**4. Conclusions**

246 Lipid Metabolism

**fermentation in colon** 

(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

Microbial metabolites have been shown to modulate gene expression, for instance butyrate acts as a histone deacetylase (HDAC) inhibitor, and affects gene transciption [141]. Polydextrose has been shown to increase expression of PPARγ in the colon of mice [142]. This has been attributed to be mediated at least by butyrate, which can not only up regulate gene expression of PPARγ, but also activate it [143]. When intestinal epithelial cells were treated with polydextrose fermentation metabolites, a gene expression signature was induced that approached the response of butyrate [144]. In the study [144] 1 or 2 % polydextrose was fermented in a four-stage semicontinuous colon simulation model, in which each vessel in sequence represents different parts of the colon. Caco-2 cells were treated with the polydextrose fermentation metabolites from each vessel, and the idea was to analyse gene expression pattern of the Caco-2 cells treated with fermentation metabolome representing the whole colon. The weakness of this study was that the cells were not differentiated, but were used as a cancer cell model, and that fermentation metabolites originated from a fecal sample only from one individual. In the gene ontology analysis of this study, enrichment of class "lipid metabolism" by the polydextrose fermentation metabolites was noted, which indicated that genes involved in energy metabolism were regulated. Indeed, induction of PPARα, PGC-1α, and Lipin 1which are major regulators of the metabolism, were observed. Additionally, some PPARα responsive genes were observed to be up regulated, such as SORBS1, LPIN1, NPC1, FATP1, HMOX1, and ACSL1 [144].

In the intestine, activation of PPARα results in the specific induction of genes involved in fatty acid uptake, binding, transport, and catabolism. In addition, genes involved in triacylglycerol and glycerolipid metabolism have been suggested to function as fatty acid sensors, and in nutrient absorption [145, 146]. PGC-1α participates to the regulation of both carbohydrate and lipid metabolism, and it has been involved in the adaptation of and maintenance of energy homeostais in caloric restriction [147]. Drosophila PGC-1α homolog increases mitochondrial gene expression and activity and protects against age-related loss of intestinal homeostasis and integrity, and is suggested to extend life span [148]. Lipin 1 is induced by PGC-1α in liver and acts to amplify PGC-1α and to activate many of the genes of mitochondrial fatty acid oxidative metabolism [149]. Lipin 1 has been associated with insulin sensitivity in adipose tissue and liver which indicates that it has a profound role in

One of the genes regulated by polydextrose fermentation metabolites was Niemann Pick C1 (NPC1), a significant contributor to plasma HDL cholesterol formation [152]. NPC1 facilitates the movement of cholesterol to ABCA1, a cholesterol transporter that is located in

maintaining systemic metabolic homeostasis [150, 151].

ingestion causes changes in these peptide hormones remains to be investigated.

**3.5. Modulation of genes regulating energy metabolism by polydextrose** 

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 that polydextrose could interfere with cholesterol and triglyceride absorption.

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 there is no evidence for this.

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].

Polydextrose in Lipid Metabolism 249

biosynthesis is supressed in most organs by fasting, the intestine becomes the major site of cholesterol biosynthesis, and its contribution can increase up to 50 %[160, 161]. Mixtures of short chain fatty acids have been show to suppress cholesterol synthesis in the rat liver and intestine [162], and whether fermentation metabolites from polydextrose can inhibit

Michael Bond, Stuart Craig, and Kirsti Tiihonen (DuPont Nutrition and Health) are thanked

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cholesterol biosynthesis in the intestine, or even in the liver, is an open question.

*DuPont Nutrition and Health, Active Nutrition, Kantvik, Finland* 

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**Author details** 

**Acknowledgement** 

**5. References** 

129.

(S2) S1-S63.

Heli Putaala

**Figure 3.** Summary of the polydextrose function in lipid metabolism.

It could be worthwhile to investigate to what extent polydextrose fermentation metabolites cause systemic effects for instance in liver, and its de novo cholesterol synthesis, not forgetting the role of the intestine. When lipidemic conditions are normal, the liver is the most important site of cholesterol biosynthesis, followed by the intestine. Biosynthesis in the liver and intestine account for about 15 and 10 %, respectively, in the total amount of cholesterol biosynthesis each day [158] [159]. In hypercholesterolemia, when cholesterol biosynthesis is supressed in most organs by fasting, the intestine becomes the major site of cholesterol biosynthesis, and its contribution can increase up to 50 %[160, 161]. Mixtures of short chain fatty acids have been show to suppress cholesterol synthesis in the rat liver and intestine [162], and whether fermentation metabolites from polydextrose can inhibit cholesterol biosynthesis in the intestine, or even in the liver, is an open question.
