the intestine (73). In rats and mice, age-related differences are also observed with a decrease in transport system expression and/or specific activity from birth or 1 or 2 days after birth until weaning (72,75–81). Similarly, due to the massive growth of the intestine during this suckling period, total uptake capacity increases with age (79). Expression of apical amino acid transport systems increases with age in neonatal chickens, whereas that of basolateral transporters tends to decrease perinatally (82). This difference in evolution of amino acid transporters between the apical and basolateral sides of the enterocyte probably reflects the switch from parenteral to enteral nutrition that occurs at birth in altricial species.
In summary, expression of intestinal peptide and amino acid transport systems during the perinatal period seems designed to ensure maximum protein absorption. Before birth, the intestine seems to prepare for this task by increasing peptide and amino acid transport capacity. After birth until weaning, the decline in most of the peptides and amino acid transport capacity (when expressed per kilogram of body weight) probably reflects the decrease in protein requirements (Fig. 1) (83).
Various minerals are present in breast milk and are added to infant formula. In this section we review the absorption of the 3 major minerals, Ca2+, Pi, and Mg2+, which make up 98% of the body's mineral content and are essential for tissue and bone formation. We also review the absorption of 2 major trace minerals, iron and zinc. All of these minerals are absorbed both actively and passively, and, in this review, we focus on the active transport and the transporters involved. The function, recommended AI, and diseases associated with excess or deficient intake of minerals are summarized in Table 4 (84).
Phosphorus is found as inorganic phosphate (Pi) in the body and is involved in the maintenance of pH, storage and transfer of energy, synthesis of nucleotides, and growth. It is found mostly in bones and teeth.
Iron (Fe) is a component of hemoglobin and numerous enzymes. It is added in infant formulas as ferrous (Fe2+) sulfate. The transport of dietary Fe2+ from the intestinal lumen across the epithelial apical membrane is by the divalent metal transporter 1 (DMT1 [also known as DCT1]). In the cytosol, dietary iron is bound to iron-binding proteins and exits the cell via the basolateral transporter called ferroportin (FPN1, Slc40a1, 2q32) (116,117). FPN1 is thought to associate with hephaestin, a multicopper ferroxidase protein required for the export of iron across the basolateral membrane. Mice without a functional hephaestin absorb iron normally but are unable to export it out of the intestinal cells so that the iron trapped in the cytosol is lost during intestinal cell turnover (118).
Regulation of rates of iron absorption is complicated. Hepcidin is a peptide hormone whose secretion by the liver varies with iron deficiency or overload. Under conditions of overload, increased hepcidin secretion into the blood binds to ferroportin causing it to internalize and degrade, thus preventing export of iron out of the cell (121). This internalization and degradation of the ferroportin involves activation of Janus kinase 2 (Jak 2) (122). Hepcidin levels are low in patients with hemochromatosis, an iron overload disorder (123). The important ability to regulate iron absorption depends on the developmental stage. Human infants cannot regulate iron absorption at 6 months of age, but older infants at 9 months of age can significantly increase iron absorption when dietary iron intake is low (124). Likewise, neonatal rat pups are unable to downregulate DMT1 and FPN1 expression in response to iron supplementation until the time of weaning (119). FPN1 expression increases in iron-deficient states (116).
Water-soluble vitamins are essential for development and must be provided in the neonatal diet, with the possible exception of niacin, a vitamin, which can be synthesized endogenously from tryptophan. The amounts of vitamins in infant formulas based on bovine milk normally meet the newborn's needs. In contrast, the concentration of water-soluble vitamins in breast milk is highly dependent on maternal status and dietary intake. Generally, after birth, the blood concentration of most of these vitamins is relatively greater in the neonate compared with that of the mother's (133). Subsequently, inadequate intake by the neonate of these essential micronutrients due to inadequate dietary sources or, more important, the inability of the neonatal gut to absorb these compounds will lead to deficiency states. The recommended daily intake (RDI) of these micronutrients increases proportionately as the neonate grows and matures. Hence, the intestine is critical in maintaining and regulating their homeostases in the body, and it is imperative that the ability of the neonatal gut to assimilate these nutrients from the diet be optimal.
The level considered as AI reflects the average intake of vitamin B for infants consuming human milk produced by well-nourished breast-feeding mothers (Table 5) (134). Generally, AI values for each vitamin B meet infant needs. There are no reports of full-term infants exclusively fed human milk from healthy mothers and later manifested signs of vitamin B deficiency. Because breast milk from mothers who are vegetarian or who have untreated pernicious anemia has lower amounts of vitamin B12, their infants may begin to show clinical signs of B12 deficiency at about 4 months of age (135).
In the following section, the mechanisms as well as regulation of intestinal absorption for each water-soluble vitamin are discussed briefly. Because most of the B vitamins are bound to proteins and other compounds in the diet, each vitamin needs to be initially liberated from its bound form and then absorbed by its specific transport system from the intestinal lumen. With the exception of cobalamin, whose intestinal absorption is via a receptor-mediated mechanism, the rest of the water-soluble vitamins are transported by carrier-mediated systems (11). For almost all water-soluble vitamins, there are 2 significant sources: diet and colonic bacteria (136,137).
Intestinal absorption of dietary thiamine takes place mainly in the jejunum by both active (at lower concentrations) and passive (at higher concentrations) mechanisms. For a review of thiamine transport, refer to Rindi and Laforenza's article (138). Dietary thiamine is first hydrolyzed into its phosphorylated form, coenzyme thiamine pyrophosphate, in the intestinal lumen and enters the mucosal cell via an Na+-independent, H+-dependent, carrier-mediated mechanism involving the thiamine transporters THTR-1 and THTR-2, which are products of Slc19a2 (1q23.3) and Slc19a3 (2q37), respectively (139–143). In humans, both transporters are expressed along the length of the intestinal tract (144,145), but THTR-1 is expressed in both the apical and basolateral membranes whereas THTR-2 is expressed only in the apical (145,146). Intestinal thiamine uptake decreases with maturity. The mechanism underlying colonic absorption of bacterial thiamine is similar to the carrier-mediated process of thiamine uptake in the small intestine (136).
Most dietary riboflavin is consumed as a complex of food protein with flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) (147). Gastric acidification in the stomach releases most of the coenzyme forms of riboflavin (FAD and FMN) from the protein. The noncovalently bound coenzymes are then hydrolyzed to riboflavin by nonspecific pyrophosphatases and phosphatases in the upper gut (147,148). Dietary riboflavin absorption occurs in the proximal small intestine via a rapid, saturable, Na+-independent, carrier-mediated transport system (147–149), which predominates at lower dietary concentrations. At higher concentrations, the rate of absorption in adult humans is proportional to the amount of intake, and absorption increases when riboflavin is ingested along with other foods (150) and in the presence of bile salts (150,151). A small amount of riboflavin circulates via the enterohepatic system (148). There is an adaptive regulation induced by extracellular riboflavin levels wherein a deficiency or an oversupply of riboflavin leads to an up- or downregulation, respectively, in intestinal riboflavin uptake (149,152). Riboflavin may exit the intestinal cell by another carrier located in the basolateral membrane (152). A small amount of colonic riboflavin absorption occurs via a carrier-mediated, Na+-independent transport system similar to that in the small intestine (153,154). The molecular identities of the apical and basolateral riboflavin transporters are still not known. Moreover, developmental and dietary regulation of riboflavin absorption in infants and children have not been studied.
Niacin requirement is met not only by dietary nicotinic acid and nicotinamide but also by the metabolic conversion of the amino acid tryptophan to niacin. The relative contribution of tryptophan is estimated to be 60 mg of tryptophan to 1 mg of niacin or 1 mg of niacin equivalents (155). Dietary niacin is absorbed via an Na+-independent, H+-dependent, carrier-mediated mechanism (156). Intestinal absorption is rapid (157). At higher concentrations, passive diffusion predominates. Although the molecular identity and regulation of this transport system is still not known, some evidence suggests that the transport system may be under the regulation of an intracellular protein tyrosine kinase–mediated pathway (156).
Most tissues transport pantothenic acid into cells for the synthesis of coenzyme A (CoA). CoA in the diet is hydrolyzed in the intestinal lumen to dephospho-CoA, phosphopantetheine, and pantetheine, with the pantetheine subsequently hydrolyzed to pantothenic acid (158). Active transport occurs at low vitamin concentrations and by passive transport at higher concentrations (159). Active transport is via the SMVT (Slc5a6, 2p23) transport system, which is a carrier-mediated system shared with another vitamin, biotin (160). It is unclear how this shared transport system is regulated by the substrate levels of these micronutrients. Intestinal microflora have been observed to synthesize pantothenic acid in mice (161), but the physiological contribution of bacterial synthesis to systemic pantothenic acid levels or fecal losses in humans has not been quantified. Colonic absorption of bacterially produced pantothenic acid is via the same system found in the small intestine (162).
Pyridoxine absorption involves phosphatase-mediated hydrolysis followed by transport of the nonphosphorylated form into the mucosal cell. PN glucoside is absorbed less effectively than are PLP and PMP and, in humans, is deconjugated by a mucosal glucosidase (166). Intestinal pyridoxine absorption is via an Na+-independent, H+-dependent, carrier-mediated mechanism and that appears to be under the regulation of an intracellular protein kinase A (PKA)–mediated pathway (167). Colonocyte pyridoxine transport is via the same specific and regulatable carrier-mediated process as in the small intestine (168). To date, the molecular identity of the intestinal vitamin B6 uptake system and its gene has not been elucidated.
Drugs that can react with carbonyl groups have the potential to interact with PLP. Isoniazid, which is used in the treatment of tuberculosis, and L-DOPA, which is metabolized to dopamine and used in the treatment of Parkinson disease and dopamine-responsive dystonia, have been reported to reduce plasma PLP concentrations (169). Thus, vitamin B6 supplementation is routinely recommended for infants receiving isoniazid and infants breast-fed by mothers receiving isoniazid or L-DOPA.
A biotin carrier located in the intestinal brush border membrane transports biotin against an Na+ concentration gradient. The carrier is structurally specific, temperature dependent, and electroneutral. At pharmacological concentrations of dietary biotin, diffusion predominates (173). Human intestinal biotin uptake is via the SMVT (Slc5a6, 2p23) transport system that is also shared by pantothenic acid (162,174). Human intestinal biotin uptake is adaptively upregulated during biotin deficiency, which occurs via an increase in SMVT protein and mRNA levels (175). Regulation is mediated by transcriptional mechanisms involving binding sites for the transcriptional factor gut-protein Kruppel-like factor (GKLF) in the human SMVT promoter (176). Colonic biotin uptake occurs via the same Na+-dependent, carrier-mediated mechanism that operates in the small intestine (162).
Folic acid (pteroylmonoglutamic acid), which is the most oxidized and stable form of folate, is the form used in vitamin supplements and in fortified food products. Folate deficiency has been identified in small-for-gestational-age infants. Use of drugs, such as phenobarbital, phenytoin, and sulfasalazine, may increase the need for folate (133). The premature infant is at particular risk for folate deficiency because of insufficient hepatic stores, rapid growth, increased erythropoiesis, use of antibiotics and anticonvulsants, and inherent fat malabsorption states (133). Iron deficiency may lead to a decrease in folate utilization. Folic acid therapy may lead to zinc deficiency (177).
Intestinal folate transport is carried out by 2 transport systems: reduced folate carrier (RFC, Slc19a1, 21q22.3) and proton-coupled folate transporter (PCFT, Slc46a1, 17q11.2). Dietary folates (polyglutamate derivatives) are hydrolyzed to monoglutamate forms in the gut before absorption across the intestinal mucosa. This cleavage is accomplished by a γ-glutamylhydrolase, more commonly called folate conjugase. The monoglutamate form of folate is actively transported across the brush border membrane of proximal small intestinal cells by both RFC and PCFT, which are both saturable H+-dependent processes (178,179). Although PCFT transports folic acid at more acidic pH compared with RFC, both transporters have similar affinities for reduced and oxidized folates (179,180). When pharmacological doses of the monoglutamate form of folate are consumed, some are also absorbed by a nonsaturable mechanism involving passive diffusion (133). A product of Slc19a1, RFC, also known as RFT (reduced folate transporter) is responsible for intestinal folate transport (141) at the basolateral membrane domains of polarized enterocytes. Dietary deficiency of folate leads to an upregulation in its intestinal uptake. Intestinal folate transport process is ontogenetically regulated and decreases with age (181). Colonic folate absorption is similar to the carrier-mediated process in the small intestine (182). Coexisting iron or vitamin B12 deficiency may interfere with the diagnosis of folate deficiency (183).
Vitamin C acts as a cofactor in a number of metabolic reactions and as a free radical scavenger (184). It exists in reduced (ascorbic acid) or oxidized (dehydro-L-ascorbic acid [DHAA]) forms. Intestinal transport of vitamin C by passive diffusion is negligible. Other known transport mechanisms are facilitated diffusion or secondary active transport (184). There are 2 human isoforms of ascorbic acid transporters: Na+-dependent vitamin C transporters 1 and 2 (SVCT1 and SVCT2), which share the same homology with one another (185). In the small intestine, SVCT1 (5q31.2–31.3), the product of the Slc23a1 gene, is expressed at the apical membrane (185), whereas the expression of SVCT2 (Slc23a2, 20p13) is at the basolateral membrane of the enterocytes (186). Absorption sites occur throughout the entire length of the small intestine. Intestinal ascorbic acid transport is regulated by extracellular substrate levels and by an intracellular PKC-mediated pathway (187).
The lipid content in human milk is ∼38 g/L and represents 45% to 55% of the newborn infant's energy requirements. Lipid requirements decrease to 30% for infants 6 to 12 months of age (Table 6) (188–190). Lipids in breast milk consist mostly of triacylglycerols (∼99%) with some contributions from cholesterol esters (<1%, 10–15 mg/dL) and phospholipids (<1%, 15–20 mg/dL). A small proportion (<0.1%) is found as diacylglycerols and free fatty acids. The lipid fraction of human milk provides not only energy but also cholesterol and essential fatty acids or long-chain polyunsaturated fatty acids (LC-PUFA), which are the precursors of eicosanoids, endocannabinoids, other fat-soluble hormones, as well as liposoluble vitamins. Hence, the amount of triacylglycerols and the composition of their fatty acids have health relevance for the neonate.
Because the triacylglycerols provide ∼9 kcal/g, they are the best dietary source of energy. During the first 6 months of life, the energy required for growth alone represents 20% to 30% of the total energy needs, whereas at 12 months of age, the total energy cost for growth falls to 5%—under both conditions, the energy released from lipid metabolism alone would be sufficient to meet these needs (188) (Table 6).
Linoleic (LA, C18:2n-6) and α-linolenic (LNA, C18:3n-3) acids are the essential fatty acid precursors of LC-PUFA of n-6 and n-3 families. The major metabolite arising from successive elongation and desaturation of LA is arachidonic acid (ARA, C20:4 n-6) and those of LNA are eicosapentaenic (EPA, C20:5n-3) and docosahexaenoic (DHA, C22:6 n-3) acids. The n-6 and n-3 LC-PUFA play a major role in the early development of the skin, brain, and retina. In neonates, there is a rapid accretion of ARA in the whole body as well as of ARA and DHA in various organs such as the brain and retina. This indicates that specific PUFAs play important unique roles in the development of certain organ systems. Even if the preterm and full-term neonates are capable of de novo synthesis of LC-PUFA (191), most of the required LC-PUFA would have to be present in breast milk to ensure that sufficient levels of these nutrients would be available to the infant (Tables 6 and 7). It is not clear whether preterm infants have lipid and LC-PUFA requirements different from full-term babies (189,192).
The n-6 and n-3 LC-PUFA also contribute to synthesis of plasma membranes and to immune, visual, cognitive, and motor functions (193–198). High levels of LC-PUFA in early life may be beneficial as they diminish the incidence of insulin resistance, obesity, and cardiovascular problems in later life (199). However, LC-PUFA like ARA may also be detrimental because they may induce precocious development of adiposity (200,201).
Although the amounts of cholesterol are especially high in breast milk (6 to 18 mg/100 mL) (202), its role in early tissue development or later adult cholesterol metabolism remains unclear. On the one hand, cholesterol is the major lipid component of some nervous cell membranes such as myelin, and an increase in neonatal plasma cholesterol concentrations is positively associated with enhancement of cerebrum weight gain and development of normal behavior and reflexes (203,204). On the other hand, adult rat offsprings display a negative correlation between serum cholesterol concentrations and the cholesterol content of their mothers' milk, suggesting the potential “protective” role of early dietary cholesterol exposure to hypercholesterolemia in adulthood (205). However, other studies do not support the hypothesis (206); thus, the influence of infant high cholesterol intake on cholesterol metabolism in adulthood remains unclear.
The lipid content and composition of breast milk vary depending on stage of lactation (early, mid, or late lactation), time of feeding (foremilk vs hindmilk), time of day (morning vs evening), and mother's diet (207,208), making it difficult to simulate a complete lipid profile for use in infant formulas. Despite efforts to replicate human milk, numerous qualitative and quantitative differences persist between breast and formula milk (Table 7). Currently, vegetable oils are added to infant formula to improve lipid absorption, to increase the level of essential unsaturated fatty acids (LA and LNA), and to decrease the LA/LNA ratio (188). Whereas LA is abundant in most of the vegetable oils, LNA and other n-3 PUFA are only found in rapeseed, canola, and soy oil (188). In addition, the positions of fatty acids esterified to the glycerol backbone in various oils used to supplement the infant formulae may differ from those found in human milk. As discussed later below, these fatty acid positions are relevant because the vulnerability of esterified fatty acid to lipase digestion is dependent in part on its position in the glycerol backbone. Indeed, fatty acids in triglycerides from breast milk are mostly long-chain fatty acids (LC-FA), for example palmitic (C16:0, ∼20%–25% of triglyceride fatty acids) and stearic acids (C18:0, ∼10%) for the saturated fatty acids, and oleic acids (C18:1, ∼30%–35%) for the monounsaturated ones (209). Palmitic acid constitutes the highest proportion (53% to 70%) of saturated fatty acids at the sn-2 position of the triacylglycerol backbone (210), whereas oleic acids are mainly localized on the sn-3 and sn-1 positions. The location of palmitic acid at the sn-2 position is critical because that increases its absorption in the lumen of infants (211). Consequently, to establish in infant formula an optimal amount of palmitic acid esterified at the sn-2 position, triacylglycerols must be modified by enzymatic interesterification of tripalmitin with vegetable oil mixes and fish oil to change the positional distribution of fatty acids in the glycerol backbone. Fish, algal, and fungal oils as well as lipids from eggs are mainly used for supplementation of infant milk formulae to balance the n-3 and n-6 LC-PUFAs.
The process of digestion begins in the stomach where ∼15% of the triacylglycerols are released by lingual and gastric lipases, but most of the hydrolysis occurs in the duodenum by pancreatic lipases. Fatty acids in sn-1 and sn-3 positions are mostly hydrolyzed by pancreatic lipases and later on become incorporated in micelles. The fatty acids in the sn-2 position remain as monoglycerides and are mainly absorbed because these monoglycerides are polar and later easily solubilized. Pancreatic lipases are secreted by the pancreas from approximately 30 weeks of gestation but remain at low concentrations until the first year of life (212). Because lipid digestion is critical for neonatal development, it is hypothesized that other lipases such as pancreatic lipase–related protein 2 (213,214) or carboxyl ester lipase from breast milk (215) may compensate for this deficiency in levels of pancreatic lipases. Increases in luminal concentration of triacyglycerols in the duodenum stimulates the release of bile acids, whose detergent properties solubilize the products of lipid hydrolysis (sn-2-monoacylglcyerol and free fatty acids) and form mixed micelles. Micelles whose surfaces are hydrophilic diffuse through the aqueous luminal contents and eventually come into close proximity to the brush border of enterocytes and would release free fatty acids and acylglycerols, which subsequently either are taken by specific carrier molecules or diffuse into the mucosal cell.
Intestinal lipid absorption is a multistep process, traditionally divided into 3 components: apical absorption into the enterocyte, intracellular processing, and subsequent release into the lymphatic and portal circulation (216).
Although the short-chain fatty acids diffuse passively across the enterocyte membrane, the relative importance of simple diffusion as opposed to carrier-mediated absorption in the apical absorption of LC-FA and cholesterol remains unclear. Because of their lipophilic nature, LC-FA were once thought to diffuse freely through the plasma membrane (217,218). Several studies in the last 10 years have shown evidence for carrier-mediated lipid absorption (Fig. 3). These transporters for lipids have, however, been studied mainly in adults, and little is known about their relative contribution to intestinal lipid absorption in the neonate. Several transporters for LC-FA have initially been discovered in other tissues, and 3 of these were later found expressed in the small intestine: the plasma membrane fatty acid–binding protein (FABPpm, Got2, 16q21) involved mainly in the intestinal uptake of LC-PUFA (219–222), the fatty acid transport protein 4 (FATP4, Slc27a4, 9q34.11) (223), and the rat homologue of human fatty acid translocase (FAT/CD36, Cd36, 7q11.2). FAT/CD36 is not a specific transporter of fatty acid and is also involved in the apical uptake of cholesterol (224). Intestinal cholesterol absorption was also reported to be facilitated by the scavenger receptor SR-BI (Scarb1, 12q24.31–32) (225–227) and by Niemann-Pick C-1-like 1 (NPC1L1, Npc1l1, 7p13) (228,229). Lipid transport may be bidirectional, and some lipids may be secreted by intestinal cells. For example, the ABCG5–ABCG8 (Abcg5-Abcg8, 2p21) heterodimeric transporter localized on the apical side is thought to transport intracellular cholesterol back across the apical membrane to the intestinal lumen (230).
Although the regulation of FATP and FABPpm in the placenta during gestation is well documented (239), little is known about the developmental regulation of these 2 transporters as well as of the transporters NPC1L1, SR-B1, and FAT/CD36 in the intestine of the fetus and the neonate. The expression level of FATP2 (Scl27a2, 15q21.2) mRNA appears to decrease by 60% between 10 and 20 days of age. SR-B1 expression increases after 20 weeks of gestation in humans (240), but postnatal regulation was not studied.
In contrast, regulation of intracellular processing during neonatal development has received some attention, and evidence suggests that the major players of lipid processing are synthesized during gestation and that the entire process may be operational at birth. Rat fetal explants (17–20 weeks of gestation) are able to synthesize and secrete chylomicrons, VLDL, and HDL. I-FABP and L-FABP gene transcription begins in late fetal life (∼17 days of gestation in rats) (241). In humans and pigs, the expression of Apo B-48 and MTP increases drastically at birth (242,243) and Apo IV is already present in the intestine of neonatal pigs (244). During the suckling phase, the intestine is capable of a better adaptation to a high-lipid diet by increasing uptake of lipids than during the weaning period (245). Greater lipid uptake during the suckling phase may result from an increased fluidity of the brush border membrane (246,247) and/or from greater rates of facilitated, carrier-mediated lipid transport. After weaning, alterations in lipid composition of brush border membrane decrease its fluidity (247), which may result in decreased rates of facilitated lipid transport. During suckling but not in weaning rats and in adults, jejunal apo B-48 and apo A-IV protein levels are stimulated by dietary fatty acids (242,244,248–250). In piglets, jejunal and ileal MTP expressions are also enhanced by high level of lipids in the lumen during the suckling phase (242).
Because of limited transplacental transfer, mammalian newborns typically have low stores of vitamins A, D, E, and K (251,260,261) during parturition. Thus, the neonate is highly dependent on colostrum and milk consumption to establish normal tissue stores of these vitamins. Unfortunately, breast milk contains low levels (between 40 and 50 IU/L) of vitamin D as well as vitamin K, and hence AI of these vitamins cannot be met with human milk (251,252). The complicated processing of vitamins A, D, E, and K and their metabolites is beyond the scope of this review.
The digestion of fat-soluble vitamins requires bile salts and pancreatic lipases for micelle formation and enzymatic hydrolysis, respectively, similar to the process described above for dietary lipids (262). Although diffusive intestinal absorption remains the only pathway described for vitamin D and K, the uptake of vitamins A and E may also be mediated by lipid transporters (Fig. 3). SR-BI is clearly involved in the uptake of vitamin E in Caco2 cells (263), whereas FAT/CD36 is not. NPC1L1 and ABCA1 may also play a role in the facilitated transport of the carotenoids, a form of vitamin A, in Caco2 cells (264). However, vitamin A does not appear to be transported by CD36 or SRB1 (264). These findings were made in cultured cells, however, and the role of the active transporters in the intestinal absorption of fat-soluble vitamins remains little known in neonates.
After absorption into enterocytes, vitamin A or retinol is bound to cellular retinol-binding protein type II (CRBPII, Rbp2, 3q23) (265). The retinol/CRBPII complex serves as a substrate for reesterification of the retinol by the enzyme lecithin:retinol acyltransferase (266). The retinol esters are then incorporated into chylomicrons containing other dietary lipids (267). The molecular and cellular mechanisms involved in the intracellular trafficking, assembly, and/or efflux of dietary vitamin E in intestine-derived lipoproteins remain mostly unknown. It is possible that intestinal Apo E and Apo A-IV may contribute to intestinal vitamin E absorption because subjects bearing different single nucleotide polymorphisms in Apo A-IV and Apo E display lower plasma levels of vitamin E (268). In CaCo2 cells, the main subcellular destinations of vitamin E are microsomal membranes (269); then vitamin E is incorporated into chylomicrons and secreted with I-HDL, which require, respectively, MTP for chylomicron assembly and ABCA1 for HDL excretion (269).
There is little information available on the intestinal transcellular processing of vitamin K. The subcellular destination of vitamin K and the identity of its intracellular transporters in the enterocytes remain to be discovered. After absorption from the intestinal lumen, vitamin K becomes associated with chylomicrons in the blood (270,271).
Several diseases are associated with mutations of various lipid transporters. However, because these transporters are involved in lipid transport in many tissues other than the intestinal mucosa, the disorders resulting from their mutation appear to be linked to a deficiency of lipid transport into those cells rather than that in the intestine. Thus, only a few mutations have consequences that are clearly linked to impairment of intestinal lipid uptake. For example, mutations of ABCG5 or ABCG8 lead to the development of sitosterolemia (272,273). This rare autosomal, recessively inherited disorder is characterized by hyperabsorption of cholesterol and phytosterols and reduced secretion of these sterols into bile. Hypobetalipoproteinemia, an autosomal-dominant disorder, is defined by low levels (<5th percentile) of total apoB and/or of low-density lipoprotein cholesterol in plasma. Hypobetalipoproteinemia is due to a variety of genetic defects in MTP (274), impairing the assembly of lipids with apoB in lipoprotein production. Interestingly, hypobetalipoproteinemia is also associated with vitamin E deficiency (275).
There is another extremely serious defect of nutrient malabsorption that is not specific to any nutrient but is induced by nutrients in general. Loss of function mutations in the transcription factor Neurog3 results in almost total absence of neuroendocrine cells in the small intestine (276). Patients had chronic unremitting diarrhea that was malabsorptive in nature. Feeding of carbohydrate-free, water plus tryglycerides, water plus amino acids, fructose-free, soy-based, and even oral rehydration solutions each resulted in diarrhea. Only water feeding did not cause diarrhea. This extremely rare disease highlights the selective pressures imposed by GI malabsorption on their carriers who survive only with modern medical care.
For water-soluble vitamins, it is not known why dietary supplementation of some vitamins does not translate into increase in blood levels of the vitamin being supplemented.
Because the recently identified lipid transporters are found in low abundance in the neonatal intestine, they may mainly facilitate the absorption of essential LC-PUFAs critical for neonatal development. Unfortunately, the ontogenetic development of these transporters as well as their interaction with lipids present in breast milk has not been studied. Specifically, there is little information available concerning the expression, functionality, and potential growth-limiting role of these lipid transporters in preterm versus full term.
There is also little known about the uptake, intracellular processing, and basolateral transport of vitamins E and K. Developmental regulation of transport systems participating in the transport of the vitamins A, E, and K needs further study.
The postnatal development of nutrient transporter has mostly been described in suckled animals. However, considering the difference in nutrient composition between formulas and breast milk on one hand and the extreme reactivity of transporter to dietary modulations on the other hand, studies on the exact postnatal evolution of transporters in bottle-fed animals would certainly help to improve formulas to closely match formulas' composition with bottle-fed neonate requirements and absorptive capacities.
Besides their classical transport function, a novel role in immunomodulation of the mucosa has been recently described for some transporters (SGLT1, PEPT1) (277,278). The neonatal period is a critical period in terms of dialogue between the GALT and the microbiota, which shapes the gut immune system for the rest of our life. The role of such transporters in immunomodulation of the gut during the neonatal period and later in health consequences warrants further studies.
The authors thank Ms Jackie Lee for valuable help in manuscript preparation.
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