Integrated Metagenomics and Metabolomics to Reveal the Effects of Policosanol on Modulating the Gut Microbiota and Lipid Metabolism in Hyperlipidemic C57BL/6 Mice

Abstract

The aim of the study was to investigate the regulatory effects of policosanol on hyperlipidemia, gut microbiota and metabolic status in a C57BL/6 mouse model. A total of 35 C57BL/6 mice were assigned to 3 groups, chow (n=12), high fat diet (HFD, n=12) and HFD+policosanol (n=11), then treated for 18 weeks. Policosanol supplementation significantly reduced serum triglycerides and total cholesterol, as well as the weight of brown adipose tissue (BAT) (p<0.05), without affecting body weight in HFD-fed mice (p>0.05). Combined 16S rRNA gene sequencing and untargeted metabolomic analysis demonstrated that policosanol had regulatory effects on gut microbiota and serum metabolism in mice. In obese mice, policosanol increased the proportion of Bacteroides, decreased the proportion of Firmicutes, and increased the ratio of Bacteroides to Firmicutes (p<0.05). Policosanol promoted lipolysis and thermogenesis process, including tricarboxylic acid (TCA) cycle and pyruvate cycle, correlated with the increasing level of Bacteroides, Parasutterella, and decreasing level of Lactobacillus and Candidatus_Saccharimonas. Moreover, policosanol decreased fatty acid synthase (FAS) in the iWAT of obese mice. Policosanol also increased peroxisome proliferators-activated receptor-γ (PPARγ), uncoupling Protein-1 (UCP-1), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and PR domain containing 16 (PRDM16) in brown adipose tissue (BAT) obese mice (p<0.05). This study presents the new insight that policosanol may inhibit the synthesis of fatty acids, and promote lipolysis, thermogenesis related gene expression and regulate gut microbiota constituents, which provides potential for policosanol as an antihyperlipidemia functional food additive and provide new evidence for whole grain food to replace refined food.

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“…Policosanol reduced LDL-cholesterol and triglyceride levels, increased HDL-cholesterol levels, and reduced systolic blood pressure in a double-blind, placebo-controlled, and parallel clinical trial with women with prehypertension [ 285 ]. In comparison to a high-fat diet, healthy C57BL/6 mice that were fed a high-fat diet with 0.5% policosanol for 18 weeks developed a better lipid profile, a reduction in brown and white inguinal adipose tissue, a distinctive microbiota profile, and enhanced lipolysis and thermogenesis [ 292 ], while, in a similar study, 60 mg/kg of either octacosanol or policosanol protected against visceral fat hyperplasia and liver steatosis [ 293 ]. Beneficial effects of phytosterols on LDL-cholesterol are well established, with a mean reduction of 8–10% [ 294 ] and significant reductions in ApoCII and ApoE [ 295 ].…”