**4. The whole microflora view**

Intestinal microbes not only *Lactobacillus* could also exhibit a bile salt deconjugating effect [40], suggesting that other microbes had lipid-reducing potential. Thus, overall intestinal microflora was taken into account for lipid metabolism evaluation. In the past few years, research has focused on new areas of microflora and lipid metabolism with the development of culture-independent methods for understanding the total microbial diversity [41].

The Effect of Probiotics on Lipid Metabolism 447

Leptin, an antiobesity hormone produced by adipose tissue, has been reported to regulate body weight by controlling food intake and energy expenditure [55]. However, obesity tend to display markedly higher serum leptin level with a leptin-resistant symptom. Several studies reported a decrease of leptin by probiotic administration. In high-fat fed mice, Lee et al confirmed that *Lactobacillus rhamnosus* PL60 exhibited a reduction in leptin level and antiobesity effect due to production of conjugated linoleic acid [56]. Moreover, serum leptin concentration was reduced by *Lactobacillus gasseri* SBT205 in lean Zucker rats linked with lowered adipocyte size [57]. Another study also report leptin level was reduced by a combined bifidobacteria (*B. pseudocatenulatum* SPM 1204, *B. longum* SPM 1205, and *B. longum*  SPM 1207) in obese rats [58]. Interestingly and controversially, direct injection of *Lactobacillus acidophilus* supernatants (germ free) into the brains of rats lead to weight loss

Leptin-lowering effect of probiotics was also observed in human. Similarly, Naruszewicz et al investigated whether oral administration of *L. plantarum* 299v exert beneficial effect on smokers by detection of cardiovascular risk factors [60]. In this study, smokers showed a great decrease in plasma leptin concentrations and anti-inflammatory properties when supplement of probiotic. Discouragingly, two months of *Lactobacillus acidophilus* and *Bifidobacterium longum*

As an adipocyte-derived serum protein, adiponectin play an important role in glucose and lipid metabolism since adiponectin deficiency are associated with insulin resistance, inflammation, dyslipidemia and risk of atherogenic vascular disease [62]. In parallel, adiponectin has also been shown to suppress macrophage foam cell formation in atherosclerosis [63]. Several studies showed that probiotic therapy improved adiponectin level or adiponectin gene expression. One comparative research performed in normal microflora (NMF) and germ-free (GF) mice revealed that adiponectin gene expression (Adipoq) was up-regulated in the groups of *Lactobacillus*-treated germ free mice [64]. Moreover, Higurashi et al reported a probiotic cheese could prevent abdominal adipose accumulation and maintained serum adiponectin concentrations in high-calorie fed rats [65]. However, *Lactobacillus plantarum* strain No. 14 exert a white adipose-reducing effect in high-

Kadooka et al used a probiotic *L. gasseri* SBT2055 to regulate abdominal adiposity in obese adults, where the probiotic treatment involved a significant reduction in abdominal visceral and subcutaneous fat areas from baseline and significantly increased high-molecular weight adiponectin in their serum [67]. Furthermore, a recent large scale clinical study conducted by Luoto et al confirmed that pregnant women with a consumption of combined *Lactobacillus rhamnosus* GG and *Bifidobacterium lactis* probiotics possessed higher colostrum adiponectin concentration compared to placebo which was correlated inversely with

with an increase in leptin expression in neurons and adipose tissue [59].

consumption failed to lower plasma leptin levels in male equol excretors [61].

**5.1. Leptin** 

**5.2. Adiponectin** 

fat fed mice with no change of adiponectin [66].

maternal weight gain during pregnancy [68].

The human gut is consisting of a microbial community of 1014 bacteria with at least 1000 species and the whole microbiome is more than 100-fold the human genome [42].These researches highlight the significance of the whole gut microbiome contribute to energy harvest and the relationship between obesity and changes of gut microbiome [43]. More detailed, obese is mainly characterized by elevated *Firmicutes/Bacteroidetes* ratio in gut [44]. Probiotics serve as one of effective agents for regulation of gut microflora, they can exext benefits on lipid metabolism through downregulating the ratio of *Firmicutes/Bacteroidetes*. Other bacteria such as *Methanobrevibacter smithii* are also at low level in obese people [45]. Interestingly, atherosclerotic disease, which caused by accumulation of cholesterol and inflammation, was recently found its atherosclerotic plaque microbiota was associated with oral and gut microbiota through high throughput 454 pyrosequencing of 16S rRNA genes [46].

Besides, such a huge microflora provide a large reservoir of LPS molecules to circulation through colonizing of Gram-negative bacteria in the gut [47]. A recent study showed *Bifidobacteria* with genes encoding an ATP-binding-cassette-type carbohydrate transporter could protect against Gram-negative *E. coli* O157:H7 colonization in gut due to acetate production [48]. Thus, probiotic can restrict LPS-related microbial communities in the gut.

The whole gut microflora is also known as a target for drug metabolism because of diverse microbial transformations [49]. Manipulation of commensal microbial composition through antibiotics, probiotics or prebiotics was thought to enhance the metabolic activity and production of effective metabolites [50]. Simvastatin, which is an inhibitor of HMG-CoA and widely used for regulating hepatic cholesterol production, was proposed to possess altered pharmacological properties by microflora degradation via changing its capacity to bind to the corresponding receptors [51]. It is indicated that probiotics have potential to influence the metabolism of lipid-regulating drugs in gut.
