Ezetimibe and simvastatin modulate gut microbiota and expression of genes related to cholesterol metabolism.
OBJECTIVE
Hypolipidemic drugs are prescribed in the most of cases for the treatment of cardiovascular diseases. Several studies have showed that the gut microbiota is able to regulate the host cholesterol metabolism. This study aimed to investigate the potential impact of hypolipidemic drugs on the gut microbiota in mice, and to correlate it to the regulation of cholesterol metabolism.


METHODS
Male C57Bl/6J mice were divided into four groups fed either a control diet alone (CT), or supplemented with simvastatin (0.1% w/w, Zocor®, MSD), or ezetimibe (0.021% w/w, Ezetrol®, MSD) or a combination of simvastatin and ezetimibe (0.1% and 0.021%, respectively) for one week.


RESULTS
The combination of ezetimibe and simvastatin is required to observe a drop in cholesterolemia, linked to a huge activation of hepatic SREBP-2 and the consequent increased expression of genes involved in LDL cholesterol uptake and cholesterol synthesis. The gut microbiota analysis revealed no change in total bacteria, and in major Gram positive and Gram negative bacteria, but a selective significant increase in Lactobacillus spp. in mice treated with the ezetimibe and a decrease by the combination. The changes in lactobacilli level observed in ezetimibe or combination treated-mice are negatively correlated to expression of genes related to cholesterol metabolism.


CONCLUSIONS
The present study showed that ezetimibe taken alone is able to modify the composition of gut microbiota in favor of Lactobacillus spp. These results suggest that members of the genus Lactobacillus play an important role in cholesterol metabolism, even in normocholesterolemic mouse model.
Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
Emilie
E
Catry
Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
Barbara D
BD
Pachikian
Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
Nuria
N
Salazar
Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
Audrey M
AM
Neyrinck
Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
Patrice D
PD
Cani
Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium. Electronic address: nathalie.delzenne@uclouvain.be.
Nathalie M
NM
Delzenne
D000704:Analysis of Variance; D000818:Animals; D001384:Azetidines / Q000494:pharmacology*; D015153:Blotting, Western; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D041981:Gastrointestinal Tract / Q000382:microbiology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D007778:Lactobacillus / Q000187:drug effects / Q000254:growth & development; D008099:Liver / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota / Q000187:drug effects*; D060888:Real-Time Polymerase Chain Reaction; D019821:Simvastatin / Q000494:pharmacology*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism
D001384:Azetidines; D017931:DNA Primers; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; D019821:Simvastatin; D000069438:Ezetimibe
Cholesterol; Ezetimibe; Lactobacillus; Microbiota; SREBP-2; Simvastatin