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Int.J.Curr.Microbiol.App.Sci (2016) 5(11): 721-732

International Journal of Current Microbiology and Applied Sciences ISSN: 2319-7706 Volume 5 Number 11 (2016) pp. 721-732 Journal homepage: http://www.ijcmas.com

Review Article http://dx.doi.org/10.20546/ijcmas.2016.511.083

Lactulose: Significance in Milk and Milk Products

Sonali L. Parekh*, Smitha Balakrishnan, Subrota Hati and K. D. Aparnathi

Department of Dairy Chemistry, SMC College of Dairy Science, Anand Agricultural University, Anand-388110, India *Corresponding author

ABSTRACT

K e yw or ds Many kinds of derivatives can be obtained using various methods, including

epimerization, oxidation and reduction. Lactulose is not only utilized as an Epimer, Isomerization, indicator substance for milk heat treatment but it also represents one of the most Prebiotic, valuable lactose derivatives with therapeutical applications dating back to the Endotoxemia. middle of the last century. Lactulose is a non-caloric, synthetic formed from one molecule each of and . Technologically, lactulose can be produced by the isomerization of lactose molecule in which a new

Article Info from by regrouping the residue to the fructose molecule. It is widely

Accepted: used in pharmaceutical and food industries because of its beneficial effects on 26 October 2016 human health. In particular, lactulose, and are used Available Online: in foodstuffs and pharmaceuticals, and new lactose derivatives such as epilactose 10 November 2016 and have also recently received attention.

Introduction Chemistry and Properties of Lactulose Lactose, a unique disaccharide, occurring exclusively in the mammalian milk plays an Lactulose (4-O-β-D-Galactopyranosyl-D- important role in nutrition. Most of the fructofuranose), the isomerized lactose, is a lactose that is manufactured on an industrial disaccharide consisting of galactose and scale is produced from whey derived from fructose with a molecular weight 342. It the production of cheese, casein or paneer belongs to the few other than using crystallization and purification lactose that play an important role in the technologies. Lactose can be converted to dairy fields (Gaenzle et al., 2008). Although various derivatives like lactitol, lactobionic Lactulose was first systhesized in 1929 acid, galacto-, epilactose (Montgomery and Hudson, 1930) etc., using laboratory or industrial processes. physically, its significance was not They are widely used in food and in recognized until 1957 when Petuely pharmaceutical fields due to their special discovered that it act as a growth factor for characteristics. Lactulose is a derivative of Bifidobacteria (Petuely, 1957).

lactose obtained by Isomerization of glucose It is more soluble in water than lactose and moiety of lactose to fructose (Claeys et al., about half as sweet as and does not 2001). crystallize easily even in concentrated

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Int.J.Curr.Microbiol.App.Sci (2016) 5(11): 721-732 solutions. Lactulose is much less stable in Production of lactulos Chemical methods solution than lactose and may subsequently degrade via process of β-elimination to give Industrial production of lactulose is galactose, tagatose and saccharinic acids and exclusively carried out by chemical other low molecular weight products (Olano isomerization of lactose via the Lobry de and Martinez-Castro, 1981). Subsequently, Bruyn-Alberda van Ekenstein (LA) lactulose may epimerize via a 2,3-enediol to rearrangement. Three different methods form epilactose (4-O-β-D-galactopyranosyl- namely alkalising catalysts, complexing D-).It reduces Fehling's solution on agents and ion-mediated process are heating. employed for lactulose production by chemical methods. As per Speck (1958) two main pathways should exist since the pH range of milk Alkalising catalysts systems permits the possibilities of transformation in two ways. The first path is Alkaline catalysts like triethylamine, sodium theLobry de Bruyn-Alberda van Ekenstein hydroxide, and sulfites, (LA) transformation. This is in essence an provoking a pH of 10-12 in the reaction alkaline isomerization. The second theory of mixture, have been successfully employed the mechanism of lactulose formation for the isomerization of lactose assumes the formation of lactosylamine (Montgomery and Hudson, 1930). A new which undergoes Amadori rearrangement to group of catalysts was introduced with lactulose by hydrolytic degradation. calcium carbonate-based by-products like egg and oyster shells (Montilla et al., 2004; Formation in Milk during Heat Villamiel et al., 2002). Treatment Complexing agents Temperatures above 100°C as applied in the production of sterilized and UHT milk The employed catalysts are borate and enhanced product stability, but also induce aluminate which form an insoluble complex several chemical reactions of milk with ketose like lactulose under components, such as the isomerization of alkaline conditions (Hicks and Parrish, lactose into lactulose. In the case of 1980; Kozempel and Kurantz, 1994). lactulose formation, the glucosemoiety of Zokaee et al. (2002) reported that under lactose is isomerized into its keto-analogue similar reaction conditions Ylactu/lacto was fructose, a process which is favoured by heat about 80% for borate, whereas with and alkaline conditions. Observed lactulose aluminate less lactulose was formed concentrations vary between 0.3 g/l for UHT (Ylactu/lacto ¼ 70%) and its degradation was milk and 1.6 g/l for sterilized milk increased (Hicks et al., 1984). (Mendoza et al., 2005). Ion-mediated processes Increasing the content of lactulose in milk by extending heating time or temperature is Alkalisation of whey was achieved by not possible due to a heat-induced drop of circulation over strong ion exchange resins pH and a simultaneous thermal degradation activated with hydroxide ions. The exchange of lactulose. of ions like chloride and the subsequent release of hydroxide ions from the resin

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Int.J.Curr.Microbiol.App.Sci (2016) 5(11): 721-732 increased the pH of whey and induced the (Hua et al., 2010). Mayer et al., (2010) LA-transformation of lactose into lactulose developed a continuous enzymatic process (Khramtcov et al., 2004). Ion-mediated for the production of lactulose through processes have not been established in transgalactosylation using free and industrial processes yet. Evdokimov and immobilized β-glycosidase from Pyrococcus Alieva (2004) suggested using the alkaline furiosus. fraction of electrochemically activated water or lactose solutions obtained by electro- Using whole cells membranous methods for the production of lactulose. Whole cells used as biocatalyst for the production of lactulose often causes very Enzymatic Method low reaction rates due to permeability barrier of the cell envelope for substrates Enzymatic synthesis of lactulose is and products. The permeabilized commonly carried out with classes of Kluyveromyces marxianus cells as a source enzyme β-galactosidase and glycosidase. β- of β-D-galactosidase were used to overcome galactosidase is a well-known biocatalyst for this problem. Ethanol permeabilization of transgalactosylation reaction and for the yeast cells has been shown to be an synthesis of lactose based derivatives economical, easy, convenient and safe (Lee including galacto- (Panesar et al., 2004). et al., 2006; 2010). Extraction and Purification of Lactulose Using free enzymes During lactulose production, the reaction Mayer et al.(2004)reported the production of mixture is generally not pure, and usually lactulose by enzymatic transgalactosylation contains appreciable quantities of other from lactose to fructose by using β- substances such as lactose, glucose, galactosidase from Aspergillus oryzae and galactose, epilactose etc. The recovery of the hyperthermostable β- glycosidase from lactulose during downstream processing has Pyrococcus furiosus.Further, gene encoding been found to be an important reaction a thermostable β-galactosidase from because the amount of purified lactose was Sulfolobus solfataricus has been cloned and affected by both physical and chemical expressed in Escherichia coli for lactulose treatments. A strong acidification of production (Kim et al., 2006).Enzymatic obtained solution has been carried out at synthesis of lactulose from whey permeate temperature in order to release lactulose and was affected by β-galactosidase preparation, to induce precipitation of borate as boric substrate concentration and by theratio of acid and sodium aluminate as gel like lactose and fructose (Adamczak et al.,2009). aluminium hydroxide (Kozempel et al., 1995). Moreover, separation steps have been Using immobilized enzymes evolved for the removal of borate by the crystallization of boric acid of 50% in a Lactulose has also been successfully solution with 20% (w/w) carbohydrates and synthesized by dual enzymatic consisting of 15% (w/w) borate (Kozempel et al., 1995). immobilized lactase and immobilized But, in case of heterogeneous catalysts (like glucose isomerase. Immobilized lactase is powdered egg shells), centrifugation method prepared by cross-linking the free lactase has been used for recovery of lactulose and - into Fe3O4 magnetic microspheres the obtained sugar solution has been 723

Int.J.Curr.Microbiol.App.Sci (2016) 5(11): 721-732 decolourized using activated carbon without Physiological Effects of Lactulose decreasing the concentration of recovered lactulose (Montilla et al., 2005). The The β-glycosidic linkage of the disaccharide purification of lactulose from a mixture with lactulose is not hydrolyzed by mammalian lactose has also been carried out by using digestive enzymes and ingested lactulose pressurized liquid extraction (PLE) at 1500 passes the stomach and psi for 30 min and the recovery of lactulose without degradation. This selective reached up to 84.4% with a purity of over metabolism of lactulose alters the microbial 90% (Ruiz-Matute et al., 2007). balance and the biochemical composition of caecal contents. Several in-vivo studies have Analysis demonstrated that lactulose favours the

A range of methodologies have been growth of grampositive cocci and rods reported to determine the lactulose mostly belonging to the genera including, gas-liquid chromatography (GC), Bifidobacterium and Lactobacillus (Bouhnik thin-layer chromatography (TLC) and high- et al., 2004), while bacterial counts of performance liquid chromatography galactosidase negative microorganisms like (HPLC), capillary electrophoresis, subspecies of the genera Clostridium and differential pH methods and flow analysis Bacteroides have been shown to decrease methods. A high pressure liquid (Mizota et al., 2002). Lactulose is now a chromatography was also used for the commonly used drug worldwide, and is separation of galactose, tagatose, lactose and listed in the US Pharmacopeia, European lactulose with a commercial Pharmacopoeia and Japanese analysis column (Parrish et al., 1980). Pharmacopoeia.

Khan et al., (2006) developed a method by colonic bacteria based on hydrolysis of lactulose under acidic conditions followed by reaction of the Sahota et al., (1982) screened sixty-four hydrolysed product with resorcinol, giving bacteria cultured under anaerobic conditions absorption peaks at 398 and 480 nm. A in lactulose containing media to assess their simple and rapid flow system was developed ability to ferment lactulose. Some organisms for the determination of lactulose in milk were unable to metabolize the disaccharide, samples, which is based on the hydrolysis of while others, e.g. clostridia and lactobacilli, lactulose to galactose and fructose by the metabolized lactulose extensively. enzyme β-galactosidase immobilized in a Quantitative analyses of the fermentation reactor (Moscone et al., 1999). products indicated that the major non- gaseous metabolites were acetic, lactic and Amine et al. (2000) developed an enzymatic butyric acids and hydrogen and carbon spectrophotometric assay for the dioxide were the only gases detected. determination of lactulose in milk samples by the hydrolysis of lactulose to fructose and Treatment of and hepatic galactose, and fructose dehydrogenase reacts encephalopathy with fructose in presence of a tetrazolium salt giving a coloured compound which can Lactulose is widely established as a be detected spectrophotometrically at 570 agent in the treatment of constipation nm. (Schumann, 2002).Theextent of purgative action depends on various facts, including

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Int.J.Curr.Microbiol.App.Sci (2016) 5(11): 721-732 the health status, age, weight, gender and low doses as a higher intake would probably diet of the concerned person. Oku and cause frequent bowel movements or Okazaki (1998) determined the laxative . A survey of studies focussing the threshold concentration of lactulose to be dose-response of lactulose indicates that 0.26 g per kg (body weight) in 20 Japanese single doses of lactulose exert prebiotic females. Assuming an average body weight action from a daily intake of 4 to 10 g in of 55 kg, a healthy female may consume up adult (Mizota et al., 2002). to14.3 g lactulose in a single dose without suffering diarrhea. Studies confirmed that In the work carried out by Oliveira et al. lactulose cured the neuropsychiatric (2011) use of lactulose in fermented milk symptoms of , improved the quality of skim milk fermented although the mode of its action remained by Lactobacillus acidophilus, Lactobacillus unclear (Schumann, 2002). Minimal hepatic rhamnosus, Lactobacillus bulgaricus and encephalopathy (MHE) could be treated Bifidobacterium lactis in co-culture with with 30-60 ml lactulose (adult) (approx. 20- Streptococcus thermophilus. Compared to 40 g lactulose), thus clearly improving of the control without lactulose, the health related quality of life of cirrhotic addition of such a prebiotic in skim milk patients (Sharma et al., 2008). increased the counts of all probiotics, with particular concern toB.lactis. Enhancement of mineral absorption Treatment of colon carcinogenesis The improved absorption of minerals has been generally described for prebiotics and Lactulose appear to reduce the risk of colon is presumably mediated by an increased cancer (Schumann, 2002). Challa et al. permeability of intestinal mucosa and an (1997) investigated the influence of enhanced solubility of minerals in the colon Bifidobacterium longum and lactulose on the at low pH (MacFarlane et al., 2006). Studies chemical induction of aberrant crypt foci by Seki et al., (2007) and Van den Heuvel et (ACF), a precursor of colonic adenoma, in al. (1999) showed Ca and Mg absorption rats. They showed that lactulose decreased can be improved by lactulose administration. the incidence of ACF, a phenomenon that was partly ascribed to the lowering of caecal Prebiotic action pH.

The prebiotic action of lactulose has been Anti-endotoxin effects documented throughout the last five decades. According to Bovee-Oudenhoven Lactulose treatment before operation can et al. (2003) lactulose inhibited the prevent endotoxindependent complications colonisation of Salmonella in rats. Lactulose such as renal dysfunction (Özçelik et al., leads to a sharp drop of the colonic pH, 1997; Pain et al., 1991). The anti-endotoxin which makes Salmonella difficult to survive. effect of lactulose has also important Lactulose therapy clears faecal Salmonella medical applications in metabolic diseases and Shigella species and reduces the like the hepatorenal syndrome (Kramer, prevalence of urinary-tract infection and 1988), exocrine pancreatic dysfunction respiratory tract infections (Liao et al., (Mack et al., 1992), diabetes mellitus 1994).The application of lactulose as a (Yelich et al., 1992) and hyperchole- beneficial, prebiotic nutrient is restricted to sterolemia (Liao and Florin, 1995).

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under acidic conditions is considered one of Blood glucose and insulin its most advantageous characteristics and allows it to be utilized in acidic foods such Lactulose has also an important application as fruit juice. Incorporation of 0.5% in lowering blood glucose level (Bianchi et lactulose in the infant formula is considered al., 1994). Cornell (1985) also suggested adequate to stimulate Bifidobacteria flora to that endotoxin reduces the pancreatic insulin the extent observed in breast-fed babies, production and thus lactulose shows anti- while the presence of lactulose at 1% level diabetic effect. in the formula may also provide laxative effect (Nagendra et al., 1995). Adriana et al. Tumour prevention and immunology (2002) found that lactulose contents of infant formulas containing lactose were Bifidobacteria play an important role in between 29 and 108 mg/l of reconstituted tumour prevention. The antitumour and formulas based on milk and 97 and 312 mg/l immunologic effects of Bifidobacteria can of reconstituted formulas based on milk be enhanced by intake of lactulose enriched with whey. Although no limit to (Schumann, 1997). lactulose content in infant formulas has been Inflammatory bowel disease established, the lactulose contents in these formulas were well below this limit Oral administration of lactulose abolishes suggested by IDF (1992) and EU and prevents systemic endotoxemia of gut commission (1992) for commercial UHT origin. Obstructive jaundice is often milk. The addition of lactulose reduced the accompanied by bacterial translocation and incubation period in the manufacture of bio- subsequent sepsis and the administration of yogurt containing Lactobacillus acidophilus lactulose may prevent systemic and Bifidobacterium bifidum and caused a endotoxaemia and the subsequent significant increase in the cell counts of inflammatory response in an experimental B.bifidum during cold storage (<6°C, 14 model of obstructive jaundice (Koutelidak et days) (Ozer et al., 2005).Pham and Shah al., 2003). Fermentation of lactulose by (2008) observed that the addition of 0.5% bacteria, can produce a (w/v) of lactulose to soy milk appeared to considerable amount of mobilized favour the growth of B. longum and B. endogenous hydrogen, which is protective Animalis which in turn enables for DSS-induced colitis as a unique transformation of isoflavone glycosides to antioxidant, which can reduce oxidative biologically active isoflavone aglycones. stress and ameliorate symptoms of inflammatory bowel disease in human An Indicator for Heat Treated Milk beings (Chen et al., 2011). Assuming that only minimal lactulose Applications degradation occurs within traditional milk heating, lactulose can be used to Food Applications characterize the heat load and to distinguish between differently processed batches of The use of lactulose as a food ingredient was milk. Concentration of lactulose in sterilized introduced in 1957 by Petuely (Petuly, milk differs significantly from UHT milk, 1957) who was the first to favour the growth which itself can be assigned to either direct of the bifidus flora in infants by adding or indirect heating by the amount of formed lactulose to diet. Its high thermostability

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Int.J.Curr.Microbiol.App.Sci (2016) 5(11): 721-732 lactulose (Olano et al., 1989). Lactulose was overgrowth in the small intestine (Nucera et proposed by the International Dairy al., 2005). Federation (IDF) and the European Union (EU) as a parameter capable of Safety and Regulatory Status differentiating between UHT milk and in- container sterilized milk (EU Commission, European Food Safety Authority (2010) 1992; IDF, 1992, 1993) with 600 mg/l of released a ―scientific opinion on the lactulose as a marker for distinguishing substantiation of health claims related to between two milk types. lactulose and decreasing potentially pathogenic gastro-intestinal microorganisms With regard to pasteurized, microfiltered (ID 806) and reduction in intestinal transit and pasteurised, high temperature time (ID 807)‖. The European chemical pasteurized milk and reconstituted powered Substances Information System (ESIS) milk, upper limits (threshold) of lactulose provides a detailed description of chemical concentration cannot be proposed since the and pharmacological properties of lactulose. methods available for lactulose Included data on the acute oral toxicity of determination are neither sufficiently commercial lactulose preparations sensitive (level of detection 50mg/l) summarize various animal studies with (Moscone et al., 1999). Marconi et al. values for the median lethal dose LD50 (2004) derived a sensitive enzymatic assay ranging from 25 to 65 g per kg body weight. method to distinguish lactulose content, not Drugbank, a Canadian database operated by only in-container sterilized milk, indirect the University of Alberta additionally and direct UHT, but also UHT milk specifies that pure lactulose could provoke produced by mild technologies such as milk slight irritations in case of skin or eye treated by infusion, high temperature contact. According to the Anatomical pasteurized milk and low temperature Therapeutical Chemical Classification pasteurized milk. Cho et al. (2012) reported System for pharmaceutical drugs established that lactulose and furosine concentration by the World Health Organization, lactulose ratio is a suitable milk quality indicators of is an osmotically acting laxative substance heat damage and for demonstrating (ATC Code ATC06AD11). For this purpose improper addition of reconstituted milk the recommended administration of powder. lactulose, expressed as the defined daily dose (DDD) is indicated with 6.7 g. But Diagnostic Applications apart from its status as a pharmaceutical drug, lactulose is regarded as a functional Lactulose is applied in the diagnosis of . The Japanese Ministry of colonic disorders by means of the breath Health and Welfare has acknowledged the hydrogen test. This test consists of the oral nutritional benefits of lactulose by including administration of a single dose of lactulose it in the list of functional foods with the and the determination of exhaled hydrogen official label FOSHU (Food of Specified formed by means of bacterial metabolism of Health Use). In the European Union, the lactulose in the intestine. The amount and labelling of food containing lactulosewith the time of hydrogen production and thehealthrelated claims ―prebiotic‖ and exhalation conclude the colonic transit time ―lowers colonic transit time‖ has been and microbial colonization (Simren and proposed for products with a minimum dose Stotzer, 2006). The lactulose breath test is of 2.5 g lactulose. also applied for the diagnosis of bacterial 727

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How to cite this article:

Sonali L. Parekh, Smitha Balakrishnan, Subrota Hati and K.D. Aparnathi. 2016. Lactulose: Significance in Milk and Milk Products. Int.J.Curr.Microbiol.App.Sci. 5(11): 721-732. doi: http://dx.doi.org/10.20546/ijcmas.2016.511.083

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