Importance of Milk and Diet on the Ontogeny and Adaptation of the Intestine (1997)

The influences of diet on intestinal development have been reviewed (1-3). Diet modulates the timing of age-related changes in intestinal structure and function, but it does not override the genetic determinants responsible for them. The composition of human milk provides important factors stimulating the developmental changes that occur following birth (4-8). Alterations in the mother's diet result in variations in the composition of her milk (9-12). Thus, the diets of both mother and child are important for the normal development of the intestine. Studies of the effect of maternal dietary changes on infant tissue composition are important in determining dietary requirements for lactating women, as well as for making appropriate recommendations regarding the composition of infant formulas. The following is a review of the importance of milk and diet in the ontogeny and adaptation of the intestine. NUTRITION AND ONTOGENETIC DEVELOPMENT OF THE INTESTINE The influences of diet on intestinal growth and development are critical issues in nutritional research. These are especially evident for the intestine, as it responds to qualitative and to quantitative changes in dietary inputs as animals develop from fetuses to adults (1,2). Research has focused on the relative roles of diet and intrinsic timing mechanisms in causing changes in intestinal structure and function. The amount of dietary input is known to modulate the timing of, but not to override, the genetic determinants responsible for age-related alterations in intestinal structure and function. The small intestine is exposed to a continuously changing composition of intraluminal contents and has the capacity to adapt its structure and function in response to variations in the diet. Food in the gastrointestinal tract initiates a variety of events: the release of trophic hormones, the stimulation of nerves, and the activation of secretion, motility, and absorption. The normal diet also may contain substances such as amines and polyamines that directly stimulate the growth of the intestinal mucosal cell independently of their nutritive role (13). For mammals, an abrupt change in the diet occurs at birth, when the intestine is switched from processing amniotic fluid to digesting milk, and again at weaning when the animal begins eating the adult diet. The patterns of changes are responsive to the types and quantities of nutrients as well as to the luminal exposure to nonnutritive, biologically active subtances such as growth factors and hormones (14). The development of the upper gastrointestinal tract depends on nutrients provided both by the placenta (15,16) and by swallowed amniotic fluid (16). Fetal swallowing has an essential role in small intestinal development, including the maturation of small intestinal nutrient transport. Amniotic fluid contains nutrients and biologically active substances such as epidermal growth factor (EGF) (17) and gastric inhibitory peptide (18) that may influence intestinal function. Infusing galactose into amniotic fluid of rabbits between 77 and 97% of completion of their gestation increases fetal mucosal weights and total intestinal capacities to transport aldohexoses (19). This importance of nutrients in amniotic fluid has stimulated interest in using transamniotic nutrition for the treatment of intrauterine growth retardation caused by placental insufficiency. Some of the most striking interactions between diet and intestinal development occur immediately after birth. In some species, the neonatal intestine undergoes rapid growth and reorganization, possibly as a result of the expression of genes associated with the immediate response to milk (20). The stomach and intestines of newborn rats, rabbits, and dogs increase in mass within hours after the initiation of enteral nutrition (21). Interestingly, human breast milk possesses the ability to enhance the mitogenesis of fibroblasts in cell culture (22). Animals fed milk have a greater DNA, RNA, and protein content in their stomach and intestine than do birth animals that have not yet consumed milk (23). The milk of mammals contains a range of trophic factors, hormones, and other biologically active substances (4). These may exert growth-modulating effects on the gastrointestinal mucosa (5). Different patterns of gastrointestinal hormone release in response to feeding have been described in human neonates fed breast milk versus cow's milk formula (24). Factors in milk that may be important for intestinal development include EGF, insulin, and insulin-like growth factors, polyamines, and glucocorticosteroids (6-8). Their concentrations are higher in colostrum than in mature milk (4). Intestinal growth and maturation are faster in animals fed colostrum than in those fed mature milk (25) or formula (26). The concentration of DNA and the rate of synthesis of DNA in the intestine are greater in rats fed colostrum than in those fed mature milk (21). Suckled animals have 75% more intestinal mucosal mass, a 56% increase in DNA, and a protein content nearly double that found in animals that have received artificial feed (27). These data suggest that this early, rapid growth of the small intestine in naturally fed pups is the result of the specific composition of natural milk. In some species, the proliferative response to colostrum coincides with a decline in the specific activities of brush border membrane (BBM) hydrolyses and transporters. The BBM lactase activity declines 43% in pigs fed colostrum (28). It has been suggested that products of lactation influence this rate of decline. The candidates implicated in this ontogenic decline are the glucocorticoid and thyroid hormones present in mammalian milk (29). Thus, lactation products play an important role in early intestinal development. The ontogenic decline in lactase activity can be promoted or delayed by changing the time when rats are switched from milk to the adult-type diet (30). Force-feeding preweanted rats with an artificial formula without lactose and sucrose causes a precocious decline of lactase activity and a rise in sucrase activities from the proximal to the distal portions of the intestine (30). These changes are delayed in suckling rats submitted to prolonged nursing until 26 days of age (30). Thus, although the ontogenic decline in intestinal lactase is intrinsically programmed, luminal factors modulate this process. During the third week of life, the rat small intestine displays dramatic changes of cellularity and of BBM enzymes. These changes are coordinated with the dietary transition from milk to solid food. This is marked by a shift from a liquid diet rich in lipids to a solid diet rich in carbohydrates. There is also a shift from a lactose-rich diet to one rich in complex carbohydrates. Intrinsic timing mechanisms are important in triggering intestinal maturation at weaning, but the transition to the adult diet is required for the normal progression of events. Weaning coincides with or is preceded by the appearance of the BBM hydrolytic and transport functions that are characteristic of adults. Also, weaning is accompanied by increases in circulating concentrations of several hormones that are capable of influencing intestinal development (29,31). Early weaning and exposure of the neonatal intestine to food antigens have been implicated in delaying the maturation of the intestine (32) and in increasing the risk of food allergies (33). Intestinal maturation is delayed but not prevented if suckling is prolonged or if animals are weaned to diets that mimic the composition of milk (34). Furthermore, the normal decline in BBM lactase activity is also retarded when weaning is prolonged (35). Rats do not grow as well and have a decreased intestinal weight when they are nourished solely on the milk of their mothers for 10-15 days after they would have ingested solid food (35). Prevention of weaning from 14 to 24 days of age results in a marked reduction in the growth of the small intestine, as evidenced by its decreased weight and decreased DNA, RNA, and protein content (36). EFFECTS OF THE MATERIAL DIET ON THE COMPOSITION OF MILK Human milk is the ideal food for healthy infants born at term, and an exclusive diet of human milk is thought to meet the infant's nutrient requirement during its first 4-6 months of life. A close correlation exists between the diet of a nursing mother and the composition of her milk (37). Significant variations in the composition of human milk occur between individuals, depending on the stage of lactation and the time of day (38). There are diurnal changes in the composition of mother's milk (39), and there are different diurnal patterns of human milk lipids in milk samples from either German or English mothers; it has been speculated that these varying patterns are caused by their different dietary habits (37). High-fat/low-carbohydrate diets cause the secretion of milk with a relative low triglyceride (TG) content (37), whereas low-fat/high-carbohydrate diets lead to an increase in plasma TG concentrations (40). Plasma TG of the corresponding mothers is also affected in the same way, and these lipid concentrations are lower in mothers on high-fat/low-carbohydrate diets. Fatty acids are cleaved from plasma TG by the mammary gland-associated lipoprotein lipases. The fatty acids are then absorbed by the secretory cells and are used with glycerol-3-phosphate for the synthesis of milk fat (41). Thus, the fatty acids found in milk lipids are derived from two sources, from the circulation and from the de novo synthesis of lipids within the mammary gland. The major lipogenic precursor is glucose, and 70% of the fatty acids synthesized from glucose within the mammary gland are medium-chain length (C8 to C12) fatty acids (42). These fatty acids are synthesized within the mammary gland as a result of the activity of a specific medium-chain thioesterase, and it prematurely terminates chain elongation by the fatty acid synthetase (43,44). The yield of medium-chain fatty acids in the mother's milk does not correspond to the respective maternal plasma levels (37). A low-fat/hihg-carbohydrate diet increases medium-chain fatty acid concentration in milk, whereas plasma levels are hardly affected (35). Feeding a high-fat diet during lactation decreases the rate of mammary gland lipogenesis as well as the proportion of medium-chain fatty acids in milk (42). A high intake of carbohydrate increases the lauric acid (12:0) and myristic acid (14:0) content of breast milk, while simultaneously the amount of fatty acids derived directly from plasma TG declines (11). When the carbohydrate intake is high, the nature of ingested fat has little effect on the fatty acid composition of milk. In contrast, with a low level of carbohydrate intake, the content of linoleic acid (18:2) in the diet is reflected in breast milk (12). There are marked diurnal changes in the rate of mammary gland lipogenesis in lactating rats fed a normal chow diet (45). Lipogenesis reaches its peak rate at night and falls dramatically during the day when less food is consumed. Removal of food for 6 h results in a 90% depression of the rate of mammary gland lipogenesis (46). Short-term refeeding of chow rapidly reverses this inhibition of glucose utilization. Thus, the rate of mammary gland lipogenesis is very sensitive to the amount of food consumed. Medium-chain fatty acids constitute ≈35% of milk TG. Human milk does not contain significant amounts of short-chain fatty acids (47). As lactation progresses, concentrations of the small- and medium-chain fatty acids increase. With the mammary gland making predominantly medium-chain fatty acids, the long-chain fatty acids (in particular C18 acids) of the milk fat must come from the circulation and in most cases these will originate from the diet (48). When rat mothers are fed marine oil during pregnancy and lactation, the levels of long-chain monoenoic acids 18:1, 20:1, and 22:1 in milk make up approximately half the fatty acids secreted in the milk. This signifies that lipids absorbed from the intestine readily pass into the milk (9). In milk, TG constitutes 98% of the lipids, while diacyglycerol, free fatty acids, phospholipids, cholesterol, and cholesterol esters account for the remainder (49). During the neonatal period, ≈70% of the suckling animals' energy intake originates from milk lipids, primarily TG (50). The suckling rat uses milk lipid efficiently and gains weight rapidly. The dietary fatty acid content is reflected in human milk (37,10), and the amount and type of milk fatty acids may have important effects on infant development. The longer-chain fatty acids, in particular arachidonic (AA) and docosahexaenoic acids (DHA), are the major fatty acids present in nervous tissue (51,52). Importantly, the brain accumulates ≤80% of its adult long-chain polyunsaturated fatty acid content before weaning. Changes in the lipid composition of the developing but not the mature central nervous system have potentially important implications because of the possibility that these changes might result in some long-term deficit in emotional or intellectual development. Polyunsaturated fatty acids are indispensable components of all biological membranes, and they modulate membrane properties such as fluidity, permeability, and the activity of membrane-bound enzymes and receptors (53). Dietary fat provides n-6 and n-3 fatty acids, which are essential for normal cell function and cannot be made by the body. Decreased amounts of n-3 and n-6 fatty acids have been found in the tissue phospholipids of rats fed a fat-free diet (54). Under these conditions, there are changes consistent with alteration of the properties and functions of membranes (54). The longer-chain polyunsaturated fatty acids, AA (20:4n-6) and DHA (22:6n-3), are derived from linoleic (18:2n-6) and linolenic acids (18:3n-3), respectively, by elongation-desaturation mechanisms. These give rise to two separate series of polyunsaturated fatty acids: the n-6 and n-3 series, respectively. Dietary 18:2n-6 and 18:3n-3 are quantitatively less effective than 20:4n-6 and 22:6n-3 as sources of 18:2n-6 and 18:3n-3 for incorporation into membrane lipids (55). This is due to the lack of quantitative desaturation of 18:2n-6 to 20:4n-6, and of 18:3n-3 to 22:6n-3. Tissue levels of 20:4n-6 are reduced by dietary 22:5n-3 and 22:6n-3, and to a lesser extent by high intakes of 18:3n-3 (55). This is explained by the reduced synthesis of 20:4n-6 due to inhibition of 18:2n-6 desaturation and by the competition for acylation into phospholipids. Piglets fed milk with 1.5% 22:6n-3 have lower levels of 20:4n-6 in their plasma, liver phospholipid, red blood cells, and central nervous system phospholipids than piglets fed milk with 0.1% 22:6n-3, even though the milks contain similar levels of 20:4n-6 (56). This reduction in the levels of 20:4n-6 is of concern because of possible effects in the development of the central nervous system. The sum of all n-6 and n-3 fatty acids does not usefully describe the nutritional quality of milk fatty acids because of the differences in metabolism between 18:2n-3 and 20:4n-6 and between 18:3n-3 and 22:6n-3 (57). Competitive inhibition of 18:2n-6 or 18:3n-3 desaturation should not be of concern in breast-fed infants, because milk also provides 20:4n-6 and 22:6n-3. The 18:2n-6-to-18:3n-3 ratio in human milk ranges from about 8:1 to 45:1 (58). The levels of AA and DHA are lower in the plasma of infants fed formula rather than human milk and are not enhanced with an increased supply of formula 18:2n-6 and 18:2n-3 (59). The levels of AA are higher in milk phospholipids from rats fed diets with low linoleic acid levels (60). These observations of an increased formation of long-chain fatty acids of the n-6 series with low dietary levels of the precursor linoleic acid, and vice versa, suggest that there is a control of the supply of polyunsaturated fatty acids to the suckling animals in conditions of reduced maternal intake of essential fatty acids (60). Milk levels of 20:5n-3 and 22:6n-3 increase ten-fold or more when the diet is supplemented with fish oils or when the diet contains predominantly marine lipids (61). Supplementing the usual North American diet with concentrated fish oil increases breast milk 20:5n-3 and 22:6n-3 (10). The amounts of 20:5n-3 and 22:6n-3 are higher in the milk from Inuit women, who consume relatively large amounts of marine mammal flesh, than in the milk from mothers in Vancouver, who eat the usual North American diet (61). Supplementing breast-feeding mothers with fish oil results in a dose-dependent increase in the n-3 long-chain fatty acids in their milk (10). The increase in milk 22:6n-3 is associated with increased 22:6n-3 in the circulating and in the liver phospholipids as well as in brain and synaptic plasma membrane lipids of natural milk-fed piglets (62). Since the fatty acid composition of human milk varies with changes in the type of dietary fat and carbohydrate, differences in breast milk composition between vegetarians and nonvegetarians would be expected. Children nursed by vegetarian mothers consume milk with a fat composition similar to that of the vegetarian diet, with reduced levels of long-chain saturated fatty acids and increased levels of polyunsaturated fatty acids (63). Lactose synthesis in the mammary gland also uses glucose as a precursor. Measurements of the rate of lactose synthesis in the mammary gland in rats fed a high-carbohydrate diet have shown diurnal variations that parallel those of food intake in the lactating rat (62). Decreased food intake causes greater diurnal fluctuations in the rate of lactose synthesis, and overall a lower rate of synthesis than occurs in rats eating normally (64). The neonatal rat pup depends highly on the amount of lactose supplied in rat milk for early glycogen accumulation. Pups nursed by dams fed by a low-carbohydrate diet have reduced levels of liver glycogen (16). It is likely that some factor circulates in the bloodstream at a concentration that varies with the nutritional state of the mother and exerts a controlling effect on lactose synthesis in the mammary gland (65). EFFECT OF PROTEIN-CALORIE MALNUTRITION ON THE DEVELOPING INTESTINE Tragically, malnutrition and diarrheal diseases are responsible for millions of infant deaths each year (66). Chronic severe protein-calorie malnutrition has a significant impact on the intestine of the developing child. The finding that the intestinal epithelium from animals with chronic malnutrition has increased permeability is of considerable clinical importance. This increase in porosity could lead to an enhanced fluid loss and contribute to the increased severity of diarrhea noted in malnourished children (67). A progressive decrease in the protein content of maternal diets is reflected in an increasingly severe effect on suckling litters, their survival, their body weight, their gut weight, and the protein content of the intestine (67). The protein and DNA content of the intestine and the total activity of a variety of small intestinal BBM enzymes decrease in pups as the maternal dietary protein content falls The intestines of pups fed to less protein than control pups on days are and contain less DNA than do the intestines of the control pups The more severe the dietary the more marked is the impact on the of the small intestinal and function in adult rats, after has alterations of intestinal by delayed normal BBM and enhanced glucose and acid transport of malnutrition in infant rats have a decrease in intestinal mass, alterations in patterns of intestinal and cell malnutrition during the early the maturation of the intestinal epithelium malnutrition in rabbits a reduction in small and weights intestinal and liver weights even when for body This that the impact of protein-calorie malnutrition on these is more severe than that on the animal in causes a reduction in the of cell and mucosal DNA There is a mucosa and a depression of the in human infants with severe protein-calorie malnutrition pups from mothers on a diet have reduced and is into the of small intestinal less and the rate of the is reduced development of the small intestine of is by marked variations in BBM activities that occur at the time of weaning (29). These changes include a in lactase activity and an increase in sucrase and In malnourished there is a delayed in BBM lactase activity as well as a rise in and sucrase activities These and observations in infant rats and rabbits that suggest that early nutrient maturation of BBM The specific activities of BBM sucrase and are lower in the whereas lactase activity is higher in the of malnourished animals with healthy activity is or increased in several adult rats to to or to protein weaning rats and malnourished suckling rats The specific activity of an normally associated with cell in the intestinal is in the distal of the malnourished rat pups In the in development of mucosal activity caused by early malnutrition rapidly with the of nutrition A of refeeding to of intestinal mucosal mass, and mucosal function in malnourished infant The gastrointestinal epithelium is exposed to a continuously changing composition of intraluminal and this may the and function of the intestinal The composition of the nursing mother's diet influences the composition of her milk, which in influences the expression of and transport functions in the intestine of the suckling Thus, the diets of both the mother and the child are important for the normal development of the intestine.