Multi‐Omics Evidence Linking Gualou Xiebai Banxia Decoction Intervention to Atherosclerosis Mitigation and Gut Microbiota–Bile Acid Signatures in <scp>ApoE</scp> ^−/− Mice

Atherosclerosis presents a persistent health challenge, with limited therapies addressing residual cardiovascular risk. Gualou Xiebai Banxia Decoction (GXBD), a classical Chinese herbal formula traditionally used for chest obstruction syndromes, was evaluated as a dietary-style intervention in ApoE^-/- mice fed a high-fat diet for 14 weeks. Using a multi-omics strategy that combined UHPLC-QE-MS/MS chemical profiling, network pharmacology, 16S rRNA sequencing, targeted bile acid metabolomics, and biological validation, we assessed vascular and metabolic outcomes alongside gut ecology. Chemical profiling identified 348 constituents, including bioactive flavonoids and saponins. In vivo, GXBD intervention significantly improved lipid profiles by reducing serum TC, TG, and LDL-C, and by raising HDL (<i>p</i> < 0.05). It markedly reduced aortic plaque burden and alleviated hepatic steatosis (<i>p</i> < 0.05). Mechanistically, GXBD reshaped the gut microbiota, characterized by the enrichment of beneficial <i>Bacteroides</i> and <i>Alloprevotella</i> and the depletion of pro-inflammatory <i>Blautia</i> and <i>Bilophila</i>. This microbial shift coincided with significantly higher levels of protective secondary bile acids, such as 11-LCA and 23-DCA, and fewer cytotoxic chenodeoxycholic acid-derived metabolites (<i>p</i> < 0.05). Correlation and constrained ordination analyses linked these microbial-bile acid signatures to the concordant modulation of vascular hub targets, including the downregulation of <i>MMP9</i> and <i>CASP3</i> and upregulation of <i>PPARG</i> and <i>SIRT1</i>. These findings suggest that GXBD mitigates atherosclerosis in this murine model through a coordinated remodeling of the gut microbiota-bile acid-host axis, supporting its potential as a microbiome-informed, multi-component adjunct for cardiometabolic health.