**2. Lactose derivatives with health benefits**

### **2.1 Lactitol**

Lactitol is a lactose-derived compound defined as synthetic sugar alcohol (C12H24O11; 4-O-ß-D-galactopyranosyl-D-glucitol; molecular weight (MW),

*Lactose and Lactose Derivatives*

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**Table 1.**

*Chemical composition of different types of cheese whey.*

**Figure 1.**

*Overview of value-added functional compounds using lactose from cheese whey as substrate.*

**Cheese whey type Total solids Lactose Protein Fat Ash** Sweet cheese whey 6.7 4.8 0.6 0.25 0.54 Sweet cheese whey permeate 5.5 4.7 0.05 <0.01 0.51 Acid cheese whey 5.1 4.4 0.73 0.05 0.6 Acid cheese whey pemeate 5.8 4.3 0.06 <0.01 0.56

**Chemical composition (g/100 g)**

344.31 g/mol) comprising galactose (D-Gal) and D-sorbitol. This compound is synthetized by catalytic hydrogenation reactions using lactose as substrate. Industrially, this chemical process is based on the addition of molecular hydrogen to the carbonyl group of the glucose molecules. This chemical reaction needs 110°-150°C temperature, 20–70 bars of hydrogen gas pressure, as well as 1.5–10% Ni, Pd or Ru transition metals in either carbon or alumina. Lactitol is the primary reaction product with reaction yields of >90%. This polyol has been used in the food industry as a relevant ingredient in desserts, bakery products, chewing gums, chocolate and confectionary products. One of the advantages of lactitol used as sweetener is that it can be metabolized by saccharolytic bacteria providing only 2 kcal/g. It also exerts properties such as cryoprotectant, dryoprotectant, stabilizer agent, hydrogel delivering bioactive compounds and additive for the development of biosensors [19].

Several human health benefits have been associated to lactitol intake. Clinical trials have demonstrated positive gastrointestinal health benefits of this polyol [20]. A random-effect meta-analysis of lactitol supplementation on adult constipation demonstrated favorable efficacy and tolerance when it was compared to stimulant laxatives and placebo. Lactitol was able to induce increased fecal volume by stimulating peristalsis [21]. In fact, lactitol is one of the most frequently prescribed osmotic laxative agents to treat constipation [22]. Investigations performed on the effectiveness of lactitol for treatment of several types of hepatic encephalopathy in infants, children and elderly subjects have demonstrated positive results. Actually, lactitol is recommended as a first-line treatment for hepatic encephalopathy as a result of decreasing the absorption and production of ammonia and reducing the intestinal pH [23, 24]. Indeed, in the last years advances in the field of nanomedicine had led to the development of polylactitol as a multifunctional carrier for liver cancer therapy [24].

Lactitol is a non-digestible carbohydrate with prebiotic effect. Prebiotic is a substrate that is selectively utilized by host microorganisms conferring a health benefit [25]. Previous studies have reported relevant lactitol symbiotic effects. Medical practitioners frequently recommend them as therapeutics. Recently, it was demonstrated that the consumption of the symbiotic combination with this lactosederived prebiotic, *Bifidobacterium bifidum* and *Lactobacillus acidophilus* was able to eradicate OXA-48-producing *Enterobacteriaceae*. The measure of this metabolite is used as prophylaxis to prevent intestinal translocations in neutropenic patients and for the prevention of pneumonia [26]. Also, the symbiotic supplementation on the gut microbiota of healthy elderly volunteers with *Lactobacillus acidophilus* NCFM and lactitol improved their health status modifying the intestinal environment and the microbiota composition. It was observed an increasing lactobacilli and bifidobacteria and a possible stabilizing effect on *Blautia coccoides*-*Eubacterium rectale* and *Clostridium cluster* XIV levels [27]. Even though the Federal and Drug Administration (FDA) agency categorized lactose-derived prebiotic as "GRAS" (Generally Recognized as Safe), the excess consumption has adverse effects such as osmotic diarrhea, abdominal pain and vomiting [20]. It has been reported that the maximum permissive dosage of lactitol for Japanese adults not to induce transitory diarrhea was 0.36 g/kg of body weight [28]. It was also found that the dose of this lactose-derived prebiotic treatment is age- and case-dependent [20].

#### **2.2 Lactulose**

Lactulose is a semi-synthetic disaccharide (C12H22O11; 4-O-ß-Dgalactopyranosyl-ß-D-fructofuranose; MW, 342.30 g/mol) comprising D-galactose (D-Gal) and D-fructose (D-Fru) linked by ß-1-4 glycosidic bond [16, 29].

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properties [35].

**2.3 Sialyllactose**

*Value-Added Compounds with Health Benefits Produced from Cheese Whey Lactose*

Commercially, this artificial disaccharide is synthetized by alkaline isomerization of lactose via the Lobry de Bruyn e Alberda van Ekenstein rearrangement in which the D-glucose unit at the reducing end of the lactose molecule is converted to D-fructose. The maximum yield of lactulose relative to initial lactose concentration adding complexing agents may reach up to 88% [30]. Electro-activation is a novel eco-friendly technology able to synthetize lactulose from CW-lactose at maximum yield of 35% [31]. In the last decade lactulose has been synthetized at lab scale using lactose as substrate by the transgalactosylation activity of ß-glucosidase [29]. This disaccharide is formed in milk during heat treatments also, so pasteurized milk usually has <100 mg/L lactulose content, meanwhile ultra-high temperature (UHT) milk generally has a lactulose content over 500 mg/L [32]. Actually, this polyol has demonstrated versatile applications in pharmaceutical and food industries. Lactulose can be found as relevant functional ingredient of infant food formulae, fermented dairy products, bakery products, confectionary products and

Previous studies have reported remarkable health benefits associated to lactulose consumption. In fact, this disaccharide is used in clinical practice since 1957. This disaccharide is lactose-derived prebiotic able to prevent and to treat diseases [35]. Lactulose is only metabolized by specific species of colonic microbiota through ß-glucosidase activity altering the microbial balance by increasing the probiotic growth and reducing putrefactive bacteria. Consequently, lowering intestinal pH, enhanced colonic motility, reduced concentration of ammonia and improved absorption of minerals are also benefits of the physiological action of lactulose upon

*In silico*, *in vitro* and *in vivo* studies have demonstrated the efficacy of lactulose in the treatment of several diseases [35]. Since the 1960s, patients of all ages have been prescribed with lactulose to treat constipation, even if it is chronic. This lactose-derived prebiotic is an osmotic laxative [33]. The effect of lactulose was studied in healthy volunteers. A significant increase of *Bifidocaterium*, *Lactobacillus* and *Streptococcus* was reached, meanwhile the population of coliforms, *Bacteroides*, *Clostridium* and *Eubacterium* was significantly decreased. These changes in the microbiota reduced activity of pro-carcinogenic enzymes, increased short-chain fatty acids in feces and pH decreased [36]. Clinical trials also have reported favorable results using lactulose to treat hepatic encephalopathy and chronic kidney disease [30]. Recently, the prebiotic effect of lactitol, raffinose, oligofructose and lactulose was evaluated on *Lactobacillus* spp. and bacterial vaginosis-associated organisms (BV) and *Candida albicans*. Results showed that lactulose had the most broadly and specifically growth stimulation on vaginal lactobacilli and did not to stimulate BV or *Candida albicans* [37]. On the other side, *in vitro* and *in vivo* studies have confirmed that lactulose possesses patient- and dose-dependent prebiotic

Sialyllactose (C23H39NO19; NeuAcα2-xD-galactopyranosyl-α-D-glucopyranoside;

MW, 633.6 g/mol) is essentially sialic acid (N-acetylneuraminic acid, NeuAc) bound to a lactose molecule. This lactose-derived compound is naturally found in high concentrations at the beginning of lactation in colostrum and decreases towards the end of lactation [16]. The predominant forms of sialyllactose are 6′-sialyllactose and 3′-sialyllactose. The concentrations of 6′-sialyllactose in human colostrum is 250–1300 mg/L, meanwhile the concentration of 3′-sialyllactose in bovine colostrum is 354–1250 mg/L [38]. These lactose-derived compounds are extracted from CW using ultra and nanofiltration processes on a tangential flow

*DOI: http://dx.doi.org/10.5772/intechopen.94197*

bacterial metabolism in the large intestine [30].

soy milk [33, 34].

#### *Value-Added Compounds with Health Benefits Produced from Cheese Whey Lactose DOI: http://dx.doi.org/10.5772/intechopen.94197*

Commercially, this artificial disaccharide is synthetized by alkaline isomerization of lactose via the Lobry de Bruyn e Alberda van Ekenstein rearrangement in which the D-glucose unit at the reducing end of the lactose molecule is converted to D-fructose. The maximum yield of lactulose relative to initial lactose concentration adding complexing agents may reach up to 88% [30]. Electro-activation is a novel eco-friendly technology able to synthetize lactulose from CW-lactose at maximum yield of 35% [31]. In the last decade lactulose has been synthetized at lab scale using lactose as substrate by the transgalactosylation activity of ß-glucosidase [29]. This disaccharide is formed in milk during heat treatments also, so pasteurized milk usually has <100 mg/L lactulose content, meanwhile ultra-high temperature (UHT) milk generally has a lactulose content over 500 mg/L [32]. Actually, this polyol has demonstrated versatile applications in pharmaceutical and food industries. Lactulose can be found as relevant functional ingredient of infant food formulae, fermented dairy products, bakery products, confectionary products and soy milk [33, 34].

Previous studies have reported remarkable health benefits associated to lactulose consumption. In fact, this disaccharide is used in clinical practice since 1957. This disaccharide is lactose-derived prebiotic able to prevent and to treat diseases [35]. Lactulose is only metabolized by specific species of colonic microbiota through ß-glucosidase activity altering the microbial balance by increasing the probiotic growth and reducing putrefactive bacteria. Consequently, lowering intestinal pH, enhanced colonic motility, reduced concentration of ammonia and improved absorption of minerals are also benefits of the physiological action of lactulose upon bacterial metabolism in the large intestine [30].

*In silico*, *in vitro* and *in vivo* studies have demonstrated the efficacy of lactulose in the treatment of several diseases [35]. Since the 1960s, patients of all ages have been prescribed with lactulose to treat constipation, even if it is chronic. This lactose-derived prebiotic is an osmotic laxative [33]. The effect of lactulose was studied in healthy volunteers. A significant increase of *Bifidocaterium*, *Lactobacillus* and *Streptococcus* was reached, meanwhile the population of coliforms, *Bacteroides*, *Clostridium* and *Eubacterium* was significantly decreased. These changes in the microbiota reduced activity of pro-carcinogenic enzymes, increased short-chain fatty acids in feces and pH decreased [36]. Clinical trials also have reported favorable results using lactulose to treat hepatic encephalopathy and chronic kidney disease [30]. Recently, the prebiotic effect of lactitol, raffinose, oligofructose and lactulose was evaluated on *Lactobacillus* spp. and bacterial vaginosis-associated organisms (BV) and *Candida albicans*. Results showed that lactulose had the most broadly and specifically growth stimulation on vaginal lactobacilli and did not to stimulate BV or *Candida albicans* [37]. On the other side, *in vitro* and *in vivo* studies have confirmed that lactulose possesses patient- and dose-dependent prebiotic properties [35].

### **2.3 Sialyllactose**

Sialyllactose (C23H39NO19; NeuAcα2-xD-galactopyranosyl-α-D-glucopyranoside; MW, 633.6 g/mol) is essentially sialic acid (N-acetylneuraminic acid, NeuAc) bound to a lactose molecule. This lactose-derived compound is naturally found in high concentrations at the beginning of lactation in colostrum and decreases towards the end of lactation [16]. The predominant forms of sialyllactose are 6′-sialyllactose and 3′-sialyllactose. The concentrations of 6′-sialyllactose in human colostrum is 250–1300 mg/L, meanwhile the concentration of 3′-sialyllactose in bovine colostrum is 354–1250 mg/L [38]. These lactose-derived compounds are extracted from CW using ultra and nanofiltration processes on a tangential flow

*Lactose and Lactose Derivatives*

of biosensors [19].

cancer therapy [24].

344.31 g/mol) comprising galactose (D-Gal) and D-sorbitol. This compound is synthetized by catalytic hydrogenation reactions using lactose as substrate. Industrially, this chemical process is based on the addition of molecular hydrogen to the carbonyl group of the glucose molecules. This chemical reaction needs 110°-150°C temperature, 20–70 bars of hydrogen gas pressure, as well as 1.5–10% Ni, Pd or Ru transition metals in either carbon or alumina. Lactitol is the primary reaction product with reaction yields of >90%. This polyol has been used in the food industry as a relevant ingredient in desserts, bakery products, chewing gums, chocolate and confectionary products. One of the advantages of lactitol used as sweetener is that it can be metabolized by saccharolytic bacteria providing only 2 kcal/g. It also exerts properties such as cryoprotectant, dryoprotectant, stabilizer agent, hydrogel delivering bioactive compounds and additive for the development

Several human health benefits have been associated to lactitol intake. Clinical trials have demonstrated positive gastrointestinal health benefits of this polyol [20]. A random-effect meta-analysis of lactitol supplementation on adult constipation demonstrated favorable efficacy and tolerance when it was compared to stimulant laxatives and placebo. Lactitol was able to induce increased fecal volume by stimulating peristalsis [21]. In fact, lactitol is one of the most frequently prescribed osmotic laxative agents to treat constipation [22]. Investigations performed on the effectiveness of lactitol for treatment of several types of hepatic encephalopathy in infants, children and elderly subjects have demonstrated positive results. Actually, lactitol is recommended as a first-line treatment for hepatic encephalopathy as a result of decreasing the absorption and production of ammonia and reducing the intestinal pH [23, 24]. Indeed, in the last years advances in the field of nanomedicine had led to the development of polylactitol as a multifunctional carrier for liver

Lactitol is a non-digestible carbohydrate with prebiotic effect. Prebiotic is a substrate that is selectively utilized by host microorganisms conferring a health benefit [25]. Previous studies have reported relevant lactitol symbiotic effects. Medical practitioners frequently recommend them as therapeutics. Recently, it was demonstrated that the consumption of the symbiotic combination with this lactosederived prebiotic, *Bifidobacterium bifidum* and *Lactobacillus acidophilus* was able to eradicate OXA-48-producing *Enterobacteriaceae*. The measure of this metabolite is used as prophylaxis to prevent intestinal translocations in neutropenic patients and for the prevention of pneumonia [26]. Also, the symbiotic supplementation on the gut microbiota of healthy elderly volunteers with *Lactobacillus acidophilus* NCFM and lactitol improved their health status modifying the intestinal environment and the microbiota composition. It was observed an increasing lactobacilli and bifidobacteria and a possible stabilizing effect on *Blautia coccoides*-*Eubacterium rectale* and *Clostridium cluster* XIV levels [27]. Even though the Federal and Drug Administration (FDA) agency categorized lactose-derived prebiotic as "GRAS" (Generally Recognized as Safe), the excess consumption has adverse effects such as osmotic diarrhea, abdominal pain and vomiting [20]. It has been reported that the maximum permissive dosage of lactitol for Japanese adults not to induce transitory diarrhea was 0.36 g/kg of body weight [28]. It was also found that the dose of this

lactose-derived prebiotic treatment is age- and case-dependent [20].

Lactulose is a semi-synthetic disaccharide (C12H22O11; 4-O-ß-D-

(D-Gal) and D-fructose (D-Fru) linked by ß-1-4 glycosidic bond [16, 29].

galactopyranosyl-ß-D-fructofuranose; MW, 342.30 g/mol) comprising D-galactose

**78**

**2.2 Lactulose**

type laboratory scale membrane filtration system [39]. Even though this still an expensive procedure to extract sialyllactose, some infant formulae use it as functional ingredient [16, 40].

*In vivo* studies have demonstrated the ability of sialyllactose to improve positively in health. Pathogenic microorganisms have been effectively inhibited using it [16, 40]. It was reported that the consumption of dietary sialyllactose modified the colonic microbiota, e.g. Bacteroidetes were significantly increased, meanwhile Firmicutes and Cyanobacteria were significantly decreased. Moreover, this lactosederived prebiotic was able to diminish stressor-induced alterations in colonic mucosa and anxiety-like behavior [41]. One of the major causes of morbidity and mortality in premature infants is necrotizing enterocolitis (NEC). Recently, it was found that human milk oligosaccharides 2′-fucosyllactose and 6′-sialyllactose can reduce NEC and attenuate NEC inflammation [42]. In addition, intact sialylated oligosaccharides can be absorbed in concentrations high enough to modulate the immunological system and facilitate proper brain development during infancy [43].
