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Studies showed that AEE had a significant therapeutic effect on hyperlipidemia and is likely to be associated with the up-regulation of cholesterol 7-alpha hydroxylase (CYP7A1), the key enzyme for cholesterol conversion to bile acids, but no research confirmed whether the effect of AEE on hyperlipidemia was related to the gut microbiota and liver lipids. At the same time, more and more studies have shown that gut microbiota and lipids are closely related to hyperlipidemia. Hence, in this study, we investigated the effects of AEE on liver lipids through LC-MS-based untargeted lipidomics and the effects of AEE on gut microbiota based on cecal contents metagenomics by Illumina sequencing in HFD-induced hyperlipidemia ApoE\u2212\/\u2212 mice at the overall level. The results of lipidomics showed that AEE relieved hyperlipidemia by decreasing the concentration of 10 PEs and 12 SMs in the liver and regulating the pathways of glycerophospholipid metabolic pathway, sphingolipid signaling pathway, and NF-kB signaling pathway. The results of metagenomics concluded that AEE treatment changed the composition of gut microbiota and regulated the functions of lipid transport and metabolism, as well as the metabolism of bile acids and secondary bile acids. The results of the joint analysis between lipidomics and metagenomics showed that the abundance of Verrucomicrobia, Verrucomicrobiales, Candidatus_Gastranaerophilales, and Candidatus_Melainabacteria was significantly positively correlated with the concentration of SM (d18:1\/18:0) and PE (16:0\/18:1) in the process of AEE alleviating hyperlipidemia in mice. In conclusion, these results suggested that the effect of AEE on hyperlipidemia was closely related to the gut microbiota by the change of bile acids and liver lipids.<\/jats:p>","DOI":"10.3389\/fnut.2022.1030528","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T04:44:13Z","timestamp":1671425053000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Untargeted lipidomics and metagenomics reveal the mechanism of aspirin eugenol ester relieving hyperlipidemia in ApoE\u2212\/\u2212 mice"],"prefix":"10.3389","volume":"9","author":[{"given":"Xiao-Rong","family":"Lu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xi-Wang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shi-Hong","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhe","family":"Qin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-Xia","family":"Bai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Bo","family":"Ge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian-Yong","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya-Jun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.jnutbio.2016.01.005","article-title":"Dietary interesterified fat enriched with palmitic acid induces atherosclerosis by impairing macrophage cholesterol efflux and eliciting inflammation.","volume":"32","author":"Afonso","year":"2016","journal-title":"J Nutr Biochem."},{"key":"B2","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1007\/s11154-019-09512-0","article-title":"Dietary lipids, gut microbiota and lipid metabolism.","volume":"20","author":"Schoeler","year":"2019","journal-title":"Rev Endocr Metab Disord."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/molecules25245971","article-title":"Proanthocyanidins should be a candidate in the treatment of cancer, cardiovascular diseases and lipid metabolic disorder.","volume":"25","author":"Wang","year":"2020","journal-title":"Molecules."},{"key":"B4","first-page":"455","article-title":"[Hyperlipidemia and cardiovascular diseases. 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