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Home , Trehalase, Trehalose

Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2013; 17(Suppl 2): 26-29 , trehalose and sorbitol malabsorption

M. MONTALTO, A. GALLO, V. OJETTI, A. GASBARRINI

Institute of Internal Medicine, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy

Abstract. malabsorption is a , such as fructose, trehalose and sorbitol frequent clinical condition, often associated may be incorrectly absorbed in the small intestine. with abdominal symptoms. Although Whether malabsorption of these may represents the most commonly malabsorbed , also other , such as fruc - be clinically relevant and may be detected by tose, trehalose and sorbitol may be incorrectly validate diagnostic techniques, will represent the absorbed in the small intestine. topic of this paper. Fructose malabsorption seems more com - It is well known that unabsorbed carbohy - mon in patients with functional bowel disease, drates reaching the colon are fermented by the even if randomized and controlled studies on colonic microflora to short-chain fatty acids and these topic were few and on small samples. In - to hydrogen, carbon dioxide and methane 1. They terpretation of breath hydrogen testing is diffi - cult. In particular, neither studies comparing also cause an increased osmotic load in the bow - el lumen, leading to a greater secretion of elec - this test with a gold standard, nor validated 1-2 doses and concentrations to be used, are avail - trolytes and fluids . Sugar malabsorption does able . Trehalose malabsoption due to trehalase not necessarily result in the development of in - deficiency represents a very rare condition and tolerance symptoms (e.g. abdominal bloating and available studies do not support its relevance pain, flatulence, nausea, borborygmi, diarrhea), in clinical practice. Sorbitol absorption is dose the condition occurring, for example, only in and concentration related, and depends on the 3 entity of intestinal absorption surface. Never - about one third to half of lactose maldigesters . theless, the finding of its malabsorption is not expression of a specific cause of intestinal bowel damage. Fructose From available data, it is not possible to draw definite conclusions about clinical rele - Fructose is a six-carbon that vance of fructose, trehalose and sorbitol mal - absorption, as well as, about diagnostic accu - is ingested in three forms: pure monosaccharide; racy of commonly used tests to detect all these , the , where fructose is com - conditions. On the other hand, in patients who plexed with ; and polymerized forms as refer abdominal discomfort after ingestion of and 4. Fructose different carbohydrate-containing foods, a is naturally present in fruits and vegetables, such small intestinal bacterial overgrowth, should be as apples, peaches, prunes etc. It is also produced promptly considered. This is because the large amount of intestinal bacteria may unspecifical - enzymatically from corn as high fructose corn ly ferment sugars, causing an abnormal H2 pro - syrup and this form of fructose is commonly duction and consequently a misleading diagno - used in many food sweeteners, soft drinks, dia - 5 sis of sugar malabsorption. betic and diet foods . In the last years, there has been a marked rise KeyWords: 4-6 Fructose, Trehalose, Sorbitol, Malabsorption, Breath test. in free frucose ingestion . In general, the daily in - take of fructose varies across the world, depending significantly on dietary habits and the use of fruc - 5 Introduction tose as a sweetener . A United States Department of Agriculture study estimated that the annual con - sumption of fructose has risen from less than a ton Carbohydrate malabsorption is a frequent clini - in 1966 to 8.8 million tons in 2003 6. cal condition, often associated with abdominal Unlike other sugars such as sucrose or lactose, symptoms. Although lactose represents the most which are digested by or commonly malabsorbed sugar and the most of stud - produced by the intestinal brush border, fructose ies are focused on this condition, also other carbo - is not digested by a specific but is ab -

26 Corresponding Author: Massimo Montalto, MD; e-mail: [email protected] Fructose, trehalose and sorbitol malabsorption sorbed, by a “diffusional pathway”, dose and con - (IBS) compared with healthy individuals 6, even if centration related 4-6 . Fructose is transported by fa - there is a consensus that symptoms are more fre - cilitated diffusion by GLUT 5 7, a protein able to quent in this group 4-10 . As a consequences, the drive net movement across the membrane through Rome Consensus Conference on “Methodology the energy of the solute concentration gradient. and indications of H 2-breath testing in gastroin - GLUT 5 is specific for fructose and cannot trans - testinal diseases” stated that fructose breath test is port glucose or 6. When fructose is in - not recommended in clinical practice 11 . gested in large quantities, the capacity of the gut to absorb fructose can be easily overwhelmed Trehalose leading to fructose malabsorption and abdominal symptoms 4-7 . More recently, it has been shown that also GLUT-2, a transporter carrying glucose Trehalose is a disaccharide composed of two and galactose, may also be involved in fructose glucose molecules, found in mushrooms, algae absorption by a paracelluar transport system in - and haemolymph 12 . Intestinal trehalase, a volving opening of tight junctions 4,6 . GLUT-2 is brush border enzyme, is a beta-galactosidase constitutively found on the basolateral membrane, which catalyses the of trehalose to but, under specific conditions, it can also be ex - two glucose molecules for absorption. It is pre - pressed in the apical membrane 4. It has been sug - sent throughout the small intestine with highest gested that a way of altering the absorption of levels in the proximal jejunum 12-13 . Isolated tre - free fructose is to modulate the ability of small halase deficiency represents an autosomic domi - epithelial cells to insert GLUT-2 into the apical nant condition, and occurs in at least 8% of the membrane in response to luminary dietary sugars; Greenland population 14 . Nevertheless, only three therefore, the co-ingestion of glucose or galactose cases have been reported elsewhere, two of considerably enhance fructose absorption 4,6 . whom were first degree relatives. Hydrogen breath tests have become a key tool The high concentration of trehalose in crypto - in identifying those who malabsorb sugars. The biotic is responsible for their remarkable principle of the test lies in unabsorbed carbohy - ability to go through cycles of desiccation and re - drate reaching and being fermented by intestinal hydration without injury. This has led to interest bacteria which generate hydrogen or methane. As by the food industry, as the addition of trehalose regard fructose malabsorption, interpretation of to foodstuffs improves the quality of dried food 12 . breath hydrogen testing is difficult, since there are Up to now, only a study by Arola is available 4 still several issues of concern . Firstly, studies about trehalose malabsorption and H 2 breath comparing breath test with a gold standard for test 13 . In this work, a 25-g oral trehalose load test fructose malabsorption (for example carrier lev - was performed in 64 subjects. Trehalase activity els), are lacking; then, both for dose and concen - was determined in serum and on a duodenal biop - tration to be administered, as well as, for the opti - sy specimen and symptoms of intolerance were mal cut-off, there is not a univocal opinion 4. recorded. Intolerant subjects were best differenti - Moreover, there is a lack of information about the ated from tolerant subjects by changes in breath prevalence of incomplete absorption of fructose in gases (hydrogen and methane) and duodenal tre - the healthy population 4-6 . It has been estimated halase /sucrase ratio. The change in breath gases that a dose of 25 g at a concentration of 10% more correlated inversely with duodenal trehalase ac - closely approaches daily intake, whereas in the tivity 13 . Nevertheless, no conclusive evidences are paediatric population a dose of 1 g/kg has been still available to support the trehalose H 2 breath considered as appropriate 4. It has been suggested test in clinical practice and , therefore , the perfor - that healthy subjects have the capacity to absorb mance of this test is not recommended 11 . up to 25 g of fructose, whereas many have incom - plete absorption and intolerance with intake of 50 8 Sorbitol g of fructose . Fructose malabsorption seems more common in patients with functional bowel disease, and can be present in up to 80% of cases 9,10 . How - Sorbitol is a sugar alcohol widespread in ever, randomized controlled studies on these topic plants, particularly in fruits and juice 15 . It is also were few and on small samples, and not showing produced synthetically for commercial purposes a greater prevalence of fructose malabsorption by the catalytic reduction of glucose and it is among patients with irritable bowel syndrome found in sweets, chewing-gum, dietetic food, and

27 M. Montalto, A. Gallo, V. Ojetti, A. Gasbarrini drugs. It does not produce a rise in blood sugar physicians and patients should pay attention to when taken by mouth, and because of its sweeten- which foods are responsible for occurrence of ing power it is widely used as a sugar substitute symptoms, i.e. milk and dairy foods for lactose in dietetic food and beverages and as a vehicle for intolerance, or sweet and fruits for fructose or suspending active drugs15. Sorbitol is poorly ab- sorbitol intolerance, etc. Nevertheless, it is very sorbed from the small intestine, as demonstrated common to find patients who refer abdominal by a dose as low at 5 g giving a positive response discomfort, bloating and pain after ingestion of in more than 50% of subjects tested by H2 breath different carbohydrate-containing foods, such as testeath hydrogen analysis15,16. bread, pasta, pizza, sweets etc. In these cases, a Sorbitol absorption occurs by a not mediated small intestinal bacterial overgrowth (SIBO) diffusion pathway, is dose and concentration relat- should be promptly considered. SIBO is charac- ed, and depends on the entity of intestinal absorp- terized by a wide spectrum of manifestations, tion surface. In patients with malabsorption as a ranging from unspecific abdominal symptoms result of untreated coeliac disease, the ingestion of (e.g. bloating, abdominal discomfort, flatulence), the smallest and least concentrated dose used, 5 g very similar to those derived from sugar malab- in a 2% solution, provoked a highly significant in- sorption, to less frequent severe generalized mal- crease in H2 excretion as compared with healthy absorption and nutrient deficiency (diarrhea, subjects15. Corazza et al15 found that all the un- steatorrhea, weight loss)20. In normal individuals, treated coeliac patients resulted as sorbitol malab- gut bacteria are primarily located in the colon sorbers and this, to a certain extent, was pre- and in the distal small intestine. In contrast, when dictable as in villous atrophy and the consequent SIBO is present, the bacterial population over- reduced intestinal surface to absorb sugars. growths proximally into the small intestine21. More studies17 also suggested the use of sor- This shift in the fermentation site might lead to bitol H2 breath test in all subclinical/silent coeli- falsely abnormal sugar breath test, even in pa- ac patients, since a strict correlation between cut- tients with normal absorption ability21. A study off value and histologic lesions. Moreover, sor- by Nucera et al22 found a significant association 18 bitol H2 breath test was proposed as a better di- between positivity to breath test (used agnostic tool than antiendomysial antibodies in for diagnosis of SIBO), and positivity to H2 lac- revealing histological recovery in the follow-up tose, fructose and sorbitol breath tests. Moreover, of coeliac patients after the start of gluten-free the normalization of lactulose breath test one diet, due to its good correlation with histological month after antibiotic treatment was associated damage. Finally, also in screening relatives of with a normalization of the majority of previous- coeliac patients, it was proposed as a more effec- ly positive lactose, fructose and sorbitol breath tive diagnostic test than serological testing19. tests. Therefore, in presence of SIBO, the large Therefore, sorbitol H2 breath test should be ef- amount of intestinal bacteria may unspecifically fective in detecting small bowel damage with a ferment sugars, causing an abnormal H2 produc- relevant reduction of absorption surface, but it is tion and consequently a misleading diagnosis of not specific for any condition responsible for in- lactose, fructose or sorbitol malabsorption. testinal malabsorption. Therefore, as stated in the The role played by intestinal bacterial flora Rome Consensus Conference on “ Methodology (and eventually by SIBO) in the pathogenesis of and indications of H2-breath testing in gastroin- IBS is controversial, with a prevalence of SIBO testinal diseases”, sorbitol H2 breath test should in patients with IBS fluctuating between 30% and not be recommended in clinical practice in both 46%, as compared to 4% in healthy controls23. adults and children while its use may be indicat- Moreover, antibiotic therapy also led to a signifi- ed for research purpose11. cant improvement in IBS symptoms23. Pimentel et al showed that in a group of 202 IBS patients with a prevalence of SIBO of about 78%, after Discussion eradication therapy, 50% of subjects did not fulfill anymore Rome I criteria for diagnosis of IBS24. It has to been underlined that when a sugar, Therefore, from available data, it is not possible that is lactose, fructose, trehalose or sorbitol, is to draw definite conclusions about clinical rele- malabsorbed, the abdominal clinical picture is vance of fructose, trehalose and sorbitol malabsorp- unspecific, often mimicking that of IBS, and it tion, as well as, about diagnostic accuracy of com- does not help for a specific diagnosis. Therefore, monly used tests to detect all these conditions. It is

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