Xanthoceras sorbifolium Oil Attenuates Hyperlipidemia Through Dual Modulation of Gut Microbiota and Lipid Metabolites: Mechanistic Insights from Lipidomics and 16S rRNA Sequencing

<b>Background/Objectives</b>: <i>Xanthoceras sorbifolium</i> oil (XSO), containing nervonic acid and unsaturated fatty acids (93%), exhibits lipid-lowering potential; yet, its mechanisms involving gut-liver crosstalk remain unclear. This study investigated XSO's anti-hyperlipidemic effects and gut microbiota interactions. <b>Methods</b>: Forty-eight Sprague Dawley male rats were divided into: normal control (NC), high-fat diet (HFD), XSO prevention (XOP, 1.4 mL/kg pre-HFD), and XSO treatment (XOT, post-HFD). Serum lipids, fecal short-chain fatty acids (SCFAs), gut microbiota (16S rRNA), and lipidomics (UPLC-MS/MS) were analyzed after 12 weeks. <b>Results</b>: XOP significantly reduced serum total cholesterol (TC, 26.8%), triglycerides (TG, 35.9%), and low-density lipoprotein cholesterol (LDL-C, 45.9%) versus HFD (<i>p</i> < 0.05), while increasing high-density lipoprotein cholesterol (HDL-C, 7.98%). XOP showed enhanced hepatoprotection (AST↓ 32.6%, <i>p</i> < 0.01). Although XSO elevated fecal acetate (1.5-fold) and butyrate (1.3-fold), these changes lacked significance (<i>p</i> > 0.05). The analysis of gut microbiota showed that the pro-inflammatory <i>Coriobacteriaceae</i> and <i>Erysipelibacteriaceae</i> were reduced at the family level in the XOP group (<i>p</i> < 0.05). Lipidomics identified 69 differential metabolites: XSO downregulated atherogenic cholesteryl esters and triglycerides, upregulated six phosphatidylethanolamines, and modulated aberrant lysophosphatidylcholines. <b>Conclusions</b>: XSO alleviates hyperlipidemia through direct modulation of lipid metabolism pathways and suppression of pro-inflammatory gut microbiota. While its prebiotic potential warrants further validation, these findings highlight XSO as a functional dietary adjunct for improving lipid homeostasis and mitigating cardiovascular risks. XSO alleviates hyperlipidemia through direct modulation of lipid metabolism pathways and suppression of pro-inflammatory gut microbiota, while its prebiotic potential warrants further validation. These findings support XSO as a dietary adjunct for lipid homeostasis improvement, offering a nutritional strategy for early-stage cardiovascular risk management.