Several investigators, using breath H2 tests for the demonstration of incomplete absorption, have observed limited small intestinal uptake of fructose given as a single dose in adults (1,2) and children (3,4). Unlike free fructose, the fructose moiety in the disaccharide sucrose is well-absorbed, and so is fructose when ingested with an equimolar amount of glucose (2,3,5) or galactose (3). At the moment, the mechanism of this facilitating effect of glucose on fructose absorption, which is dose-dependent (2,3,6), is not adequately understood. In rats, the study of Fujisawa et al. suggested that equal quantities of fructose and glucose (or galactose) could use a sucrase-related transport system; acarbose, a blocker of brush-border α-glucosidases, inhibited the glucose-facilitated fructose absorption (7). An alternative explanation is that, under these circumstances, fructose profits from the water movement caused by the uptake of glucose through the well-defined glucose-transport systems, especially the glucose-Na+ cotransporter.
Sorbitol, which is also a part of natural foods, is incompletely absorbed at a rate much slower than that of fructose (8). When sorbitol is given as a single oral dose, the intestinal absorptive capacity has been estimated to be no more than 2-10 g (9-12); furthermore, it has been suggested that, when given together, sorbitol and fructose compete for absorption (12). As perfusion studies have indicated similar kinetics of absorption (8), Rumessen and Gudmand-Høyer suggested a common carrier for fructose and sorbitol (12). In one study, sorbitol absorption was shown to be enhanced by glucose (13), but these results were disputed (14).
The present study was conducted to investigate more closely the mechanisms influencing fructose and sorbitol absorption. We reasoned that acarbose could be used to ascertain the existence of a sucrase-related transport system in humans (7). On the other hand, if the effect of glucose on absorption is mediated by water movement, amino acids should show similar effects (15). Such studies have not previously been performed in humans.
SUBJECTS AND METHODS
The study group consisted of 15 randomly selected healthy children who had no history of GI symptoms or recent therapy with antibiotics or laxatives. All participated in a number of tests recording breath H2 excretion as an indicator of carbohydrate malabsorption following ingestion of various combinations of sugars and amino acids. The amino acids used were those that are absorbed through Na+ -coupled transport systems: L-alanine, L-phenylalanine, L-glutamine, and L-proline, all of which are transported by separate systems (16).
To limit the number of tests per child—and because the adverse effects of sorbitol and acarbose, that is, diarrhea and abdominal pain, could be a greater problem in younger children—we choose to perform some tests in well-informed older children only. The fructose tests were confined to the younger children because of their anticipated higher H2 production (4). Three groups were created (Table 1).
Group I consisted of five older children (two boys, three girls; age, 11.1-18.2 years; mean, 14.6).
For the sorbitol, sorbitol-fructose, sorbitol-glucose, and sorbitol-alanine tests, 10 g of sorbitol 20% was given separately and in combination with a deliberate fivefold excess of the other component of the mixture: 55 g of glucose 20% (equimolar to 50 g of fructose), 27.5 g of L-alanine (equimolar to 50 g of fructose), or 50 g of fructose 20%.
For the acarbose-sucrose and acarbose-fructose-glucose tests, tablets containing 200 mg of acarbose (Glucobay, Bayer Pharmaceutical Company, Wuppertal, Germany) were chewed and swallowed immediately before the ingestion of the test solutions, which contained either 47 g of sucrose 20% (equimolar to 25 g of fructose) or 25 g of fructose 20% plus 27.5 g of glucose 20%.
Group II included 10 children (five boys, five girls; age, 1.6-8.3 years; mean, 5.3).
For the fructose, fructose-glucose, and fructose-alanine tests, all children were given 2 g/kg of fructose 20% (maximum of 37.5 g), alone and in combination with equimolar amounts of glucose or L-alanine—i.e., 2.2 g/kg of glucose 20% or 1 g/kg of L-alanine 20%.
Five of the children in group II (group IIa) were also tested with 2 g/kg of fructose 20% in combination with alanine 20% at half of the original dose (0.5 g/kg) or with L-glutamine 20% in an equimolar amount (1.6 g/kg).
The other five children of group II (group IIb) were tested with 2 g/kg of fructose 20% in combination with equimolar amounts of L-phenylalanine 20% (1.85 g/kg) or L-proline 20% (1.3 g/kg).
All amino acids were obtained from Merck (Darmstadt, Germany). After an overnight fast of at least 10 h, a breath H2 test was performed after the subject drank one of the test solutions (in random order), with at least 2 days between tests. Before ingestion and at 30-min intervals thereafter, end-expiratory 20-ml breath samples were collected in duplicate. The total sampling time was 180 min in group I and 150 min in group II. H2 was estimated using the Lactoscreen breath tester (Hoek Loos, Rotterdam, The Netherlands), which measures H2 content of samples with an accuracy of 1 ppm. A breath H2 increase of ≥20 ppm over basal values was considered indicative of incomplete absorption. During the test and for 4 h thereafter, the children or their parents were asked to record any symptoms of diarrhea, gas, bloating, or cramps.
The studies were approved by the local ethical committee. Informed written consent was obtained from the parents. The results are expressed as means ± SD as well as 95% confidence intervals (CIs). Statistical analysis was done with the Student t test for paired data (two-sided).
Sorbitol ingestion resulted in H2 production in all children tested, as witnessed by peak H2 concentrations of 115 ± 54 ppm (95% CI, 47-182; Fig. 1). The addition of glucose to the sorbitol solution resulted in significantly lower peak H2 concentrations (42 ± 25 ppm; 95% CI, 11-74); this effect was even more pronounced in the L-alanine-containing solution (7 ± 5 ppm; 95% CI, 1-13; Fig. 1). Figure 2 illustrates breath H2 excretion following the three test solutions as a function of time. At the end of the test, breath H2 concentrations were significantly lower in the sorbitol-L-alanine solution than in the sorbitol-glucose solution. The H2 responses obtained following ingestion of the sorbitol-fructose solution were higher than those following sorbitol, but the difference did not reach significance. Adverse reactions to the solutions were only noted in two children following the sorbitol-fructose mixtures; they experienced abdominal discomfort and diarrhea.
Acarbose pretreatment resulted in positive breath H2 tests in all children following the sucrose solution (62 ± 18 ppm) but not the fructose-glucose solution (2 ± 1 ppm; Fig. 3). The acarbose-sucrose tests caused mild symptoms with abdominal pain, flatulence, and diarrhea in all five children tested, while no problems were noted with the acarbose-fructose-glucose solution.
All 10 children had positive fructose breath H2 tests (68 ± 38 ppm; 95% CI, 41-95); glucose addition resulted in a significant decrease of breath H2 excretion (8 ± 10 ppm; 95% CI, 1-15; Fig. 4). An even more positive effect on fructose absorption was obtained with the addition of an equimolar dose of L-alanine (3 ± 3 ppm; 95% CI, 1-5; Fig. 4). On further evaluation, with tests performed in five children each, the solution containing half of the previous L-alanine dose was shown to promote fructose absorption as well (17 ± 4 ppm; 95% CI, 12-22), as did the other amino acids tested: L-glutamine (21 ± 12 ppm; 95% CI, 6-36), L-phenylalanine (8 ± 9 ppm; 95% CI, 0-19), and L-proline (19 ± 16 ppm; 95% CI, 0-39; Fig. 5). For all of these experiments, symptoms were only noted following the ingestion of the fructose solution, with six children experiencing mild abdominal symptoms with pain and diarrhea.
In the human diet, fructose is present mainly as a constituent of the disaccharide sucrose (17). In its free form, fructose is present in fruits, vegetables, and honey (18). Due to the development of an inexpensive industrial process for enzymatic conversion of corn starch into fructose, high-fructose corn syrups are used as sweeteners in soft drinks and other commercial food products. The Western diet includes an increasing amount of industrially added sugars and a growing percentage of free fructose (19,20). The notion that fructose absorption is far more limited than absorption of glucose and galactose is recent (1,3). Fructose malabsorption has been suggested to be a cause of chronic nonspecific diarrhea in toddlers (21). Interestingly, the degree of fructose malabsorption seems to be higher in this age group (4).
Sorbitol is also a natural constituent of several foods, including certain fruits and fruit juices, but the average daily intake from natural sources has been estimated to be as low as 0.2 g (22). As sorbitol, like xylitol, is a very popular sweetener in so-called sugar-free food products, the actual daily intake can mount to 10 g or more. Sorbitol, which is believed to be absorbed through a passive mechanism (8,13), may also cause abdominal pain and diarrhea in children (23,24) and adults (9,10).
The absorption of fructose was the subject of extensive studies in laboratory animals in the 1970s (25-28). Fructose was shown to be absorbed at rates faster than could be accounted for by passive diffusion alone, and an Na+-independent carrier-mediated mechanism was suggested (25-29). In recent years, strong evidence has been produced that fructose enters the cell through GLUT5, a specific fructose transporter expressed on the apical membranes of the enterocytes in the human small intestine (29-31). However, sucrose and fructose-glucose breath H2 tests have been interpreted to suggest a different pathway for fructose absorption. The presumed disaccharidase-related, high-capacity, glucose-dependent fructose cotransport mechanism (2,3) could represent a logical adaptation in the course of human evolution as fructose and glucose occur together in many natural food products.
It has been shown that diets high in sucrose and diets high in fructose increase human jejunal disaccharidase activity (32). Acarbose is a competitive inhibitor of small intestinal α-glucosidase. It interferes with the digestion of sucrose and starch (33) without affecting glucose absorption (34). In the rat, sucrase isomaltase inhibition by acarbose was shown to counteract the facilitating effect of glucose on fructose absorption, but the ensuing H2 production was highly variable and decreased with repeated administration of the test solutions to the same animal, necessitating the use of a different group of animals for each experiment (7). In contrast to these results obtained in rats, our results clearly show that in children, acarbose pretreatment has no effect on fructose absorption from a fructose-glucose solution, which is against the theory of a disaccharidase-related transport system for combinations of fructose and glucose.
As sorbitol is absorbed at slower rates than is fructose, we deliberately used a higher-than-equimolar dose of glucose to study its influence on sorbitol uptake. Thus, sorbitol absorption is stimulated by the presence of glucose in a similar way as occurs with fructose. Beaugerie et al. (13) studied sorbitol absorption in vivo with high luminal glucose concentrations, using human jejunal tissue preparations mounted in Ussing chambers. Their results are in accordance with our data. Since, in addition we found (not significantly) higher breath H2 excretion with the sorbitol-fructose solution than with sorbitol alone, our findings tend to underline the suggestion of Rumessen and Gudmand-Høyer (12) concerning competition for the same transport mechanism between fructose and sorbitol. In this respect, it would be very interesting to know whether GLUT5 is involved in sorbitol transport.
Our experiments investigating the effects of equimolar solutions of amino acids on fructose (and sorbitol) absorption provide an alternative explanation for the facilitating effect of glucose. We suggest that the facilitating effects of glucose as well as of amino acids on both fructose and sorbitol absorption are a consequence of the water flow through the apical membrane, which is generated by Na+-coupled substrate transport (35). On one hand, there is the so-called solvent drag, the force that requires that water and solute (i.e., fructose) traverse the mucosa through the same pathway (35). On the other hand, the increase in intraluminal fructose concentration caused by water removal from the lumen, also caused by actively absorbed substrates, might lead to increased transport of fructose. These two mechanisms together have recently been shown to account for 99% of glucose-stimulated D-xylose absorption (35). Therefore, the previously established dose-related enhancement of fructose transport by glucose would not be explained by a direct molecular relationship but by the fact that the increases in water flux also are dose-dependent.
Most amino acids are transported at the apical membrane by Na+-dependent carriers that are distinct from the monosaccharide-Na+ cotransport carrier (16,36,37). Both glucose and amino acid absorption, therefore, result in important water movement (15). The effects on water flow of alanine and glycine addition to oral rehydration solutions has been tested extensively in animals (38,39) and in humans (40,41). Both amino acids have a similar promoting effect on water absorption. The passage of amino acids from the small intestinal lumen to the blood involves transport through apical and basolateral membranes as well as paracellular routes (37). Multiple pathways have been established with different specificities (16,36,42). The L-alanine transporter is the Na+-dependent apical NBB system, which is responsible for the majority of neutral amino acids (43). Another transporter, the PHE system, which is less active than the NBB system, is responsible for the uptake of the neutral amino acid L-phenylalanine (42). The Na+-dependent IMINO carrier is highly specific for L-proline transport, but it too is less active than the NBB system (43). Finally, L-glutamine, which is the primary metabolic fuel for the enterocyte, is efficiently absorbed by the human small intestine with kinetic parameters approaching those of glucose (44). In contrast to alanine, glutamine equally stimulates electrogenic and electroneutral NaCl absorption (45).
Although it is clear that the active mucosal transport of these amino acids results in substantive water absorption, there are no data available with regard to the relative efficacy of the various amino acids. There may be a general rule that amino acids absorbed at higher rates result in the absorption of more water. This would be in accordance with our finding that L-alanine improves fructose absorption better than other amino acids do and that L-alanine has an even more profound effect on the absorption of fructose and sorbitol than has glucose. As is shown in Figs. 2 and 4, which exhibit breath H2 excretion as a function of time, glucose addition results in a minor peak at the end of the test that is not seen with L-alanine. An additional explanation for this difference may be found in the absorption profiles of glucose and L-alanine, as protein (42,46) and amino acid absorption (42) is more evenly distributed along the whole of the small intestine than is glucose absorption, supporting fructose absorption over a longer distance.
Theoretically, the inhibition of H2 production by the colonic flora in the presence of L-alanine, which in this dose might be incompletely absorbed, could be an alternative explanation for the lack of H2 response following the fructose-L-alanine mixture, In healthy adults, however, 27.5 g of L-alanine did not prevent the increase in breath H2 excretion following ingestion of 20 g of lactulose (unpublished observations), which excludes such a mechanism.
In conclusion, our results cast doubt on the existence of a sucrase-related fructose-transport system as an explanation for glucose-facilitated fructose absorption. It would rather seem that the enhancing effect of glucose is nonspecific as it is exhibited also by amino acids. The enhancement could therefore be better explained by the effects of water movement across the brush border induced by Na+-coupled substrate transport, either due to pure “solvent drag” or to a positive influence on fructose transport. The nonspecific nature of this kind of facilitation could also help to explain the fate of fructose and sorbitol in human nutrition, because it would explain why both sorbitol and fructose are better absorbed when given in a meal than in a solution (47).
Acknowledgment: We thank Gerald Staaks for technical support and Dr. C. M. Frank Kneepkens (Amsterdam, The Netherlands) for critically reviewing the manuscript. This study was supported by a grant from the Peribosch Foundation.
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