ABSTRACT
This study aimed to evaluate the possible anti-obesity effects of orlistat and ezetimibe and determine the mechanism by which they alter the composition of gut microbiota and short-chain fatty acids (SCFAs) in mice with a high-fat diet (HFD)-induced obesity. Eighty male, specific pathogen-free C57BL/6J mice aged 3 weeks were divided into four groups (n = 20). The NCD group was fed with a normal diet, and the HFD, HFD+ORL, and HFD+EZE groups were fed with HFD for 20 weeks. From the 13th week onward, the HFD+ORL and HFD+EZE groups were administered with orlistat and ezetimibe, respectively. The glucose and lipid metabolism of the tested mice were evaluated by analyzing blood biochemical indicators during the intervention. Furthermore, the changes in the structure of the fecal microbiota and the fecal SCFA content were analyzed by 16S rRNA sequencing and gas chromatography-mass spectrometry, respectively. HFD induced the obesity phenotype in mice. Compared to the HFD group, the body weight, visceral fat-to-body weight ratio, serum total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), and oral glucose tolerance test (OGTT) of the HFD+ORL group significantly decreased, whereas fecal butyric acid levels significantly increased. Ezetimibe intervention significantly reduced the OGTT, serum TC, and HDL-C levels only. The α-diversity of the gut microbiota significantly decreased after intervention with orlistat and ezetimibe. Orlistat altered the relative abundance of some bacteria in the fecal microbiota. The populations of Firmicutes, Alistipes, and Desulfovibrio decreased, whereas those of Verrucomicrobia and Akkermansia significantly increased. Ezetimibe caused changes only in some low-abundance bacteria, as manifested by a decrease in Proteobacteria and Desulfovibrio, and an increase in Bacteroides. The administration of orlistat and ezetimibe can characteristically influence the body weight and serum lipid metabolism, and glucolipid levels in diet-induced obese mice and is accompanied by significant changes in the gut microbiota and SCFAs. These results suggest that the two drugs might exert their own specific anti-obesity effects by modulating the gut microbiota in a different manner. The enhanced health-promoting effect of orlistat might result from its stronger ability to alter the gut microbiota and SCFAs, at least partly.
ABSTRACT
This study investigated the gut microbiota and short chain fatty acids (SCFAs) characteristics of subjects with obesity from Xinjiang in northwestern China, a region with a multiethnic culture and characteristic lifestyle, and to explore the potential microbes that respond to a 12-wk medication of orlistat and ezetimibe with a randomized controlled open-label trial manner. The gut microbiota profile of patients with overweight and obesity with dyslipidemia in Xinjiang was distinctive and characterized by enrichment of Lactobacillus and the reduction of the diversity and the depletion of Actinobacteria, Bacteroides, Bifidobacterium, and Bacteroides fragilis. Prevotella-type, Gemmiger-type, and Escherichia/Shigella-type were the gut microbial patterns of the Xinjiang population. However, the fecal SCFAs levels and enterotypes were similar between healthy individuals and patients. These results indicated that the contribution of the gut microbiota to obesity was highly dependent on geography and dietary habits. Waist circumference, total triglyceride (TG), and fasting blood glucose (FBG) were significantly decreased after orlistat therapy, whereas TG, total cholesterol (TC), and low density lipoprotein cholesterol (LDL-C) were significantly decreased by ezetimibe. Overall, the gut microbiota and their SCFAs metabolites were relatively stable after treatment with the two drugs, with alteration of some low-abundant bacteria, i.e., significantly increased Proteobacteria and decreased Alloprevotella after orlistat, and increased Fusobacteria and Fusobacterium after ezetimibe therapy. These results indicated that intestinal malabsorption of dietary fat and cholesterol caused by orlistat and ezetimibe had a limited effect on the overall gut microbial community and their metabolites. Nevertheless, significant correlations between several core microbes that responded to the medications and biochemical data were found; in particular, Actinomyces and Bacteroides were positively correlated with FBG after orlistat intervention, while Clostridium XVIII and Lachnospiracea incertae sedis were negatively correlated with TC and LDL-C after ezetimibe intervention, thus indicating their roles in improving glucolipid metabolism in obesity by acting as potential microbial targets.
ABSTRACT
AIM: Aberrantly expressed microRNAs (miRNAs) are involved in many diseases including cancer. The expression of miR-15a was reported to be downregulated in papillary thyroid carcinoma (PTC) compared to control tissue. However, the mechanism underlying this downregulation remains unclear. METHODS: The effects of miR-15a on the proliferation and invasion of PTC cells were evaluated by CCK-8 and transwell assays, respectively. Expression levels of AKT and rearranged during transfection (RET) in cells were assessed using Western blotting. The correlation of RET and miR-15a was validated by luciferase reporter assay. Moreover, in vivo assay was performed to demonstrate the effect of miR-15a on tumor growth. RESULTS: We confirmed that the expression of miR-15a was significantly lower in PTC tissue than that in normal tissue. Overexpression of miR-15a notably inhibited PTC cell proliferation and invasion via promoting apoptosis. Additionally, RET was found to be a target of miR-15a and this correlation was confirmed by dual-luciferase assay and Western blot. Furthermore, in vivo study revealed that overexpression of miR-15a inhibited tumor growth via downregulating the levels of RET and phosphorylated AKT. CONCLUSION: In the present study, we demonstrated that miR-15a played an antitumor role in regulating PTC via targeting RET/AKT pathway. Therefore, miR-15a may serve as a potential molecular target for the treatment of PTC.
