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J Lipid Res. 2017 Mar;58(3):519-528. doi: 10.1194/jlr.M072165. Epub 2017 Jan 27.

Commensal bacteria at the crossroad between cholesterol homeostasis and chronic inflammation in atherosclerosis.

Author information

1
Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
2
Department of Bacteriology, University of Wisconsin-Madison, Madison, WI.
3
RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan.
4
Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan tomoya@med.kobe-u.ac.jp.
5
AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan.

Abstract

The gut microbiota were shown to play critical roles in the development of atherosclerosis, but the detailed mechanism is limited. The purpose of this study is to clarify the influence of gut microbiota on atherogenesis via lipid metabolism and systemic inflammation. Germ-free or conventionally raised (Conv) ApoE-deficient (ApoE-/-) mice were fed chow diet and euthanized at 20 weeks of age. We found that the lack of gut microbiota in ApoE-/- mice caused a significant increase in the plasma and hepatic cholesterol levels compared with Conv ApoE-/- mice. The absence of gut microbiota changed the bile acid composition in the ileum, which was associated with activation of the enterohepatic fibroblast growth factor 15, fibroblast growth factor receptor 4 axis, and reduction of cholesterol 7α-hydroxylase and hepatic bile acid synthesis, resulting in the accumulation of liver cholesterol content. However, we found that the lack of microbiota caused a significant reduction in atherosclerotic lesion formation compared with Conv ApoE-/- mice, which might be associated with the attenuation of lipopolysaccharide-mediated inflammatory responses. Our findings indicated that the gut microbiota affected both hypercholesterolemia and atherogenesis in mice.

KEYWORDS:

bile acid metabolism; cholesterol/metabolism; gut microbiota; macrophages; nuclear receptors/farnesoid X receptor

PMID:
28130274
PMCID:
PMC5335582
DOI:
10.1194/jlr.M072165
[Indexed for MEDLINE]
Free PMC Article

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