The intestinal microbiota regulates host cholesterol homeostasis

Tiphaine Le Roy,Philippe Giral,Philippe Gérard,Maryse Guerin,Karine Clément,Benoit Chassaing,Emelyne Lécuyer,Samira Boudebbouze,Philippe Lesnik,Nathalie Kapel,Moez Rhimi,Farid Ichou,Emmanuelle Maguin,Júlia Haro Barceló,Thierry Huby,Marie Lhomme

doi:10.1186/s12915-019-0715-8

Abstract

BackgroundManagement of blood cholesterol is a major focus of efforts to prevent cardiovascular diseases. The objective of this study was to investigate how the gut microbiota affects host cholesterol homeostasis at the organism scale.ResultsWe depleted the intestinal microbiota of hypercholesterolemic female Apoe−/− mice using broad-spectrum antibiotics. Measurement of plasma cholesterol levels as well as cholesterol synthesis and fluxes by complementary approaches showed that the intestinal microbiota strongly regulates plasma cholesterol level, hepatic cholesterol synthesis, and enterohepatic circulation. Moreover, transplant of the microbiota from humans harboring elevated plasma cholesterol levels to recipient mice induced a phenotype of high plasma cholesterol levels in association with a low hepatic cholesterol synthesis and high intestinal absorption pattern. Recipient mice phenotypes correlated with several specific bacterial phylotypes affiliated to Betaproteobacteria, Alistipes, Bacteroides, and Barnesiella taxa.ConclusionsThese results indicate that the intestinal microbiota determines the circulating cholesterol level and may thus represent a novel therapeutic target in the management of dyslipidemia and cardiovascular diseases.

Highlights

Management of blood cholesterol is a major focus of efforts to prevent cardiovascular diseases
Cholesterol in the plasma exists mainly packaged in the form of lipoproteins: chylomicrons, very-lowdensity lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL)
Quantitative analysis of cholesterol distribution among lipoproteins separated by gel filtration revealed an increase of the abundance of VLDL and LDL subclasses in Antibiotic-induced microbiota depletion (AB-Mdpl) mice, whereas the HDL fraction was similar in conventionally raised (Conv-R) and AB-Mdpl mice (Fig. 1c)

Summary

Introduction

Management of blood cholesterol is a major focus of efforts to prevent cardiovascular diseases. Transplant of the microbiota from humans harboring elevated plasma cholesterol levels to recipient mice induced a phenotype of high plasma cholesterol levels in association with a low hepatic cholesterol synthesis and high intestinal absorption pattern. In normolipidemic wild type mice, germ-free (GF) condition as well as microbiota depletion through the administration of antibiotics upregulates de novo cholesterol synthesis with no raise in plasma cholesterol [22,23,24]. Transfer of intestinal microbiota into GF animals demonstrated that microbiota composition/activity determines recipient phenotype and susceptibility to several diseases [29, 30], this approach has not yet been applied for plasma cholesterol levels nor with human microbiota

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