**3.5. Modulation of genes regulating energy metabolism by polydextrose fermentation in colon**

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 maintaining systemic metabolic homeostasis [150, 151].

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 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 cholesterol formation is reduced [155].
