3. New perspectives in biotechnology of foods, low-glycemic index and the microbiota

In context where health and feeding are the main concerns of the human being, food innovation takes a special interest to people that look for a healthy diet or demands a greater number of functional products, such as nutraceutical, that often generates more contribution than nutrients, helping to improve the prevent of different diseases [79].

3.1. Non-caloric sweeteners and gut microbiota

Non-caloric sweeteners (NCSs) are food additives widely used as sugar substitutes; these sweeteners enhance tastes and simultaneously reduce calories consumption. Some epidemiological studies have shown that artificial sweeteners are beneficial for weight loss, principally for subjects having glucose intolerance and type 2 diabetes [86]. Historically, the consumption of NCSs was restricted to people who have diseases such as diabetes; however, their consumption has increased in recent decades for general population. For their approval for human consumption, there are rigorous procedures required to consider them safe, however, today a controversy exist in its safety and it has been noted the possibility that the NCSs alter intestinal microbiota (IM). IM is involved in the metabolism of the host and plays a crucial role in food digestion and energy homeostasis. However, multiple environmental factors, such as diet, antibiotics and heavy metals, can disrupt the ecological balance of microbiota in the intestine [87]. A study in male Sprague-Dawley rats who were subjected to oral probe of 100, 300, 500, or 1000 mg/kg of Splenda for 12 weeks showed at the end of the treatment period, the number of total anaerobes, Bifidobacteria, Lactobacilli, Bacteroides, Clostridia and total aerobic bacteria decreased significantly. These changes occurred in Splenda doses containing sucralose at 1.1– 11 mg/kg (FDA's acceptable daily intake for sucralose is 5 mg/kg) [88]. Other study realized in 8 weeks old C57B1 mice, two experiments were performed. Experiment 1, 4-week-old male mice were divided into three groups (n = 8 x group) and treated for 8 weeks as follows: mice in control group received distilled water; mice in the low dose sucralose group (LS) a sucralose solution of 1.5 mg/kg body weight per day were given; and mice in the high-dose sucralose group (HS) received a sucralose solution of 15 mg/kg body weight per day, which is equal to the maximum IDA. In Experiment 2, 4-week-old male mice were divided into two groups and treated for 8 weeks as follows: Mice in control group received distilled water (n = 8); and acesulfame-K mice were given an acesulfame-K solution of 15 mg/kg body weight per day, which is equal to the ADI (n = 9), resulting that consumption of sucralose, but not of acesulfame-K, reduced the relative amount of Clostridium cluster XIVa in feces. Meanwhile, sucralose and acesulfame-K did not increase food intake [89]. Acesulfame k is genotoxic, and can inhibit the fermentation of glucose by intestinal bacteria [90]. A study in CD-1 mice (~8 weeks of age), were given a dose of 37.5 mg/kg body weight/day of acesulfame-K during 4 weeks, in males Bacteroides showed increased instead in females mice drastically decreased the relative abundance of multiple genres, including Lactobacillus, Clostridium, Ace-K disrupts the composition of the intestinal microbiome in a sex-dependent manner [90]. Another study in adult male C57B1/6 WT mice, gave two groups of mice a high in fat diet (60%) and commercial saccharin (equivalent to one human IDA) or glucose [91], resulting in an alteration in the glucose tolerance, the authors concluded that glucose intolerance was mediated by change in the microbiota (increase of Bacteroidetes and Clostridium). To corroborate the latter, a fecal transplantation to germ-free mice w performed, after 6 days an altered glucose tolerance was present in these mice. A similar study was carried out this time in seven humans (five men and two women), who were given 5 mg/kg/weight of saccharin (IDA equivalent) for 7 days, four of whom had altered glycemic responses. Other study, carried out in 31 humans that evaluated the consumption of aspartame and acesulfame k, showed that the consumers of these NCSs presented a different bacterial diversity to those who did not consume these

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A functional food has been defined as a: (i) natural food, (ii) food which a component with some technology or biotechnology has been added or removed, (iii) food where the nature of one or more components has been varied, (iv) food which the bioavailability of one or more of its components has been modified, and/or (v) any combination of the above possibilities [80]. The world commercialization for functional foods and beverages have grown from \$ 33 billion in 2000 to 67.7 billion pesos in 2013, that mean the 5% of the global food commercialization, and the growth of investment in food industry as a whole. Latin America is currently a potential producer and consumer of functional foods, because of its large natural resources, a wide biodiversity of flora and fauna having a variety of plants and edible fruits with potential and beneficial effects for health [78].

Bioactive molecules works mainly modifying cellular signaling and causing changes in expression of certain genes, for instance producing a defensive response to harmful processes like differentiation and cell proliferation, inflammation, it is the base of the understanding for most prevalent diseases. New technology applied for food and nutrition sciences are closely related to the biomedical area, researchers require strong training in molecular biology, genetics and nutritional biochemistry, among others disciplines [81]. The current "omics" technologies, such as genomics, transcriptomics, proteomics, metagenomics, metatranscriptomics and metabolomics, have introduced important strides in the fields of health, biotechnology, ecology, and food [81]. The increase of the importance of (I + D) from academy, where food and pharmaceutical industry have worked together to promote healthy feeding, functional foods and nutraceuticals developing, those products when are consumed in a regular way, contribute to the prevention and/or treatments of certain diseases [82]. Genetic engineering plays an important role in the improvement of functional foods, which involves biological and technological research and also normative and ethical communication [83]. New probiotic strains isolated from natural niches and other produced by genetically engineered organisms (GMOs) have broadened the spectrum of organisms with improved probiotic properties for incorporation into functional foods [84]. More than 500 probiotic food products have been introduced into the world stores over the last couple of decades [81]. The contribution of biotechnology to production of prebiotics is remarkable. Prebiotic such as inulin and fructose polymer are produced by extraction of natural products (mainly chicory for fructose polymer), other prebiotics are produced by bioprocesses involving microorganisms or enzymes specifically conditioned for efficient synthesis of non-digestible oligosaccharides. On the other hand, inulin is the most used prebiotic, although it is probably not the most effective, actually, in the formulation of functional foods, also providing textural and rheological properties to the food matrix [83]. Another example of innovation is the design and development of product with intestinal microbiota and/or GI control effects, such as powdered additive, that incorporates also beneficial bacteria to the food. This development, achieved by researchers from National Institute Food Technology in Chile and Conicet Argentina, incorporated as an additive to certain foods—cold or lukewarm liquids—enriches the digestive system, balances the intestinal microbiota with a positive impact on the immune system [85].

#### 3.1. Non-caloric sweeteners and gut microbiota

of functional products, such as nutraceutical, that often generates more contribution than

A functional food has been defined as a: (i) natural food, (ii) food which a component with some technology or biotechnology has been added or removed, (iii) food where the nature of one or more components has been varied, (iv) food which the bioavailability of one or more of its components has been modified, and/or (v) any combination of the above possibilities [80]. The world commercialization for functional foods and beverages have grown from \$ 33 billion in 2000 to 67.7 billion pesos in 2013, that mean the 5% of the global food commercialization, and the growth of investment in food industry as a whole. Latin America is currently a potential producer and consumer of functional foods, because of its large natural resources, a wide biodiversity of flora and fauna having a variety of plants and edible fruits with potential

Bioactive molecules works mainly modifying cellular signaling and causing changes in expression of certain genes, for instance producing a defensive response to harmful processes like differentiation and cell proliferation, inflammation, it is the base of the understanding for most prevalent diseases. New technology applied for food and nutrition sciences are closely related to the biomedical area, researchers require strong training in molecular biology, genetics and nutritional biochemistry, among others disciplines [81]. The current "omics" technologies, such as genomics, transcriptomics, proteomics, metagenomics, metatranscriptomics and metabolomics, have introduced important strides in the fields of health, biotechnology, ecology, and food [81]. The increase of the importance of (I + D) from academy, where food and pharmaceutical industry have worked together to promote healthy feeding, functional foods and nutraceuticals developing, those products when are consumed in a regular way, contribute to the prevention and/or treatments of certain diseases [82]. Genetic engineering plays an important role in the improvement of functional foods, which involves biological and technological research and also normative and ethical communication [83]. New probiotic strains isolated from natural niches and other produced by genetically engineered organisms (GMOs) have broadened the spectrum of organisms with improved probiotic properties for incorporation into functional foods [84]. More than 500 probiotic food products have been introduced into the world stores over the last couple of decades [81]. The contribution of biotechnology to production of prebiotics is remarkable. Prebiotic such as inulin and fructose polymer are produced by extraction of natural products (mainly chicory for fructose polymer), other prebiotics are produced by bioprocesses involving microorganisms or enzymes specifically conditioned for efficient synthesis of non-digestible oligosaccharides. On the other hand, inulin is the most used prebiotic, although it is probably not the most effective, actually, in the formulation of functional foods, also providing textural and rheological properties to the food matrix [83]. Another example of innovation is the design and development of product with intestinal microbiota and/or GI control effects, such as powdered additive, that incorporates also beneficial bacteria to the food. This development, achieved by researchers from National Institute Food Technology in Chile and Conicet Argentina, incorporated as an additive to certain foods—cold or lukewarm liquids—enriches the digestive system, balances the intes-

nutrients, helping to improve the prevent of different diseases [79].

tinal microbiota with a positive impact on the immune system [85].

and beneficial effects for health [78].

190 Diabetes Food Plan

Non-caloric sweeteners (NCSs) are food additives widely used as sugar substitutes; these sweeteners enhance tastes and simultaneously reduce calories consumption. Some epidemiological studies have shown that artificial sweeteners are beneficial for weight loss, principally for subjects having glucose intolerance and type 2 diabetes [86]. Historically, the consumption of NCSs was restricted to people who have diseases such as diabetes; however, their consumption has increased in recent decades for general population. For their approval for human consumption, there are rigorous procedures required to consider them safe, however, today a controversy exist in its safety and it has been noted the possibility that the NCSs alter intestinal microbiota (IM). IM is involved in the metabolism of the host and plays a crucial role in food digestion and energy homeostasis. However, multiple environmental factors, such as diet, antibiotics and heavy metals, can disrupt the ecological balance of microbiota in the intestine [87]. A study in male Sprague-Dawley rats who were subjected to oral probe of 100, 300, 500, or 1000 mg/kg of Splenda for 12 weeks showed at the end of the treatment period, the number of total anaerobes, Bifidobacteria, Lactobacilli, Bacteroides, Clostridia and total aerobic bacteria decreased significantly. These changes occurred in Splenda doses containing sucralose at 1.1– 11 mg/kg (FDA's acceptable daily intake for sucralose is 5 mg/kg) [88]. Other study realized in 8 weeks old C57B1 mice, two experiments were performed. Experiment 1, 4-week-old male mice were divided into three groups (n = 8 x group) and treated for 8 weeks as follows: mice in control group received distilled water; mice in the low dose sucralose group (LS) a sucralose solution of 1.5 mg/kg body weight per day were given; and mice in the high-dose sucralose group (HS) received a sucralose solution of 15 mg/kg body weight per day, which is equal to the maximum IDA. In Experiment 2, 4-week-old male mice were divided into two groups and treated for 8 weeks as follows: Mice in control group received distilled water (n = 8); and acesulfame-K mice were given an acesulfame-K solution of 15 mg/kg body weight per day, which is equal to the ADI (n = 9), resulting that consumption of sucralose, but not of acesulfame-K, reduced the relative amount of Clostridium cluster XIVa in feces. Meanwhile, sucralose and acesulfame-K did not increase food intake [89]. Acesulfame k is genotoxic, and can inhibit the fermentation of glucose by intestinal bacteria [90]. A study in CD-1 mice (~8 weeks of age), were given a dose of 37.5 mg/kg body weight/day of acesulfame-K during 4 weeks, in males Bacteroides showed increased instead in females mice drastically decreased the relative abundance of multiple genres, including Lactobacillus, Clostridium, Ace-K disrupts the composition of the intestinal microbiome in a sex-dependent manner [90]. Another study in adult male C57B1/6 WT mice, gave two groups of mice a high in fat diet (60%) and commercial saccharin (equivalent to one human IDA) or glucose [91], resulting in an alteration in the glucose tolerance, the authors concluded that glucose intolerance was mediated by change in the microbiota (increase of Bacteroidetes and Clostridium). To corroborate the latter, a fecal transplantation to germ-free mice w performed, after 6 days an altered glucose tolerance was present in these mice. A similar study was carried out this time in seven humans (five men and two women), who were given 5 mg/kg/weight of saccharin (IDA equivalent) for 7 days, four of whom had altered glycemic responses. Other study, carried out in 31 humans that evaluated the consumption of aspartame and acesulfame k, showed that the consumers of these NCSs presented a different bacterial diversity to those who did not consume these

obtained from lactose. This sweetener with natural origin can be obtained artificially from lactose. Through food technology, glucose is separated and galactose is extracted, whose

New Insights into Alleviating Diabetes Mellitus: Role of Gut Microbiota and a Nutrigenomic Approach

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D-tag would have an antihyperglycemic potential through its beneficial effects increasing postprandial serum glucose and hyperinsulinemia. Recent studies indicate that D-tag has a potent anti-diabetic effect and could be eventually associated with significant benefits for the treatment of obesity. The hypothesis regarding the mechanism of action proposed for this hypoglycemic effect would consider the interference with carbohydrates absorption by inhibition of intestinal disaccharidases and glucose transport, an also a mechanism of inhibition of hepatic glycogenolysis [37]. Another important characteristics of the D-tag is it low GI, considering white bread and glucose as reference foods, the D-tag GI is 3 and 4, respectively [63]. The potential applications of D-tag in the pharmaceutical industry and in food industry have reached a great boom [41]. However, the use of D-tag is limited by its high cost of production [36]. Another characteristic of D-tag is its potential prebiotic activity, and in order to preserve this effect the processing and storing of the food must ensure the maintenance of the chemical structure of the sweetener [35]. It has been determined that D-tag can be used for the formulation of diabetic beverages with minimal chance of degradation and very low loss of prebiotic activity [31, 33, 36], maintaining adequate thermal stability. Preliminary results suggest that D-tag would have an effect on the reduction of total cholesterol, VLDL, and LDL compared to sucrose in diabetic patients [53]; the contribution of D-tag to increase levels of HDL cholesterol has also been shown [54]. These clinical studies and wonderful advances in food technology make this molecule an ideal sweetener in functional products for patients with diabetes [62–64], with the ability to positively affect the intestinal microbiota of these patients, making its consumption more interesting and useful in a little explored area [85, 87]. On the other hand, the incorporation of novel functional sources of fiber, as well as oligosaccharides of potential prebiotic activity, has generated great scientific interest in the formulation of healthy foods aimed at diabetics. This new direction of science could be the anticipation of a new line of research that is beginning to emerge. Finally, future projection of personalized nutrigenomics foresees a great challenge toward the integration of different sciences as transcriptomics, epigenetics, proteomics, and metabolomics, with the purpose of positively modifying the microbiome, generating impact in the gene expression of the

molecule is transformed into D-tagatose through an isomerization process [43].

human organism, and avoiding manifestation of chronic diseases such as DM2.

The use of prebiotics obtained from functional fiber sources such as fructo-oligosaccharides and beta-glucans, as well as lignin and prebiotics such as keffir, can contribute to the development of a healthy HIM by promoting the growth of bacterial species that have been associated with obesity and diabetes prevention. On the other hand, it has been described that some low GI monosaccharides can positively modify the composition of the HIM in animal models, by regulating the mechanism of insulin sensitivity. More investigations are needed to evaluate the effect of saccharides, such as fructose, lactose and isomaltose in the human microbiome. Although, some NCS such as sucralose, saccharin, and acesulfame-K can modify the balance of HIM, mainly through the alteration in the number of Bacteroidetes species. Nevertheless, more studies in humans are required. In this sense, a new caloric sugar called D-tag has proposed

4. Conclusions

Figure 1. NCSs: sucralose, saccharin and acesulfame-K have been found to modify the balance of the HIM, either by decreasing or increasing the number of Bacteroidetes.

NCS [92]. This group also performed a smaller trial of seven healthy volunteers (five males, two females, and ages 28–36) who did not normally consume NCS and who received saccharin for 1 week at a dose of 5 mg/kg, IDA for these sweeteners. Most of these (4/7), known as "NCSs responders" developed lower glucose tolerance and altered IM compared to "non-responders of NCS" [92]. Microbiome of "NCS responders" showed changes in composition by 16S rRNA analysis. Due this control group was not included in the design, it is unclear whether some healthy individuals exposed to seven consecutive tests of oral glucose tolerance (daily intake of 75 g of glucose) would have developed changes in glucose metabolism in the absence of saccharin. Palmnas et al. [107], demonstrated that 8 weeks of exposure to aspartame (at an equal dose to subjects consuming approximately 2–3 sodas/day) disrupted the intestinal microbiota; aspartame + high fat diet vs. water + high fat diet increased total bacteria; Enterobacteraceae, Clostridium leptum, and Roseburia spp. reduced Bifidobacterium sp. On the contrary, when the diet was low fat + aspartame or low-fat + water, Clostridium leptum increased, resulting in elevated levels of fasting glucose and insufficiency tolerance to insulin in rats [51]. However, the mechanism by which aspartame disrupted the IM is unclear, as aspartame is metabolized before it reaches the colon by intestinal esterases and peptidases in amino acids and methanol (Figure 1) [49].

#### 3.2. Tagatose and prebiotic potential activity

D-tagatose (D-tag) is an isomer of fructose approximately 90% sweeter than sucrose. Only 20% of the oral intake of tagatose is completely metabolized, mainly in the liver [49]. The mayor part of this molecule is not digested or absorbed and passes through colon where water is absorbed and D-tag is fermented by colonic bacteria. This natural sweetener can be artificially obtained from lactose. This sweetener with natural origin can be obtained artificially from lactose. Through food technology, glucose is separated and galactose is extracted, whose molecule is transformed into D-tagatose through an isomerization process [43].

D-tag would have an antihyperglycemic potential through its beneficial effects increasing postprandial serum glucose and hyperinsulinemia. Recent studies indicate that D-tag has a potent anti-diabetic effect and could be eventually associated with significant benefits for the treatment of obesity. The hypothesis regarding the mechanism of action proposed for this hypoglycemic effect would consider the interference with carbohydrates absorption by inhibition of intestinal disaccharidases and glucose transport, an also a mechanism of inhibition of hepatic glycogenolysis [37]. Another important characteristics of the D-tag is it low GI, considering white bread and glucose as reference foods, the D-tag GI is 3 and 4, respectively [63]. The potential applications of D-tag in the pharmaceutical industry and in food industry have reached a great boom [41]. However, the use of D-tag is limited by its high cost of production [36]. Another characteristic of D-tag is its potential prebiotic activity, and in order to preserve this effect the processing and storing of the food must ensure the maintenance of the chemical structure of the sweetener [35]. It has been determined that D-tag can be used for the formulation of diabetic beverages with minimal chance of degradation and very low loss of prebiotic activity [31, 33, 36], maintaining adequate thermal stability. Preliminary results suggest that D-tag would have an effect on the reduction of total cholesterol, VLDL, and LDL compared to sucrose in diabetic patients [53]; the contribution of D-tag to increase levels of HDL cholesterol has also been shown [54]. These clinical studies and wonderful advances in food technology make this molecule an ideal sweetener in functional products for patients with diabetes [62–64], with the ability to positively affect the intestinal microbiota of these patients, making its consumption more interesting and useful in a little explored area [85, 87]. On the other hand, the incorporation of novel functional sources of fiber, as well as oligosaccharides of potential prebiotic activity, has generated great scientific interest in the formulation of healthy foods aimed at diabetics. This new direction of science could be the anticipation of a new line of research that is beginning to emerge. Finally, future projection of personalized nutrigenomics foresees a great challenge toward the integration of different sciences as transcriptomics, epigenetics, proteomics, and metabolomics, with the purpose of positively modifying the microbiome, generating impact in the gene expression of the human organism, and avoiding manifestation of chronic diseases such as DM2.
