Atherosclerosis (AS) is exacerbated in the perimenopausal period, which significantly increases the incidence rate of cardiovascular disease. The disruption of the gut microbiota has been associated with AS or menopause, but the specific changes of AS-associated gut microbiota in the perimenopausal period remain largely unknown. As lipid abnormalities are mainly responsible for AS, the relationship between lipid metabolism abnormalities and gut microbiota disruptions during menopause is rarely reported hitherto. In the present study, ApoE^-/- mice fed with a high-fat diet (HFD) were subjected to ovariectomy and supplemented with estrogen. The ovariectomized HFD-fed ApoE^-/- mice underwent significant AS damage, hepatic lipid damage, hyperlipidemia, and changes of lipid metabolism- and transport-related enzymes. There was significantly higher abundance of some lipid metabolites in the plasma of ovariectomized HFD-fed ApoE^-/- mice than in non-ovariectomized ones, including cholesterol esters, triglycerides, phospholipids, and other types of lipids (free fatty acids, acylcarnitine, sphingomyelins, and ceramides). The administration of estrogen significantly reduced the contents of most lipid metabolites. The diversity and composition of gut microbiota evidently changed in ovariectomized HFD-fed ApoE^-/- mice, compared to HFD-fed ApoE^-/- mice without ovariectomy. In contrast, with estrogen supplementation, the diversity and composition of gut microbiota were restored to approach that of non-ovariectomized HFD-fed ApoE^-/- mice, and the relative abundances of some bacteria were even like those of C57BL/6 mice fed with a normal diet. On the other hand, the transplantation of feces from C57BL/6 mice fed with normal diet to ovariectomized HFD-fed ApoE^-/- mice was sufficient to correct the hyperlipidemia and AS damage, and to reverse the characteristics changing of lipid metabolomics in ovariectomized HFD-fed ApoE^-/- mice. These phenomena were also been observed after transplantation of feces from estrogen-treated ovariectomized HFD-fed ApoE^-/- mice to ovariectomized HFD-fed ApoE^-/- mice. Moreover, the gut microbiota and lipid metabolites were significantly correlated, demonstrating that the changes of serum lipids may be associated with the gut microbiota disruptions in the perimenopausal period. In conclusion, the gut microbiota during the progression of AS in the perimenopausal period showed specific compositional changes and significant correlations with circulating lipid metabolites. Estrogen supplementation may exert beneficial effects on gut bacteria and lipid metabolism.

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