In infancy the diet undergoes a change, from a single food with fat and lactose as major energy sources, to an increasing variety of foods in which starch is the principal source of energy. Many weaning foods are cereal-based, and starch represents a novel nutrient to the digestive system of the hitherto exclusively milk-fed infant. Much of the thrust of recommendations on infant feeding has focused on the benefits of breast-feeding in establishing optimal nutrition in early (1). The importance of weaning has received less emphasis (2,3). The purpose of this review is to summarise what is known about the digestibility of starch and how well the young infant can make use of dietary starch during weaning.
Weaning may be defined as the period from first introduction of a nonmilk diet to the cessation of breast-(or formula-) feeding. In some rodents there are abrupt and clearly definable changes in the gut's capacity to digest nonmilk carbohydrates at weaning, such as a surge in enterocyte proliferation and the expression of sucrose-isomaltase activities (4). However, in the human infant, the physiology of the digestive system is less well understood, particularly the timing of the processes involved in adaptation to a nonmilk diet.
Complex carbohydrates are polymers of sugar molecules. Those with 10 or fewer sugar residues are called oligosaccharides, and those with 10 or more are called polysaccharides. Polysaccharides can be very large polymers, which are natural or synthetic. Examples of natural polysaccharides include dietary fibre (nonstarch polysaccharide) and starch. Synthetic glucose polymers, made by modifying natural products, can be used to increase the energy content of formulas.
Starches are plant storage complex carbohydrates with molecular weights often exceeding 100 kDa, which comprise glucose polymers with α1,4 amylose (straight-chain) and α1,6 amylopectin (branched-chain) linkages. The proportions of amylose and amylopectin vary between different starches, as does the size and shaped of the storage granules. Three crystalline forms of starch, A, B, and C, are recognised that differ in their digestibility (5). Type A (e.g., raw wheat or rice starch) has an easily digestible, open-helical structure. The densely packed hexagonal pattern of the double helices of the B type (e.g., raw potato starch) reduces digestibility by denying access to amylases (5,6) (Fig. 1). Type C (e.g., peas or other legumes) is considered to be a mixture of types A and B.
Starches have also been classified empirically by their digestibility in vitro, into rapidly digestible, slowly digestible, and resistant forms (6) (Table 1). Rapidly digestible and slowly digestible starches are digested completely in the small intestine, whereas resistant starch is defined as the sum of starch and the products of starch degradation that are not absorbed in the small intestine of healthy adults (7). The digestibility of starch is determined by its structure, the kinetics of oligosaccharide release from the starch after hydrolysis (8), and the degree of inhibition of α-amylase in vitro by other nutrients such as leguminous glycoproteins and antinutrients such as tannins (9). All three starch types (A, B, and C) can be rapidly digested in the cooked state. Types B and C are more likely to form retrograded starch on cooling or during processing. Retrogradation is recrystallisation of starch to an indigestible product, which may occur during cooking and cooling cycles or under processing conditions of high moisture, pressure, and temperature. Studies of the digestibility of starches in vivo have been largely confined to adults (10,11). In infants the lower luminal pancreatic α-amylase concentrations give rise to an increased proportion of resistant to digestible starch.
There is a wide range in digestibility of commonly used first weaning foods in vitro. Rice starch is rapidly digestible. Freshly cooked potato is also rapidly digestible but may become retrograded and resistant and resistant if cooled after cooking. Sterilising techniques in the canning of commercial weaning foods may considerably increase the resistant starch content of the diet of the young child (12), and the consequent effects on energy absorption and growth potential are unknown (13).
Recently, some benefits of resistant starch in infant diets have been identified. In preterm infants, formulas that contain maltodextrins are associated with increased calcium absorption (14), believed to be caused by enhancement of passive absorption (15). In infant pigs, this same effect, attributed to resistant starch, also leads to increased absorption of iron, and possibly zinc (16). Counterbalancing this is a concern that resistant starch, particularly the lower molecular weight portions escaping digestion in the small intestine or after hydrolysis by the colonic microflora, can generate an excessive osmotic load in the large bowel (17), leading to diarrhoea in infancy.
Breakdown of starch begins in the mouth under the action of the glycoprotein enzyme α-amylase, which is secreted in saliva and human milk and cleaves the α-1,4 linkages in the starch molecule. α-Amylase is inactivated by gastric acid, but digestion continues in the alkaline duodenal lumen, where the salivary isozyme is reactivated, and further α-amylase is secreted by the exocrine pancreas. The products of this digestive step are maltose, isomaltose, maltotriose, and maltodextrins (branched-chain oligosaccharides) which undergo further digestion in the brush border of the jejunal mucosa where free glucose is liberated by the action of glucoamylase, maltase, and isomaltase. Glucose is thereafter actively transported across the mucosa.
Breast Milk Amylase
Human milk contains α-amylase, which may help breast-fed infants to digest starches in early weaning. It is structurally identical with salivary amylase but has a broader pH optimum and retains its activity in the stomach (18). There are large interindividual variations in breast milk concentrations, but associations have been found with gestational age at birth (mothers who deliver prematurely have highest activity) (19) and parity (decreased with increasing parity) (20). Human breast milk amylase is found in its highest concentrations in colostrum (19) and decreases thereafter during the course of lactation (20).
Salivary amylase is detectable from 20 weeks' gestation (21). Its activity increases rapidly after birth to reach near adult levels from 6 months to 1 year (22), but there is large interindividual variation (23). It is inactivated by low pH but remains active in the poorly acidified neonatal stomach where the pH may be more than 4 until 3 to 4 weeks (24), and where it is also protected by binding to small-chain glucose polymers (25). Salivary amylase may serve an important role in the young infant in whom there is a physiological deficiency of the pancreatic isozyme, and it has been proposed that the small amounts of amylase detected in the duodenum of young infants (26) may be of salivary origin (27).
The physiology of the neonatal gastrointestinal tract is different from that of the adult (Fig. 2) with most digestive enzymes found at lower concentrations. Pancreatic α-amylase concentrations in the neonatal duodenum are much lower than in adults (26,27) (Table 2). Serum concentrations at birth are 1.6% of adult levels and do not reach mature levels until 5 to 12 years (28). Explanation for low duodenal concentrations of pancreatic α-amylase may be low synthesis or secretion of the enzyme. Seventy years ago, the existence of α-amylase in the fetal pancreas from 22 weeks' gestation was reported (29), but more recently, none was found in the pancreas of 3-week-old infants (30). Pancreatic α-amylase has been detected in the amniotic fluid from 16 weeks' gestation (30), although in much reduced concentrations compared with salivary amylase (31). Pancreatic fluid and electrolyte secretion increase in response to secretin and cholecystokinin (32), but specific assays for α-amylase show that infants under 1 month are unresponsive to cholecystokinin and have only a minimal response to secretin (27). However, the plasma concentrations of gastrointestinal hormones, including secretin, are themselves low until the sixth day of life (33). The question remains therefore, whether in early infancy, there is low synthesis or secretion of α-amylase, low production of, or response to, secretagogues, or a combination of all these factors.
Small Intestinal Brush Border Enzymes
The small intestinal brush border enzymes catalyse hydrolysis of oligosaccharides and disaccharides to glucose. They are considered as two complexes, sucrase-isomaltase and glucoamylase-maltase, with differing specificities for α-1,4 or α-1,6 bonds and for oligosaccharides of different sizes (34). Glucoamylase-maltase has a maximal affinity for straight-chain glucose polymers of between five and nine residues (35). Sucrase-isomaltase has maximal activity against maltose and maltotriose, as well as α-1,6 bonds (34). Enzyme activity is detectable in fetal life (36-39,40) with a marked third trimester increase such that at birth their activity is comparable with that of adults (41,42). In the early months of postnatal life, glucoamylase-maltase may help compensate for the physiological lower concentrations of pancreatic α-amylase if an infant is fed starch at this age (43).
Regulation of Starch Enzymes
Dietary starches may increase the concentration of pancreatic α-amylase. Higher duodenal concentrations of amylase in term and preterm infants were found in response to starch (26), but the difference in concentrations before and after ingestion were negligible in comparison with concentrations in older children. In functional studies there are discrepant results. Shulman et al. (44) found greater absorption of glucose polymers with age and increased duration of feeding. Senterre (45), however, found no increased absorption of starch after prolonged administration in low-birth-weight infants. The two studies used similar subjects but different techniques, making direct comparisons difficult. There appear to be no published studies regarding the induction of salivary amylase or glucoamylase by dietary starch.
A late gestational maturation of glucose transport is suggested by a review of several glucose perfusion studies (46). Glucose transport in the newborn small intestine per unit length is a quarter that in adults (47). This is probably the result of a relatively small mucosal surface area, less glucose transporters, or limited active transport capacity. However, this does not appear to be a rate-limiting process, nor is there evidence that starch or oligosaccharides can be transferred across the intestinal mucosa during the immediate neonatal period when the gut is more permeable to some molecules (48)
COLONIC FERMENTATION OF STARCH
Endogenous bacteria in the large intestine, principally in the proximal colon where substrate availability is highest may ferment carbohydrate that escapes digestion and absorption in the small intestine. Many nutrients reaching the colon can be substrates for fermentation, but of these, starch and dietary fibre (nonstarch polysaccharide) are thought to be of most biologic significance.
The adult colonic flora is a stable population of up to 400 different bacterial species (49). During infancy, there is a continuous evolution of the bacterial flora (50), influenced initially by the type of milk fed. A difference is first evident between the faecal bacteria of breast- and formula-fed infants by 7 days, with significantly greater counts of Bacteroides fragilis isolated from the stools of the latter (51). Later, the flora of breast-fed babies contains less facultative anaerobes and more lactobacilli and bifidobacteria (52,53), in particular the bifidobacterial species Bifidobacterium longum and B. adolescentis(54). Weaning introduces starch and other novel food-stuffs that are less digested in the small intestine, resulting in further changes to the colonic environment that favour the development of an adult-type flora. The microflora of breast-fed infants is more immature, and there is an increase in certain anaerobic species such as Bacteroides after the introduction of a diet containing starch, oligossacharides, dietary fibre, and pathogens (55). This may account for the vulnerable period soon after the cessation of breast-feeding when infants are more susceptible to dehydrating diarrhoea (56), quite apart from the risk they face from contaminated complementary food (57).
The products of fermentation include gases (hydrogen, carbon dioxide, and methane), lactate, and short-chain fatty acids (SCFA). Because the colon is the home of such a multitude of diverse and interdependent bacterial species, it is at present impossible to identify the contribution of each to the fermentation reactions taking place. The principal polysaccharide-degrading bacteria are Bacteroides spp (58) although bifidobacteria, more common in the infant colon, are also capable of degrading polysaccharides (59).
Short-Chain Fatty Acids
The main SCFAs produced by colonic fermentation are acetic, propionic, and butyric. Most studies have been conducted in adults in whom it has been calculated that SCFAs are usually generated in the respective molar ratio of 60:20:18 (60). Both direct measurements of SCFA from dialysis bags in vivo (61) and estimates of SCFA production in the colon, in combination with measurement of their faecal concentrations (62), show that they are rapidly and well absorbed in the human colon, probably in their nonionised form by concentration-dependent passive diffusion (63).
Butyrate has been shown to be a preferential fuel for colonic epithelial cells in adults (64,65), although much less is detected in infant faeces (66). Significant amounts of propionate and acetate are transported to the liver, where they may be oxidised or used for gluconeogenesis (propionate) or the synthesis of long-chain fatty acids (acetate). Almost all propionate and butyrate reaching the liver is utilised there, but acetate can be further transported and utilised in peripheral tissues, such as muscle (67).
A small but significant amount of energy is gained by the colonic absorption of SCFA. In animal studies the partial utilisation of SCFAs has been shown to be 82% from intracaecal infusions, and most of it is retained as fat (68). In adult humans the energy is estimated to be approximately 2 kcal/g of nonabsorbable carbohydrate (69) or a contribution of 5% to 10% of energy requirements (70,71). Kien et al. (72) estimated that 24% to 74% of lactose may be converted into acetate in preterm infants with a potential 30% loss in adenosine triphosphate (73), but there appear to be no data on energy salvage from fermentation of starch in infancy at a time when the limited digestive capacity of the small intestine means that more starch will pass undigested into the colon.
Studies of the effects of SCFAs have been carried out almost exclusively in animals or in adult humans in whom some properties are related to all the SCFAs and some attributed to specific ones (74,75). All SCFAs appear to have trophic effects on the gastrointestinal mucosa, both in the upper and lower gut (64,67,76,77). Butyrate is the preferred fuel for colonocyte metabolism (64,78) and may protect against colonic cancer (79), although this may not happen at physiological concentrations (80). Propionate has been associated with cholesterol-lowering effects (81,82). Basal levels of insulin and glucagon are suppressed by increased loads of SCFA in ruminants (83), and although their metabolism differs considerably from that of humans, similar increases in insulin sensitivity have been demonstrated in humans (84). Insulin has anabolic effects in the human infant, and it is possible that by this means, starch fermentation may indirectly influence growth (73).
Development of the Fermentative Ability of the Infant Colonic Flora
Bacterial populations and diet influence fermentation products. Different components of the diet encourage the growth of particular bacterial species. The faecal flora of formula-fed infants produce more propionate than that of breast-fed infants (85). Fermentation reactions are directly affected by the substrate; for example, butyrate is preferentially produced by the fermentation of resistant starch (86,87). The capacity of infants to ferment complex carbohydrates does not increase significantly until 7 to 9 months (88). In infants before weaning, fermentation products are mainly acetate with small amounts of propionate and n-butyrate. By 9 months the mean faecal concentrations of acetate, propionate and n-butyrate are as high or higher than adult values (88).
The net effect of the fermentation of polysaccharides to SCFA is an increase in the osmotic load within the colon, although unfermented, resistant starch itself causes an increased osmotic load. If the capacity for SCFA absorption is limited, then diarrhoea results, but in young piglets the presence of SCFA in the colon enhances water and sodium absorption (89). Absorption of SCFA from the colon of adults is rapid, and more than half of 14C-labelled SCFA appears in the breath within 6 hours (90). Lifschitz et al. (91) demonstrated that colonic acetate absorption in malnourished infants increases with age, but there are few other human studies of the development of colonic absorption of SCFA.
FUNCTIONAL CAPACITY FOR DIGESTION AND FERMENTATION OF STARCH IN INFANCY
Various methods have been used to measure the digestion and absorption of starches in early life. These include measurement of blood glucose, balance studies, and the use of 13C stable isotope breath tests. Studies have been mainly performed in infants aged 1 month or less, often born prematurely, whose formulas contain glucose polymers to increase energy content. There is a glycaemic response after the ingestion of corn starch (92), glucose polymers (93), and lactose in term and preterm (94) infants. By measuring the intake of starch and the amount of residual starch in faeces, investigators have attempted to draw conclusions about whole-gut digestion with conflicting results (17,95). Such studies require meticulous measurements and do not usually take into account losses from methane and CO2 production. Results of total gut balance studies show that the individual contributions of upper and lower gut to starch digestion cannot be distinguished.
Calculations of intake and stool carbohydrate output are made easier by the use of starches enriched with the stable isotope 13C, but inconsistencies in results of balance studies have suggested a potential confounding effect from the excretion of bacterially derived carbohydrate, either contained within the cell walls or as fermentation product (96,97). Concomitant measurement of breath hydrogen allows estimation of the amount of starch that reaches the colon. Hydrogen is a bacterial fermentative product and cannot be produced by mammalian cells. The hydrogen breath test has been used in young infants to investigate the fermentation of lactose (98), although it may be difficult to use quantitatively (99), particularly in young infants (100). Shulman et al. (101) used it semiquantitatively to measure the utilisation of corn cereal in young infants, including information on the site of utilisation. Although young infants clearly possess the functional capacity to digest starch, this may be associated with a relatively decreased absorption of energy and nitrogen (102), highlighting the limitations of studying the digestion of a single nutrient alone.
There is much still to be learned about the ontogeny of the gastrointestinal tract during the weaning period and its capacity to make use of dietary starch. Existing work has focused mainly on the site or mechanism of starch digestion, but there is plainly a need to define the contributions of the small and large intestines and to quantify the various fates of different starches in infants of different ages.
The emergence of stable isotope biotechnology (103) to measure nutrient digestion in vivo offers a means of studying the fate of ingested starch. Because stable isotopes are nonradioactive, 13C breath tests are safe, and sampling breath rather than blood makes them particularly attractive for the study of infants (104,105). The appearance of 13CO2 in the breath after the ingestion of a particular substrate labelled with 13C depends upon exogenous and endogenous factors that control the digestion, absorption and metabolism of that substrate. The ratio of 13CO2:12CO2 in breath can be measured by isotope ratio mass spectrometry and, assuming constant or complete oxidation of the products of digestion or fermentation, the site, rate and extent of starch digestion and absorption quantified. 13C breath tests have been used by several investigators to measure starch digestion in the small intestine (101) or fermentation in the colon of infants (72,91). Their potential as a tool for the study of the digestion of starch in the whole gut is underrealised. Shulman et al. (101) reported 13CO2 recovery curves over time without remarking on their shape, which showed later maximal abundance of 13CO2 and the suggestion of a more twin-peaked curve with increasing carbohydrate complexity (Fig. 3). Amarri et al. (106) noted a similar twin-peaked curve in their study of starch digestion in children with cystic fibrosis using 13C-labelled wheat flour biscuits and speculated that the second peak represented 13CO2 derived from oxidised SCFA as a result of colonic fermentation of the starch.
This biotechnology enables the use of mathematical models to analyse whole-gut starch digestion curves. Mathematical models have been used in gastric emptying studies (107), adapting an equation that forms the basis of the χ2 distribution. Assumptions about curve interpretation would be strengthened if a gold standard for colonic absorption could be found. There is some hope that lactose-ureide, a synthetic condensation product of lactose and 13C-labelled urea, which resists breakdown by small intestinal enzymes (108), may provide such a standard.
Another way of quantifying the colonic fate of starch is by stoichiometry-calculation of the numerical relationship between the molecular species entering a chemical reaction and the amount and type of molecules produced. Stoichiometric equations for carbohydrate have been produced for adult humans and ruminant animals (69,109), based on known proportions of SCFAs in faeces and known production of carbon dioxide and methane. From these, the energy derived from fermentation reactions can be calculated: 34.5 C6H12O6 → 48 acetate + 11 propionate + 5 butyrate + 23.75 CH4 + 34.25 CO2 + 10.5 H2O
Energy calculations have been made on the whole gut by balance studies, separating the carbohydrate from the fat and protein component of stool and then calculating carbohydrate energy absorption (102,110). An attempt to quantify energy absorption by site of digestion was made for lactose using a stable isotope dilution method to measure the rate of entry of acetate into the peripheral circulation (72), and from the results, energy uptake was estimated from known thermal losses of potential adenosine triphosphate (110). The results show wide variability. A more complex whole-gut model could be developed by combining stoichiometry from fermentation models with data from stable isotope breath tests, and carbohydrate energy source quantified for infants of different ages.
Energy from SCFA produced as a result of colonic fermentation of starches is variously considered as loss (111) or gain, as though the infant small intestine were an inefficiently functioning organ (73,110). However, the small intestinal digestion and colonic fermentation that occur in the infant are interrelated physiological processes that together ensure efficient overall gut function. The need to understand the individual proportions of carbohydrate energy derived from small intestine and colon is underlined by observations that SCFA may have important effects on energy balance and growth by influencing insulin concentrations (73).
In the most recent United Kingdom guidelines (3) it is recommended that weaning should begin between 4 and 6 months and that the diet should contain adequate energy. Recommended first solid foods are nonwheat cereals. Cooked starches are advised in preference to raw starches because of their greater digestibility, and rice in particular is recommended. In comparison with the space given to recommendations for other nutrients, the small amount devoted to starches reflects the relative paucity of data in this field. Yet, the dramatic changes in the source of dietary energy at weaning and its potential metabolic effects suggest that this is an area that requires fuller understanding. A greater insight into the physiology of the infant gut, in particular the small intestinal digestibility of starch in vivo, its fermentability in the colon, the properties of SCFA, and the metabolic fate of starch, is needed to evaluate the overall nutritional value of different starches to define sensible and evidence-based weaning advice.
Acknowledgment: The authors thank Dr. Simon Ling for his helpful comments and The Nutricia Research Foundation and the Royal College of Physicians and Surgeons of Glasgow for their financial support.
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