**3.1. Role of polydextrose in enterohepatic bile circulation and in cholesterol absorption**

One of the mechanisms by which soluble viscous fibers induce hypocholesterolemic responses is the disruption of enterohepatic bile acid circulation, which reduces absorption of intestinal bile acids. The major route by which cholesterol in the liver is eliminated is through the de novo synthesis of primary bile acids from cholesterol [70]. The bile is released into the small intestine, where bile salt micelles help in the solubilisation of lipophilic components, such as cholesterol, fat soluble vitamins, and other lipids [70]. The diffusion of the micelles with solubilised components as well as the biliary and dietary cholesterol across the unstirred water layer, covering the luminal side of the enterocytes facilitate the uptake of cholesterol and other lipophilic components by the enterocytes [71]. When the bile salt micelles have accomplished their role they transit the remainder of small and large intestine where they are progressively absorbed into the enterohepatic circulation by the hepatic portal vein [70]. The bile salts that escape the intestinal absorption are transformed through colonic bacterial enzymatic activity to form secondary bile salts, from which deoxycholic acid is absorbed passively through colonic epithelium into the enterohepatic circulation, while lithocholic acid is secreted into the feces [72]. The amount of bile salts, both primary and secondary, is maintained in a rather constant level, and the daily bile salt losses are compensated by de novo hepatic biosynthesis [73]. The enterohepatic circulation is very efficient, as 95 % of the bile salts released into the intestine is absorbed back to the liver [70].

The presence of viscous soluble fiber has been shown to prevent bile salt reabsorption, which leads to enhanced excretion of bile salts into feces [35, 36]. This depletes the bile acids from liver and leads to rapid catabolisation of cholesterol through activation of 7alphahydroxylase. At the same time cholesteryl esters are metabolised, and in order to replace these production of LDL surface membrane receptors and concomitant LDL cholesterol uptake from blood stream are increased. This leads to lowering of the blood cholesterol concentration [74]. The fibers presumably interact with bile acids directly at the molecular level or entrap bile salt micelles in the gelatinous network formed by the polymeric fiber [35, 75]. The fiber can also form a barrier which can prevent the formation of bile acid micelles, and increase the unstirred water layer lining the intestinal mucosal surface [76].

Polydextrose is a non-viscous fiber and its capacity to bind bile salts has been studied in one clinical intervention study [77]. In this study, administration of polydextrose in healthy adults at 8 g/day for three weeks was not found to increase fecal excretion of total bile acids and secondary bile acids, but rather decreased values were observed during the intervention period compared to the run-in period before [77]. A similar observation was made in normal rats, in which administration of 5 % polydextrose for 6 weeks did not increase the fecal output of bile acids [42]. The low ability of polydextrose to bind bile acids is not, however, surprising. In order for a fiber to bind bile acids, it is required to be viscous in nature, and polydextrose is lower in viscosity for instance in comparison to pectin and guar gum which have high water binding capacity with higher viscosity and thus increased capability to bind bile acids [42, 78]. Polydextrose has a high capacity to bind water, and it can for instance relieve constipation presumably due to this characteristic, but there is no gel formation by polydextrose in water and little viscosity [43, 79, 80].

240 Lipid Metabolism

observed.

**absorption** 

back to the liver [70].

Table 2 summarizes the different human clinical intervention studies done with polydextrose in relation to HDL, LDL, total cholesterol and triglycerides. From these studies it can be concluded that polydextrose in the diet can lower serum total and LDL cholesterol and triglycerides. There are two studies in which definite increases in HDL have been

**3.1. Role of polydextrose in enterohepatic bile circulation and in cholesterol** 

One of the mechanisms by which soluble viscous fibers induce hypocholesterolemic responses is the disruption of enterohepatic bile acid circulation, which reduces absorption of intestinal bile acids. The major route by which cholesterol in the liver is eliminated is through the de novo synthesis of primary bile acids from cholesterol [70]. The bile is released into the small intestine, where bile salt micelles help in the solubilisation of lipophilic components, such as cholesterol, fat soluble vitamins, and other lipids [70]. The diffusion of the micelles with solubilised components as well as the biliary and dietary cholesterol across the unstirred water layer, covering the luminal side of the enterocytes facilitate the uptake of cholesterol and other lipophilic components by the enterocytes [71]. When the bile salt micelles have accomplished their role they transit the remainder of small and large intestine where they are progressively absorbed into the enterohepatic circulation by the hepatic portal vein [70]. The bile salts that escape the intestinal absorption are transformed through colonic bacterial enzymatic activity to form secondary bile salts, from which deoxycholic acid is absorbed passively through colonic epithelium into the enterohepatic circulation, while lithocholic acid is secreted into the feces [72]. The amount of bile salts, both primary and secondary, is maintained in a rather constant level, and the daily bile salt losses are compensated by de novo hepatic biosynthesis [73]. The enterohepatic circulation is very efficient, as 95 % of the bile salts released into the intestine is absorbed

The presence of viscous soluble fiber has been shown to prevent bile salt reabsorption, which leads to enhanced excretion of bile salts into feces [35, 36]. This depletes the bile acids from liver and leads to rapid catabolisation of cholesterol through activation of 7alphahydroxylase. At the same time cholesteryl esters are metabolised, and in order to replace these production of LDL surface membrane receptors and concomitant LDL cholesterol uptake from blood stream are increased. This leads to lowering of the blood cholesterol concentration [74]. The fibers presumably interact with bile acids directly at the molecular level or entrap bile salt micelles in the gelatinous network formed by the polymeric fiber [35, 75]. The fiber can also form a barrier which can prevent the formation of bile acid micelles,

Polydextrose is a non-viscous fiber and its capacity to bind bile salts has been studied in one clinical intervention study [77]. In this study, administration of polydextrose in healthy

and increase the unstirred water layer lining the intestinal mucosal surface [76].

**3. Mechanisms for polydextrose action on lipid values** 

Even though no clear effect on bile acid binding can be detected, the fact that cholesterol and triglyceride absorption can still be modulated, are indications that polydextrose can retard the transportation of lipids from the intestinal lumen to the lymph. When polydextrose was infused as 5 % and 10 % to duodenum together with cholesterol and triglyceride on mesenteric lymph-fistulated rats, the amount of cholesterol and triglycerides in the lymph decreased dose-dependently, and concomitantly the amount of the unabsorbed lipids increased in the lumen of the intestine [81]. It was concluded that since most of the luminal triglyceride and cholesterol was detected in the proximal part of the small intestine, the absorption of the lipids was inhibited. There was a tendency to have increased amount of cholesterol and a significant increase of triglycerides remaining in the colon which could indicate that some of the lipids were not absorbed [81]. However, polydextrose did not seem to increase secretion of cholesterol into feces in rats even though some tendency was observed in another study [82].

In an acute response study of polydextrose in combination with lactitol in rats with lipid load similar to the composition of chocolate an increase in luminal triglyceride in the cecum was observed with concomitant decrease in serum triglycerides [46]. This would indicate that the combination of polydextrose and lactitol reduced either the level of fat absorption in the earlier part of small intestine or promoted the transit time of fat through the intestine [46].

Cholesterol that escapes absorption is partially degraded to coprostanol and coprostanone by colon microbes [83]. A decrease of the degradation products coprostanol, coprostanon and cholestanol has been observed [77] which would indicate that the amount of cholesterol entering the colon is less in humans receiving polydextrose.

#### **3.2. Role of polydextrose on intestinal microbiota and its impact on cholesterol metabolism**

When soluble fiber enters the large intestine, it is fermented by the residual microbes forming short-chain fatty acids (SCFAs), butyrate, acetate, and propionate, end-products of bacterial carbohydrate fermentation. The SCFAs have been indicated to possess different physiological functions. Butyrate has been implicated to be the most important SCFA for colonic and immune cells due to its ability to serve as energy source for colonic epithelium as well as regulate cell growth and differentiation [84, 85]. It is a preferred energy source by colonocytes over glucose, glutamine, or other SCFA, and 70 to 90 % of butyrate is metabolized by colonocytes [86]. It has been implicated to inhibit intestinal cholesterol biosynthesis [87]. Acetate, as a direct substrate for acetyl-CoA synthetase, an enzyme that converts acetate to acetyl-CoA for entering to the cholesterol and fatty acid synthesis cycle, has been implicated to increase liver cholesterol, and fatty acid levels [41, 88]. Acetate has been shown to associate negatively with visceral adipose tissues and insulin levels in obese people [89]. Propionate has been shown to possess antilipogenic and cholesterol-lowering effects. While acetate is a substrate for sterol and fatty acid synthesis, propionate counteracts this by inhibiting acetate incorporation to serum lipids [41]. Propionate has been shown to to reduce the rate of cholesterol synthesis [87, 90], to inhibit fatty acid synthesis [91], to decrease liver lipogenesis [92], and to decrease hepatic and plasma and serum cholesterol levels [93, 94]. Propionate supplementation has been shown increase serum HDL cholesterol and triglyceride levels without effect on total cholesterol [92, 95]. However, contradictory results about its efficacy on cholesterol metabolism has been also observed [96-98].

Polydextrose in Lipid Metabolism 243

**Figure 2.** Concentration (mM) of short chain fatty acids (SCFAs) in the different vessels V1, V2, V3, and V4 after 48h in vitro colon fermentation simulation. An increase in the concentration of SCFAs can be observed both dose-dependently as well as from vessels representing proximal colon V1 towards

When polydextrose enters the colon, it is fermented by the indigenous microbiota, thus serving as an energy-source to promote their growth and survival. In germ-free mice, the transplantation of the colonic microbiota from normal mice resulted in a 60 % increase in body fat in an unchanged diet [110] and there are an increasing number of reports that the gut microbiota may play an important role in cholesterol and lipid homeostasis, in obesity

Bacterial DNA of fecal samples from 20 individuals consuming 21 g of polydextrose in 3 doses per day were pyrosequenced, and the amount of Clostridiaceae, and Veillonea increased while Lachnospiraeae and Eubacteriaceae decreased compared to the control group without additional supplemental fiber [114]. Well-known butyrate-producers were increased in number, such as Faecalibacterium, and especially Faecalibacterium prausnitzii, whereas other SCFA producers, such as Lachnospiraceae, and Eubacteriaceae were reduced in number by administration of polydextrose [114]. Polydextrose also decreased the number of Coriobacteriaceae, which have been shown to have a positive association to non-HDL cholesterol [111, 114]. Interestingly, bifidobacteria have shown a positive correlation with HDL-cholesterol [111], but the bifidobacterial counts were decreased by polydextrose when studied with pyrosequencing [114]. In other studies polydextrose administration has been shown to increase the amount of bifidobacteria and lactobacilli [17, 18, 49, 106, 107, 115] while in some studies this effect has not been noted [103] or that there was no effect on the growth of lactobacilli [102]. This kind of inconsistency in the response could reflect the interindividual differences in indigenous microbiota to begin with. These kind of fluctuations in the indigenous microbiota, however, might explain why there are

vessels representing more distal parts of the colon, V3 and V4.

and metabolic syndrome [111-113].

The production of short-chain fatty acids during polydextrose fermentation has been studied with batch fermentations, colon simulators as well as from feces in animal and human studies. The differences in the results reflect individual variation, sampling, and differences in the methods used. Fecal SCFA concentration measurements are not the best indicators of SCFA produced as the majority of fecal SCFA is absorbed rapidly by the colonic epithelial cells [99]. Polydextrose has been observed to increase the production of butyrate, acetate and propionate in vitro [18, 100-102], in rats [20], pigs [11], in dogs [103] and in humans [17, 49]. When compared to other fibers, polydextrose produced similar quantities of SCFAs, and the molecular ratio of acetate/propionate/butyrate produced was found to be similar to that of fructo-oligosaccharides and xylo-oligosaccharides and other carbohydrates, such as inulin, pectin, and arabinose [104, 105] while in other studies polydextrose produced less total SCFAs compared to FOS, inulin and GOS [102, 106, 107]. The lower production of SCFAs by polydextrose can be explained by the lower digestability of polydextrose and its more sustained fermentation throughout the gut due to its branched complex structure. Furthermore, polydextrose fermentation has been shown to reduce putrefactive microbial metabolites, or branched-chain fatty acids and biogenic amines produced from protein fermentation [11, 20, 49, 100, 101, 107-109] but the decrease of these in relation to lipid metabolism and absorption is unknown. Figure 2 shows an example of how fermentation of polydextrose increases the amount short chain fatty acids in an in vitro colon simulation both when the amount of polydextrose is increased, and when the simulation proceeds from vessel V1 representing proximal part of the colon towards the vessels representing more distal parts of the colon [108].

242 Lipid Metabolism

bacterial carbohydrate fermentation. The SCFAs have been indicated to possess different physiological functions. Butyrate has been implicated to be the most important SCFA for colonic and immune cells due to its ability to serve as energy source for colonic epithelium as well as regulate cell growth and differentiation [84, 85]. It is a preferred energy source by colonocytes over glucose, glutamine, or other SCFA, and 70 to 90 % of butyrate is metabolized by colonocytes [86]. It has been implicated to inhibit intestinal cholesterol biosynthesis [87]. Acetate, as a direct substrate for acetyl-CoA synthetase, an enzyme that converts acetate to acetyl-CoA for entering to the cholesterol and fatty acid synthesis cycle, has been implicated to increase liver cholesterol, and fatty acid levels [41, 88]. Acetate has been shown to associate negatively with visceral adipose tissues and insulin levels in obese people [89]. Propionate has been shown to possess antilipogenic and cholesterol-lowering effects. While acetate is a substrate for sterol and fatty acid synthesis, propionate counteracts this by inhibiting acetate incorporation to serum lipids [41]. Propionate has been shown to to reduce the rate of cholesterol synthesis [87, 90], to inhibit fatty acid synthesis [91], to decrease liver lipogenesis [92], and to decrease hepatic and plasma and serum cholesterol levels [93, 94]. Propionate supplementation has been shown increase serum HDL cholesterol and triglyceride levels without effect on total cholesterol [92, 95]. However, contradictory

results about its efficacy on cholesterol metabolism has been also observed [96-98].

vessels representing more distal parts of the colon [108].

The production of short-chain fatty acids during polydextrose fermentation has been studied with batch fermentations, colon simulators as well as from feces in animal and human studies. The differences in the results reflect individual variation, sampling, and differences in the methods used. Fecal SCFA concentration measurements are not the best indicators of SCFA produced as the majority of fecal SCFA is absorbed rapidly by the colonic epithelial cells [99]. Polydextrose has been observed to increase the production of butyrate, acetate and propionate in vitro [18, 100-102], in rats [20], pigs [11], in dogs [103] and in humans [17, 49]. When compared to other fibers, polydextrose produced similar quantities of SCFAs, and the molecular ratio of acetate/propionate/butyrate produced was found to be similar to that of fructo-oligosaccharides and xylo-oligosaccharides and other carbohydrates, such as inulin, pectin, and arabinose [104, 105] while in other studies polydextrose produced less total SCFAs compared to FOS, inulin and GOS [102, 106, 107]. The lower production of SCFAs by polydextrose can be explained by the lower digestability of polydextrose and its more sustained fermentation throughout the gut due to its branched complex structure. Furthermore, polydextrose fermentation has been shown to reduce putrefactive microbial metabolites, or branched-chain fatty acids and biogenic amines produced from protein fermentation [11, 20, 49, 100, 101, 107-109] but the decrease of these in relation to lipid metabolism and absorption is unknown. Figure 2 shows an example of how fermentation of polydextrose increases the amount short chain fatty acids in an in vitro colon simulation both when the amount of polydextrose is increased, and when the simulation proceeds from vessel V1 representing proximal part of the colon towards the

**Figure 2.** Concentration (mM) of short chain fatty acids (SCFAs) in the different vessels V1, V2, V3, and V4 after 48h in vitro colon fermentation simulation. An increase in the concentration of SCFAs can be observed both dose-dependently as well as from vessels representing proximal colon V1 towards vessels representing more distal parts of the colon, V3 and V4.

When polydextrose enters the colon, it is fermented by the indigenous microbiota, thus serving as an energy-source to promote their growth and survival. In germ-free mice, the transplantation of the colonic microbiota from normal mice resulted in a 60 % increase in body fat in an unchanged diet [110] and there are an increasing number of reports that the gut microbiota may play an important role in cholesterol and lipid homeostasis, in obesity and metabolic syndrome [111-113].

Bacterial DNA of fecal samples from 20 individuals consuming 21 g of polydextrose in 3 doses per day were pyrosequenced, and the amount of Clostridiaceae, and Veillonea increased while Lachnospiraeae and Eubacteriaceae decreased compared to the control group without additional supplemental fiber [114]. Well-known butyrate-producers were increased in number, such as Faecalibacterium, and especially Faecalibacterium prausnitzii, whereas other SCFA producers, such as Lachnospiraceae, and Eubacteriaceae were reduced in number by administration of polydextrose [114]. Polydextrose also decreased the number of Coriobacteriaceae, which have been shown to have a positive association to non-HDL cholesterol [111, 114]. Interestingly, bifidobacteria have shown a positive correlation with HDL-cholesterol [111], but the bifidobacterial counts were decreased by polydextrose when studied with pyrosequencing [114]. In other studies polydextrose administration has been shown to increase the amount of bifidobacteria and lactobacilli [17, 18, 49, 106, 107, 115] while in some studies this effect has not been noted [103] or that there was no effect on the growth of lactobacilli [102]. This kind of inconsistency in the response could reflect the interindividual differences in indigenous microbiota to begin with. These kind of fluctuations in the indigenous microbiota, however, might explain why there are

#### 244 Lipid Metabolism

differencies in the studies with polydextrose and its effect on cholesterol values, for instance in [45] in which a responder group with a decrease in LDL was observed.

Polydextrose in Lipid Metabolism 245

replaced with polydextrose. In volunteers with type 2 diabetes, cranberries with 10g of polydextrose showed attenuated plasma glucose and insulin response compared to cranberries with glucose [127]. In one study with healthy adults, significantly lower postprandial glucose levels were observed after ingestion of strawberry jam with 40 % polydextrose than after ingestion of strawberry jam sweetened with sugar, corn syrup, or

These above results indicate that polydextrose might have a role in postprandial glucose absorption and insulin response. One good candidate to modify insulin response is again the SCFAs, especially propionate, which have been shown to improve insulin sensitivity during glucose tolerance tests [95]. Polydextrose also might interfere the release and absorption of the glucose in the small intestine which would lead to slower and lower blood sugar rise [5]. In some of these studies the response is observed because polydextrose was used as sugar substitute to lower the caloric content of the snack/product [127, 128]. In [127] the beneficial insulin reduction was observed not to be in 1:1 ratio with caloric reduction so there might be additional beneficial effect apart from lowering the overall calorie content.

Meals dense in fiber have also been demonstrated to be able to control the sense of hunger, satiety, inhibit the desire for another meal, or induce satiation, limit the size of the meal, possibly by lowering caloric density or slowing down gastric emptying [40, 129] This would further decrease the sugar load of the individual, since high-fiber diets usually have a lower

Polydextrose has been observed to significantly reduce the feeling of hunger in subjects with impaired glucose metabolism [52], and to have tendency towards reduced snacking [10]. It has been shown to increase satiety and to reduce food intake when combined with yoghurt preloads [130]. However, evidence has been conflicting - in one study when 25 g polydextrose was preloaded in two servings before lunch, no difference in the desire to eat, sense of hunger and fullness was observed beween polydextrose and the other fibers tested [131]. In this study polydextrose did not decrease the energy consumed in lunch. In another study when polydextrose was consumed as 9.5 g in a muffin no difference in the feeling of hungriness or food intake was observed between polydextrose and the other fibers studied [132]. In the two most recent studies, polydextrose intake of 12 g in a fruit smoothie, consumed as a single dose preload, significantly reduced the intake of energy in a buffet lunch 1 hour after the consumption of the smoothie [133]. Similar observations with a single dose of 6.25 g or 12.5 g of polydextrose before a test lunch were also made in another study

Both butyrate and propionate have been shown to induce gut hormones and reduce food intake [136]. Propionate has been shown to act as a satiety-inducing agent, with strong effects on energy intake and feeding behaviour with significantly greater feeling of fullness and lower desire to eat [137, 138]. This could be introduced by the modulation of the colonic mucosa secreted peptide hormones that regulate appetite, such as glucagon like peptide -1

apple juice, but this study did not measure insulin [128].

**3.4. Polydextrose as a satiety increasing agent** 

glycemic load.

[134, 135].

#### **3.3. Polydextrose effect on glycemic control and insulin response**

Fibers can affect blood glucose levels by decreasing the glycemic load of a meal or by affecting glucose absorption or release of glucose [5], and especially soluble fiber has been shown to attenuate the absorption of glucose [27]. Soluble dietary fibers may affect total and LDL cholesterol levels through effects on postprandial glycemia, as reduction in the glucose absorption, which would lower the insulin level and its production in the pancreas, would then lead to a decrease in cholesterol synthesis [116]. When soluble dietary fibers are being digested they delay the emptying of digested food from the stomach to the small intestine, slow down the transportation and mixing of digestive enzymes in the chyme and increase the resistance of the unstirred water layer lining the mucosa [117, 118]. This leads to reduction in the absorption of glucose and macronutrients, and lowered level of postprandial glucose is accompanied with lowered insulin level which would possibly lead to lowered hepatic cholesterol synthesis. [39]. There has been studies describing inverse relationship between glycemic load and HDL cholesterol [119, 120], and an indirect regulation of intestinal lipid uptake by dietary glucose has been presumed. Short-term incubation with intestinal epithelial cells, Caco-2 cells, with glucose on the apical side induces a significant uptake of cholesterol in a dose-dependent manner [121], and in addition cholesterol synthesis seems to dependent on glucose intake [122].

The effect of polydextrose ingestion on glucose and postprandial insulin response has been investigated in several studies. Polydextrose has a very low glycemic index (4 to 7) with glycemic load of 1 compared to the reference glucose (100) [7, 123]. Polydextrose has been reported to attenuate the blood glucose raising potential of glucose, as the glycemic index of glucose was reduced from 100 to 88 when 12 grams of polydextrose was ingested together with glucose by healthy adults [49]. Similar results were observed in a study with healthy adults when 14 g was ingested together with 50 g of glucose or 106 g of bread [124]. Plasma glucose levels were decreased by 28 % and 35 %, compared to glucose and bread without polydextrose, respectively, with significantly reduced serum insulin levels in the glucose plus polydextrose group [124]. These observations indicate that polydextrose could reduce the absorption of glucose. When the effect of polydextrose was studied with human subjects with impaired glucose tolerance or impaired fasting glucose, no change in plasma glucose or insulin has been observed [52]. However, this study [52] had a moderately high fructose intake which could have affected the results as fructose does not induce endogenous secretion of insulin [125]. Diurnally polydextrose did not seem to change plasma sugar levels, but a decrease in insulin after meals was noted [69]. In dogs, polydextrose showed an attenuated postprandial glycemic and lower relative insulin responses than the control sugar maltitol [126].

Polydextrose has been also studied in trials in which the reference group received a normal meal/snack with glucose, and the intervention group the same but with the glucose partially replaced with polydextrose. In volunteers with type 2 diabetes, cranberries with 10g of polydextrose showed attenuated plasma glucose and insulin response compared to cranberries with glucose [127]. In one study with healthy adults, significantly lower postprandial glucose levels were observed after ingestion of strawberry jam with 40 % polydextrose than after ingestion of strawberry jam sweetened with sugar, corn syrup, or apple juice, but this study did not measure insulin [128].

These above results indicate that polydextrose might have a role in postprandial glucose absorption and insulin response. One good candidate to modify insulin response is again the SCFAs, especially propionate, which have been shown to improve insulin sensitivity during glucose tolerance tests [95]. Polydextrose also might interfere the release and absorption of the glucose in the small intestine which would lead to slower and lower blood sugar rise [5]. In some of these studies the response is observed because polydextrose was used as sugar substitute to lower the caloric content of the snack/product [127, 128]. In [127] the beneficial insulin reduction was observed not to be in 1:1 ratio with caloric reduction so there might be additional beneficial effect apart from lowering the overall calorie content.

#### **3.4. Polydextrose as a satiety increasing agent**

244 Lipid Metabolism

sugar maltitol [126].

differencies in the studies with polydextrose and its effect on cholesterol values, for instance

Fibers can affect blood glucose levels by decreasing the glycemic load of a meal or by affecting glucose absorption or release of glucose [5], and especially soluble fiber has been shown to attenuate the absorption of glucose [27]. Soluble dietary fibers may affect total and LDL cholesterol levels through effects on postprandial glycemia, as reduction in the glucose absorption, which would lower the insulin level and its production in the pancreas, would then lead to a decrease in cholesterol synthesis [116]. When soluble dietary fibers are being digested they delay the emptying of digested food from the stomach to the small intestine, slow down the transportation and mixing of digestive enzymes in the chyme and increase the resistance of the unstirred water layer lining the mucosa [117, 118]. This leads to reduction in the absorption of glucose and macronutrients, and lowered level of postprandial glucose is accompanied with lowered insulin level which would possibly lead to lowered hepatic cholesterol synthesis. [39]. There has been studies describing inverse relationship between glycemic load and HDL cholesterol [119, 120], and an indirect regulation of intestinal lipid uptake by dietary glucose has been presumed. Short-term incubation with intestinal epithelial cells, Caco-2 cells, with glucose on the apical side induces a significant uptake of cholesterol in a dose-dependent manner [121], and in

in [45] in which a responder group with a decrease in LDL was observed.

**3.3. Polydextrose effect on glycemic control and insulin response** 

addition cholesterol synthesis seems to dependent on glucose intake [122].

The effect of polydextrose ingestion on glucose and postprandial insulin response has been investigated in several studies. Polydextrose has a very low glycemic index (4 to 7) with glycemic load of 1 compared to the reference glucose (100) [7, 123]. Polydextrose has been reported to attenuate the blood glucose raising potential of glucose, as the glycemic index of glucose was reduced from 100 to 88 when 12 grams of polydextrose was ingested together with glucose by healthy adults [49]. Similar results were observed in a study with healthy adults when 14 g was ingested together with 50 g of glucose or 106 g of bread [124]. Plasma glucose levels were decreased by 28 % and 35 %, compared to glucose and bread without polydextrose, respectively, with significantly reduced serum insulin levels in the glucose plus polydextrose group [124]. These observations indicate that polydextrose could reduce the absorption of glucose. When the effect of polydextrose was studied with human subjects with impaired glucose tolerance or impaired fasting glucose, no change in plasma glucose or insulin has been observed [52]. However, this study [52] had a moderately high fructose intake which could have affected the results as fructose does not induce endogenous secretion of insulin [125]. Diurnally polydextrose did not seem to change plasma sugar levels, but a decrease in insulin after meals was noted [69]. In dogs, polydextrose showed an attenuated postprandial glycemic and lower relative insulin responses than the control

Polydextrose has been also studied in trials in which the reference group received a normal meal/snack with glucose, and the intervention group the same but with the glucose partially Meals dense in fiber have also been demonstrated to be able to control the sense of hunger, satiety, inhibit the desire for another meal, or induce satiation, limit the size of the meal, possibly by lowering caloric density or slowing down gastric emptying [40, 129] This would further decrease the sugar load of the individual, since high-fiber diets usually have a lower glycemic load.

Polydextrose has been observed to significantly reduce the feeling of hunger in subjects with impaired glucose metabolism [52], and to have tendency towards reduced snacking [10]. It has been shown to increase satiety and to reduce food intake when combined with yoghurt preloads [130]. However, evidence has been conflicting - in one study when 25 g polydextrose was preloaded in two servings before lunch, no difference in the desire to eat, sense of hunger and fullness was observed beween polydextrose and the other fibers tested [131]. In this study polydextrose did not decrease the energy consumed in lunch. In another study when polydextrose was consumed as 9.5 g in a muffin no difference in the feeling of hungriness or food intake was observed between polydextrose and the other fibers studied [132]. In the two most recent studies, polydextrose intake of 12 g in a fruit smoothie, consumed as a single dose preload, significantly reduced the intake of energy in a buffet lunch 1 hour after the consumption of the smoothie [133]. Similar observations with a single dose of 6.25 g or 12.5 g of polydextrose before a test lunch were also made in another study [134, 135].

Both butyrate and propionate have been shown to induce gut hormones and reduce food intake [136]. Propionate has been shown to act as a satiety-inducing agent, with strong effects on energy intake and feeding behaviour with significantly greater feeling of fullness and lower desire to eat [137, 138]. This could be introduced by the modulation of the colonic mucosa secreted peptide hormones that regulate appetite, such as glucagon like peptide -1

#### 246 Lipid Metabolism

(GLP-1), peptide YY (PYY), oxyntomodulin, or SCFA receptors, GPR43 or GPR41, which have been localized in intestinal enteroendocrine L cells, that are responsible for the production of the appetite regulating hormones [139, 140] but whether polydextrose ingestion causes changes in these peptide hormones remains to be investigated.

Polydextrose in Lipid Metabolism 247

the basolateral membrane of enterocytes, that is involved in the efflux process of cholesterol to circulating HDL particles [153]. Approximately 30 % of the steady-state HDL was contributed by the intestinal ABCA1 in mice [154]. In NPC1 deficient cells the HDL

Based on the current research there is clear evidence that polydextrose has the ability to attenuate glucose absorption, reduce insulin response and lower blood LDL, total cholesterol and triglyceride levels. HDL cholesterol shows a tendency to be increased, but this has not been consistently demonstrated in all studies. This kind of ability to increase HDL would be quite unique among soluble fermentable fibers. Animal studies also indicate

Figure 3 summarises the possible mechanisms of how polydextrose could affect cholesterol and lipid metabolism. Polydextrose is used as a bulking agent, and increases the bulk of the material that transits along the colon. This can provide a sense of fullness and satiety. The effect of polydextrose on bile acid secretion cannot be definitely concluded at this point but is unlikely due to its non-viscous characteristic. It seems, that polydextrose attenuates the blood glucose raising potential of glucose itself, and the insulin response. Glucose and insulin are linked to hepatic de novo cholesterol synthesis, cholesterol absorption and HDL formation. The mechanism of the lipid metabolism modulating effect of polydextrose might be indirect, through its fermentation by the indigenous microbiota either the luminal or mucosal, that at the same time increase SCFA production. The microbiota can affect cholesterol degradation, but could also for instance affect chylomicron formation and cholesterol absorption. The absorbed SCFAs, propionate and butyrate, are linked to diminishing de novo cholesterol synthesis in the liver. Acetate, in contrast, has an opposite effect. Whether SCFAs are the molecules exerting the effect of the polydextrose is not known. During the fermentation of soluble fibers other metabolites apart from SCFAs are formed [156]. The complex structure of polydextrose facilitates its fermentation throughout colon. This differentiates it from other fibers which are fermented early in the colon, and it serves as an energy source for bacteria throughout the colon, and changes in the composition of the microbiota are observed with an increase in butyrate-producing bacteria [114]. It is possible that due to its fermentation characteristics the long-term effect on microbiota composition might be different to other soluble fibers. The mechanism of polydextrose might also be direct, through modulation of surface receptors, but currently

The microarray study has given ideas of how polydextrose fermentation metabolites might affect the intestinal tissue. The evidence is, however, at the transcriptional level only, and is speculative. Additional studies in the possible regulation of PPARα, PGC1α, Lipin1, NPC1, and others by polydextrose is thus needed. In vitro studies could be used for instance to study the role of polydextrose fermentation in HDL formation using a differentiated Caco-2 cell

model which has shown to be good model to study de novo ApoA-I production [157].

that polydextrose could interfere with cholesterol and triglyceride absorption.

cholesterol formation is reduced [155].

**4. Conclusions** 

there is no evidence for this.
