Gut microbiota mediates positive effects of liraglutide on dyslipidemia in mice fed a high-fat diet

Abstract

Except for improving glycemic control, liraglutide, one of the glucagon-like peptide-1 receptor agonists, has exerted promising therapeutic effects for dyslipidemia. It has been proved that gut microbiota plays a dramatic role in regulating lipid metabolism. This study aims to explore whether liraglutide could improve dyslipidemia by modulating the gut microbiota in mice fed a high-fat diet (HFD). The C57BL/6 mice were fed a HFD to establish an animal model of dyslipidemia, and then administered with liraglutide or normal saline (NS) for 12 weeks. Indices of glucolipid metabolism were evaluated. Gut microbiota of the mice was analyzed by 16S rRNA gene sequencing. Compared with HFD group, liraglutide significantly alleviated weight, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) levels, meanwhile elevating high-density lipoprotein cholesterol (HDL) levels (all p < 0.05). The gut microbiota analysis revealed that liraglutide greatly reduced the relative abundance of Firmicutes and augmented that of Bacteroidetes, with a concomitant drop in the Firmicutes/Bacteroidetes ratio. Meanwhile, liraglutide dramatically changed the overall composition, promoted the growth of beneficial microbes (Akkermansia, Lactobacillus, Parabacteroides, Oscillospira, etc.), and inhibited the growth of harmful microbes (AF12, Shigella, Proteobacteria, Xenorhabdus, etc.). Especially, the relative abundance of Akkermansia increased the most after liraglutide treatment. Correlation analysis suggested that TC and LDL were positively correlated with some harmful bacteria, and negatively associated with beneficial bacteria. This study confirmed that liraglutide had a certain therapeutic effect on dyslipidemia in HFD-fed mice and could regulate the composition of the gut microbiota associated with lipid metabolism, especially Akkermansia. Thus, affecting gut microbiota might be a potential mechanism of liraglutide in attenuating dyslipidemia.

Sexual Dimorphism in Lipid Metabolism and Gut Microbiota in Mice Fed a High-Fat Diet

“…Additionally, Akkermansia increased thermogenesis by stimulating uncoupling protein 1 gene expression in brown adipose tissue, improved glucose homeostasis, and ameliorated metabolic disease by stimulating glucagon-like peptide-1 (GLP-1) secretion in C57BL/6 mice after HFD consumption [48]. More recently, it was reported that Akkermansia was negatively correlated with total cholesterol and low-density lipoprotein cholesterol levels in mice fed HFD [49]. Thus, the findings suggest that the considerable enrichment of Akkermansia observed in female mice could be a key factor for protecting from dyslipidemia at the microbiota level in female mice fed HFD.…”

Gut microbiota and therapy for obesity and type 2 diabetes

“…GLP-1 receptor agonists (GLP-1RAs) increased intestinal Bacteroidetes to Firmicutes ratio, decreased obesity-related but increased lean-related microbiota phenotypes ( 61 , 82 , 83 ). Studies in mice treated with liraglutide showed a decrease in Erysipelotrichaceae Incertae Sedis , Marvinbryantia , Roseburia , Candidatus , Arthromitus , and Proteobacteria , which were obesity-related phylotypes and an increase in Akkermansia , Blautia , Lactobacillus Parabacteroides and Coprococcus , which were lean-related phylotypes ( 61 , 62 ), with Akkermansia muciniphila contributing to intestinal health and glucose homeostasis ( 84 ). In studies in humans, the genera Collinsella , Akkermansia and Clostridium were enriched in the post-liraglutide-treatment group whereas Alistipes was decreased ( 63 , 64 ).…”

Liraglutide and sibutramine: similarities and differences in pharmacotherapy of obesity

“…В ряде работ, выполненных на животных, было показано, что путем модулирования состава кишечной микрофлоры лираглутид оказывает положительный эффект на липидный обмен, содержание жира в печени [36,37]. В экспериментальной работе британских и немецких исследователей, выполненной на основе применения методов метагеномики, у грызунов линии Wistar изучали влияние на микробиом 4 препаратов: иммуносупрессора такролимуса/FK506, бупропиона, налтрексона и сибутрамина.…”