Intestinal Fructose Absorption: Clinical and Molecular Aspects

Sweetening with sugars has long been a favorite means of improving the acceptability of foods. The use of sugar as a sweetening agent occurred relatively late in human history. Until the development of the sugar-refining industry, sweetening agents were largely limited to honey and fruits. Approximately 10,000 years ago, the first sugar cane appeared in Papua, New Guinea (1). There was a low spread from the originating area through Asia and the Arabic countries, and it was only after The Crusades, that sucrose in the form of cane sugar became available in Europe. Later, Columbus introduced it in the New World. It was only 200 years ago that the beet root was recognized as a source of sucrose, and in Europe many factories emerged. For the production of fructose, the United States has relied principally on sugar cane (1). The political problems in the 1960s with Cuba prompted many North American companies to replace sugar cane with a substitute. At that time, technical advances made it possible to use cornstarch to produce corn syrup as a sweetening agent. With changes in lifestyles that rely more on mass production of packaged foods, increasing amounts of simple sugars are now added to processed foods and beverages (2,3). Fructose in free form, or contained in sucrose, is appreciated for its taste and is the sweetest of all naturally occurring carbohydrates (4). In addition, fructose can enhance the perception of sweetness of other sugars. The combination of sweetness, low cost, and stable supply has made high-fructose-containing syrups (HFCS) a favored substitute for sucrose (3,5). The intake of HFCS is expected to surpass sucrose in the next decade as the primary sweetening agent of food (3). Efficient technology may further result in a change from HFCS-42 (containing 42% fructose) to sweeter tasting HFCS-55 and even syrups containing 80% to 95% fructose. In these syrups, a higher fructose-to-glucose ratio adds to the sweetness and flavor profile (4). The ease of handling this liquid, low production costs, and advances in technology have accelerated its acceptance by food and beverage producers. Quite recently, the development of crystallization processes resulted in a new-generation fructose sweetener in dry form and thus new commercial applications (4). Natural products have a wide range of fructose, glucose, and sucrose content (6,7). Over the past decades a small increase in the consumption of fructose from natural sources such as fruits, vegetables, and cereal products has been noted (3). In certain populations the increase is even more pronounced, as in the consumption of fruit (apple) juice by toddlers (4,8). Natural foods contain only the D-fructose isomer. As a result of normal changes in feeding habits, mean daily fructose intake increases sharply after weaning. The highest body weight-adjusted intake of fructose occurs in toddlers (≈2.2 g/kg) (3). When mean fructose intake is represented as a percentage of total carbohydrate intake (16-20%) or as a percentage of total energy intake (7-9%) there is less of an age difference (3), although each age group has a wide range of intake. FRUCTOSE IN HEALTH AND DISEASE Absorption of ingested carbohydrates by the small intestine is accomplished through the coordinated expression of a variety of digestive and transport proteins that break down complex polysaccharides and effect the transcellular delivery of monosaccharides from the intestinal lumen to the blood. Three major dietary carbohydrates-glucose, galactose, and fructose-represent most ingested sugars. The physiology and pathologic mechanism of glucose and galactose transport have been reported on extensively (9-11), whereas fructose has been less well studied. Investigations of human fructose absorption must be separated into studies examining the absorption of free fructose from those investigating fructose ingested in combination with other actively transported solutes. The other solutes may be free monosaccharides, in particular glucose, either as the free sugar or as the disaccharide sucrose. Limited Absorption In contrast to glucose, it is clear that fructose is not absorbed in the intestine by an active sodium-dependent system (12). However, the rate of transport is greater than would have been expected from simple diffusion but much less than that seen with the actively transported sugars glucose and galactose (13-16). Fructose absorption is also associated with less water and sodium absorption than glucose absorption (13). In earlier perfusion studies, investigators clearly overestimated the absorptive capacity for dietary carbohydrates (13,14,17). Results in more recent studies in healthy adults and children have demonstrated a limited intestinal absorption capacity after ingestion of fructose. Using the well-established technology of hydrogen (H2) breath tests, which can detect small-intestinal malabsorption through the resulting colonic fermentation, studies are possible in larger groups of adults and children. Breath H2 tests after ingestion of a solution clearly show a limitation of small intestinal fructose absorption (18-21). Between 37% and 80% of otherwise healthy adults experience malabsorption of 50 g of fructose administered in a 10% solution, with even a greater percentage of malabsorption when fructose is provided in a 20% solution (18). Kneepkens et al. found incomplete absorption in 71% of a group of normal children aged between 1 month and 17 years after ingestion of 2 g/kg body weight, with a maximum ingestion of 50 g (19). Using a lower 1-g/kg dose we elicited the highest percentage of malabsorption and the highest peak H2 values in children aged 1-3 years (Fig. 1) (22).FIG. 1: (A) Mean (± standard error of the mean) of peak H2 excretion in children fed 1 g/kg or 2 g/kg fructose in six age groups. The number of children in each group is indicated under respective columns. (B) The percentage of children fed 1 g/kg or 2 g/kg fructose in each age group with peak breath H2 excretion of ≥20 ppm. (From Hoekstra et al. [22]; with permission.)Although the breath H2 test detects the fraction of fructose that is not absorbed, it is only semiquantitative. Carbohydrate absorption can also be studied by the use of carbon-labeled substrates. The 13CO2 breath test is based on the premise that metabolic processes directly convert part of the absorbed fructose into 13CO2 and excrete it in breath over time (23). However, in our experiments using fructose-13C-6 (99% enrichment), 13CO2 excretion in breath reflects not only the absorbed fructose fraction, but also the fraction formed as a result of colonic fermentation of unabsorbed fructose. Because both processes could not be separated over time, the 13CO2 breath test appears to be of limited value in studies of fructose absorption (23). Thus, although it reflects only malabsorption, we think breath H2 may provide a more reproducible method for studying intestinal fructose transport in people and populations. In another type of study, the 13C label was valuable for investigating internal fructose metabolism (e.g., the amount of glucose synthesized from fructose and fructose oxidation) (24). Among people with significant breath hydrogen production after fructose ingestion, symptoms of malabsorption may vary as a result of an adaptation of the intestinal bacterial flora. It appears that the colonic flora can efficiently process the nonabsorbed fructose with fermentation into short-chain fatty acids, hydrogen, methane, and carbon dioxide. These adaptive processes vary among people and may therefore account for the discrepancy in clinical symptoms produced by gas and acid in the colon (25,26). These adaptations are well illustrated in patients with congenital glucose-galactose malabsorption. Their main carbohydrate intake consists of free fructose, because its absorption is unaffected (16). In these patients, a high dietary fructose intake does not result in major symptoms, whereas hydrogen production remains high (27). In infants, viral gastroenteritis may result in extensive villus damage resulting in life-threatening intractable diarrhea with secondary intolerance of glucose-galactose, disaccharides, and polymeric glucose. In this situation, fructose was shown to be the only carbohydrate tolerated, illustrating good tolerance in an extreme situation (28). Absorption in Combination With Other Nutrients A number of studies have indicated that fructose absorption is greatly facilitated by the presence of glucose (13,21). These studies performed in man with intestinal perfusion techniques (13), breath hydrogen tests (19,21,29), and in the intact rat (30) demonstrate, that this facilitation occurs in a dose-dependent manner with maximal augmentation of uptake as occurs with an equimolar amount of glucose. This latter situation may reflect efficient absorption of the fructose-glucose disaccharide sucrose (15,20). Galactose has the same facilitating effect as glucose (19). Although investigators have suggested an important role for the enzyme sucrase-isomaltase for a facilitated fructose transport (20,30), our investigations in healthy children favor an alternative explanation (29). In contrast with results in the studies by Fujisawa et al. (30) in rats, sucrase-isomaltase inhibition by acarbose did not alter glucose-facilitated fructose transport in humans (29). In addition, we found that amino acids, in particular those that induce bulk water movements (e.g., L-alanine), resulted in significantly better facilitated fructose absorption when compared with that of glucose (Fig. 2) (29).FIG. 2: Breath H2 profiles of 10 children (age 1.6-8.3 years, mean 5.3) after ingestion of 2 g/kg fructose separately and in combination with equimolar amounts of glucose and L-alanine. (From Hoekstra and van den Aker [29]; with permission.)In our investigations with structurally related sorbitol, comparable results were obtained. We found an increased absorption of sorbitol by the coadministration of glucose and L-alanine (29). These data are consistent with the reported glucose-facilitated xylose transport (31). The facilitated fructose absorption probably occurs as increased fructose absorption as a consequence of glucose-induced water streaming through the mucosal layer. This process is known as solvent drag and traditionally requires the same paracellular pathways for water and solutes. Moreover, osmotic water absorption results in an increase in luminal fructose concentration caused by the removal of intraluminal water, which in turn may result in enhanced absorption by the intestinal fructose transporter. All these observations help to explain why both fructose and sorbitol are better absorbed in a meal than in a solution. Using breath H2 tests in adults with abdominal pain, Rumessen and Gudmand-Høyer (32) reported increased fructose malabsorption when structurally related sorbitol is coadministered. They suggested competition between sorbitol and fructose at the small intestinal transporter level. Alternatively, these results may also be explained by a laxative effect of sorbitol decreasing intestinal fructose absorption through increased transit. Chronic Diarrhea and Abdominal Pain Chronic nonspecific diarrhea or toddler's diarrhea is a prominent problem in this age group (33). Although the pathophysiology is not completely understood, dietary factors have been shown to contribute to the occurrence or persistence of symptoms (33). These children tend to consume high amounts of simple carbohydrates in liquid form, in particular apple juice, in which high fructose concentrations (≈60 g/l) are present. The observation that only elimination of this juice from the diet makes symptoms disappear focuses on fructose malabsorption as a primary pathogenic factor (34,35). As mentioned previously, fructose malabsorption is more pronounced in the typical age group for this condition (22). However, fructose breath hydrogen in these children failed to separate these patients from healthy controls and, more important, the group with toddler's diarrhea had no diarrhea in the hours after ingesting fructose (36). In a randomized clinical trial, a group of children with a diagnosis of toddler's diarrhea could tolerate cloudy (unprocessed) apple juice, whereas the (processed) clear apple juice resulted in re-appearance of diarrhea (37). The products differ in the amount of dietary fiber and the amounts of indigestible monosaccharides and oligosaccharides. Moreover, because the amounts of fructose (and sorbitol) were identical in both products, these studies question the role of fructose malabsorption in toddler's diarrhea and underscore the complex interaction between food ingredients (38). In a few children a specific defect of fructose transport has been reported (39-41). These patients had pronounced symptoms, with colicky abdominal pains and frequent diarrhea after ingestion of low amounts of fructose. The symptoms in these children resolved when they consumed a fructose-free diet. In addition, all had similar responses after sucrose ingestion, which suggests a sucrase-isomaltase deficiency, but measured jejunal disaccharidase levels were normal (39-41). These children may have rare but real, isolated fructose transport defects. Recently, details from a group of nine children with these symptoms were described (42). With advancing ages the symptoms in some of these children seem to improve. Patients with general monosaccharide malabsorption, including fructose, have been described directly after birth and also after severe, acute rotavirus gastroenteritis at young age (43,44). In these latter children, virus-induced villus atrophy seems to recover without a restoration of monosaccharide transport (43). This condition has a high mortality rate and most of the surviving children remain dependent on glucose (43,44). children and adults show a tolerance for fructose, with similar symptoms after ingestion of sorbitol In children and abdominal is reported more than For this condition the fructose tolerance seems to be more than fructose to this condition from fructose the metabolic caused by However, this fructose (and sorbitol) tolerance seems to a role in only a of patients with In children with abdominal we have no In a dietary may a between fructose and sorbitol tolerance and These children may a elimination of fructose and sorbitol from In a recent of patients with a tolerance for fructose was seen in combination with sorbitol and intolerance These observations more a general intestinal of or colonic fermentation than a primary transport of Fructose of dietary fructose the intestinal is through the The is a a in with the and a in with the Using rat the transporter for the luminal uptake of dietary fructose has been to be energy and for fructose a fructose transporter with a concentration for of to to the transporter to the sugar transporter and by the glucose transporter Fructose the by transport the Using rat the of fructose transporter has been to be energy and a of fructose and glucose and to and The data have shown that the absorption of dietary fructose is by the expression of the of these to suggests that they are of the of transporter and of and transport of in is by either the glucose transporter by a of the of transporter transporter have been and and and small has also been although this for a The intestinal were isolated from human and using a Using the human was and its to in the has also been and its to the of 1 in the The of and proteins containing to amino to 80% between with the the most For an to between rats, and has been and of and expression to be in human and intestinal In has in the lower and of the with expression in the villus and no expression in the was also in the although expression levels were intestinal studies found the transporter to be to the of with no expression in the or to were in the lower and of the with expression in the villus or However, studies have to be to the of with no expression in the or (Fig. of rat jejunal (A) and (B) and in of rat of from Hoekstra The small intestinal fructose of dietary perception and for and fructose with from role of intestinal and could not be transport were in have sugar transport capacity and have therefore provided a in the transport of the of the When and rat were in fructose uptake increased In contrast to the the increase in fructose uptake in was to and rat in transported a small amount of glucose, whereas human did not (Fig. The for the between the and data are It is possible that in the between alter the sugar and There is also that and are in For is for fructose in whereas in both fructose and glucose Although the and of these are investigators are this area of transporter In with the expression of human in an increase in fructose and glucose uptake which is by (Fig. of or by with water as a human and rat or human concentration was 1 and uptake time was The indicated were added at a concentration of significant in carbohydrate uptake compared with transport in the of (From et al. with is that dietary fructose is transporter into the through the Fructose is to the supply by the through the transporter (Fig. of glucose and fructose transport the of the small As the of glucose and sodium occurs through in the of the and through Fructose is transported the and through and Fructose the is by resulting in a increase in the of and the of of and The development of the can be into and These changes a number of digestive and to of in dietary content It has therefore been suggested that the development of the intestinal is of a For at the of the the rat intestine a significant increase in fructose transport the of dietary fructose These changes in fructose transport capacity have been to an in the expression levels of and In the intestine of rat and are from 10 expression the and and is from the In and expression levels increase the and levels of expression after weaning. In further of the of a high and diet did not the of expression expression is not clear to and are all although the is are and 80% of the In of this luminal intestinal processes increase in the of and glucose and This of expression appears to be to the daily process into and are also with a peak in expression occurring even with a fructose is as as and This suggests that is in Recently, have expression of to be at the In this the factor was suggested to be for in either or have to be The for the expression of and therefore remain and expression levels also vary over a with a peak in expression occurring at the of In contrast to expression levels are low the which suggests that at the the intestine is to dietary of carbohydrate transport in is and by the amount of sugar in the diet When were fed a to diet for a in luminal uptake of fructose was and that feeding a diet for significantly increased the maximum of fructose Because the in is also it has been suggested that dietary fructose is by the In of dietary glucose has also been shown to be by the We and have that feeding a diet significantly increases the intestinal and expression studies of and show and expression to be to the villus with no expression in the Thus, the intestinal to dietary fructose is to the with the of and to fructose. Although expression levels increase significantly hours of fructose the of fructose transport does not change the of fructose feeding This suggests that expression and of the fructose transporter are not experiments are to these and of Because was as a glucose most studies have been with the of glucose on expression and Results in the few studies in which investigators have at the of fructose feeding on For the expression of is by feeding a fructose diet In when were from a diet to a levels were significantly increased Because of the dietary from a to a we think the latter most reflects its of than a specific in the same was by dietary fructose data have also been on the of by fructose. a luminal perfusion of fructose, isolated a to increase in the for fructose transport This increased capacity to transport fructose occurred of changes in expression These data that the of could be by fructose, of changes in the expression levels of the In a diet and expression levels by The for the in the to luminal fructose are Moreover, these responses in the could also be by of 1 and 2 1 can be in by the of the glucose The with type 1 is by and In addition, the intestine an increased capacity to transport sugar This has been in part to an increase in the expression levels of and transporter and of the has also been in the that are from the dietary The for the of the normal intestine to that seen in type 1 are However, it has been suggested that the of to the intestine that the is resulting in the enhanced We have the expression of the intestinal in the fatty rat The rat has been as a for type 2 and is by and the expression levels of the intestinal were in the rat We have suggested that the the of increased feeding and on transporter The type 1 and 2 data that in the long is the adaptive to the than glucose. in are in the for because of the of the using intact for such studies would be to use a intestinal or are from a human colon that This in and and that are by to small intestinal expression is from However, after the is and to the in has been found to be and to fructose, glucose, and of the In expression is by dietary fructose and not glucose. It is therefore intestinal The has also been to the of human Approximately of human has been with and a Although was shown to expression of as no fructose have been Investigations The increased use of corn syrup as a sweetener over the past few decades has increased the amount of fructose in the diet. In symptoms have also In people with isolated fructose malabsorption, the for malabsorption are For when was no were (42). Although the appeared normal in these patients, it is possible that fructose malabsorption is a result of or of the transporter. These of are but could result in the of the of intestinal in the of intestinal transporter expression can have clinical For the that carbohydrates increase specific intestinal suggests that of fructose in in people have had intestinal or extensive small intestinal as could fructose malabsorption when more complex are dietary In patients with type 1 are not under the of glucose and fructose may the by more absorption of of as has been in the past in seems metabolic is in intestinal transporter expression could also be to or to feeding in pathologic of this were by The for and and and the of the